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Torus mandibularis Other namesTori mandibulares, mandibular torus, mandibular tori Mandibular torus in premolar area SpecialtyOral and Maxillofacial surgery Torus mandibularis seen at axial CT and volume rendering. Torus mandibularis is a bony growth in the mandible along the surface nearest to the tongue. Mandibular tori are usually present near the premolars and above the location of the mylohyoid muscle's attachment to the mandible.[1] In 90% of cases, there is a torus on both the left and right sides. The prevalence of mandibular tori ranges from 5-40%. It is less common than bony growths occurring on the palate, known as torus palatinus. Mandibular tori are more common in Asian and Inuit populations, and slightly more common in males.[2][3] In the United States, the prevalence is 7-10% of the population. It is believed that mandibular tori are caused by several factors.[1] They are more common in early adulthood and are associated with bruxism. The size of the tori may fluctuate throughout life, and in some cases the tori can be large enough to touch each other in the midline of mouth. Consequently, it is believed that mandibular tori are the result of local stresses and not due solely to genetic influences. Mandibular tori are usually a clinical finding with no treatment necessary. It is possible for ulcers to form in the area of the tori due to trauma. The tori may also complicate the fabrication of dentures. If removal of the tori is needed, surgery can be done to reduce the amount of bone, but the tori may reform in cases where nearby teeth still receive local stresses. ## References[edit] 1. ^ a b Neville, B.W. & Damm, D. & Allen, C. & Bouquot, J. (2002). Oral & Maxillofacial Pathology (Second ed.). p. 21. ISBN 0-7216-9003-3.CS1 maint: uses authors parameter (link) 2. ^ "Torus Mandibularis - Patient Care". consultantlive.com. 3. ^ Gillis, Julie M., DDS (12 December 2013). "What are Tori, And Why Do I Have Them?". juliegillisdds.com.CS1 maint: multiple names: authors list (link) ## External links[edit] Classification D * ICD-10: K10.0 * ICD-9-CM: 526.81 * "Oral & Maxiollofacial Pathology Cases: What Could This Be?". Marquette University School of Dentistry. Archived from the original on 2006-10-17. * "What are mandibular tori?". dentagama.com. * v * t * e Dental disease involving the jaw General * Jaw abnormality * malocclusion * Orthodontics * Gnathitis Size * Micrognathism * Maxillary hypoplasia Maxilla and Mandible * Cherubism * Congenital epulis * Torus mandibularis * Torus palatinus Other * Jaw and base of cranium * Prognathism * Retrognathism * Dental arch * Crossbite * Overbite * Temporomandibular joint disorder * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Torus mandibularis	c0266980	3,500	wikipedia	https://en.wikipedia.org/wiki/Torus_mandibularis	2021-01-18T19:02:17	{"umls": ["C0266980", "C1184914"], "icd-9": ["526.81"], "icd-10": ["K10.0"], "wikidata": ["Q5644824"]}
Cilio et al. (2000) reported a neonate who developed hyperglycemia, glycosuria, and moderate acidosis 12 hours after birth. Islet autoimmunity was indicated by the presence of autoantibodies to insulin and glutamic acid decarboxylase and was confirmed by the finding of marked lymphocytic infiltration in the pancreas (with insulitis), heart, and lungs. At 6 days of age, persistent diffuse eczematous lesions, diarrhea, and eosinophilia developed, and the infant died of necrotizing enterocolitis on day 26. The patient's mother was healthy, with no autoantibodies of the type that were positive in the son. Because severe beta-cell impairment was present at birth, Cilio et al. (2000) concluded that autoreactive T cells had been primed and reacted against self-antigens during fetal life. Furthermore, they suggested that this rare autoimmune syndrome may have a genetic basis, because the mother of the patient had a great-uncle, a second cousin, and 2 brothers who had died of undetermined causes within 6 months after birth, as well as an uncle and a daughter who had died before birth. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	DIABETES MELLITUS, CONGENITAL AUTOIMMUNE	c1857958	3,501	omim	https://www.omim.org/entry/605026	2019-09-22T16:11:37	{"mesh": ["C565730"], "omim": ["605026"]}
1q21.1 microdeletion is a chromosomal change in which a small piece of chromosome 1 is deleted in each cell. The deletion occurs on the long (q) arm of the chromosome in a region designated q21.1. This chromosomal change increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems. However, some people with a 1q21.1 microdeletion do not appear to have any associated features. About 75 percent of all children with a 1q21.1 microdeletion have delayed development, particularly affecting the development of motor skills such as sitting, standing, and walking. The intellectual disability and learning problems associated with this genetic change are usually mild. Distinctive facial features can also be associated with 1q21.1 microdeletions. The changes are usually subtle and can include a prominent forehead; a large, rounded nasal tip; a long space between the nose and upper lip (philtrum); and a high, arched roof of the mouth (palate). Other common signs and symptoms of 1q21.1 microdeletions include an unusually small head (microcephaly), short stature, and eye problems such as clouding of the lenses (cataracts). Less frequently, 1q21.1 microdeletions are associated with heart defects, abnormalities of the genitalia or urinary system, bone abnormalities (particularly in the hands and feet), and hearing loss. Neurological problems that have been reported in people with a 1q21.1 microdeletion include seizures and weak muscle tone (hypotonia). Psychiatric or behavioral problems affect a small percentage of people with this genetic change. These include developmental conditions called autism spectrum disorders that affect communication and social interaction, attention-deficit/hyperactivity disorder (ADHD), and sleep disturbances. Studies suggest that deletions of genetic material from the 1q21.1 region may also be risk factors for schizophrenia. Some people with a 1q21.1 microdeletion do not have any of the intellectual, physical, or psychiatric features described above. In these individuals, the microdeletion is often detected when they undergo genetic testing because they have a relative with the chromosomal change. It is unknown why 1q21.1 microdeletions cause cognitive and physical changes in some individuals but few or no health problems in others, even within the same family. ## Frequency 1q21.1 microdeletion is a rare chromosomal change; only a few dozen individuals with this deletion have been reported in the medical literature. ## Causes Most people with a 1q21.1 microdeletion are missing a sequence of about 1.35 million DNA building blocks (base pairs), also written as 1.35 megabases (Mb), in the q21.1 region of chromosome 1. However, the exact size of the deleted region varies. This deletion affects one of the two copies of chromosome 1 in each cell. The signs and symptoms that can result from a 1q21.1 microdeletion are probably related to the loss of several genes in this region. Researchers are working to determine which missing genes contribute to the specific features associated with the deletion. Because some people with a 1q21.1 microdeletion have no obvious related features, additional genetic or environmental factors are thought to be involved in the development of signs and symptoms. Researchers sometimes refer to 1q21.1 microdeletion as the recurrent distal 1.35-Mb deletion to distinguish it from the genetic change that causes thrombocytopenia-absent radius syndrome (TAR syndrome). TAR syndrome results from the deletion of a different, smaller DNA segment in the chromosome 1q21.1 region near the area where the 1.35-Mb deletion occurs. The chromosomal change related to TAR syndrome is often called the 200-kb deletion. ### Learn more about the chromosome associated with 1q21.1 microdeletion * chromosome 1 Additional Information from NCBI Gene: * ACP6 * BCL9 * CHD1L * FMO5 * GJA5 * GJA8 * GPR89B * HYDIN * PRKAB2 ## Inheritance Pattern 1q21.1 microdeletion is inherited in an autosomal dominant pattern, which means that missing genetic material from one of the two copies of chromosome 1 in each cell is sufficient to increase the risk of delayed development, intellectual disability, and other signs and symptoms. In at least half of cases, individuals with a 1q21.1 microdeletion inherit the chromosomal change from a parent. In general, parents who carry a 1q21.1 microdeletion have milder signs and symptoms than their children who inherit the deletion, even though the deletion is the same size. About one-quarter of these parents have no associated features. A 1q21.1 microdeletion can also occur in people whose parents do not carry the chromosomal change. In this situation, the deletion occurs most often as a random event during the formation of reproductive cells (eggs or sperm) in a parent or in early embryonic development. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	1q21.1 microdeletion	c2675897	3,502	medlineplus	https://medlineplus.gov/genetics/condition/1q211-microdeletion/	2021-01-27T08:25:40	{"gard": ["10813"], "mesh": ["C567291"], "omim": ["612474"], "synonyms": []}
Intellectual disability-spasticity-ectrodactyly syndrome is a rare intellectual disability syndrome characterized by severe intellectual disability, spastic paraplegia (with wasting of the lower limbs) and distal transverse defects of the limbs (e.g. ectrodactyly, syndactyly, clinodactyly of the hands and/or feet). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Intellectual disability-spasticity-ectrodactyly syndrome	c0796001	3,503	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1891	2021-01-23T18:34:11	{"gard": ["3523"], "mesh": ["C537446"], "omim": ["246555"], "umls": ["C0796001"], "synonyms": ["Jancar syndrome"]}
Isolated hemihyperplasia is a rare overgrowth syndrome characterized by an asymmetric regional body overgrowth, involving at least one limb, and associated with an increased risk of developing embryonal tumors, principally nephroblastoma (see this term) and hepoblastoma. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Isolated hemihyperplasia	c0332890	3,504	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2128	2021-01-23T18:19:12	{"gard": ["2630"], "omim": ["235000"], "umls": ["C0332890", "C1856184"], "icd-10": ["Q87.3"], "synonyms": ["Hemi 3 syndrome", "Hemicorporal hypertrophy", "Isolated hemihypertrophy"]}
Ancylostomiasis Other namesAnchylostomiasis, Ankylostomiasis Infective larva of Necator americanus SpecialtyTropical medicine, infectious disease, parasitology Ancylostomiasis is a hookworm disease caused by infection with Ancylostoma hookworms. The name is derived from Greek ancylos αγκύλος "crooked, bent" and stoma στόμα "mouth". Ancylostomiasis is also known as miner's anaemia, tunnel disease, brickmaker's anaemia and Egyptian chlorosis. Helminthiasis may also refer to ancylostomiasis, but this term also refers to all other parasitic worm diseases as well. In the United Kingdom, if acquired in the context of working in a mine, the condition is eligible for Industrial Injuries Disability Benefit. It is a prescribed disease (B4) under the relevant legislation.§[1] Ancylostomiasis is caused when hookworms, present in large numbers, produce an iron deficiency anemia by sucking blood from the host's intestinal walls. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Depending on the organism, the signs and symptoms vary. Ancylostoma duodenale and Necator americanus can enter the blood stream while Ancylostoma braziliensis cannot. Signs and symptoms of Ancylostoma duodenale and Necator americanus are given in corresponding page.[citation needed] In Ancylostoma braziliensis as the larvae are in an abnormal host, they do not mature to adults but instead migrate through the skin until killed by the host's inflammatory response. This migration causes local intense itching and a red serpiginous lesion. Treatment with a single dose of oral ivermectin results in cure rates of 94–100%.[2] ## Causes[edit] The infection is usually contracted by people walking barefoot over contaminated soil. In penetrating the skin, the larvae may cause an allergic reaction. It is due to the itchy patch at the site of entry that the early infection gets its nickname "ground itch". Once larvae have broken through the skin, they enter the bloodstream and are carried to the lungs (however, unlike ascarids, hookworms do not usually cause pneumonia). The larvae migrate from the lungs up the windpipe to be swallowed and carried back down to the intestine. If humans come into contact with larvae of the dog hookworm or the cat hookworm, or of certain other hookworms that do not infect humans, the larvae may penetrate the skin. Sometimes, the larvae are unable to complete their migratory cycle in humans. Instead, the larvae migrate just below the skin producing snake-like markings. This is referred to as a creeping eruption or cutaneous larva migrans. [3] ## Diagnosis[edit] They commonly infect the skin, eyes, and viscera in humans. * Ancylostoma brasiliensis causes cutaneous larva migrans. * Toxocara causes visceral larva migrans.[4] ## Prevention[edit] Control of this parasite should be directed against reducing the level of environmental contamination. Treatment of heavily infected individuals is one way to reduce the source of contamination (one study has estimated that 60% of the total worm burden resides in less than 10% of the population). Other obvious methods are to improve access to sanitation, e.g. toilets, but also convincing people to maintaining them in a clean, functional state, thereby making them conducive to use.[citation needed] ## Treatment[edit] The drug of choice for the treatment of hookworm disease is mebendazole which is effective against both species, and in addition, will remove the intestinal worm Ascaris also, if present. The drug is very efficient, requiring only a single dose and is inexpensive. However, treatment requires more than giving the anthelmintic, the patient should also receive dietary supplements to improve their general level of health, in particular iron supplementation is very important. Iron is an important constituent of a multitude of enzyme systems involved in energy metabolism, DNA synthesis and drug detoxification.[citation needed] An infection of N. americanus parasites can be treated by using benzimidazoles, albendazole, and mebendazole. A blood transfusion may be necessary in severe cases of anemia. Light infections are usually left untreated in areas where reinfection is common. Iron supplements and a diet high in protein will speed the recovery process.[5] In a case study involving 56–60 men with Trichuris trichiura and/or N. americanus infections, both albendazole and mebendazole were 90% effective in curing T. trichiura. However, albendazole had a 95% cure rate for N. americanus, while mebendazole only had a 21% cure rate. This suggests albendazole is most effective for treating both T. trichiura and N. americanus.[6] ## Epidemiology[edit] An epidemic of "miner's anaemia" caused by Ancylostoma duodenale among workers constructing the Gotthard Tunnel contributed to the understanding of ancylostomiasis.[7] Hookworm anaemia was first described by Wilhelm Griesenger in Egypt, Cairo in 1852. He found thousands of adult ancylostomes in the small bowel of a 20-year old soldier who was suffering from severe diarrhoea and anaemia (labelled at the time as Egyptian chlorosis).[8] The subject was revisited in Europe when there was an outbreak of "miner's anaemia" in Italy.[9] During the construction of the Gotthard Tunnel in Switzerland (1871–81), a large number of miners suffered from severe anaemia of unknown cause.[10][7] Medical investigations let to the understanding that it was caused by Ancylostoma duodenale (favoured by high temperatures and humidity) and to "major advances in parasitology, by way of research into the aetiology, epidemiology and treatment of ancylostomiasis".[7] Hookworms still account for high proportion of debilitating disease in the tropics and 50–60,000 deaths per year can be attributed to this disease.[11] ## References[edit] 1. ^ "14. Appendix 1: List of diseases covered by Industrial Injuries Disablement Benefit: B4 Ankylostomiasis...". Guidance: Industrial Injuries Disablement Benefits: technical guidance. UK Department for Work & Pensions. 20 May 2015. 2. ^ Hochedez P, Caumes E (July 2008). "Common skin infections in travelers". J Travel Med. 15 (4): 252–62. doi:10.1111/j.1708-8305.2008.00206.x. PMID 18666926. 3. ^ "Hookworm Disease". Adoption Health: Parasistes. ComeUnity. Retrieved 2008-10-30. 4. ^ "Definition: larva migrans". Retrieved 2008-10-30. 5. ^ "Hookworm Disease". Encyclopædia Britannica Online. 2009. 6. ^ Holzer, B.R.; Frey, F.J. (February 1987). "Differential efficacy of mebendazole and albendazole against Necator americanus but not for Trichuris Trichiura infestations". European Journal of Clinical Pharmacology. 32 (6): 635–37. doi:10.1007/BF02456002. PMID 3653234. 7. ^ a b c Peduzzi, R.; Piffaretti, J.-C. (1983). "Ancylostoma duodenale and the Saint Gothard anaemia". Br Med J (Clin Res Ed). 287 (6409): 1942–45. doi:10.1136/bmj.287.6409.1942. JSTOR 29513508. PMC 1550193. PMID 6418279. 8. ^ Grove, David I (2014). Tapeworms, lice and prions: a compendium of unpleasant infections. Oxford: Oxford University Press. pp. 1–602. ISBN 978-0-19-964102-4. 9. ^ Grove, David I (1990). A history of human helminthology. Wallingford: CAB International. pp. 1–848. ISBN 0-85198-689-7. 10. ^ Bugnion, E. (1881). "On the epidemic caused by Ankylostomum among the workmen in the St. Gothard Tunnel". British Medical Journal. 1 (1054): 382. doi:10.1136/bmj.1.1054.382. JSTOR 25256433. PMC 2263460. PMID 20749811. 11. ^ "Hookworms: Ancylostoma spp. and Necator spp". Archived from the original on 27 October 2008. Retrieved 2008-10-30. ## External links[edit] Classification D * ICD-10: B76.0 * ICD-9-CM: 126.9 * MeSH: D000724 External resources * eMedicine: ped/96 * v * t * e Parasitic disease caused by helminthiases Flatworm/ platyhelminth infection Fluke/trematode (Trematode infection) Blood fluke * Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum * Schistosomiasis * Trichobilharzia regenti * Swimmer's itch Liver fluke * Clonorchis sinensis * Clonorchiasis * Dicrocoelium dendriticum / D. hospes * Dicrocoeliasis * Fasciola hepatica / F. gigantica * Fasciolosis * Opisthorchis viverrini / O. felineus * Opisthorchiasis Lung fluke * Paragonimus westermani / P. kellicotti * Paragonimiasis Intestinal fluke * Fasciolopsis buski * Fasciolopsiasis * Metagonimus yokogawai * Metagonimiasis * Heterophyes heterophyes * Heterophyiasis Cestoda (Tapeworm infection) Cyclophyllidea * Echinococcus granulosus / E. multilocularis * Echinococcosis * Taenia saginata / T. asiatica / T. solium (pork) * Taeniasis / Cysticercosis * Hymenolepis nana / H. diminuta * Hymenolepiasis Pseudophyllidea * Diphyllobothrium latum * Diphyllobothriasis * Spirometra erinaceieuropaei * Sparganosis * Diphyllobothrium mansonoides * Sparganosis Roundworm/ Nematode infection Secernentea Spiruria Camallanida * Dracunculus medinensis * Dracunculiasis Spirurida Filarioidea (Filariasis) * Onchocerca volvulus * Onchocerciasis * Loa loa * Loa loa filariasis * Mansonella * Mansonelliasis * Dirofilaria repens * D. immitis * Dirofilariasis * Wuchereria bancrofti / Brugia malayi / \|B. timori * Lymphatic filariasis Thelazioidea * Gnathostoma spinigerum / G. hispidum * Gnathostomiasis * Thelazia * Thelaziasis Spiruroidea * Gongylonema Strongylida (hookworm) * Hookworm infection * Ancylostoma duodenale / A. braziliense * Ancylostomiasis / Cutaneous larva migrans * Necator americanus * Necatoriasis * Angiostrongylus cantonensis * Angiostrongyliasis * Metastrongylus * Metastrongylosis Ascaridida * Ascaris lumbricoides * Ascariasis * Anisakis * Anisakiasis * Toxocara canis / T. cati * Visceral larva migrans / Toxocariasis * Baylisascaris * Dioctophyme renale * Dioctophymosis * Parascaris equorum Rhabditida * Strongyloides stercoralis * Strongyloidiasis * Trichostrongylus spp. * Trichostrongyliasis * Halicephalobus gingivalis Oxyurida * Enterobius vermicularis * Enterobiasis Adenophorea * Trichinella spiralis * Trichinosis * Trichuris trichiura (Trichuriasis / Whipworm) * Capillaria philippinensis * Intestinal capillariasis * C. hepatica Authority control * NDL: 00575111 * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Ancylostomiasis	c0002831	3,505	wikipedia	https://en.wikipedia.org/wiki/Ancylostomiasis	2021-01-18T18:47:42	{"mesh": ["C538433", "D000724"], "icd-9": ["126.0", "126.9"], "icd-10": ["B76.0"], "orphanet": ["78"], "wikidata": ["Q137597"]}
Najjar et al. (1974) described a Lebanese family in which 5 of 6 brothers, aged 4 months to 10 years, had small external genitalia with particularly small testes. The parents were first cousins. The 3 brothers of the mother were unaffected. Except for the small external genitalia, the patients were clinically and chromosomally normal. Najjar et al. (1974) predicted that in time these children would manifest hypergonadotropic hypogonadism. The disorder was first described by Bergada et al. (1962), who observed 4 unrelated males at the Johns Hopkins Hospital. Endocrine \- Hypergonadotropic hypogonadism GU \- Small external genitalia \- Small testes Lab \- Normal chromosomes Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	TESTES, RUDIMENTARY	c1848901	3,506	omim	https://www.omim.org/entry/273150	2019-09-22T16:21:56	{"omim": ["273150"]}
## Clinical Features While most patients with cystic fibrosis (219700) suffer from pancreatic enzyme insufficiency, 10 to 15% of patients have a pancreatic-sufficient phenotype, which has been correlated with a group of mild CFTR (602421) mutations characterized by their ability to confer residual chloride-channel function. Meconium ileus (MI) is a severe intestinal obstruction detected in 15 to 20% of CF patients at birth. Although MI usually occurs in patients with pancreatic insufficiency, no specific CFTR mutations have been found to determine MI. A familial recurrence rate of 29% suggests that other genetic factors are involved in the expression of the MI phenotype (Kerem et al., 1989). No independent correlation between CFTR genotype and CF lung disease has been described, indicating that the extreme variability in the lung pathology is also determined by modifier genes and environmental factors (Zielenski et al., 1999). Mapping Rozmahel et al. (1996) identified a CF modifier locus mapped to the proximal region of mouse chromosome 7 that modulated the generally fatal intestinal disease in homozygous mutant mice. Zielenski et al. (1999) demonstrated the existence of a similar CF modifier on human chromosome 19, in a region syntenic to the mouse locus. They examined 9 polymorphic microsatellite markers spanning a 7.65-Mb region of 19q13.2-q13.4 in 197 CF sib pairs and parents from 161 nuclear families ascertained in 10 CF centers worldwide. All CF sib pairs had identical genotypes at the CFTR locus, confirming their parental origins. Two clinical phenotypes were evaluated: the intestinal phenotype was scored by absence or presence of MI at birth, and the pulmonary phenotype was measured by a standard deviation score of age-adjusted forced expiratory volume in 1 second (FEV1), a parameter regarded as the best predictor of pulmonary morbidity and mortality in CF. Nadeau (2001) reviewed modifier genes in mice and humans and discussed the cystic fibrosis modifier locus on chromosome 7 and 19, respectively. By analyzing F508del (602421.0001)-CFTR homozygous sib pairs with contrasting cystic fibrosis phenotypes for variation at the 19q13.1 locus, Stanke et al. (2010) found that SNPs in the CEACAM6 gene (163980) and in a regulatory element near the 3-prime end of the CEACAM3 gene (609142) were associated with disease modification of CF. A 7-SNP haplotype involving the CEACAM6 gene (rs1549960-rs11548735) was identified as differing between mildly and severely affected patients. A 5-SNP haplotype downstream of the CEACAM3 gene (rs6508999-rs10414823) was identified as differing between concordant and discordant sib pairs. The involvement of genes from the CEACAM family in host defense and innate immunity designated these proteins as likely modifiers of the multiorgan disease, which is known for its cytokine imbalance and proinflammatory phenotype. See also TGFB1 (190180), which maps to chromosome 19q13.1 and may be a modifier of lung disease in CF (e.g., 190180.0007). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CYSTIC FIBROSIS, MODIFIER OF, 1	c1859047	3,507	omim	https://www.omim.org/entry/603855	2019-09-22T16:12:35	{"omim": ["603855"]}
A number sign (#) is used with this entry because of evidence that immunodeficiency-54 (IMD54) is caused by homozygous mutation in the MCM4 gene (602638) on chromosome 8q11. Description Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012). Clinical Features Eidenschenk et al. (2006) described a large consanguineous kindred with NK cell deficiency in 4 members in 3 sibships related as first cousins, including 1 patient with Epstein-Barr virus (EBV)-driven lymphoproliferative disorder and 2 patients with severe pneumonitis of probable viral origin. The index patient presented at age 18 months with failure to thrive, hepatomegaly, splenomegaly, and peripheral lymphadenopathy. His condition may have reflected primary EBV infection. He had relatively benign viral infections of childhood, with recurrent respiratory tract infections, herpetic stomatitis, and molluscum contagiosum. At age 2 years and 9 months, he developed an EBV-related lymphoproliferative disorder in the small bowel, and the resulting tumor was surgically removed. He remained well thereafter up to the age of report (9 years). Two of the 3 other affected family members had frequent lung infections. All 4 affected family members presented with a selective and profound deficiency of NK cells in blood, unlike the 14 healthy family members tested. Three of the NK-deficient patients were tested before the onset of any unusual infectious disease associated with EBV infection. This kindred lived in Ireland, and its members were all of Irish Nomadic descent. In a follow-up of this kindred, Gineau et al. (2012) noted that all patients had low NK cell counts in peripheral blood (less than 5% of normal), severe intra- and extrauterine growth retardation, microcephaly, and adrenal insufficiency requiring corticosteroid replacement therapy. Hughes et al. (2012) reported 7 children from 3 kindreds within the Irish Traveller community who had NKGCD. All had isolated glucocorticoid deficiency, increased ACTH, and normal renin and aldosterone. The cortisol deficiency generally became apparent in childhood following a period of normal adrenal function. Affected children also had poor growth, short stature, and a specific NK deficiency. However, only 1 showed increased susceptibility to recurrent infections. Patient lymphocytes showed increased chromosomal breakage. Casey et al. (2012) reported further analysis of members of 3 clans from the Irish Traveller population, including the family reported by Eidenschenk et al. (2006). In the first highly consanguineous pedigree, there was intrauterine growth retardation, failure to thrive, clinodactyly, some episodes of hypoglycemia, and delayed bone age. In the second pedigree, which had been described by Eidenschenk et al. (2006), there was familial glucocorticoid deficiency, as well as natural killer cell deficiency and DNA repair disorder. In the third pedigree, affected individuals were referred for possible Russell-Silver syndrome (see 180860) but were diagnosed with familial glucocorticoid deficiency (FGD; see 202200) on the basis of the development of increased pigmentation and subsequent biochemical investigations. Eventually, Casey et al. (2012) tested members of all 3 clans for the 3 different phenotypes (i.e., familial glucocorticoid deficiency, DNA repair disorder, and NK cell deficiency) and found that some who had FGD also had low levels of NK cells, and some showed defective DNA repair. The DNA repair disorder was classified as mosaic Fanconi anemia (FA; see 227650), but the patients did not have the typical mosaic FA test result or the expected clinical features of the disorder. In mosaic FA, patients have 2 subpopulations of cells, one of which is hypersensitive to crosslinking agents, while the other behaves normally in response to these agents. Upon testing, patients with mosaic FA have some cells with high levels of DNA damage and others that are completely normal. However, often the patients reported by Casey et al. (2012) had a relatively low level of DNA damage in a minority of cells. The observed chromosome breakage was greater than that expected from a healthy individual but less than that of mosaic FA. O'Riordan et al. (2008) had described the endocrine abnormalities in some of these patients. Eight of the 10 patients studied by Casey et al. (2012) had been small for gestational age (SGA). The majority had microcephaly, failure to thrive, and hyperpigmentation; all had short stature. Two had low growth hormone levels, 2 were normal, and the others were not tested. Two had episodes of hypoglycemia; there was 1 person without evidence of hypoglycemia, and the others were not tested. Five patients had biochemical evidence of mosaic Fanconi anemia; in 2 evidence was unclear, 2 were either untested or unknown, and 1 patient had no biochemical evidence of this abnormality. Six patients had evidence of NK cell deficiency and the others were not tested. Inheritance The transmission pattern of IMD54 in the family reported by Eidenschenk et al. (2006) was consistent with autosomal recessive inheritance. Mapping By homozygosity mapping and linkage analysis, Eidenschenk et al. (2006) located the natural killer cell deficiency in their family to the centromeric region of chromosome 8 (8p11.23-q11.21). Molecular Genetics In affected members of 2 consanguineous kindreds within the Irish Traveller community with IMD54, Gineau et al. (2012) identified a homozygous mutation in the MCM4 gene (602638.0001). One of the families had previously been reported by Eidenschenk et al. (2006). In vitro functional expression studies indicated that the mutation resulted in translation of a hypomorphic isoform. Cells transfected with the mutant allele showed a lower proportion of cells in the G1 and S phases and a higher proportion of cells in the G2/M phase compared to controls. The findings suggested that mutant MCM4 adversely disrupted the coordination of DNA replication and impaired the normal control of the prevention of re-replication, with an impact on the mitotic phase. Patient cells showed increased genomic instability and increased DNA breakage compared to control. Hughes et al. (2012) identified the same homozygous truncating mutation in 8 children from 3 consanguineous Irish Traveller kindreds with NKGCD. Casey et al. (2012) identified homozygosity for the same mutation in the MCM4 gene in 10 individuals from 3 clans from the Irish Traveller population manifesting natural killer cell deficiency, DNA repair disorder, and familial glucocorticoid deficiency. Population Genetics O'Riordan et al. (2008) identified 9 children with familial glucocorticoid deficiency among 22,557 individuals in the Irish Traveller population, yielding a disease prevalence of 1 in 2,506 with a carrier frequency of 1 in 25. In the 4- to 15-year old group, the prevalence increased to 1 in 665, with a carrier frequency of 1 in 13. The study focused on endocrinologic features, and the diagnosis was based on high ACTH and low cortisol levels with normal levels of renin and aldosterone. Initial biochemical testing, up to 2.5 years of age, was normal in all patients except 1; the mean age at diagnosis was 5 years. Clinical history indicated that most had hyperpigmentation, short stature, and a history of failure to thrive. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation \- Postnatal growth retardation \- Poor overall growth HEAD & NECK Head \- Microcephaly RESPIRATORY \- Recurrent respiratory infections \- Respiratory failure (in some patients) Lung \- Lung fibrosis ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Hyperpigmentation NEUROLOGIC Central Nervous System \- Delayed cognitive development, mild (reported in 1 family) ENDOCRINE FEATURES \- Adrenal insufficiency \- Corticosteroid deficiency IMMUNOLOGY \- Decreased numbers of circulating NK cells (less than 5%) \- Lymphadenopathy \- Recurrent viral infections NEOPLASIA \- Increased susceptibility to cancer \- Lymphoproliferative disorders LABORATORY ABNORMALITIES \- Cell studies show increased DNA breakage \- Increased ACTH MISCELLANEOUS \- Growth retardation onset in utero \- Glucocorticoid deficiency occurs in mid-childhood \- Founder effect in Irish Traveler population MOLECULAR BASIS \- Caused by mutation in the homolog of the S. Cerevisiae minichromosome maintenance 4 gene (MCM4, 602638.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	IMMUNODEFICIENCY 54	c1864947	3,508	omim	https://www.omim.org/entry/609981	2019-09-22T16:05:18	{"mesh": ["C566492"], "omim": ["609981"], "orphanet": ["75391"], "synonyms": ["NATURAL KILLER CELL DEFICIENCY, FAMILIAL ISOLATED", "Alternative titles", "NATURAL KILLER CELL AND GLUCOCORTICOID DEFICIENCY WITH DNA REPAIR DEFECT", "Primary immunodeficiency due to MCM4 deficiency"]}
HDN due to anti-RhE alloimmunization Other namesanti-RhE SpecialtyPediatrics Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy. The anti-RhE antibody is quite common especially in the Rh genotype CDe/CDe; it usually only causes a mild hemolytic disease, but can cause a severe condition in the newborn. It can occur with other antibodies, usually the anti-Rhc antibody, which can also cause a severe hemolytic disease.[1] One study done by Moran et al., found that titers are not reliable for anti-E. Their most severe case of hemolytic disease of the newborn occurred with titers 1:2. Moran states that it would be unwise routinely to dismiss anti-E as being of little clinical consequence.[2] ## Contents * 1 Presentation * 1.1 Complications * 2 Mechanism * 2.1 Antibody specific * 3 Testing * 3.1 Mother * 3.2 Father * 3.3 Fetus * 3.4 MCA scans * 4 Intervention * 4.1 Early pregnancy * 4.2 Mid to late pregnancy * 5 After birth * 5.1 Testing * 6 Treatment * 7 Transfusion reactions * 8 See also * 9 References * 10 Further reading * 11 External links ## Presentation[edit] ### Complications[edit] * High at birth or rapidly rising bilirubin[3] * Prolonged hyperbilirubinemia[3] * Bilirubin-induced neurological dysfunction[4] * Cerebral palsy[5] * Kernicterus[6][7][8] * Thrombocytopenia[7] * Hemolytic anemia – must not be treated with iron[9] * Late onset anemia – must not be treated with iron. Can persist up to 12 weeks after birth.[10][11][12] ## Mechanism[edit] Hemolytic disease of the fetus and newborn (HDN) is a condition where the passage of maternal antibodies results in the hemolysis of fetal/neonatal red cells. The antibodies can be naturally occurring such as anti-A, and anti-B, or immune antibodies developed following a sensitizing event.[13] Isoimmunization occurs when the maternal immune system is sensitized to red blood cell surface antigens. The most common causes of isoimmunization are blood transfusion, and fetal-maternal hemorrhage.[14] The hemolytic process can result in anemia, hyperbilirubinemia, neonatal thrombocytopenia, and neonatal neutropenia.[7] With the use of RhD Immunoprophylaxis, (commonly called Rhogam), the incidence of anti-D has decreased dramatically and other alloantibodies are now a major cause of HDN.[13] ### Antibody specific[edit] One study done by Moran et al., found that titers are not reliable for anti-E. Their most severe case of hemolytic disease of the newborn occurred with titers 1:2. Moran states that it would be unwise routinely to dismiss anti-E as being of little clinical consequence.[2] In the case of anti-E, the woman should be checked around 28 weeks to see if she has developed anti-c as well.[citation needed] ## Testing[edit] Testing for HDN involves blood work from both mother and father, and may also include assessment with amniocentesis and Middle Cerebral Artery scans. ### Mother[edit] Blood testing for the mother is called an indirect Coombs test (ICT) or an indirect agglutination test (IAT). This test tells whether there are antibodies in the maternal plasma. If positive, the antibody is identified and given a titer. Critical titers are associated with significant risk of fetal anemia and hydrops.[1] Titers of 1:8 or higher is considered critical for Kell. Titers of 1:16 or higher are considered critical for all other antibodies. After critical titer is reached, care is based on MCA scans. If antibodies are low and have a sudden jump later in pregnancy, an MCA scan is warranted. If the titer undergoes a 4 fold increase, it should be considered significant regardless of if the critical value has been reached. Maternal titers are not useful in predicting fetal anemia after the first affected gestation and should not be used for the basis of care.[15] Titers are tested monthly until 24 weeks, after which they are done every 2 weeks.[14] "In only 2 situations are patients not monitored identically to patients who are Rh sensitized. The first is that of alloimmunization to the c, E, or, C antigens. Some concern exists that hemolysis may occur in these patients with a lower than 1:16 titer. Thus, if the initial titer is 1:4 and stable but increases at 26 weeks' gestation to 1:8, assessment with MCA Doppler velocity at that point is reasonable. However, if the patient presents in the first trimester with a 1:8 titer that remains stable at 1:8 throughout the second trimester, continued serial antibody titers are appropriate. The second situation in which patients should not be treated identically to patients who are Rh D sensitized is that of Kell isoimmunization because several cases of severe fetal hemolysis with anti-Kell antibodies have occurred in the setting of low titers."[1] In the case of a positive ICT, the woman must carry a medical alert card or bracelet for life because of the risk of a transfusion reaction. ### Father[edit] Blood is generally drawn from the father to help determine fetal antigen status.[16] If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen.[17] This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.[18] ### Fetus[edit] There are three possible ways to test the fetal antigen status. Free cell DNA, amniocentesis, and chorionic villus sampling (CVS). Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.[citation needed] * Cell-free DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol.[19] Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.[citation needed] * Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.[14] * CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.[14] ### MCA scans[edit] Middle cerebral artery – peak systolic velocity is changing the way sensitized pregnancies are managed.[20] This test is done noninvasively with ultrasound. By measuring the peak velocity of blood flow in the middle cerebral artery, a MoM (multiple of the median) score can be calculated. MoM of 1.5 or greater indicates severe anemia and should be treated with IUT.[21][20] ## Intervention[edit] There are several intervention options available in early, mid and late pregnancies.[citation needed] ### Early pregnancy[edit] * IVIG – IVIG stands for intravenous immunoglobulin. It is used in cases of previous loss, high maternal titers, known aggressive antibodies, and in cases where religion prevents blood transfusion. Ivig can be more effective than IUT alone.[22] Fetal mortality was reduced by 36% in the IVIG and IUT group than in the IUT alone group. IVIG and plasmapheresis together can reduce or eliminate the need for an IUT.[23] * Plasmapheresis – Plasmapheresis aims to decrease the maternal titer by direct plasma replacement.[24] Plasmapheresis and IVIG together can even be used on women with previously hydropic fetuses and losses.[25][26] ### Mid to late pregnancy[edit] * IUT – intrauterine transfusion (IUT) is done either by intraperitoneal transfusion (IPT) or intravenous transfusion (IVT).[27] IVT is preferred over IPT.[1] IUTs are only done until 35 weeks. After that, the risk of an IUT is greater than the risk from post birth transfusion.[28] * Steroids – steroids are sometimes given to the mother before IUTs and early delivery to mature the fetal lungs.[28][15] * Phenobarbital – Phenobarbital is sometimes given to the mother to help mature the fetal liver and reduce hyperbilirubinemia.[15][29] * Early delivery – delivery can occur anytime after the age of viability.[1] Emergency delivery due to failed IUT is possible, along with induction of labor at 35–38 weeks.[28][30] ## After birth[edit] ### Testing[edit] * Coombs – after birth the baby will have a direct Coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood.[3] In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur.[31] An indirect Coombs needs to be run in cases of anti-C,[32] anti-c,[32] and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.[24] * Hgb – the infant's hemoglobin should be tested from cord blood.[3] * Reticulocyte count – Reticulocytes are elevated when the infant is producing more blood to combat anemia.[3] A rise in the retic count can mean that an infant may not need additional transfusions.[33] Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell[32] * Neutrophils – as neutropenia is one of the complications of HDN, the neutrophil count should be checked.[7][8] * Thrombocytes – as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.[7] * Bilirubin should be tested from cord blood.[3] * Ferritin – because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.[9] * Newborn screening tests – transfusion with donor blood during pregnancy or shortly after birth can affect the results of the newborn screening tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions. ## Treatment[edit] * Phototherapy – Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.[34] * IVIG – IVIG has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well.[35] IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy.[36] The AAP recommends "In isoimmune hemolytic disease, administration of intravenousγ-globulin (0.5–1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34–51 μmol/L) of the exchange level. If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."[34] * Exchange transfusion – exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the nonogram provided by the American Academy of Pediatrics (Figure 4).[34] Cord bilirubin >4 is also indicative of the need for exchange transfusion.[37] ## Transfusion reactions[edit] Once a woman has antibodies, she is at high risk for a transfusion reaction.[38] For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.[citation needed] "Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."[39] Summary of transfusion reactions in the US:[40] ## See also[edit] * Coombs test * Hematology * Hemolytic anemia * Hemolytic disease of the newborn ## References[edit] 1. ^ a b c d e Erythrocyte Alloimmunization and Pregnancy at eMedicine 2. ^ a b Moran, P.; Robson, S. C.; Reid, M. M. (2000). "Anti-E in pregnancy". BJOG. 107 (11): 1436–8. doi:10.1111/j.1471-0528.2000.tb11662.x. PMID 11117776. 3. ^ a b c d e f Murray, N. A; Roberts, I. A G (2007). "Haemolytic disease of the newborn". Archives of Disease in Childhood: Fetal and Neonatal Edition. 92 (2): F83–8. doi:10.1136/adc.2005.076794. PMC 2675453. PMID 17337672. 4. ^ Shapiro, Steven M (2004). "Definition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND)". Journal of Perinatology. 25 (1): 54–9. doi:10.1038/sj.jp.7211157. PMID 15578034. S2CID 19663259. 5. ^ Blair, Eve; Watson, Linda (2006). "Epidemiology of cerebral palsy". Seminars in Fetal and Neonatal Medicine. 11 (2): 117–25. doi:10.1016/j.siny.2005.10.010. PMID 16338186. 6. ^ Lande, Lottie (1948). "Clinical signs and development of survivors of kernicterus due to Rh sensitization". The Journal of Pediatrics. 32 (6): 693–705. doi:10.1016/S0022-3476(48)80225-8. PMID 18866937. 7. ^ a b c d e Koenig, J. M.; Christensen, R. D. (1989). "Neutropenia and thrombocytopenia in infants with Rh hemolytic disease". The Journal of Pediatrics. 114 (4 Pt 1): 625–31. doi:10.1016/s0022-3476(89)80709-7. PMID 2494315. 8. ^ a b Lalezari, P; Nussbaum, M; Gelman, S; Spaet, T. H. (1960). "Neonatal neutropenia due to maternal isoimmunization". Blood. 15 (2): 236–43. doi:10.1182/blood.V15.2.236.236. PMID 14413526.[permanent dead link] 9. ^ a b Rath, M. E.; Smits-Wintjens, V. E.; Oepkes, D; Walther, F. J.; Lopriore, E (2013). "Iron status in infants with alloimmune haemolytic disease in the first three months of life". Vox Sanguinis. 105 (4): 328–33. doi:10.1111/vox.12061. PMID 23802744. 10. ^ Mitchell, S; James, A (1999). "Severe late anemia of hemolytic disease of the newborn". Paediatrics & Child Health. 4 (3): 201–3. doi:10.1093/pch/4.3.201. PMC 2828194. PMID 20212966. 11. ^ Al-Alaiyan, S; Al Omran, A (1999). "Late hyporegenerative anemia in neonates with rhesus hemolytic disease". Journal of Perinatal Medicine. 27 (2): 112–5. doi:10.1515/JPM.1999.014. PMID 10379500. S2CID 32155893. 12. ^ Jadala, Hareesh; v., Pooja; k., Raghavendra; m., Prithvish; b., Srinivas (2016). "Late onset severe anemia due to rhesus isoimmunization". International Journal of Contemporary Pediatrics: 1472–3. doi:10.18203/2349-3291.ijcp20163704. 13. ^ a b Basu, Sabita; Kaur, Ravneet; Kaur, Gagandeep (2011). "Hemolytic disease of the fetus and newborn: Current trends and perspectives". Asian Journal of Transfusion Science. 5 (1): 3–7. doi:10.4103/0973-6247.75963. PMC 3082712. PMID 21572705. 14. ^ a b c d Cacciatore, A; Rapiti, S; Carrara, S; Cavaliere, A; Ermito, S; Dinatale, A; Imbruglia, L; Recupero, S; La Galia, T; Pappalardo, E. M.; Accardi, M. C. (2009). "Obstetric management in Rh alloimmunizated pregnancy". Journal of Prenatal Medicine. 3 (2): 25–7. PMC 3279102. PMID 22439037. 15. ^ a b c Hemolytic Disease of Newborn~treatment at eMedicine 16. ^ Scheffer, PG; Van Der Schoot, CE; Page-Christiaens, Gcml; De Haas, M (2011). "Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: Evaluation of a 7-year clinical experience". BJOG: An International Journal of Obstetrics & Gynaecology. 118 (11): 1340–8. doi:10.1111/j.1471-0528.2011.03028.x. PMID 21668766. 17. ^ Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects ISBN 978-0-08-092230-0[page needed][full citation needed] 18. ^ https://www.aacc.org/publications/cln/articles/2015/march/molecular-typing-for-red-blood-cell-antigens[full citation needed] 19. ^ Finning, Kirstin; Martin, Peter; Summers, Joanna; Daniels, Geoff (2007). "Fetal genotyping for the K (Kell) and Rh C, c, and E blood groups on cell-free fetal DNA in maternal plasma". Transfusion. 47 (11): 2126–33. doi:10.1111/j.1537-2995.2007.01437.x. PMID 17958542. 20. ^ a b Mari, Giancarlo; Deter, Russell L.; Carpenter, Robert L.; Rahman, Feryal; Zimmerman, Roland; Moise, Kenneth J.; Dorman, Karen F.; Ludomirsky, Avi; Gonzalez, Rogelio; Gomez, Ricardo; Oz, Utku; Detti, Laura; Copel, Joshua A.; Bahado-Singh, Ray; Berry, Stanley; Martinez-Poyer, Juan; Blackwell, Sean C. (2000). "Noninvasive Diagnosis by Doppler Ultrasonography of Fetal Anemia Due to Maternal Red-Cell Alloimmunization". New England Journal of Medicine. 342 (1): 9–14. doi:10.1056/NEJM200001063420102. PMID 10620643. 21. ^ Mari, G. (2005). "Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: The untold story". Ultrasound in Obstetrics and Gynecology. 25 (4): 323–30. doi:10.1002/uog.1882. PMID 15789353. 22. ^ Voto, L. S.; Mathet, E. R.; Zapaterio, J. L.; Orti, J; Lede, R. L.; Margulies, M (1997). "High-dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs): A new alternative for the treatment of severe fetal hemolytic disease". Journal of Perinatal Medicine. 25 (1): 85–8. doi:10.1515/jpme.1997.25.1.85. PMID 9085208. S2CID 22822621. 23. ^ Novak, D. J.; Tyler, L. N.; Reddy, R. L.; Barsoom, M. J. (2008). "Plasmapheresis and intravenous immune globulin for the treatment of D alloimmunization in pregnancy". Journal of Clinical Apheresis. 23 (6): 183–5. doi:10.1002/jca.20180. PMID 19003884. 24. ^ a b Arora, Satyam; Doda, Veena; Maria, Arti; Kotwal, Urvershi; Goyal, Saurabh (2015). "Maternal anti-M induced hemolytic disease of newborn followed by prolonged anemia in newborn twins". Asian Journal of Transfusion Science. 9 (1): 98–101. doi:10.4103/0973-6247.150968. PMC 4339947. PMID 25722586. 25. ^ Palfi, M; Hildén, J. O.; Matthiesen, L; Selbing, A; Berlin, G (2006). "A case of severe Rh (D) alloimmunization treated by intensive plasma exchange and high-dose intravenous immunoglobulin". Transfusion and Apheresis Science. 35 (2): 131–6. doi:10.1016/j.transci.2006.07.002. PMID 17045529. 26. ^ Ruma, M. S.; Moise Jr, K. J.; Kim, E; Murtha, A. P.; Prutsman, W. J.; Hassan, S. S.; Lubarsky, S. L. (2007). "Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization". American Journal of Obstetrics and Gynecology. 196 (2): 138.e1–6. doi:10.1016/j.ajog.2006.10.890. PMID 17306655. 27. ^ Deka, Dipika (2016). "Intrauterine Transfusion". Journal of Fetal Medicine. 27 (3): 13–17. doi:10.1007/s40556-016-0072-4. PMID 26811110. S2CID 42005756. 28. ^ a b c http://www.uptodate.com/contents/intrauterine-fetal-transfusion-of-red-cells[full citation needed] 29. ^ https://www.mombaby.org/wp-content/uploads/2016/03/UNC-Isoimmunization-Detection-Prevention.pdf[full citation needed][permanent dead link] 30. ^ Rimon, E.; Peltz, R.; Gamzu, R.; Yagel, S.; Feldman, B.; Chayen, B.; Achiron, R.; Lipitz, S. (2006). "Management of Kell isoimmunization — evaluation of a Doppler-guided approach". Ultrasound in Obstetrics and Gynecology. 28 (6): 814–20. doi:10.1002/uog.2837. PMID 16941575. 31. ^ Heddle, N. M.; Wentworth, P; Anderson, D. R.; Emmerson, D; Kelton, J. G.; Blajchman, M. A. (1995). "Three examples of Rh haemolytic disease of the newborn with a negative direct antiglobulin test". Transfusion Medicine (Oxford, England). 5 (2): 113–6. doi:10.1111/j.1365-3148.1995.tb00197.x. PMID 7655573. 32. ^ a b c Hemolytic Disease of Newborn~workup at eMedicine 33. ^ https://www.ucsfbenioffchildrens.org/pdf/manuals/42_Hemol.pdf[full citation needed] 34. ^ a b c American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. (2004). "Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation". Pediatrics. 114 (1): 297–316. doi:10.1542/peds.114.1.297. PMID 15231951. 35. ^ Onesimo, R; Rizzo, D; Ruggiero, A; Valentini, P (2010). "Intravenous Immunoglobulin therapy for anti-E hemolytic disease in the newborn". The Journal of Maternal-Fetal & Neonatal Medicine. 23 (9): 1059–61. doi:10.3109/14767050903544751. PMID 20092394. S2CID 25144401. 36. ^ Gottstein, R (2003). "Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn". Archives of Disease in Childhood: Fetal and Neonatal Edition. 88 (1): F6–10. doi:10.1136/fn.88.1.F6. PMC 1755998. PMID 12496219. 37. ^ Hemolytic Disease of Newborn~followup at eMedicine 38. ^ Strobel, Erwin (2008). "Hemolytic Transfusion Reactions". Transfusion Medicine and Hemotherapy. 35 (5): 346–353. doi:10.1159/000154811. PMC 3076326. PMID 21512623. 39. ^ Transfusion Reactions at eMedicine 40. ^ https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/ucm302847.htm[full citation needed] ## Further reading[edit] * Antenatal & neonatal screening (second edition). Chapter 12: Rhesus and other haemolytic diseases, by E.A. Letsky, I. Leck, J.M. Bowman. 2000. Oxford University Press. ISBN 0-19-262826-7. ## External links[edit] Classification D * ICD-10: P55.8 * ICD-9-CM: 773.2 * v * t * e Conditions originating in the perinatal period / fetal disease Maternal factors complicating pregnancy, labour or delivery placenta * Placenta praevia * Placental insufficiency * Twin-to-twin transfusion syndrome chorion/amnion * Chorioamnionitis umbilical cord * Umbilical cord prolapse * Nuchal cord * Single umbilical artery presentation * Breech birth * Asynclitism * Shoulder presentation Growth * Small for gestational age / Large for gestational age * Preterm birth / Postterm pregnancy * Intrauterine growth restriction Birth trauma * scalp * Cephalohematoma * Chignon * Caput succedaneum * Subgaleal hemorrhage * Brachial plexus injury * Erb's palsy * Klumpke paralysis Affected systems Respiratory * Intrauterine hypoxia * Infant respiratory distress syndrome * Transient tachypnea of the newborn * Meconium aspiration syndrome * Pleural disease * Pneumothorax * Pneumomediastinum * Wilson–Mikity syndrome * Bronchopulmonary dysplasia Cardiovascular * Pneumopericardium * Persistent fetal circulation Bleeding and hematologic disease * Vitamin K deficiency bleeding * HDN * ABO * Anti-Kell * Rh c * Rh D * Rh E * Hydrops fetalis * Hyperbilirubinemia * Kernicterus * Neonatal jaundice * Velamentous cord insertion * Intraventricular hemorrhage * Germinal matrix hemorrhage * Anemia of prematurity Gastrointestinal * Ileus * Necrotizing enterocolitis * Meconium peritonitis Integument and thermoregulation * Erythema toxicum * Sclerema neonatorum Nervous system * Perinatal asphyxia * Periventricular leukomalacia Musculoskeletal * Gray baby syndrome * muscle tone * Congenital hypertonia * Congenital hypotonia Infections * Vertically transmitted infection * Neonatal infection * rubella * herpes simplex * mycoplasma hominis * ureaplasma urealyticum * Omphalitis * Neonatal sepsis * Group B streptococcal infection * Neonatal conjunctivitis Other * Miscarriage * Perinatal mortality * Stillbirth * Infant mortality * Neonatal withdrawal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hemolytic disease of the newborn (anti-RhE)	None	3,509	wikipedia	https://en.wikipedia.org/wiki/Hemolytic_disease_of_the_newborn_(anti-RhE)	2021-01-18T18:30:19	{"wikidata": ["Q17002920"]}
A number sign (#) is used with this entry because of evidence that Charcot-Marie-Tooth disease type 2S (CMT2S) is caused by homozygous or compound heterozygous mutation in the IGHMBP2 gene (600502) on chromosome 11q13. Biallelic mutation in the IGHMBP2 gene can also cause DSMA1 (604320), a more severe neurologic disorder with respiratory involvement that often results in early death. Description Charcot-Marie-Tooth disease type 2S is a relatively pure form of autosomal recessive axonal neuropathy characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy affecting the lower and upper limbs. Patients have decreased reflexes and variable distal sensory impairment (summary by Cottenie et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210). Clinical Features Cottenie et al. (2014) reported 15 patients from 11 unrelated families with an axonal neuropathy. The families were of various ethnic origins, including English, European, Serbian, Korean, Pakistani, and Vietnamese. The age at onset was in the first decade, ranging from 1 to 10 years, and about half of patients were adults at the time of the report. Most patients presented with delayed motor development and gait difficulties, including toe walking, foot drop, and steppage gait. Some patients had a foot deformity, mainly pes equinovarus. Some also had hand weakness at onset, and almost all eventually developed significant hand involvement. Six patients were wheelchair-bound, and most of the others required ankle-foot orthoses for walking. Some patients had scoliosis and mild proximal muscle weakness. Physical examination showed absent reflexes and variable distal sensory impairment. Three patients had an abnormal tongue shape, but otherwise there was no bulbar or respiratory involvement. Electrophysiologic studies were reported to be consistent with a mild motor and sensory axonal neuropathy with nerve conduction velocities between 40 and 50 m/s, although some patients had absent responses on testing. Sural nerve biopsy from 1 patient showed a moderate reduction in density of large myelinated fibers, whereas small myelinated fibers were well preserved; ultrastructural analysis showed occasional actively degenerating axonal profiles. Schottmann et al. (2015) reported 5 patients from 3 unrelated families with CMT2S. There was variable severity of the disorder. In 1 family, 1 sib presented at age 6 months with generalized hypotonia and had symptoms of respiratory insufficiency with documented diaphragmatic paralysis. He became wheelchair-bound at age 6 years. Additional features included bladder and gastrointestinal dysfunction with achalasia. His sister presented with delayed motor development and distal muscle weakness at age 2. She did not have respiratory symptoms, but lost free independent ambulation at age 10 and also had bladder and gastrointestinal dysfunction. Three patients from the other 2 families presented between 2 and 6 years of age with pes cavus and/or toe walking, but remained ambulatory between ages 14 and 37 years. None had respiratory symptoms. All patients had absent reflexes and absence of sensory symptoms, although sensory nerve action potentials were absent on electrophysiologic testing, consistent with a sensorimotor neuropathy. Inheritance The transmission pattern of CMT2S in the families reported by Cottenie et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 15 patients from 11 families with childhood onset of CMT2, Cottenie et al. (2014) identified biallelic mutations in the IGHMBP2 gene (see, e.g., 600502.0010-600502.0014). The mutations in the first family were found by whole-exome sequencing; mutations in the remaining 10 families were found by targeted sequencing of a cohort of 85 families with recessive CMT2. Most of the patients carried compound heterozygous mutations; many had a nonsense mutation in the 5-prime region and a mutation in the last exon. Patient fibroblasts and lymphoblastoid cells showed IGHMBP2 protein levels lower than controls, but higher than those observed in patients with DSMA1, suggesting that the milder phenotype in CMT2S may be related to residual protein levels. In 5 patients from 3 unrelated families with CMT2S, Schottmann et al. (2015) identified biallelic mutations in the IGHMBP2 gene (see, e.g., 600502.0010-600502.0011, 600502.0015). INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- Abnormal tongue shape (in some patients) SKELETAL Spine \- Scoliosis (in some patients) Feet \- Pes equinovarus (in some patients) MUSCLE, SOFT TISSUES \- Distal muscle weakness due to peripheral neuropathy \- Distal muscle atrophy due to peripheral neuropathy \- Lower and upper limbs affected \- Proximal muscle weakness, mild (in some patients) NEUROLOGIC Peripheral Nervous System \- Axonal sensorimotor neuropathy affecting upper and lower limbs \- Distal sensory impairment \- Distal motor impairment \- Foot drop \- Impaired gait \- Steppage gait \- Areflexia \- Hyporeflexia \- Reduction in large myelinated fibers seen on sural nerve biopsy \- Axonal degeneration MISCELLANEOUS \- Onset in first decade \- Slowly progressive \- Most patients become wheelchair-bound MOLECULAR BASIS \- Caused by mutation in the immunoglobulin mu-binding protein 2 gene (IGHMBP2, 600502.0010 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2S	c4015349	3,510	omim	https://www.omim.org/entry/616155	2019-09-22T15:49:45	{"doid": ["0110171"], "omim": ["616155"], "orphanet": ["443073"], "synonyms": ["Alternative titles", "CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL RECESSIVE, TYPE 2S", "CMT2S", "CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2S"]}
Juberg and Touchstone (1974) described type 1 metatarsus varus in 9 persons in 4 generations with male-to-male transmission. Metatarsus varus is a malformation of the anterior foot that results in inward angulation. Type 1, the most common form, shows adduction of the anterior foot, high longitudinal arch, concavity of the medial border and convexity of the lateral border of the foot, and neutral position of the heel. Type 2 is a deformity residual after correction of the more severe forms of clubfoot. The third form, the rarest, usually has a fixed valgus deformity of the heel and is often associated with other anomalies. The first and third types have been noted to 'run in families' as multifactorial traits. A mendelian form is indicated by the kindred of Juberg and Touchstone (1974). Limbs \- Metatarsus varus \- Inward foot angulation \- Adduction of anterior foot \- High longitudinal arch \- Concavity of medial foot border \- Convexity of lateral foot border \- Neutral heel position Inheritance \- Autosomal dominant form \- usually multifactorial ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	METATARSUS VARUS, TYPE I	c1834968	3,511	omim	https://www.omim.org/entry/156520	2019-09-22T16:38:15	{"mesh": ["C563585"], "omim": ["156520"]}
A rare congenital myopathy characterized ultrastructurally by the presence of tubular aggregates in the subsarcolemmal region of the muscle fiber. It most commonly presents with slowly progressive proximal muscle weakness predominantly of the lower limbs, periodic paralysis, post-exertion muscle cramps, and muscular pain. Ocular anomalies like ophthalmoplegia or pupillary abnormalities may be associated. The intensity of the symptoms is variable, cases with normal muscle strength but myalgia or fatigue, as well as clinically asymptomatic cases have been described. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Tubular aggregate myopathy	c0410207	3,512	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2593	2021-01-23T17:15:10	{"gard": ["3884"], "mesh": ["D020914"], "omim": ["160565", "615883"], "umls": ["C0410207"], "icd-10": ["G71.2"]}
Apraxia of speech (AOS) is an acquired oral motor speech disorder affecting an individual's ability to translate conscious speech plans into motor plans, which results in limited and difficult speech ability. By the definition of apraxia, AOS affects volitional (willful or purposeful) movement patterns, however AOS usually also affects automatic speech.[1] Individuals with AOS have difficulty connecting speech messages from the brain to the mouth.[2] AOS is a loss of prior speech ability resulting from a brain injury such as a stroke or progressive illness. Developmental verbal dyspraxia (DVD), also known as childhood apraxia of speech (CAS) and developmental apraxia of speech (DAS),[3][4] is an inability to utilize motor planning to perform movements necessary for speech during a child's language learning process. Although the causes differ between AOS and DVD, the main characteristics and treatments are similar.[2][5] ## Contents * 1 Presentation * 2 Causes * 2.1 Acute apraxia of speech * 2.2 Progressive apraxia of speech * 3 Diagnosis * 3.1 Possible co-morbid aphasias * 4 Management * 5 History and terminology * 6 Research * 7 See also * 8 References * 9 External links ## Presentation Apraxia of speech (AOS) is a neurogenic communication disorder affecting the motor programming system for speech production.[6][7] Individuals with AOS demonstrate difficulty in speech production, specifically with sequencing and forming sounds. The Levelt model describes the speech production process in the following three consecutive stages: conceptualization, formulation, and articulation. According to the Levelt model, apraxia of speech would fall into the articulation region. The individual does not suffer from a language deficiency, but has difficulty in the production of language in an audible manner. Notably, this difficulty is limited to vocal speech, and does not affect sign-language production. The individual knows exactly what they want to say, but there is a disruption in the part of the brain that sends the signal to the muscle for the specific movement.[7] Individuals with acquired AOS demonstrate hallmark characteristics of articulation and prosody (rhythm, stress or intonation) errors.[6][7] Coexisting characteristics may include groping and effortful speech production with self-correction, difficulty initiating speech, abnormal stress, intonation and rhythm errors, and inconsistency with articulation.[8] Wertz et al., (1984) describe the following five speech characteristics that an individual with apraxia of speech may exhibit:[8] Effortful trial and error with groping Groping is when the mouth searches for the position needed to create a sound. When this trial and error process occurs, sounds may be held out longer, repeated or silently voiced. In some cases, an AOS sufferer may be able to produce certain sounds on their own, easily and unconsciously, but when prompted by another to produce the same sound the patient may grope with their lips, using volitional control (conscious awareness of the attempted speech movements), while struggling to produce the sound.[7] Self correction of errors Patients are aware of their speech errors and can attempt to correct themselves. This can involve distorted consonants, vowels, and sound substitutions. People with AOS often have a much greater understanding of speech than they are able to express. This receptive ability allows them to attempt self correction.[9] Abnormal rhythm, stress and intonation Sufferers of AOS present with prosodic errors which include irregular pitch, rate, and rhythm. This impaired prosody causes their speech to be: too slow or too fast and highly segmented (many pauses). An AOS speaker also stresses syllables incorrectly and in a monotone. As a result, the speech is often described as 'robotic'. When words are produced in a monotone with equal syllabic stress, a word such as 'tectonic' may sound like 'tec-ton-ic' as opposed to 'tec-TON-ic'. These patterns occur even though the speakers are aware of the prosodic patterns that should be used.[10] Inconsistent articulation errors on repeated speech productions of the same utterance When producing the same utterance in different instances, a person with AOS may have difficulty using and maintaining the same articulation that was previously used for that utterance. On some days, people with AOS may have more errors, or seem to "lose" the ability to produce certain sounds for an amount of time. Articulation also becomes more difficult when a word or phrase requires an articulation adjustment, in which the lips and tongue must move in order to shift between sounds. For example, the word "baby" needs less mouth adjustment than the word "dog" requires, since producing "dog" requires two tongue/lips movements to articulate.[6] Difficulty initiating utterances Producing utterances becomes a difficult task in patients with AOS, which results in various speech errors. The errors in completing a speech movement gesture may increase as the length of the utterance increases. Since multisyllabic words are difficult, those with AOS use simple syllables and a limited range of consonants and vowels.[6][7] ## Causes Apraxia of speech can be caused by impairment to parts of the brain that control muscle movement and speech.[2][11] However, identifying a particular region of the brain in which AOS always occurs has been controversial. Various patients with damage to left subcortical structures, regions of the insula, and Broca’s area have been diagnosed with AOS. Most commonly it is triggered by vascular lesions, but AOS can also arise due to tumors and trauma.[6] ### Acute apraxia of speech Stroke-associated AOS is the most common form of acquired AOS, making up about 60% of all reported acquired AOS cases. This is one of the several possible disorders that can result from a stroke, but only about 11% of stroke cases involve this disorder. Brain damage to the neural connections, and especially the neural synapses, during the stroke can lead to acquired AOS. Most cases of stroke-associated AOS are minor, but in the most severe cases, all linguistic motor function can be lost and must be relearned. Since most with this form of AOS are at least fifty years old, few fully recover to their previous level of ability to produce speech. Other disorders and injuries of the brain that can lead to AOS include (traumatic) dementia, progressive neurological disorders, and traumatic brain injury.[11] ### Progressive apraxia of speech Recent research has established the existence of primary progressive apraxia of speech caused by neuroanatomic motor atrophy.[12][13] For a long time, this disorder was not distinguished from other motor speech disorders such as dysarthria and in particular primary progressive aphasia. Many studies have been done trying to identify areas in the brain in which this particular disorder occurs or at least to show that it occurs in different areas of the brain than other disorders.[14] One study observed 37 patients with neurodegenerative speech disorders to determine whether or not it is distinguishable from other disorders, and if so where in the brain it can be found. Using speech and language, neurological, neuropsychological and neuroimaging testing, the researchers came to the conclusion that PAS does exist and that it correlates to superior lateral premotor and supplementary motor atrophy.[13] However, because PAS is such a rare and recently discovered disorder, many studies do not have enough subjects to observe to make data entirely conclusive. ## Diagnosis Apraxia of speech can be diagnosed by a speech language pathologist (SLP) through specific exams that measure oral mechanisms of speech. The oral mechanisms exam involves tasks such as pursing lips, blowing, licking lips, elevating the tongue, and also involves an examination of the mouth. A complete exam also involves observation of the patient eating and talking. SLPs do not agree on a specific set of characteristics that make up the apraxia of speech diagnosis,[citation needed] so any of the characteristics from the section above could be used to form a diagnosis.[2] Patients may be asked to perform other daily tasks such as reading, writing, and conversing with others. In situations involving brain damage, an MRI brain scan also helps identify damaged areas of the brain.[2] A differential diagnosis must be used in order to rule out other similar or alternative disorders. Although disorders such as expressive aphasia, conduction aphasia, and dysarthria involve similar symptoms as apraxia of speech, the disorders must be distinguished in order to correctly treat the patients.[citation needed] While AOS involves the motor planning or processing stage of speech, aphasic disorders can involve other language processes.[15] According to Ziegler et al., this difficulty in diagnosis derives from the unknown causes and function of the disorder, making it hard to set definite parameters for AOS identification. Specifically, he explains that oral-facial apraxia, dysarthria, and aphasic phonological impairment are the three distinctly different disorders that cause individuals to display symptoms that are often similar to those of someone with AOS, and that these close relatives must be correctly ruled out by a Speech Language Pathologist before AOS can be given as a diagnosis. In this way, AOS is a diagnosis of exclusion, and is generally recognized when all other similar speech sound production disorders are eliminated.[16] ### Possible co-morbid aphasias AOS and expressive aphasia (also known as Broca's aphasia) are commonly mistaken as the same disorder mainly because they often occur together in patients. Although both disorders present with symptoms such as a difficulty producing sounds due to damage in the language parts of the brain, they are not the same. The main difference between these disorders lies in the ability to comprehend spoken language; patients with apraxia are able to fully comprehend speech, while patients with aphasia are not always fully able to comprehend others' speech.[17] Conduction aphasia is another speech disorder that is similar to, but not the same as, apraxia of speech. Although patients who suffer from conduction aphasia have full comprehension of speech, as do AOS sufferers, there are differences between the two disorders.[18] Patients with conduction aphasia are typically able to speak fluently, but they do not have the ability to repeat what they hear.[19] Similarly, dysarthria, another motor speech disorder, is characterized by difficulty articulating sounds. The difficulty in articulation does not occur due in planning the motor movement, as happens with AOS. Instead, dysarthria is caused by inability in or weakness of the muscles in the mouth, face, and respiratory system.[20] ## Management In cases of acute AOS (stroke), spontaneous recovery may occur, in which previous speech abilities reappear on their own. All other cases of acquired AOS require a form of therapy; however the therapy varies with the individual needs of the patient. Typically, treatment involves one-on-one therapy with a speech language pathologist (SLP).[2] For severe forms of AOS, therapy may involve multiple sessions per week, which is reduced with speech improvement. Another main theme in AOS treatment is the use of repetition in order to achieve a large number of target utterances, or desired speech usages. There are various treatment techniques for AOS. One technique, called the Linguistic Approach, utilizes the rules for sounds and sequences. This approach focuses on the placement of the mouth in forming speech sounds. Another type of treatment is the Motor-Programming Approach, in which the motor movements necessary for speech are practiced. This technique utilizes a great amount of repetition in order to practice the sequences and transitions that are necessary in between production of sounds. Research about the treatment of apraxia has revealed four main categories: articulatory-kinematic, rate/rhythm control, intersystemic facilitation/reorganization treatments, and alternative/augmentative communication.[21] * Articulatory-kinematic treatments almost always require verbal production in order to bring about improvement of speech. One common technique for this is modeling or repetition in order to establish the desired speech behavior. Articulatory-kinematic treatments are based on the importance of patients to improve spatial and temporal aspects of speech production. * Rate and rhythm control treatments exist to improve errors in patients’ timing of speech, a common characteristic of Apraxia. These techniques often include an external source of control like metronomic pacing, for example, in repeated speech productions. * Intersystemic reorganization/facilitation techniques often involve physical body or limb gestural approaches to improve speech. Gestures are usually combined with verbalization. It is thought that limb gestures may improve the organization of speech production. * Finally, alternative and augmentative communication approaches to treatment of apraxia are highly individualized for each patient. However, they often involve a "comprehensive communication system" that may include "speech, a communication book aid, a spelling system, a drawing system, a gestural system, technologies, and informed speech partners". One specific treatment method is referred to as PROMPT. This acronym stands for Prompts for Restructuring Oral Muscular Phonetic Targets,[22] and takes a hands on multidimensional approach at treating speech production disorders. PROMPT therapists integrate physical-sensory, cognitive-linguistic, and social-emotional aspects of motor performance. The main focus is developing language interaction through this tactile-kinetic approach by using touch cues to facilitate the articulatory movements associated with individual phonemes, and eventually words. One study describes the use of electropalatography (EPG) to treat a patient with severe acquired apraxia of speech. EPG is a computer-based tool for assessment and treatment of speech motor issues. The program allows patients to see the placement of articulators during speech production thus aiding them in attempting to correct errors. Originally after two years of speech therapy, the patient exhibited speech motor and production problems including problems with phonation, articulation, and resonance. This study showed that EPG therapy gave the patient valuable visual feedback to clarify speech movements that had been difficult for the patient to complete when given only auditory feedback.[23] While many studies are still exploring the various treatment methods, a few suggestions from ASHA for treating apraxia patients include the integration of objective treatment evidence, theoretical rationale, clinical knowledge and experience, and the needs and goals of the patient ## History and terminology The term apraxia was first defined by Hugo Karl Liepmann in 1908 as the "inability to perform voluntary acts despite preserved muscle strength." In 1969, Frederic L. Darley coined the term "apraxia of speech", replacing Liepmann's original term "apraxia of the glosso-labio-pharyngeal structures." Paul Broca had also identified this speech disorder in 1861, which he referred to as "aphemia": a disorder involving difficulty of articulation despite having intact language skills and muscular function.[6] The disorder is currently referred to as "apraxia of speech", but was also formerly termed "verbal dyspraxia". The term apraxia comes from the Greek root "praxis," meaning the performance of action or skilled movement.[8] Adding the prefix "a", meaning absence, or "dys", meaning abnormal or difficult, to the root "praxis", both function to imply speech difficulties related to movement. ## Research Many researchers are investigating the characteristics of apraxia of speech and the most effective treatment methods. Below are a couple of the recent findings: Sound Production Treatment: Articulatory-kinematic treatments have the strongest evidence of their use in treating Acquired Apraxia of Speech. These treatments use the facilitation of movement, positioning, timing, and articulators to improve speech production. Sound Production Treatment (SPT) is an articulatory-kinematic treatment that has received more research than many other methods. It combines modeling, repetition, minimal pair contrast, integral stimulation, articulatory placement cueing, and verbal feedback. It was developed to improve the articulation of targeted sounds in the mid-1990s. SPT shows consistent improvement of trained sounds in trained and untrained words. The best results occur with eight to ten exemplars of the targeted sound to promote generalization to untrained exemplars of trained sounds. In addition, maintenance effects are the strongest with 1–2 months post-treatment with sounds that reached high accuracy during treatment. Therefore, the termination of treatment should not be determined by performance criteria, and not by the number of sessions the client completes, in order to have the greatest long-term effects. While there are many parts of SPT that should receive further investigation, it can be expected that it will improve the production of targeted sounds for speakers with apraxia of Speech.[24] Repeated Practice & Rate/Rhythm Control Treatments: Julie Wambaugh’s research focuses on clinically applicable treatments for acquired apraxia of speech. She recently published an article examining the effects of repeated practice and rate/rhythm control on sound production accuracy. Wambaugh and colleagues studied the effects of such treatment for 10 individuals with acquired apraxia of speech. The results indicate that repeated practice treatment results in significant improvements in articulation for most clients. In addition, rate/rhythm control helped some clients, but not others. Thus, incorporating repeated practice treatment into therapy would likely help individuals with AOS.[25] Nuffield Dyspraxia Programme-3 (NDP-3) and Rapid Syllable Transition Treatment (ReST): A 2018 Cochrane review found that when delivered intensively both the NDP-3 and ReST may effect improvement in word accuracy in 4 - 12 year old children with CAS.[26] ## See also * Apraxia * Aphasia * Conduction aphasia * Developmental coordination disorder * Developmental verbal dyspraxia * Dysarthria * FOXP2 * KE family * Origin of speech * Speech and language impairment * ## References 1. ^ West, Carolyn; Hesketh, Anne; Vail, Andy; Bowen, Audrey; West, Carolyn (2005). "Interventions for apraxia of speech following stroke". Cochrane Database Syst Rev (4): CD004298. doi:10.1002/14651858.CD004298.pub2. PMID 16235357. 2. ^ a b c d e f "Apraxia of Speech". National Institute on Deafness and Other Communication Disorders. National Institutes of Health. Retrieved 12 April 2012. 3. ^ Morgan AT, Vogel AP (March 2009). "A Cochrane review of treatment for childhood apraxia of speech". Eur J Phys Rehabil Med. 45 (1): 103–10. PMID 19156019. 4. ^ Vargha-Khadem F, Gadian DG, Copp A, Mishkin M (February 2005). "FOXP2 and the neuroanatomy of speech and language" (PDF). Nat. Rev. Neurosci. 6 (2): 131–8. doi:10.1038/nrn1605. PMID 15685218. S2CID 2504002. 5. ^ Maassen, B. (Nov 2002). "Issues contrasting adult acquired versus developmental apraxia of speech". Semin Speech Lang. 23 (4): 257–66. doi:10.1055/s-2002-35804. PMID 12461725. 6. ^ a b c d e f Ogar J, Slama H, Dronkers N, Amici S, Gorno-Tempini ML (December 2005). "Apraxia of speech: an overview". Neurocase. 11 (6): 427–32. doi:10.1080/13554790500263529. PMID 16393756. S2CID 8650885. 7. ^ a b c d e Knollman-Porter K (2008). "Acquired apraxia of speech: a review". Top Stroke Rehabil. 15 (5): 484–93. doi:10.1310/tsr1505-484. PMID 19008207. S2CID 1664688. 8. ^ a b c Rosenbek, John C.; Wertz, Robert T.; LaPointe, Leonard L. (1984). Apraxia of speech in adults: the disorder and its management. New York: Grune & Stratton. ISBN 978-0-8089-1612-3. OCLC 13284954. 9. ^ van der Merwe, Anita (June–August 2007). "Self-Correction in Apraxia of Speech: The Effect of Treatment" (PDF). Aphasiology. 21 (6–8): 658–669. doi:10.1080/02687030701192174. 10. ^ Boutsen, F. R.; Christman, S. S. (November 2002). "Prosody in apraxia of speech". Seminars in Speech and Language. 23 (4): 245–56. doi:10.1055/s-2002-35799. PMID 12461724. 11. ^ a b "Apraxia of speech". American Speech-Language-Hearing Association. 2013. 12. ^ Josephs KA, Duffy JR (December 2008). "Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy". Current Opinion in Neurology. 21 (6): 688–92. doi:10.1097/WCO.0b013e3283168ddd. PMID 18989114. S2CID 34877712. 13. ^ a b Josephs KA, Duffy JR, Strand EA, et al. (May 2012). "Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech". Brain. 135 (Pt 5): 1522–36. doi:10.1093/brain/aws032. PMC 3338923. PMID 22382356. 14. ^ Ricci M, Magarelli M, Todino V, Bianchini A, Calandriello E, Tramutoli R (2008). "Progressive apraxia of speech presenting as isolated disorder of speech articulation and prosody: a case report". Neurocase. 14 (2): 162–8. doi:10.1080/13554790802060839. PMID 18569741. S2CID 31167113. 15. ^ Croot, K. (November 2002). "Diagnosis of AOS: definition and criteria". Seminars in Speech and Language. 23 (4): 267–80. doi:10.1055/s-2002-35800. PMID 12461726. 16. ^ Ziegler, W., Aichert, I, & Staiger, A. (2012). American Speech-Language-Hearing Association supplement: Apraxia of speech: Concepts and controversies. Journal of Speech, Language, and Hearing Research, 55, 1485-1501. 17. ^ Janet Choy J, Thompson CK (May 2010). "Binding in agrammatic aphasia: Processing to comprehension". Aphasiology. 24 (5): 551–579. doi:10.1080/02687030802634025. PMC 2882310. PMID 20535243. 18. ^ Robin DA, Jacks A, Hageman C, Clark HM, Woodworth G (August 2008). "Visuomotor tracking abilities of speakers with apraxia of speech or conduction aphasia". Brain Lang. 106 (2): 98–106. doi:10.1016/j.bandl.2008.05.002. PMC 2579757. PMID 18558428. 19. ^ Carlson, Neil R. (2010). Psychology: the Science of Behavior. Canada: Pearson Education. ISBN 978-0205702862. 20. ^ "Dysarthria". The American Speech-Language-Hearing Association. 21. ^ Mauszycki, Shannon C.; Wambaugh, Julie (2011). "Acquired Apraxia of Speech: A Treatment Overview". American Speech-Language-Hearing Association (ASHA). Archived from the original on 13 August 2013. Retrieved 20 October 2013. 22. ^ "Archived copy". Archived from the original on 2014-02-22. Retrieved 2014-02-13.CS1 maint: archived copy as title (link) 23. ^ Howard, Sara; Varley, Rosemary (1995). "III: EPG in Therapy Using electropalatography to treat severe acquired apraxia of speech". International Journal of Language & Communication Disorders. 30 (2): 246–255. doi:10.3109/13682829509082535. PMID 7492855. 24. ^ Wambaugh, J. (2010). "Sound Production Treatment for Acquired Apraxia of Speech" (PDF). Perspectives on Neurophysiology and Neurogenic Speech and Language Disorders. 20 (3): 67–72. doi:10.1044/nnsld20.3.67. Archived from the original (PDF) on 2013-12-03. 25. ^ Wambaugh JL, Nessler C, Cameron R, Mauszycki SC (May 2012). "Acquired apraxia of speech: the effects of repeated practice and rate/rhythm control treatments on sound production accuracy". Am J Speech Lang Pathol. 21 (2): S5–27. doi:10.1044/1058-0360(2011/11-0102). PMID 22230177. 26. ^ Morgan, Angela T.; Murray, Elizabeth; Liégeois, Frederique J. (30 May 2018). "Interventions for childhood apraxia of speech". The Cochrane Database of Systematic Reviews. 5: CD006278. doi:10.1002/14651858.CD006278.pub3. ISSN 1469-493X. PMC 6494637. PMID 29845607. ## External links * Dysarthria vs. Apraxia: A Comparison [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Apraxia of speech	c0264611	3,513	wikipedia	https://en.wikipedia.org/wiki/Apraxia_of_speech	2021-01-18T18:34:59	{"mesh": ["D001072"], "umls": ["C0264611"], "wikidata": ["Q1428145"]}
Hypophosphatasia is an inherited disorder that affects the development of bones and teeth. This condition disrupts a process called mineralization, in which minerals such as calcium and phosphorus are deposited in developing bones and teeth. Mineralization is critical for the formation of bones that are strong and rigid and teeth that can withstand chewing and grinding. The signs and symptoms of hypophosphatasia vary widely and can appear anywhere from before birth to adulthood. The most severe forms of the disorder tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases. The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of the condition in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones known as osteomalacia. In adults, recurrent fractures in the foot and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk for joint pain and inflammation. The mildest form of this condition, called odontohypophosphatasia, only affects the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss, but do not have the skeletal abnormalities seen in other forms of hypophosphatasia. ## Frequency Severe forms of hypophosphatasia affect an estimated 1 in 100,000 newborns. Milder cases, such as those that appear in childhood or adulthood, probably occur more frequently. Hypophosphatasia has been reported worldwide in people of various ethnic backgrounds. This condition appears to be most common in white populations. It is particularly frequent in a Mennonite population in Manitoba, Canada, where about 1 in 2,500 infants is born with severe features of the condition. ## Causes Mutations in the ALPL gene cause hypophosphatasia. This gene provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP), which plays an essential role in mineralization of the skeleton and teeth. Mutations in the ALPL gene lead to the production of an abnormal version of TNSALP that cannot participate effectively in the mineralization process. A shortage of TNSALP allows several other substances, which are normally processed by the enzyme, to build up abnormally in the body. Researchers believe that a buildup of one of these compounds, inorganic pyrophosphate (PPi), underlies the defective mineralization of bones and teeth in people with hypophosphatasia. ALPL gene mutations that almost completely eliminate the activity of TNSALP usually result in the more severe forms of hypophosphatasia. Other mutations, which reduce but do not eliminate the activity of the enzyme, often cause the milder forms of the condition. ### Learn more about the gene associated with Hypophosphatasia * ALPL ## Inheritance Pattern The severe forms of hypophosphatasia that appear early in life are inherited in an autosomal recessive pattern. Autosomal recessive inheritance means that two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene but do not show signs and symptoms of the disorder. Milder forms of hypophosphatasia can have either an autosomal recessive or an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Hypophosphatasia	c1840322	3,514	medlineplus	https://medlineplus.gov/genetics/condition/hypophosphatasia/	2021-01-27T08:25:28	{"gard": ["8735", "6734"], "mesh": ["C564146"], "omim": ["146300", "241510", "241500"], "synonyms": []}
Sertoli cell tumour Micrograph of a Sertoli cell tumour. H&E stain. SpecialtyOncology A Sertoli cell tumour, also Sertoli cell tumor (US spelling), is a sex cord-gonadal stromal tumor of Sertoli cells. They can occur in the testis or ovary. They are very rare and generally peak between the ages of 35 and 50. They are typically well-differentiated, and may be misdiagnosed as seminomas as they often appear very similar.[1] A tumor that produces both Sertoli cells and Leydig cells is known as a Sertoli-Leydig cell tumor. ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 4 In non-humans * 5 Additional images * 6 See also * 7 Notes * 8 External links ## Presentation[edit] In males, Sertoli cell tumours typically present as a testicular mass or firmness, and their presence may be accompanied by gynaecomastia (25%) if they produce oestrogens, or precocious pseudopuberty in young boys, especially if they produce androgens.[2] ## Diagnosis[edit] Low magnification micrograph of a Sertoli cell tumour. H&E stain. On ultrasound, a Sertoli cell tumour appears as a hypoechoic intratesticular lesion which is usually solitary. However, the large cell subtype might present as multiple and bilateral masses with large areas of calcification. An MRI may also be conducted, but this typically is not definitive.[2] Microscopy and immunohistochemistry are the only way to give a definitive diagnosis, especially when there is a suspected seminoma.[3] ## Treatment[edit] In males, due to the difficulty in identifying the tumour using imaging techniques, an orchiectomy is often performed. The majority of Sertoli cell tumours are benign, so this is sufficient. There is no documented benefit of chemotherapy or radiotherapy.[4] ## In non-humans[edit] Sertoli cell tumors are known to occur in other species, including domestic ducks,[5] dogs,[6][7] and horses. ## Additional images[edit] * Micrograph of a Leydig cell tumour. * Micrograph of a Leydig cell tumour. ## See also[edit] * Androgen-dependent syndromes * Leydig cell tumour * Sertoli-Leydig cell tumour * Sertoli cell nodule ## Notes[edit] 1. ^ Young, Robert H. (2005-01-01). "Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems". Modern Pathology. 18 (S2): S81–S98. doi:10.1038/modpathol.3800311. ISSN 0893-3952. PMID 15502809. 2. ^ a b Morgan, Matt A. "Sertoli cell tumour of the testis \| Radiology Reference Article \| Radiopaedia.org". radiopaedia.org. Retrieved 2016-12-06. 3. ^ Henley, John D.; Young, Robert H.; Ulbright, Thomas M. (2002-05-01). "Malignant Sertoli cell tumors of the testis: a study of 13 examples of a neoplasm frequently misinterpreted as seminoma". The American Journal of Surgical Pathology. 26 (5): 541–550. doi:10.1097/00000478-200205000-00001. ISSN 0147-5185. PMID 11979085. 4. ^ "Testis and epididymis - Sertoli cell tumor, NOS". www.pathologyoutlines.com. Retrieved 2016-12-06. 5. ^ Leach S, Heatley JJ, Pool RR, Spaulding K (December 2008). "Bilateral testicular germ cell-sex cord-stromal tumor in a pekin duck (Anas platyrhynchos domesticus)". J. Avian Med. Surg. 22 (4): 315–9. doi:10.1647/2007-017.1. PMID 19216259. 6. ^ Gopinath D, Draffan D, Philbey AW, Bell R (December 2008). "Use of intralesional oestradiol concentration to identify a functional pulmonary metastasis of canine sertoli cell tumour". J Small Anim Pract. 50 (4): 198–200. doi:10.1111/j.1748-5827.2008.00671.x. PMID 19037884. 7. ^ Vegter AR, Kooistra HS, van Sluijs FJ, van Bruggen LW, Ijzer J, Zijlstra C, Okkens AC (October 2008). "Persistent Mullerian Duct Syndrome in a Miniature Schnauzer Dog with Signs of Feminization and a Sertoli Cell Tumour". Reprod. Domest. Anim. 45 (3): 447–52. doi:10.1111/j.1439-0531.2008.01223.x. PMID 18954385. ## External links[edit] * Media related to Sertoli cell tumor at Wikimedia Commons Classification D * ICD-9-CM: 183.0, 256.1 * ICD-O: 8631 * MeSH: D012707 * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma * v * t * e * Tumors of the male urogenital system Testicles Sex cord– gonadal stromal * Sertoli–Leydig cell tumour * Sertoli cell tumour * Leydig cell tumour Germ cell G * Seminoma * Spermatocytic tumor * Germ cell neoplasia in situ NG * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma * Choriocarcinoma * Embryoma Prostate * Adenocarcinoma * High-grade prostatic intraepithelial neoplasia * HGPIN * Small-cell carcinoma * Transitional cell carcinoma Penis * Carcinoma * Extramammary Paget's disease * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Hirsuties coronae glandis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Sertoli cell tumour	c0036769	3,515	wikipedia	https://en.wikipedia.org/wiki/Sertoli_cell_tumour	2021-01-18T18:32:51	{"mesh": ["D012707"], "umls": ["C0036769"], "icd-9": ["256.1", "183.0"], "wikidata": ["Q4000421"]}
Adenosine deaminase (ADA) deficiency is an inherited disorder that damages the immune system and causes severe combined immunodeficiency (SCID). People with SCID lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system. The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life. Without treatment, these babies usually do not survive past age 2. In about 10 percent to 15 percent of cases, onset of immune deficiency is delayed to between 6 and 24 months of age (delayed onset) or even until adulthood (late onset). Immune deficiency in these later-onset cases tends to be less severe, causing primarily recurrent upper respiratory and ear infections. Over time, affected individuals may develop chronic lung damage, malnutrition, and other health problems. ## Frequency Adenosine deaminase deficiency is very rare and is estimated to occur in approximately 1 in 200,000 to 1,000,000 newborns worldwide. This disorder is responsible for approximately 15 percent of SCID cases. ## Causes Adenosine deaminase deficiency is caused by mutations in the ADA gene. This gene provides instructions for producing the enzyme adenosine deaminase. This enzyme is found throughout the body but is most active in specialized white blood cells called lymphocytes. These cells protect the body against potentially harmful invaders, such as bacteria and viruses, by making immune proteins called antibodies or by directly attacking infected cells. Lymphocytes are produced in specialized lymphoid tissues including the thymus, which is a gland located behind the breastbone, and lymph nodes, which are found throughout the body. Lymphocytes in the blood and in lymphoid tissues make up the immune system. The function of the adenosine deaminase enzyme is to eliminate a molecule called deoxyadenosine, which is generated when DNA is broken down. Adenosine deaminase converts deoxyadenosine, which can be toxic to lymphocytes, to another molecule called deoxyinosine that is not harmful. Mutations in the ADA gene reduce or eliminate the activity of adenosine deaminase and allow the buildup of deoxyadenosine to levels that are toxic to lymphocytes. Immature lymphocytes in the thymus are particularly vulnerable to a toxic buildup of deoxyadenosine. These cells die before they can mature to help fight infection. The number of lymphocytes in other lymphoid tissues is also greatly reduced. The loss of infection-fighting cells results in the signs and symptoms of SCID. ### Learn more about the gene associated with Adenosine deaminase deficiency * ADA ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Adenosine deaminase deficiency	c1863239	3,516	medlineplus	https://medlineplus.gov/genetics/condition/adenosine-deaminase-deficiency/	2021-01-27T08:24:41	{"gard": ["5748"], "mesh": ["C531816"], "omim": ["102700"], "synonyms": []}
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome caused by haploinsufficiency of a number of genes. Description The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36. Clinical Features Bedell et al. (1996) cited reports of 11 children who have been described with 2 or more syndromes with overlapping phenotypes and variations of the following features: short stature (9 of 10), prominent forehead (9 of 9), brachycephaly (7 of 7), microcephaly (10 of 11), midface hypoplasia (10 of 10), prominent jaw/chin (11 of 11), dysplastic pinna (6 of 7), hearing loss (3 of 11), congenital heart disease (7 of 11), hypotonia (11 of 11), DD/MR (11 of 11), facial clefting (4 of 11), and early demise (3 of 11). All patients were associated with a deletion of the terminal short arm of chromosome 1. Based on the 13 subjects described by Shapira et al. (1997), facial characteristics of the syndrome include deep-set eyes, flat nasal bridge, asymmetric ears, and pointed chin. Additional clinical characteristics include seizures, cardiomyopathy, developmental delay, and hearing impairment (Slavotinek et al., 1999; Shaffer and Heilstedt, 2001). Heilstedt et al. (2003) reported 62 patients with monosomy 1p36. Thirty were systematically examined through a specific protocol including hearing evaluations, palatal and ophthalmologic examinations, echocardiograms, neurologic assessments, and thyroid function tests. Orofacial clefting anomalies were present in 5 of 30 (17%); hypermetropia was present in 20 of 30 (67%). Six of 30 (20%) had hypothyroidism. All 30 had developmental delay and mental retardation. Twenty-six of 30 (87%) had hypotonia. Oropharyngeal dysphasia was present in 21 of 29 (72%). A history of dilated cardiomyopathy in infancy was present in 7 subjects (23%). In none did the condition worsen over time. Thirteen subjects (43%) had a structural heart defect, most frequently patent ductus arteriosus. Some hearing impairment was present in 82% of the subjects, being sensorineural type in almost all. Tan et al. (2005) reported a 16-year-old boy with features of Cantu syndrome (239850) who was found to have a distal 1p36 deletion. The boy also had features not previously described in either syndrome, including hypercholesterolemia, type II diabetes, recurrent bony fractures, and nonalcoholic steatohepatitis. Neal et al. (2006) reported a 3-year-old girl who had developmental delay, Duane syndrome anomaly, hearing loss, mild dysmorphic facial features including posteriorly rotated and slightly low-set ears and a broad nasal bridge, and scoliosis. MRI brain imaging revealed left periventricular nodular heterotopia (see PVNH1; 300049), truncation of the rostrum of the corpus callosum, slight ventricular enlargement, and patchy areas of hyperintensity consistent with delayed myelination. FISH analysis detected a deletion of 1p36 with loss of heterozygosity between D1S468 and D1S450, indicating at most a 9.6-Mb deletion region on 1pter-p36.22. Sequencing of the FLNA gene (300017), which has been shown to cause PVNH1, revealed no alterations in the coding region in this patient. Battaglia et al. (2008) evaluated 60 patients with the 1p36 deletion syndrome (41 females and 19 males). Microcephaly was reported in 95% of patients, and all patients had straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin. Other dysmorphic features included microbrachycephaly (65%), epicanthus (50%), large late-closing anterior fontanel (77%), and posteriorly rotated low-set abnormal ears (40%). Brachy/camptodactyly and short feet were prominent. Heart defects were present in 71%, including 23% with noncompaction cardiomyopathy. Other findings included visual inattentiveness (64%), visual abnormalities (52%), sensorineural deafness (28%), skeletal abnormalities (41%), abnormal genitalia (25%), and renal abnormalities (22%). Eighty-eight percent had central nervous system anomalies: 44% had seizures and 95% had hypotonia. All patients had developmental delay with poor or absent speech, and 47% had a behavior disorder. Gradual developmental progress was observed in all patients over time. Rudnik-Schoneborn et al. (2008) reported an 8-month-old girl with microcephaly and a midline brain malformation who had an interstitial deletion of 1p36 on conventional chromosome analysis; FISH and array CGH analysis documented an 8.7-Mb deletion encompassing 1p36.23-p36.13. Brain MRI at age 5 months revealed agenesis of the anterior commissure and rostral corpus callosum and partial agenesis of the septum pellucidum. The authors stated that this structural brain defect had not previously been described in proximal 1p36 deletion. Bursztejn et al. (2009) reported an 8-year-old girl with an initial clinical diagnosis of Aicardi syndrome (304050) who was subsequently found to carry a de novo 11.73-Mb terminal deletion of chromosome 1p36, thus revising the diagnosis. She had onset of infantile spasms at age 3 months, bilateral pupillary coloboma, agenesis of the corpus callosum, and delayed psychomotor development. Other features included deep-set eyes, low-set and posteriorly rotated ears, brachydactyly, and hypertrichosis. She also had interatrial and trabeculated interventricular communications. The deletion was found to occur on the maternal chromosome during oogenesis. The report emphasized the phenotypic overlap between the 2 disorders. D'Angelo et al. (2010) described 9 unrelated patients with de novo deletions of distal 1p36 ranging in size from 2.2 to 10.2 Mb. Four deletions that could be studied occurred on the maternal allele. Four of the patients were ascertained from a larger group of 154 patients with psychomotor delay associated with hyperphagia and obesity, suggesting that this is an additional variable feature of monosomy 1p36. Five of the patients were ascertained from a larger group of 83 patients suspected to have monosomy 1p36 due to mental retardation. Three of the patients with obesity did not have the typical facial features of monosomy 1p36 and had slightly milder cognitive impairment. D'Angelo et al. (2010) suggested involvement of the PRKCZ gene (176982), which was deleted in all patients, but also noted the possibility of a position effect. Dod et al. (2010) reported a 25-year-old man with monosomy 1p36 who developed symptoms of left ventricular noncompaction (LVNC; 604169) as an adult. In infancy and childhood, he had severe developmental delay, facial dysmorphism, seizures, and a cardiomyopathy with a low ejection fraction (15 to 20%). He also had scoliosis and spastic quadriparesis. Cytogenetics Heilstedt et al. (2003) evaluated the deletion sizes in 61 subjects with monosomy 1p36 from 60 families using a contig of overlapping large-insert clones for the most distal 10.5 Mb of 1p36. They found pure terminal deletions, interstitial deletions, derivative chromosomes, and more complex rearrangements. Though some clustering of breakpoints was demonstrated, there was no single common breakpoint. They found that 60% of de novo 1p36 terminal deletions arose from the maternally inherited chromosome. Heilstedt et al. (2003) ascertained 62 patients with deletions of 1p36 from 61 families. Most of the deletions occurred on the maternally derived chromosome. They identified terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. Retrospectively, 98% of deletions could be identified by routine chromosome analysis with careful attention to 1p36. Developmental delay/mental retardation was the most common clinical indication. Increased maternal serum alpha-fetoprotein (AFP; 104150) was detected in 4 of the 5 prenatally diagnosed cases. Maternal age at the time of birth of the affected child was significantly lower than the general United States population mean. The photograph of a patient demonstrated flat nasal bridge and nose, with pointed chin. To further delineate genotype/phenotype correlations in monosomy 1p36, Redon et al. (2005) applied microarray-based comparative genomic hybridization, using an overlapping clone microarray covering 99.5% of the euchromatic portion of chromosome 1, to 6 patients with clinical features characteristic of monosomy 1p36. Deletions were confirmed in all patients. Two patients who displayed very similar features (facial characteristics and mental retardation) had distinct and nonoverlapping 1p36 deletions. Redon et al. (2005) suggested that the monosomy 1p36 syndrome may be due to a positional effect of the 1p36 rearrangement rather than haploinsufficiency of contiguous genes in the deleted region. Monosomy 1p36 is characterized by marked variability in the size of the deletions, with no common breakpoints. In a review of the disorder, Gajecka et al. (2007) found no correlation between the deletion size and number of clinical features observed. An assessment of 1p36 deletions found that most (52 to 67%) were pure terminal deletions, followed by interstitial deletions (10 to 29%), unbalanced translocations (7 to 16%), and complex rearrangements (7 to 12%). El-Hattab et al. (2010) described an infant girl with OEIS complex (258040) and chromosome 1p36 deletion who displayed features of both disorders, including omphalocele, cloacal exstrophy, imperforate anus, sacral segmentation defects, renal malposition and malrotation, genital anomalies, diastasis of the symphysis pubis, microbrachycephaly, large anterior fontanel, cardiac septal defects, rib fusion, limb deformity, developmental delay, and typical facial features. At 12 months of age, the patient developed bowel obstruction which progressed to septic shock and multiorgan failure and she died. Chromosomal microarray analysis detected a 2.4-Mb terminal deletion of chromosome 1p. There was no evidence of uniparental disomy. El-Hattab et al. (2010) suggested that OEIS complex might be caused by recessive mutation of a gene located in the 1p36 region, with the deletion uncovering a mutation located on the intact homolog; however, they noted that this was the first reported case of OEIS complex in association with a 1p36 deletion and that it was also possible that this case represented the chance occurrence of 2 independent conditions. In 2 sisters who were originally described by Graham et al. (2004) and who exhibited features of Warburg Micro syndrome (see 600118), including microcephaly, cataract, microcornea, cortical blindness, increased frontal cortical thickness, enlarged ventricles, simplified irregular gyral pattern, generalized hypotonia, seizures, profound mental retardation, hypoplastic labia minora, hypertrichosis, and postnatal growth retardation, Handley et al. (2013) identified an unbalanced microdeletion/microduplication involving chromosomes 1p36 and 21q22. There was an approximately 6.9- to 7.1-Mb deletion from chromosome 1p36.33 to 1p36.23, containing the critical region for 1p36 deletion syndrome, as well as an approximately 5.6- to 6.0-Mb duplication from 21q22.3 to 21qter, distal to the Down syndrome (190685) critical region. Parental karyotyping confirmed that the sisters' father was a carrier of a balanced translocation. Genotyping of microsatellites covering the 1p36 deletion interval in both sisters revealed distinct maternal haplotypes, thus excluding the possibility that a new recessive gene was contributing to the phenotype. Diagnosis Heilstedt et al. (2003) suggested a multistep approach in cases of monosomy 1p36 to give the most accurate counseling information: first, identification of the deletion of 1p36 by careful cytogenetic analysis and FISH with a probe containing the CDC2L1 locus (176873); second, telomere region-specific FISH to identify derivative chromosomes; and third, FISH using informative probes in the parents of those with the derivative chromosomes to uncover parental translocations (obviously significant to genetic counseling). Finally, the clinician's suspicion of a diagnosis of monosomy 1p36 is invaluable for leading to the correct diagnosis. ### Prenatal Diagnosis Campeau et al. (2008) described 2 patients with monosomy 1p36 syndrome who had brain abnormalities, particularly hydrocephalus and ventriculomegaly, detected by prenatal ultrasound. In 1 patient, amniocentesis and karyotyping did not show the deletion, which became apparent only by using array comparative genome hybridization. A review of previously reported cases showed that brain abnormalities are frequent, if not consistent, findings in this deletion syndrome. Such abnormalities include hydrocephalus, polymicrogyria, cerebral atrophy, and agenesis of the corpus callosum. Campeau et al. (2008) noted that certain small or interstitial deletions may not be identified by standard methods. Molecular Genetics Bedell et al. (1996) further characterized the region of deletion in a patient with the karyotype 46,XY, del(1)(p36.3) and identified a gene that maps within the deleted region, the dishevelled-1 gene (DVL1; 601365). The authors speculated that this gene may play a role in the pathogenesis of the observed syndromes through haploinsufficiency or through genomic imprinting. Windpassinger et al. (2002) mapped the gamma-aminobutyric acid A receptor delta subunit gene (GABRD; 137163) to chromosome 1p36.33, within the critical region of gene loss for the 1p36 deletion syndrome. As the gene encodes a GABA channel in the brain, the authors suggested that it may be a candidate for the neurodevelopmental and neuropsychiatric anomalies seen in the syndrome. Rosenfeld et al. (2010) reported 5 patients with 200 to 823-kb overlapping interstitial deletions of chromosome 1p36.33 associated with classic features of the syndrome, including mental retardation, dysmorphic features, hypotonia, behavioral abnormalities, and seizures. The smallest region of overlap was 174 kb and encompassed 5 genes, 1 of which may be involved in signaling in neurons (GNB1; 139380). Two of the patients with seizures had deletions of GABRD, and 3 patients had deletions of PRKCZ (176982) and SKI (164780). In 17 of 18 patients with a deletion in chromosome 1p36 who showed evidence of heart muscle disease, including left ventricular noncompaction (LVNC) or cardiomyopathy (see 615373), Arndt et al. (2013) aligned the regions of chromosomal loss and identified a shared deleted interval at chr1:3,224,674-3,354,772 bp (GRCh37) that involved only a single gene, PRDM16 (605557). Sequencing of PRDM16 in LVNC probands or posttransplantation patients with dilated cardiomyopathy identified 7 mutations (see, e.g., 605557.0001-605557.0006) that were not present in controls or exome sequencing databases. In 14 of the 18 patients with a deletion in chromosome 1p36, the SKI gene was also deleted; however, analysis of SKI in an independent LVNC cohort revealed no mutations. De Leeuw and Houge (2014) stated that the results of their analysis of the evidence presented in the paper by Arndt et al. (2013) did not support the conclusions of those authors, and that it was unlikely that PRDM16 (605557) is a cause of cardiomyopathy in 1p36 deletion syndrome. Arndt et al. (2013) agreed that haploinsufficiency of PRDM16 is an unlikely or uncommon cause of cardiomyopathy in 1p36 deletion syndrome. However, they cited 3 additional independent lines of evidence supporting the role of PRDM16 in cardiomyopathy: first, PRDM16 mutations in nonsyndromic forms of left ventricular noncompaction (604169); second, a highly significant excess of deleterious PRDM16 variants in adult dilated cardiomyopathy (115200); and third, in vivo modeling data of several PRDM16 variants in zebrafish. INHERITANCE \- Isolated cases GROWTH Weight \- Obesity (after infancy) Other \- Growth retardation, pre- and postnatal HEAD & NECK Head \- Microcephaly \- Brachycephaly \- Large anterior fontanel \- Delayed closure of fontanel Face \- Prominent forehead \- Midface hypoplasia \- Pointed chin \- Long philtrum Ears \- Asymmetric ears \- Sensorineural hearing loss \- Thickened helices \- Posteriorly rotated ears \- Low-set ears Eyes \- Deep-set eyes \- Hypermetropia \- Visual inattentiveness \- Strabismus \- Myopia \- Nystagmus \- Optic nerve coloboma \- Epicanthal folds \- Straight eyebrows Nose \- Flat nasal bridge \- Flat nose Mouth \- Cleft lip \- Cleft palate \- Submucous cleft \- Bifid uvula \- High-arched palate CARDIOVASCULAR Heart \- Dilated cardiomyopathy (infancy) \- Noncompaction cardiomyopathy \- Ventricular septal defect \- Atrial septal defect Vascular \- Patent ductus arteriosus \- Dilated aortic root CHEST Ribs Sternum Clavicles & Scapulae \- Missing ribs \- Bifid ribs \- Fused ribs ABDOMEN Gastrointestinal \- Gastroesophageal reflux (infancy) \- Feeding problems (infancy) SKELETAL \- Flexion contractures Spine \- Scoliosis Hands \- Short fifth finger \- Fifth finger clinodactyly \- Brachydactyly Feet \- Pes cavus \- Prominent heels \- Brachydactyly \- Short feet NEUROLOGIC Central Nervous System \- Global developmental delay \- Mental retardation \- Delayed expressive language \- Delayed speech \- Seizures \- Infantile spasms \- Hypotonia \- Hydrocephalus \- Ventriculomegaly \- Cerebral atrophy \- Agenesis of the corpus callosum \- Pachygyria \- Polymicrogyria Behavioral Psychiatric Manifestations \- Behavioral disorders \- Hyperphagia ENDOCRINE FEATURES \- Hypothyroidism LABORATORY ABNORMALITIES \- Partial terminal deletion of short arm of chromosome 1 (1p36) MISCELLANEOUS \- Variable phenotype \- Contiguous gene deletion syndrome \- Marked variability in the deletion size \- Most common terminal deletion syndrome \- Incidence of 1 in 5,000 to 1 in 10,000 MOLECULAR BASIS \- A contiguous gene syndrome caused by deletion of 2.2 to 10.6Mb of terminal 1p36 ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CHROMOSOME 1p36 DELETION SYNDROME	c1842870	3,517	omim	https://www.omim.org/entry/607872	2019-09-22T16:08:43	{"doid": ["0060410"], "mesh": ["C535362"], "omim": ["607872"], "orphanet": ["1606"], "synonyms": ["Alternative titles", "MONOSOMY 1p36 SYNDROME"]}
This article discusses a natural product. For the blog commonly known as Whale Oil, see Cameron Slater A bottle of whale oil Whale oil is oil obtained from the blubber of whales.[1] Whale oil from the bowhead whale was sometimes known as train oil, which comes from the Dutch word traan ("tear" or "drop"). Sperm oil, a special kind of oil obtained from the head cavities of sperm whales, differs chemically from ordinary whale oil: it is composed mostly of liquid wax. Its properties and applications differ from those of regular whale oil, and it sells for a higher price. ## Contents * 1 Source and use * 2 Chemistry * 3 Applications * 4 Gallery * 5 In literature, fiction, and memoirs * 6 See also * 7 References * 8 Further reading * 9 External links ## Source and use[edit] Early industrial societies used whale oil in oil lamps and to make soap. In the 20th century it was made into margarine. With the commercial development of the petroleum industry and vegetable oils, the use of whale oils declined considerably from its peak in the 19th century into the 20th century. This is said to have saved whales from extinction.[2] In the 21st century, with most countries having banned whaling, the sale and use of whale oil has practically ceased. Whale oil was obtained by boiling strips of blubber harvested from whales.[3] The removal is known as "flensing" and the boiling process was called "trying out". The boiling was carried out on land in the case of whales caught close to shore or beached. On longer deep-sea whaling expeditions, the trying-out was done aboard the ship in a furnace known as a trywork and the carcass was then discarded into the water. Baleen whales were a major source of whale oil. Their oil is exclusively composed of triglycerides, whereas that of toothed whales contains wax esters.[4] The bowhead whale and right whale were considered the ideal whaling targets. They are slow and docile, and they float when killed. They yield plenty of high-quality oil and whalebone,[5] and as a result, they were hunted nearly to extinction. ## Chemistry[edit] Whale oil has low viscosity (lower than olive oil),[6] is clear, and varies in color from a bright honey yellow to a dark brown, according to the condition of the blubber from which it has been extracted and the refinement through which it went.[7] It has a strong fishy odor. When hydrogenated, it turns solid and white and its taste and odor change.[8][9] The composition of whale oil varies with the species from which it was sourced and the method by which it was harvested and processed. Whale oil is mainly composed of triglycerides[10] (molecules of fatty acids attached to a glycerol molecule). Oil sourced from toothed whales contains a substantial amount of wax esters (especially the oil of sperm whales).[4] Most of the fatty acids are unsaturated. The most common fatty acids are oleic acid and its isomers (18:1 carbon chains).[11] Whale oil is exceptionally stable.[12] Physical properties of whale oils Specific gravity 0.920 to 0.931 at 15.6 °C (60.1 °F)[13] Flash point 230 °C (446 °F)[14] Saponification value 185–202[10] Unsaponifiable matter 0–2%[10] Refractive index 1.4760 at 15 °C (59 °F)[15] Iodine number (Wijs) 110–135[10] Viscosity 35–39.6 cSt at 37.8 °C (100.0 °F)[6] ## Applications[edit] American whale oil and sperm oil imports in the 19th century The use of whale oil had a steady decline starting in the late 19th century due to the development of superior alternatives, and later, the passing of environmental laws.[1] In 1986, the International Whaling Commission declared a moratorium on commercial whaling, which has all but eliminated the use of whale oil today. The Inuit of North America are granted special whaling rights (justified as being integral to their culture), and they still use whale oil as a food and as lamp oil.[16] See Aboriginal whaling. Whale oil was used as a cheap illuminant, though it gave off a strong odor when burnt and was not very popular.[17] It was replaced in the late 19th century by cheaper, more efficient, and longer-lasting kerosene.[18] Burning fluid known as camphine was the dominant replacement for whale oil until the arrival of kerosene.[19] In the US, whale oil was used in cars as a constituent of automatic transmission fluid until it was banned by the 1973 Endangered Species Act.[20] It was also a major component of tractor hydraulic fluid (like the ubiquitous JDM Type 303 Special Hydraulic Fluid) until its withdrawal in 1974.[21] In the UK, whale oil was used in toolmaking machinery as a high-quality lubricant.[22] After the invention of hydrogenation in the early 20th century, whale oil was used to make margarine,[8] a practice that has since been discontinued. Whale oil in margarine has been replaced by vegetable oil.[23] Whale oil was used to make soap. Until the invention of hydrogenation, it was used only in industrial-grade cleansers, because its foul smell and tendency to discolor made it unsuitable for cosmetic soap.[9] Whale oil was widely used in the First World War as a preventive measure against trench foot. A British infantry battalion on the Western Front could be expected to use 10 gallons of whale oil a day. The oil was rubbed directly onto bare feet in order to protect them from the effects of immersion.[24] ## Gallery[edit] * Whalers stripping blubber from a whale * Whalers boiling blubber on the deck of their ship (1874 illustration) * Try-pots in Ilulissat, Greenland * Try pot or Blubber Pot seen in Simon's Town in South Africa * Maori cutting up the blubber of beached pilot whales (Te Arai, New Zealand, 1911) * Men boiling the blubber of a beached blackfish at Tokerau Beach. (New Zealand, 1911) * An Inuit woman tending a qulliq, a traditional whale oil lamp (Nunavut, 1999) * Whale oil lamp in brown-glazed earthenware with candle bowl for the wick and base drip pan. Lyse parish, Bohuslän – now in Nordiska museet, Stockholm, Sweden ## In literature, fiction, and memoirs[edit] The pursuit and use of whale oil, along with many other aspects of whaling, are discussed in Herman Melville's Moby-Dick (1851). In the novel, the preciousness of the substance to contemporary American society is emphasized when the fictional narrator notes that whale oil is "as rare as the milk of queens." John R. Jewitt, an Englishman who wrote a memoir about his years as a captive of the Nootka people on the Pacific Northwest Coast in 1802–1805, describes how whale oil was used as a condiment with every dish, even strawberries. Friedrich Ratzel in The History of Mankind (1896), when discussing food materials in Oceania, quoted Captain James Cook's comment in relation to "the Maoris" saying "No Greenlander was ever so sharp set upon train-oil as our friends here, they greedily swallowed the stinking droppings when we were boiling down the fat of dog-fish."[25] In the 2012 video game Dishonored, whale oil is an important source of power for ships, lighting, weaponry, and the generation of electricity. Which fits with the games fictional but heavily 19th-Century inspired aesthetic. ## See also[edit] * Oleochemical * Rendering (animals) * Spermaceti * Sperm oil * Sperm whaling * Whaling ## References[edit] 1. ^ a b Ed Butts (2019-10-04). "The cautionary tale of whale oil". The Globe and Mail. Archived from the original on 2019-10-06. Retrieved 2019-10-07. "Then in 1846, a Nova Scotian physician and geologist named Abraham Gesner invented kerosene. This pioneering form of fossil fuel, which some called coal oil, burned cleaner and brighter than whale oil, and didn’t have a pungent odour." 2. ^ https://www.dispatch.com/story/opinion/columns/2020/11/04/column-markets-and-consumers-not-president-control-oils-future/6136112002/ 3. ^ Barfield, Rodney (1995). Seasoned by Salt. Chapel Hill: University of North Carolina Press. p. 64. ISBN 0-8078-2231-0. 4. ^ a b Rice, Dale W. (2009). "Spermaceti". Encyclopedia of Marine Mammals (Second ed.). pp. 1098–1099. doi:10.1016/B978-0-12-373553-9.00250-9. ISBN 9780123735539. 5. ^ Clapham, Phil (2004). Right Whales: Natural History & Conservation. Stillwater, MN: Voyageur Press. p. 8. ISBN 0-89658-657-X. 6. ^ a b "Liquids - Kinematic Viscosities". www.engineeringtoolbox.com. 7. ^ One or more of the preceding sentences incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). "Whale-oil". Encyclopædia Britannica. 28 (11th ed.). Cambridge University Press. pp. 573–574. 8. ^ a b Tønnessen, Johan Nicolay; Johnsen, Arne Odd (1982-01-01). The History of Modern Whaling. University of California Press. ISBN 978-0-520-03973-5. 9. ^ a b Robert Lloyd Webb (1988). On the Northwest: Commercial Whaling in the Pacific Northwest, 1790-1967. pg 144 10. ^ a b c d Moninder Mohan Chakrabarty (2009). Chemistry And Technology Of Oils And Fats. pg 183 11. ^ Bottino, Nestor R. (1971). "The composition of marine-oil triglycerides as determined by silver ion-thin-layer chromatography". Journal of Lipid Research. 12 (1): 24–30. PMID 5542701. 12. ^ "Reinventing the Whale" (PDF). WDCS: Whale and Dolphin Conservation Society. May 2010. Archived from the original (PDF) on June 1, 2013. Retrieved October 29, 2012. 13. ^ Emil F Dieterichs (1916). A Practical Treatise on Friction, Lubrication, Fats and Oils. pg 23 14. ^ Frank Sims (1999). Engineering Formulas Interactive: Conversions, Definitions, and Tables. pg 132 15. ^ J. N. Goldsmith (1921). Table of Refractive Indices. pg 259 16. ^ Video on YouTube 17. ^ Wilson Heflin (2004). Herman Melville's Whaling Years. pg 232 18. ^ "Thefreemanonline.org". www.thefreemanonline.org. 19. ^ "The "Whale Oil Myth"". PBS NewsHour. 20. ^ Information, Reed Business (1 May 1975). "New Scientist". Reed Business Information – via Google Books. 21. ^ "The Yellow Bucket", Thomas Glenn, Lubes N' Greases, LND Publishing Co., Inc., Feb. 2012, Vol. 18, No. 2, p.12. 22. ^ Norman Atkinson, Sir Joseph Whitworth (Sutton Publishing 1996), p161. 23. ^ Gorman, Martyn (2002). "Whale oil and margarine". Scran. Historic Environment Scotland. Archived from the original on 2020-02-20. 24. ^ "Trench Foot". spartacus-educational.com. 25. ^ Friedrich, Ratzel. "The Races of OceaniaLabour, Dwellings and Food in OceaniaSimilarities and coincidences in labour and implements of labour, Food". inquirewithin.biz. Archived from the original on April 30, 2012. Retrieved 10 May 2018. ## Further reading[edit] * Whale oil and its uses, an overview with illustrations * Knapp, Friedrich Ludwig; Dibdin, William Joseph (1895), "Whale oil - Train oil", Chemical technology: or, Chemistry in its applications to arts and manufactures, II, Lighting, London: J & A Churchill, pp. 43–44, OCLC 3592958 * Stevenson, C H; United States Fish Commission (1903), "Conversion of blubber into whale oil, Refining sperm oil and whale oil", Aquatic products in arts and industries: Fish oils, fats, and waxes, fertilizers from aquatic products. U.S. Fish Commission Report, 1902, Washington, DC: GPO, pp. 193–204, OCLC 21059426, Includes descriptions, photographs and statistics. * Tower, Walter Sheldon (1907), A history of the American whale fishery, Series in political economy and public law, no. 20, Philadelphia: Published for the University, pp. 94–95, ISBN 1-116-72422-7, OCLC 145429333 * How Capitalism Saved the Whales, by James S. Robbins * Coleman, Jr, James L (1995), "The American Whale Oil Industry: A Look Back at the Future of the American Petroleum Industry", Natural Resources Research, 4 (3) ## External links[edit] * Media related to Whale oil at Wikimedia Commons * v * t * e Whaling History of whaling By country * Argentina * Australia * Western Australia * Basque Country * Brazil * Canada * Pacific Northwest * Faroe Islands * Germany * Greenland * Iceland * Japan * Madagascar * Netherlands * New Zealand * Norway * Philippines * Russia * Scotland * Seychelles * South Africa * United Kingdom * United States Harpoons * Explosive harpoon * Jarmann harpoon rifle * One-flue harpoon * Toggling harpoon * Two-flue harpoon Hunting type * Aboriginal whaling * Dolphin drive hunting * Drift whale * Sperm whaling * Subsistence hunting of the bowhead whale Implements * Whaling ship * Whaleboat * Grindaknívur * Harpoon cannon * Head spade * Try pot * Trywork Products * Ambergris * Ambrein * Baleen * Blubber * Cetyl alcohol * Muktuk * Scrimshaw * Spermaceti * Sperm oil * Tabua * Whale feces, meat, oil Regulations * Blue Whale Unit * International Whaling Commission * International Convention for the Regulation of Whaling * Institute of Cetacean Research * Whale conservation Sanctuaries * Australian Whale Sanctuary * Indian Ocean Whale Sanctuary * South Pacific Whale Sanctuary * Southern Ocean Whale Sanctuary * v * t * e Edible fats and oils Fats Pork fats * Fatback * Lardo * Salo * Salt pork * Szalonna * Lard * Lardon * Pork belly * Bacon * Pancetta * Tocino * Speck Beef/mutton fats * Dripping * Suet * Tallow * Tail fat Dairy fats * Butter * Clarified butter * Ghee * Niter kibbeh * Smen Poultry fats * Chicken fat * Duck fat * Schmaltz Other animal fats * Blubber * Muktuk * Whale oil Vegetable fats * Borneo tallow * Cocoa butter * Mango butter * Margarine * Shea butter * Vegetable shortening Oils Fish oils * Cod liver oil * Shark liver oil Vegetable oils Major oils * Coconut oil * Corn oil * Cottonseed oil * Olive oil * Palm oil * palm kernel oil * Peanut oil * Rapeseed oil * Canola oil and Colza oil (toxic oil syndrome) * Safflower oil * Soybean oil * Sunflower oil Nut oils * Almond oil * Argan oil * Cashew oil * Hazelnut oil * Macadamia oil * Marula oil * Mongongo nut oil * Pecan oil * Pine nut oil * Pistachio oil * Walnut oil Fruit and seed oils * Ambadi seed oil * Avocado oil * Castor oil * Grape seed oil * Hemp oil * Linseed oil (flaxseed oil) * Mustard oil * Olive oil * Perilla oil * Poppyseed oil * Pumpkin seed oil * Rice bran oil * Sesame oil * Tea seed oil * Watermelon seed oil See also List of vegetable oils Cooking oil Essential oil [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Whale oil	None	3,518	wikipedia	https://en.wikipedia.org/wiki/Whale_oil	2021-01-18T19:08:35	{"wikidata": ["Q1053334"]}
A rare, syndromic intellectual disability characterized by hypotonia, global developmental delay, limited or absent speech, intellectual disability, macrocephaly, mild dysmorphic features, seizures and autism spectrum disorder. Associated ophthalmologic, heart, skeletal and central nervous system anomalies have 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Intellectual disability-macrocephaly-hypotonia-behavioral abnormalities syndrome	c4225354	3,519	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=457279	2021-01-23T17:41:27	{"omim": ["616355"]}
A number sign (#) is used with this entry because this form of scapuloperoneal myopathy is caused by mutation in the MYH7 gene (160760). Another form (300695) is caused by mutation in the FHL1 gene (300163). Clinical Features Scapuloperoneal syndrome was initially described by Jules Broussard (1886) as 'une forme hereditaire d'atrophie musculaire progressive' beginning in the lower legs and affecting the shoulder region earlier and more severely than distal arm. Thomas et al. (1975) described 6 cases of adult-onset scapuloperoneal myopathy. Four were apparently sporadic. The other 2 cases occurred in mother and daughter. Progression was relatively slow. Electromyography and muscle biopsy showed myopathic changes in all. Facial involvement occurred in some. The authors considered that the disorder resembled that described by Ricker and Mertens (1968) and Serratrice et al. (1969). The latter group observed 9 cases in which autosomal dominant inheritance was suggested. Tawil et al. (1995) described 4 individuals in 2 generations, 1 female and 3 males, affected with a scapuloperoneal myopathy. There was male-to-male transmission. Electromyography demonstrated small polyphasic units, and muscle biopsy demonstrated necrotic and regenerating fibers as well as an increase in endomesial connective tissue, demonstrating this to be a myopathy. Although the index case fulfilled the diagnostic criteria for facioscapulohumeral dystrophy (158900), none of the other 3 affected individuals demonstrated facial weakness. Furthermore, linkage to markers on 4q35 was excluded, demonstrating this to be a distinct genetic entity. Molecular Genetics In 2 patients diagnosed with myosin storage myopathy (608358) and 2 of 17 patients diagnosed with scapuloperoneal myopathy of unknown etiology, Pegoraro et al. (2007) detected a 5533C-T mutation in the MYH7 gene (160760.0028). Eleven other mutation carriers were identified through segregation analysis. The clinical spectrum in this cohort of patients included asymptomatic hyperCKemia (elevated serum creatine kinase), scapuloperoneal myopathy, and proximal and distal myopathy with muscle hypertrophy. Muscle MRI identified a unique pattern in the posterior compartment of the thigh, characterized by early involvement of the biceps femoris and semimembranosus, with relative sparing of the semitendinosus. Muscle biopsy revealed hyaline bodies characteristic of myosin storage myopathy in only half of biopsied patients (2 of 4). These patients without hyaline bodies had been diagnosed with scapuloperoneal myopathy prior to the identification of hyaline bodies in other family members, prompting MYH7 gene analysis. The authors pointed out that patients without hyaline bodies presented later onset and milder severity. Pegoraro et al. (2007) concluded that the phenotypic and histopathologic variability may underlie MYH7 gene mutation and the absence of hyaline bodies in muscle biopsies does not rule out MYH7 gene mutations. Animal Model De Repentigny et al. (2001) described a spontaneous autosomal recessive mutation in the mouse, which they named 'degenerative muscle' (dmu), that is characterized by skeletal and cardiac muscle degeneration. Dmu mice are weak and have great difficulty in moving due to muscle atrophy and wasting in the hindquarters. Histopathologic observations and ultrastructural analysis revealed muscle degeneration in both skeletal and cardiac muscle, but no abnormalities in sciatic nerves. It is noteworthy that SPM patients with associated cardiomyopathy have been described. Using linkage analysis, the authors mapped the dmu locus to the distal portion of mouse chromosome 15 in a region syntenic to human chromosome 12q13. Intact transcripts for Scn8a (600702), the gene encoding the sodium channel 8a subunit, were present in dmu mice but their levels were dramatically reduced. Furthermore, genetic complementation crosses between dmu and med (mutation in Scn8a) mice revealed that they are allelic. The authors concluded that at least a portion of the dmu phenotype may be caused by a downregulation of Scn8a, and that SCN8A is a candidate gene for human SPM. Muscle \- Scapuloperoneal myopathy \- Facial myopathy Misc \- Slow progression Lab \- Myopathic electromyography and muscle biopsy Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SCAPULOPERONEAL MYOPATHY, MYH7-RELATED	c0751337	3,520	omim	https://www.omim.org/entry/181430	2019-09-22T16:34:58	{"doid": ["0060253"], "mesh": ["D020389"], "omim": ["181430"], "icd-10": ["G71.09"], "orphanet": ["437572"], "synonyms": ["SCAPULOPERONEAL MUSCULAR DYSTROPHY", "MYH7-related late-onset SPMD", "MYH7-related late-onset scapuloperoneal syndrome", "Alternative titles", "SCAPULOPERONEAL SYNDROME, MYOPATHIC TYPE"]}
A number sign (#) is used with this entry because of evidence that Loeys-Dietz syndrome-5 (LDS5) is caused by heterozygous mutation in the TGFB3 gene (190230) on chromosome 14q24. Description Loeys-Dietz syndrome-5 (LDS5), also known as Rienhoff (pronounced REENhoff) syndrome, is characterized by syndromic presentation of aortic aneurysms involving the thoracic and/or abdominal aorta, with risk of dissection and rupture. Other systemic features include cleft palate, bifid uvula, mitral valve disease, skeletal overgrowth, cervical spine instability, and clubfoot deformity; however, not all clinical features occur in all patients. In contrast to other forms of LDS (see 609192), no striking aortic or arterial tortuosity is present in these patients, and there is no strong evidence for early aortic dissection (summary by Bertoli-Avella et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1 (609192). Clinical Features Rienhoff et al. (2013) described a 9-year-old European American girl, born to nonconsanguineous parents, whose birth weight was in the 5th centile with length and head circumference in the 50th centiles; in addition, she was noted to have contractures of the hands and feet, most severe in the third and fourth fingers of the right hand, and mild hypotonia. At 17 months of age, her weight was below the 1st centile with height in the 5th centile, and she could not crawl or roll, but could stand with support. She had bilateral pes planus, mild pectus excavatum, hyperextensibility of the large joints, and mild retrognathia. There was a small metopic ridge, and her eyes were prominent, with blue sclerae and hypertelorism, and she had a tubular nose. Her skin was of normal texture, tension, and wound healing. She had a bifid uvula with intact hard palate, normal arch, and normal voice quality. There were marked contractures of the proximal phalangeal joints of the right second and third digits and toes bilaterally, more severe on the right. Motor examination revealed decreased bulk in all appendicular and axial muscles, decreased strength, low tone, and diminished reflexes throughout; in addition, there was markedly reduced subcutaneous fat. A 3-year trial of losartan produced no change in muscle strength or mass. At 7 years of age, her weight was still below the 1st centile and height in the 5th centile, and the physical examination was unchanged. Muscle biopsy showed a normal checkerboard pattern with type 1 fiber predominance, but there was mild focal type 1 fiber disproportion consistent with disuse or decreased usage. Yearly echocardiograms showed no cardiac defect or dysfunction, and the aortic annulus and root and pulmonary artery dimensions were consistently within the normal range. Visual acuity remained normal. Matyas et al. (2014) reported a 10.5-year-old girl who presented with tall stature, marfanoid features, and a recent history of 2 unexplained episodes of vagal syncope. Electrocardiogram revealed first-degree atrioventricular block with a borderline PR interval; echocardiography showed an aortic root diameter at the upper limit of normal, mild mitral valve prolapse, and mild aortic and mitral insufficiency. Other features included hypertelorism, long palpebral fissures, bifid uvula, cleft soft palate, low muscle mass and muscular hypotonia, reduced subcutaneous fat, generalized hyperextensibility of joints, pectus excavatum, and kyphoscoliosis. She had transient postnatal flexion of hands and feet but no arthrogryposis; ophthalmologic examination was normal, as was skin. Matyas et al. (2014) observed similarities to the patient reported by Rienhoff et al. (2013), including cleft soft palate with bifid uvula, but also noted that their patient differed in that she had overgrowth and generalized hyperextensibility, whereas the patient of Rienhoff et al. (2013) presented with growth retardation and had hyperextensible large joints but contracted small distal digits of the fingers and toes. Bertoli-Avella et al. (2015) studied a large, 3-generation Dutch pedigree with 12 affected individuals, including 7 patients between 40 years and 68 years of age who presented with aneurysms and dissections that mainly involved the descending thoracic and abdominal aorta; 3 of those patients died from aortic dissection and rupture. Two family members exhibited aneurysmal disease beyond the aorta, with involvement of the right iliac artery in 1 and the left subclavian artery in the other. In addition, 4 family members had mitral valve abnormalities, ranging from mild prolapse to severe regurgitation requiring surgical intervention. Craniofacial abnormalities were subtle and included long face, high-arched palate, and retrognathia. Pectus deformity and scoliosis were frequently observed. Other recurrent findings included velvety skin, varices, and hiatal hernia. Several family members had autoimmune disorders, including HLA-B27 (see 142830)-positive spondyloarthritis, Graves disease, and celiac disease. Pathology reports from 2 family members described extensive elastic fiber fragmentation with 'pseudo-cyst formation' in the medial layer of the dissected aorta and 'aortic medial degeneration.' Bertoli-Avella et al. (2015) summarized the clinical features in 10 families segregating heterozygous mutations in the TGFB3 gene, in which affected individuals exhibited syndromic aortic aneurysmal disease that showed significant overlap with Loeys-Dietz syndrome (LDS), although striking intrafamilial and interfamilial clinical variability was observed. No early arterial dissection, or dissection at small aortic dimension, was observed. Other cardiovascular features included persistent foramen ovale and atrial or ventricular septal defects. No striking aortic or arterial tortuosity was observed. Typical LDS findings, such as hypertelorism, bifid uvula and cleft palate, cervical spine instability, and clubfoot deformity, were also seen. Other recurrent features included dolichocephaly, high-arched palate, retrognathia, tall stature, joint hypermobility, arachnodactyly, pectus deformity, and inguinal hernia. No evidence for ectopia lentis was found in the medical records. The youngest patient in this cohort was a 3-year-old Japanese girl who had a 19.5-mm aortic root aneurysm and atrial and ventricular septal defects, as well as other features of LDS, including hypertelorism, bifid uvula, and osteoarthritis. Microscopic examination of dissected aortic wall from 1 patient showed elastic fiber fragmentation with increased collagen and proteoglycan deposition, reminiscent of findings in both Marfan syndrome (154700) and LDS. In pathology reports from 2 other families, only mild elastic fiber fragmentation was noted. Mapping In a large Dutch pedigree with syndromic aortic aneurysm, negative for mutation in 15 known thoracic aortic aneurysm/dissection (TAAD)-associated genes, Bertoli-Avella et al. (2015) performed linkage analysis and identified 2 large genomic regions on chromosomes 14 and 15 that were shared by all affected patients; the region on chromosome 14 included the candidate gene TGFB3 at 14q24. Molecular Genetics In a 9-year-old girl with low muscle mass, growth retardation, and distal arthrogryposis, who also exhibited features of Marfan, Loeys-Dietz, and Beals (121050) syndromes but did not meet the established diagnostic criteria for those syndromes, Rienhoff et al. (2013) analyzed 6 genes known to be associated with those disorders, including TGFB2 (190220), TGFBR1 (190181), TGFBR2 (190182), SMAD3 (603109), FBN1 (134797), and FBN2 (612570), but found no mutations. Exome sequencing revealed 2 heterozygous de novo changes: 1 was a nonsense mutation in the CDH2 gene (114020); however, Rienhoff et al. (2013) noted that dermal fibroblasts from the patient showed CHD2 levels that were not statistically different from 6 age-matched controls, and that Garcia-Castro et al. (2000) had shown that mice heterozygous for a null mutation in Cdh2 were phenotypically normal at 2 years and muscle mass was not affected. The other variant was a de novo missense mutation in the TGFB3 gene (C409Y; 190230.0003), encoding a nonfunctional TGFB3 ligand. Rienhoff et al. (2013) concluded that the TGFB3 mutation most likely accounted for the clinical findings. In a 10.5-year-old girl with low muscle mass, marfanoid features, and bifid uvula, who was negative for mutation in FBN1, TGFBR1, TGFBR2, TGFB2, and SMAD3, Matyas et al. (2014) identified heterozygosity for a de novo missense mutation in the TGFB3 gene (R300Q; 190230.0004). In a large Dutch pedigree with syndromic aortic aneurysm mapping to chromosome 14 or 15, Bertoli-Avella et al. (2015) sequenced the candidate gene TGFB3 at chromosome 14q24 and identified heterozygosity for a splice site mutation (190230.0005). The mutation, which segregated with disease in the family, was not found in variant databases. Analysis of TGFB3 in an additional 470 probands with syndromic or nonsyndromic TAAD, the majority of whom had been screened for mutation in all known TAAD genes, revealed TGFB3 mutations in 10 probands, including 4 different missense mutations, 2 single-base deletions, and 1 nonsense mutation (see, e.g., 190230.0006-190230.0008). INHERITANCE \- Autosomal dominant GROWTH Height \- Tall stature \- Short stature (rare) Weight \- Low birth weight (in some patients) Other \- Growth retardation (rare) HEAD & NECK Head \- Dolichocephaly (in some patients) \- Brachycephaly (rare) \- Metopic ridge, small (rare) Face \- Retrognathia, mild \- Long face (in some patients) \- Wide face (rare) \- Midface hypoplasia (rare) \- Smooth philtrum (rare) Eyes \- Hypertelorism \- Exotropia \- Blue sclerae (in some patients) \- Downslanting palpebral fissures (in some patients) \- Prominent eyes (rare) \- Ptosis (rare) Mouth \- Bifid uvula \- High-arched palate \- Cleft palate CARDIOVASCULAR Heart \- Mitral insufficiency \- Aortic insufficiency, mild (rare) \- Atrial septal defect (rare) \- Ventricular septal defect (rare) \- Patent foramen ovale (rare) \- Vagal syncope (rare) \- First-degree atrioventricular block (rare) \- Borderline PR interval (rare) Vascular \- Aortic root dilation \- Aneurysm of thoracic aorta \- Aneurysm of abdominal aorta \- Aneurysmal dissection or rupture \- Elastic fiber fragmentation observed in aneurysmal aortic wall \- Aneurysm of iliac artery (rare) \- Aneurysm of subclavian artery (rare) \- Aneurysm/dissection of cerebral artery (rare) \- Varices CHEST External Features \- Pectus excavatum \- Pectus carinatum Ribs Sternum Clavicles & Scapulae \- Scapulae alata (rare) Diaphragm \- Hiatal hernia ABDOMEN External Features \- Inguinal hernia SKELETAL \- Osteoarthritis, early onset (in some patients) Skull \- Dolichocephaly (in some patients) \- Brachycephaly (rare) \- Metopic ridge, small (rare) Spine \- Kyphoscoliosis \- Spondylolisthesis (rare) \- Cervical spine instability (rare) Pelvis \- Bilateral coxa valga (rare) Limbs \- Joint hypermobility \- Increased arm span Hands \- Arachnodactyly \- Bilateral contractures of fingers (rare) \- Palmar flexion, transient postnatal (rare) Feet \- Pes planus \- Clubfeet (in some patients) \- Camptodactyly of toes (in some patients) \- Pes adductus, transient postnatal (rare) SKIN, NAILS, & HAIR Skin \- Easy bruising (in some patients) \- Thin translucent skin (in some patients) \- Soft velvety skin (in some patients) MUSCLE, SOFT TISSUES \- Subcutaneous fat markedly reduced (in some patients) \- Decreased muscle mass (in some patients) NEUROLOGIC Central Nervous System \- Congenital hypotonia, mild (in some patients) \- Delayed motor development (in some patients) \- Cerebral hemorrhage (rare) MISCELLANEOUS \- Autoimmune manifestations are present in some patients MOLECULAR BASIS \- Caused by mutation in the beta-3 transforming growth factor gene (TGFB3, 190230.0003 ) ▲ 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	LOEYS-DIETZ SYNDROME 5	c3810012	3,521	omim	https://www.omim.org/entry/615582	2019-09-22T15:51:36	{"doid": ["0070236"], "omim": ["615582"], "orphanet": ["91387"], "synonyms": ["Alternative titles", "RIENHOFF SYNDROME", "Familial TAAD"], "genereviews": ["NBK1133"]}
Cheiralgia paresthetica Other namesWartenberg's syndrome Radial nerve SpecialtyNeurology Cheiralgia paraesthetica (Wartenberg's syndrome) is a neuropathy of the hand generally caused by compression or trauma to the superficial branch of the radial nerve.[1][2] The area affected is typically on the back or side of the hand at the base of the thumb, near the anatomical snuffbox, but may extend up the back of the thumb and index finger and across the back of the hand.[1][3] Symptoms include numbness, tingling, burning or pain. Since the nerve branch is sensory there is no motor impairment.[3] It may be distinguished from de Quervain syndrome because it is not dependent on motion of the hand or fingers.[4] ## Contents * 1 Cause * 2 Diagnosis * 3 History * 4 See also * 5 References ## Cause[edit] The most common cause is thought to be constriction of the wrist, as with a bracelet or watchband (hence reference to "wristwatch neuropathy"). It is especially associated with the use of handcuffs and is therefore commonly referred to as handcuff neuropathy. Other injuries or surgery in the wrist area can also lead to symptoms, including surgery for other syndromes such as de Quervain's.[5] The exact etiology is unknown, as it is unclear whether direct pressure by the constricting item is alone responsible, or whether edema associated with the constriction also contributes.[3] ## Diagnosis[edit] Symptoms commonly resolve on their own within several months when the constriction is removed; NSAIDs are commonly prescribed.[4] In some cases surgical decompression is required.[4] The efficacy of cortisone and laser treatment is disputed.[4] Permanent damage is possible. ## History[edit] This neuropathy was first identified by Robert Wartenberg in a 1932 paper.[6] Recent studies have focused on handcuff injuries due to the legal liability implications, but these have been hampered by difficulties in followup, particularly as large percentages of the study participants have been inebriated when they were injured.[7] Diagnostically it is often subsumed into compression neuropathy of the radial nerve as a whole (e.g. ICD-9 354.3), but studies and papers continue to use the older term to distinguish it from more extensive neuropathies originating in the forearm. ## See also[edit] * Radial neuropathy ## References[edit] 1. ^ a b Buttaravoli, Philip M.; Stair, Thomas O. "9.20 Cheiralgia Paresthetica (Handcuff Neuropathy)". Common Simple Emergencies. Washington: Longwood Information. 2. ^ Wartenberg, R. (1932). "Cheiralgia paraesthetica.(Isolierte neuritis des Ramus superficialis nervi radialis.)" (PDF). Zeitschrift für die gesamte Neurologie und Psychiatrie (in German). 141 (1): 145–155. 3. ^ a b c Pećina, Marko; Krmpotić-Nemanić, Jelena; Markiewitz, Andrew D. (2001). "Chapter 26: Syndrome of the Superficial Branch of the Radial Nerve". Tunnel syndromes: peripheral nerve compression syndromes. CRC Press. pp. 152–155. 4. ^ a b c d Dang, Alan C.; Rodner, Craig M. (December 2009). "Unusual Compression Neuropathies of the Forearm, Part I: Radial Nerve" (PDF). Journal of Hand Surgery. 34A (10): 1912–1914. doi:10.1016/j.jhsa.2009.10.016. PMID 19969199. 5. ^ Chodoroff, G.; Honet, J. C. (Sep 1985). "Cheiralgia paresthetica and linear atrophy as a complication of local steroid injection". Archives of Physical Medicine and Rehabilitation. 66 (9): 637–639. PMID 4038032. 6. ^ Braidwood, A. S. (1975). "Superficial Radial Neuropathy". Journal of Bone and Joint Surgery. 57-B (3): 380–383. doi:10.1302/0301-620X.57B3.380. Archived from the original on 2011-07-24. 7. ^ Grant, Arthur C.; Cook, Albert A. (2000). "A Prospective Study of Handcuff Neuropathies" (PDF). Muscle and Nerve. 23 (6): 933–938. doi:10.1002/(SICI)1097-4598(200006)23:6<933::AID-MUS14>3.0.CO;2-G. Archived from the original (PDF) on 2011-07-08. * 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cheiralgia paresthetica	c4305399	3,522	wikipedia	https://en.wikipedia.org/wiki/Cheiralgia_paresthetica	2021-01-18T19:03:27	{"mesh": ["D020425"], "wikidata": ["Q699508"]}
Focal facial dermal dysplasia Other namesFFDD SpecialtyDermatology Focal facial dermal dysplasia is a rare genetically heterogeneous group of disorders that are characterized by congenital bilateral scar like facial lesions, with or without associated facial anomalies. It is characterized by hairless lesions with fingerprint like puckering of the skin, especially at the temples, due to alternating bands of dermal and epidermal atrophy. This condition is also known as Brauer syndrome (hereditary symmetrical aplastic nevi of temples, bitemporal aplasia cutis congenita, bitemporal aplasia cutis congenita: OMIM 136500) and Setleis syndrome (facial ectodermal dysplasia: OMIM 227260). ## Contents * 1 Presentation * 2 Genetics * 2.1 Pathology * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 History * 6 References * 7 External links ## Presentation[edit] This condition is characterised by symmetrical lesions on the temples resembling forceps marks. It is characterized a puckered skin due to a virtual absence of subcutaneous fat. It is apparent at birth. Other lesions that may be present include puffy, wrinkled skin around the eyes and/or abnormalities of the eyelashes, eyebrows, and eyelids. The eyebrows may be up slanting or outward slanting. Occasionally the bridge of the nose may appear flat, while the tip may appear unusually rounded. The chin may be furrowed. The upper lip may be prominent with a down turned mouth. Other features that have been reported include dysplastic and low set ears, linear radiatory impressions on the forehead and congenital horizontal nystagmus. Those with the Setleis syndrome may be missing eyelashes on both the upper and lower lids or may have multiple rows of lashes on the upper lids but none on the lower lids.[citation needed]A possible association with intra abdominal cancer has been reported but to date this has not been confirmed in other studies.[1] ## Genetics[edit] Type II appears to be due to mutations in the transcription factor TWIST2 on chromosome 2.[2] Type IV is due to mutations in the Cyp26c1 gene.[3] ### Pathology[edit] Under the temporal lesions the skeletal muscle is almost in direct continuity with the epidermis. ## Diagnosis[edit] ### Classification[edit] There are at least four types of FFDD:[4] * Type I: autosomal dominant FFDD * Type II: autosomal recessive FFDD * Type III: FFDD with other facial features : Setleis syndrome[5] * Type IV: facial lesions resembling aplasia cutis in a preauricular distribution along the line of fusion of the maxillary and mandibular prominences. Autosomal recessive. ## Treatment[edit] This section is empty. You can help by adding to it. (January 2017) ## History[edit] The syndrome was first described by Brauer in 1929 in a large five generation family (38 members).[6] The affected progenitor (Johann Jokeb Van Bargen) was a man who had migrated to Germany from Holland in the 16th century. As many as 155 family members were thought to have been affected. ## References[edit] 1. ^ McGeoch AH, Reed WB (June 1971). "Familial focal facial dermal dysplasia". Birth Defects Orig. Artic. Ser. 7 (8): 96–9. PMID 5173318. 2. ^ Franco HL, Casasnovas JJ, Leon RG, et al. (October 2011). "Nonsense mutations of the bHLH transcription factor TWIST2 found in Setleis Syndrome patients cause dysregulation of periostin". Int. J. Biochem. Cell Biol. 43 (10): 1523–31. doi:10.1016/j.biocel.2011.07.003. PMC 3163740. PMID 21801849. 3. ^ Slavotinek AM, Mehrotra P, Nazarenko I, et al. (November 2012). "Focal Facial Dermal Dysplasia, Type IV, is caused by mutations in CYP26C1". Hum. Mol. Genet. 22 (4): 696–703. doi:10.1093/hmg/dds477. PMC 3554199. PMID 23161670. 4. ^ Kowalski DC, Fenske NA (October 1992). "The focal facial dermal dysplasias: report of a kindred and a proposed new classification". J. Am. Acad. Dermatol. 27 (4): 575–82. doi:10.1016/0190-9622(92)70225-5. PMID 1401310. 5. ^ Orphanet : Focal facial dermal dysplasia type III 6. ^ Brauer A (1929) Hereditaerer symmetrischer systematisierter Naevus aplasticus bei 38 Personen. Derm. Wschr. 89: 1163-1168 ## External links[edit] Classification D * OMIM: 136500 227260 * MeSH: C537068 External resources * GeneReviews: Focal Dermal Hypoplasia * 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Focal facial dermal dysplasia	c1744559	3,523	wikipedia	https://en.wikipedia.org/wiki/Focal_facial_dermal_dysplasia	2021-01-18T18:45:16	{"gard": ["8416"], "mesh": ["C537068", "C536385"], "umls": ["C1744559"], "orphanet": ["398166"], "wikidata": ["Q5463849"]}
This syndrome is characterized by intellectual deficit, short stature, obesity, genital abnormalities, and hand and/or toe contractures. It has been described in two brothers and in one isolated case. The patients also present with generalized osteoporosis and a history of frequent fractures. This syndrome is similar to Prader-Willi syndrome, but the hand contractures and osteoporosis, together with the lack of hypotonia, indicate this is a different entity. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Urban-Rogers-Meyer syndrome	c0796189	3,524	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3409	2021-01-23T17:37:46	{"gard": ["5426"], "mesh": ["C538276"], "omim": ["264010"], "umls": ["C0796189"], "icd-10": ["Q87.8"], "synonyms": ["Intellectual disability-short stature-hand contractures-genital anomalies syndrome", "Prader-Willi habitus-osteopenia-camptodactyly syndrome"]}
Pattern hair loss Other namesMale pattern baldness; Female pattern baldness; Androgenic alopecia; Androgenetic alopecia Male-pattern hair loss shown on the vertex of the scalp SpecialtyDermatology, plastic surgery Pattern hair loss is hair loss that primarily affects the top and front of the scalp.[1] In male-pattern hair loss (MPHL), the hair loss often presents itself as either a receding hairline, loss of hair on the crown (vertex) of the scalp or a combination of both, while in female-pattern hair loss (FPHL), it typically presents as a thinning of the hair.[1] Male pattern hair loss seems to be due to a combination of genetics and circulating androgens.[1] The cause in female pattern hair loss remains unclear.[1] Management may include simply accepting the condition.[1] Otherwise, common medical treatments include minoxidil, finasteride, dutasteride, or hair transplant surgery.[1] Use of finasteride and dutasteride in women is not well-studied, and it may result in birth defects if taken during pregnancy.[1] Pattern hair loss by the age of 50 affects about half of males and a quarter of females.[1] It is the most common cause of hair loss. ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Hormones and genes * 3 Diagnosis * 4 Treatment * 4.1 Androgen-dependent * 4.2 Androgen-independent * 4.3 Female pattern * 4.4 Procedures * 4.5 Alternative therapies * 5 Prognosis * 5.1 Psychological * 6 Epidemiology * 7 Society and culture * 7.1 Myths * 7.1.1 Weight training and other types of physical activity cause baldness * 7.1.2 Baldness can be caused by emotional stress, sleep deprivation, etc. * 7.1.3 Bald men are more 'virile' or sexually active than others * 7.1.4 Frequent ejaculation causes baldness * 7.2 Names * 8 Other animals * 9 References * 10 External links ## Signs and symptoms[edit] Classic male-pattern hair loss begins above the temples and at the vertex (calvaria) of the scalp. As it progresses, a rim of hair at the sides and rear of the head remains. This has been referred to as a 'Hippocratic wreath', and rarely progresses to complete baldness.[2] Pattern hair loss is classified as a form of non-scarring hair loss. Female-pattern hair loss more often causes diffuse thinning without hairline recession; similar to its male counterpart, female androgenic alopecia rarely leads to total hair loss.[3] The Ludwig scale grades severity of female-pattern hair loss. These include Grades 1, 2, 3 of balding in women based on their scalp showing in the front due to thinning of hair. ## Causes[edit] ### Hormones and genes[edit] Androgens can interact with the Wnt signalling pathway to cause hair loss KRT37 is the only keratin that is regulated by androgens.[4] This sensitivity to androgens was acquired by Homo sapiens and is not shared with their great ape cousins. Although Winter et al. found that KRT37 is expressed in all the hair follices of chimpanzees, it was not detected in the head hair of modern humans. As androgens are known to grow hair on the body but decrease it on the scalp, this lack of scalp KRT37 may help explain the paradoxical nature of Androgenic alopecia as well as the fact that head hair anagen cycles are extremely long.[citation needed] Research indicates that the initial programming of pilosebaceous units of hair follicles begins in utero.[5] The physiology is primarily androgenic, with dihydrotestosterone (DHT) being the major contributor at the dermal papillae. Men with premature androgenic alopecia tend to have lower than normal values of sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH), testosterone, and epitestosterone when compared to men without pattern hair loss.[6] Although hair follicles were previously thought to be permanently gone in areas of complete hair loss, they are more likely dormant, as recent studies have shown the scalp contains the stem cell progenitor cells from which the follicles arose.[7][non-primary source needed] Transgenic studies have shown that growth and dormancy of hair follicles are related to the activity of insulin-like growth factor (IGF) at the dermal papillae, which is affected by DHT. Androgens are important in male sexual development around birth and at puberty. They regulate sebaceous glands, apocrine hair growth, and libido. With increasing age, androgens stimulate hair growth on the face, but can suppress it at the temples and scalp vertex, a condition that has been referred to as the 'androgen paradox'.[8] Men with androgenic alopecia typically have higher 5α-reductase, higher total testosterone, higher unbound/free testosterone, and higher free androgens, including DHT.[9] 5-alpha-reductase converts free testosterone into DHT, and is highest in the scalp and prostate gland. DHT is most commonly formed at the tissue level by 5α-reduction of testosterone.[10] The genetic corollary that codes for this enzyme has been discovered.[11] Prolactin has also been suggested to have different effects on the hair follicle across gender.[12] Also, crosstalk occurs between androgens and the Wnt-beta-catenin signaling pathway that leads to hair loss. At the level of the somatic stem cell, androgens promote differentiation of facial hair dermal papillae, but inhibit it at the scalp.[8] Other research suggests the enzyme prostaglandin D2 synthase and its product prostaglandin D2 (PGD2) in hair follicles as contributive.[13] These observations have led to study at the level of the mesenchymal dermal papillae.[14] Types 1 and 2 5α reductase enzymes are present at pilosebaceous units in papillae of individual hair follicles.[15] They catalyze formation of the androgens testosterone and DHT, which in turn regulate hair growth.[8] Androgens have different effects at different follicles: they stimulate IGF-1 at facial hair, leading to growth, but can also stimulate TGF β1, TGF β2, dickkopf1, and IL-6 at the scalp, leading to catagenic miniaturization.[8] Hair follicles in anaphase express four different caspases. Significant levels of inflammatory infiltrate have been found in transitional hair follicles.[16] Interleukin 1 is suspected to be a cytokine mediator that promotes hair loss.[17] The fact that hair loss is cumulative with age while androgen levels fall as well as the fact that finasteride does not reverse advanced stages of androgenetic alopecia remains a mystery but some possible explanations have been put forward: Higher conversion of testosterone to DHT locally with age as higher levels of 5-alpha reductase are noted in balding scalp, and higher levels of DNA damage in the dermal papilla as well as senescence of the dermal papilla due to androgen receptor activation and environmental stress.[18] The mechanism by which the androgen receptor triggers dermal papilla permanent senescence is not known but may involve IL6, TGFB-1 and oxidative stress. Senescence of the dermal papilla is measured by lack of mobility, different size and shape, lower replication and altered output of molecules and different expression of markers. The dermal papilla is the primary location of androgen action and its migration towards the hair bulge and subsequent signaling and size increase are required to maintain the hair follicle so senescence via the androgen receptor explains much of the physiology. Hair follicle and mesenchymal dermal papilla, labelled at top ## Diagnosis[edit] The diagnosis of androgenic alopecia can be usually established based on clinical presentation in men. In women, the diagnosis usually requires more complex diagnostic evaluation. Further evaluation of the differential requires exclusion of other causes of hair loss, and assessing for the typical progressive hair loss pattern of androgenic alopecia.[19] Trichoscopy can be used for further evaluation.[20] Biopsy may be needed to exclude other causes of hair loss,[21] and histology would demonstrate perifollicular fibrosis.[22][23] The Hamilton–Norwood scale has been developed to grade androgenic alopecia in males by severity. ## Treatment[edit] Main article: Management of hair loss ### Androgen-dependent[edit] Finasteride is a medication of the 5α-reductase inhibitors (5-ARIs) class.[24] By inhibiting type II 5-AR, finasteride prevents the conversion of testosterone to dihydrotestosterone in various tissues including the scalp.[24][25] Increased hair on the scalp can be seen within three months of starting finasteride treatment and longer-term studies have demonstrated increased hair on the scalp at 24 and 48 months with continued use.[25] Treatment with finasteride more effectively treats male-pattern hair loss at the vertex than male-pattern hair loss at the front of the head and temples.[25] Dutasteride is a medication in the same class as finasteride but inhibits both type I and type II 5-alpha reductase.[25] Dutasteride is approved for the treatment of male-pattern hair loss in Korea and Japan, but not in the United States.[25] However, it is commonly used off-label to treat male-pattern hair loss.[25] ### Androgen-independent[edit] Minoxidil dilates small blood vessels; it is not clear how this causes hair to grow.[26] Other treatments include tretinoin combined with minoxidil, ketoconazole shampoo, dermarolling (Collagen induction therapy), spironolactone,[27] alfatradiol, and topilutamide (fluridil).[28] ### Female pattern[edit] There is evidence supporting the use of minoxidil as a safe and effective treatment for female pattern hair loss, and there is no significant difference in efficiency between 2% and 5% formulations.[29] Finasteride was shown to be no more effective than placebo based on low-quality studies.[29] The effectiveness of laser-based therapies is unclear.[29] ### Procedures[edit] More advanced cases may be resistant or unresponsive to medical therapy and require hair transplantation. Naturally occurring units of one to four hairs, called follicular units, are excised and moved to areas of hair restoration.[27] These follicular units are surgically implanted in the scalp in close proximity and in large numbers. The grafts are obtained from either follicular unit transplantation (FUT) or follicular unit extraction (FUE). In the former, a strip of skin with follicular units is extracted and dissected into individual follicular unit grafts, and in the latter individual hairs are extracted manually or robotically. The surgeon then implants the grafts into small incisions, called recipient sites.[30][31] Cosmetic scalp tattoos can also mimic the appearance of a short, buzzed haircut. ### Alternative therapies[edit] Many people use unproven treatments.[32] Regarding female pattern alopecia, there is no evidence for vitamins, minerals, or other dietary supplements.[33] As of 2008, there is little evidence to support the use of lasers to treat male-pattern hair loss.[34] The same applies to special lights.[33] Dietary supplements are not typically recommended.[34] A 2015 review found a growing number of papers in which plant extracts were studied but only one randomized controlled clinical trial, namely a study in 10 people of saw palmetto extract.[35][36] ## Prognosis[edit] ### Psychological[edit] Androgenic alopecia is typically experienced as a "moderately stressful condition that diminishes body image satisfaction".[37] However, although most men regard baldness as an unwanted and distressing experience, they usually are able to cope and retain integrity of personality.[38] Although baldness is not as common in women as in men, the psychological effects of hair loss tend to be much greater. Typically, the frontal hairline is preserved, but the density of hair is decreased on all areas of the scalp. Previously, it was believed to be caused by testosterone just as in male baldness, but most women who lose hair have normal testosterone levels.[39] ## Epidemiology[edit] Female androgenic alopecia has become a growing problem that, according to the American Academy of Dermatology, affects around 30 million women in the United States. Although hair loss in females normally occurs after the age of 50 or even later when it does not follow events like pregnancy, chronic illness, crash diets, and stress among others, it is now occurring at earlier ages with reported cases in women as young as 15 or 16.[40] ## Society and culture[edit] Certain studies have suggested androgenic alopecia conveys survival advantage Studies have been inconsistent across cultures regarding how balding men rate on the attraction scale. While a 2001 South Korean study showed that most people rated balding men as less attractive,[41] a 2002 survey of Welsh women found that they rated bald and gray-haired men quite desirable.[42] One of the proposed social theories for male pattern hair loss is that men who embraced complete baldness by shaving their heads subsequently signaled dominance, high social status, and/or longevity.[43] Biologists have hypothesized the larger sunlight-exposed area would allow more vitamin D to be synthesized, which might have been a "finely tuned mechanism to prevent prostate cancer" as the malignancy itself is also associated with higher levels of DHT.[44] However, this argument is weak considering the fact that baldness is very rare in East Asians. In addition, early hominins such as the Neandertals do not possess any of the balding variants on the various association loci, who presumably would have been under positive selection for increased vitamin D synthesis. ### Myths[edit] An ancient phenomenon: Greek philosophers with and without much hair (from left to right: Socrates, Antisthenes, Chrysippus, and Epicurus, fifth to third centuries BC) Many myths exist regarding the possible causes of baldness and its relationship with one's virility, intelligence, ethnicity, job, social class, wealth, and many other characteristics. #### Weight training and other types of physical activity cause baldness[edit] Because it increases testosterone levels, many Internet forums[which?] have put forward the idea that weight training and other forms of exercise increase hair loss in predisposed individuals. Although scientific studies do support a correlation between exercise and testosterone, no direct study has found a link between exercise and baldness. However, a few have found a relationship between a sedentary life and baldness, suggesting some exercise is beneficial. The type or quantity of exercise may influence hair loss.[45][46] Testosterone levels are not a good marker of baldness, and many studies actually show paradoxical low testosterone in balding persons, although research on the implications is limited.[citation needed] #### Baldness can be caused by emotional stress, sleep deprivation, etc.[edit] Emotional stress has been shown to accelerate baldness in genetically susceptible individuals.[47] Stress due to sleep deprivation in military recruits lowered testosterone levels, but is not noted to have affected SHBG.[48] Thus, stress due to sleep deprivation in fit males is unlikely to elevate DHT, which is one cause of male pattern baldness. Whether sleep deprivation can cause hair loss by some other mechanism is not clear. #### Bald men are more 'virile' or sexually active than others[edit] Levels of free testosterone are strongly linked to libido and DHT levels, but unless free testosterone is virtually nonexistent, levels have not been shown to affect virility. Men with androgenic alopecia are more likely to have a higher baseline of free androgens. However, sexual activity is multifactoral, and androgenic profile is not the only determining factor in baldness. Additionally, because hair loss is progressive and free testosterone declines with age, a male's hairline may be more indicative of his past than his present disposition.[49][50] #### Frequent ejaculation causes baldness[edit] Many misconceptions exist about what can help prevent hair loss, one of these being that lack of sexual activity will automatically prevent hair loss. While a proven direct correlation exists between increased frequency of ejaculation and increased levels of DHT, as shown in a recent study by Harvard Medical School, the study suggests that ejaculation frequency may be a sign, rather than a cause, of higher DHT levels.[51] Another study shows that although sexual arousal and masturbation-induced orgasm increase testosterone concentration around orgasm, they reduce testosterone concentration on average, and because about 5% of testosterone is converted to DHT, ejaculation does not elevate DHT levels.[52] The only published study to test correlation between ejaculation frequency and baldness was probably large enough to detect an association (1390 subjects) and found no correlation, although persons with only vertex androgenetic alopecia had fewer female sexual partners than those of other androgenetic alopecia categories (such as frontal or both frontal and vertex). One study may not be enough, especially in baldness, where there is a complex with age.[53] Marital status has been shown in some studies to influence hair loss in cross-sectional studies (NHANES1), although the direction of effect cannot be inferred from a cross sectional study.[citation needed] ### Names[edit] Male pattern hair loss is also known as androgenic alopecia, androgenetic alopecia (AGA), alopecia androgenetica, and male pattern baldness (MPB). ## Other animals[edit] Animal models of androgenic alopecia occur naturally and have been developed in transgenic mice;[54] chimpanzees (Pan troglodytes); bald uakaris (Cacajao rubicundus); and stump-tailed macaques (Macaca speciosa and M. arctoides). Of these, macaques have demonstrated the greatest incidence and most prominent degrees of hair loss.[55][56] Baldness is not a trait unique to human beings. One possible case study is about a maneless male lion in the Tsavo area. The Tsavo lion prides are unique in that they frequently have only a single male lion with usually seven or eight adult females, as opposed to four females in other lion prides. Male lions may have heightened levels of testosterone, which could explain their reputation for aggression and dominance, indicating that lack of mane may at one time have had an alpha correlation.[57] Although primates do not go bald, their hairlines do undergo recession. In infancy the hairline starts at the top of the supraorbital ridge, but slowly recedes after puberty to create the appearance of a small forehead. ## References[edit] 1. ^ a b c d e f g h Vary JC, Jr (November 2015). "Selected Disorders of Skin Appendages--Acne, Alopecia, Hyperhidrosis". The Medical Clinics of North America (Review). 99 (6): 1195–1211. doi:10.1016/j.mcna.2015.07.003. PMID 26476248. 2. ^ "Hippocratic wreath (Baldness)". Britannica Online. Dec 15, 2012. Retrieved Dec 15, 2012. 3. ^ "Female pattern baldness". MedlinePlus. 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EurekAlert. ## External links[edit] Wikimedia Commons has media related to Androgenic alopecia. * NLM- Genetics Home Reference * Scow, D. T.; Nolte, R. S.; Shaughnessy, A. F. (1999). "Medical treatments for balding in men". American Family Physician. 59 (8): 2189–2194, 2196. PMID 10221304. Classification D * ICD-10: L64 * MeSH: D000505 * DiseasesDB: 7773 External resources * MedlinePlus: 001177 * eMedicine: derm/21 * v * t * e Human hair Classification by type * Lanugo * Androgenic * Terminal * Vellus by location * Body * Ear * Nose * Eyebrow * unibrow * Eyelash * Underarm * Chest * Abdominal * Pubic * Leg Head hairstyles (list) * Afro * Afro puffs * Asymmetric cut * Bald * Bangs * Beehive * Big hair * Blowout * Bob cut * Bouffant * Bowl cut * Braid * Brush cut * Bun (odango) * Bunches * Burr * Businessman cut * Butch cut * Buzz cut * Caesar cut * Chignon * Chonmage * Chupryna * Comb over * Conk * Cornrows * Crew cut * Crochet braids * Croydon facelift * Curly hair * Curtained hair * Devilock * Dido flip * Digital perm * Dreadlocks * Duck's ass * Eton crop * Extensions * Feathered hair * Finger wave * Flattop * Fontange * French braid * French twist * Fringe * Frosted tips * Hair crimping * Harvard clip * High and tight * Hime cut * Historical Christian hairstyles * Hi-top fade * Induction cut * Ivy League * Jewfro * Jheri curl * Kiss curl * Layered hair * Liberty spikes * Long hair * Lob cut * Marcelling * Mod cut * Mohawk * Mullet * 1950s * 1980s * Pageboy * Part * Payot * Pigtail * Pixie cut * Polish halfshaven head * Pompadour * Ponytail * Punch perm * Princeton * Professional cut * Queue * Quiff * Rattail * Razor cut * Regular haircut * Ringlets * Shag * Shape-Up * Shimada * Short back and sides * Short brush cut * Short hair * Spiky hair * Straight hair * Standard haircut * Surfer hair * Taper cut * Temple Fade * Tonsure * Updo * Undercut * Waves * Widow's peak * Wings Facial hair (list) * Beard * Chinstrap * Goatee * Shenandoah * Soul patch * Van Dyke * Moustache * Fu Manchu * handlebar * horseshoe * pencil * toothbrush * walrus * Designer stubble * Sideburns Hair loss cosmetic * Removal * waxing * threading * plucking * chemical * electric * laser * IPL * Shaving * head * leg * cream * brush * soap * Razor * electric * safety * straight other * Alopecia * areata * totalis * universalis * Frictional alopecia * Male-pattern hair loss * Hypertrichosis * Management * Trichophilia * Trichotillomania * Pogonophobia Haircare products * Brush * Clay * Clipper * Comb * Conditioner * Dryer * Gel * Hot comb * Iron * Mousse * Pomade * Relaxer * Rollers * Shampoo * Spray * Wax Haircare techniques * Backcombing * Crimping * Curly Girl Method * Hair cutting * Perm * Shampoo and set * Straightening Related topics * Afro-textured hair (kinky hair) * Beard and haircut laws by country * Bearded lady * Barber (pole) * Eponymous hairstyle * Frizz * Good hair * Hairdresser * Hair fetishism (pubic) * Hair follicle * Hair growth * Hypertrichosis * Trichotillomania * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pattern hair loss	c0162311	3,525	wikipedia	https://en.wikipedia.org/wiki/Pattern_hair_loss	2021-01-18T18:50:47	{"gard": ["9269"], "mesh": ["D000505"], "umls": ["C0162311"], "icd-10": ["L64"], "wikidata": ["Q2276095"]}
Bietti crystalline corneoretinal dystrophy is an inherited eye disease. Symptoms include crystals in the cornea (the clear covering of the eye); yellow, shiny deposits on the retina; and progressive atrophy of the retina, choriocapillaries and choroid (the back layers of the eye). This tends to lead to progressive night blindness and loss of visual acuity. Bietti crystalline corneoretinal dystrophy is caused by mutations in the CYP4V2 gene and inherited in an autosomal recessive fashion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Bietti crystalline corneoretinal dystrophy	c1859486	3,526	gard	https://rarediseases.info.nih.gov/diseases/10050/bietti-crystalline-corneoretinal-dystrophy	2021-01-18T18:01:48	{"mesh": ["C535440"], "omim": ["210370"], "umls": ["C1859486"], "orphanet": ["41751"], "synonyms": ["BCD", "Bietti tapetoretinal degeneration with marginal corneal dystrophy"]}
Alezzandrini syndrome is a very rare syndrome characterized by retinitis pigmentosa (breakdown and loss of cells in the retina—which is the light sensitive tissue that lines the back of the eye), whitish patches in the skin (vitiligo) and whitening of eyebrow and eyelashes (poliosis) all on the same side of the face. It is very similar to Vogt-Koyanagi-Harada syndrome. Other reported signs and symptoms may include vision loss and retinal detachment, a patch of white hair in the scalp, a café-u-lait spot on the neck, and hearing loss, again, all on the same side as the affected eye. The cause is unknown, but may be related to viral infections or autoimmune processes. Medical care includes eye exams, hearing tests and treatment for the vitiligo skin lesions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Alezzandrini syndrome	c1274653	3,527	gard	https://rarediseases.info.nih.gov/diseases/13023/alezzandrini-syndrome	2021-01-18T18:02:12	{"synonyms": []}
Tangier disease is an inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) - the 'good cholesterol' - in the blood. Because people with Tangier disease have very low levels of HDL, they have a moderately increased risk of cardiovascular disease. Tangier disease is caused by mutations in the ABCA1 gene. It is inherited in an autosomal recessive pattern. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Tangier disease	c0039292	3,528	gard	https://rarediseases.info.nih.gov/diseases/7731/tangier-disease	2021-01-18T17:57:26	{"mesh": ["D013631"], "omim": ["205400"], "orphanet": ["31150"], "synonyms": ["High density lipoprotein deficiency, type 1", "HDLDT1", "High density lipoprotein deficiency, Tangier type", "Analphalipo-proteinemia", "Alpha high density lipoprotein deficiency disease", "A-alphalipoprotein neuropathy", "Cholesterol thesaurismosis", "Familial high density lipoprotein deficiency disease", "Familial Hypoalphalipo-proteinemia", "Hdl lipoprotein deficiency disease"]}
A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome associated with acetylcholine receptor (AChR) deficiency-2C (CMS2C) is caused by compound heterozygous mutation in the CHRNB1 gene (100710) on chromosome 17p13. One such family has been reported. Mutation in the CHRNB1 gene can also cause slow-channel congenital myasthenic syndrome-2A (CMS2A; 616313). Description Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized clinically by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Treatment with cholinesterase inhibitors or amifampridine may be helpful (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). Clinical Features Quiram et al. (1999) reported 3 sibs with CMS and severe AChR deficiency. The proband, 8 years of age at the time of report, had severe myasthenic symptoms from birth, requiring frequent ventilation and enteric alimentation through a gastrostomy. She had a decremental electromyographic response on stimulation of motor nerves and responded partially to acetylcholinesterase inhibitors. Tests for anti-AChR antibodies were negative. The parents were unaffected. Electrophysiologic studies showed that the MEPP and MEPC were both decreased, with normal quantal release. Analysis of affected muscle fibers showed an increased number of small endplate regions distributed over a 3-fold increased span of the muscle fiber surface. Nerve terminal size and the postsynaptic area of folds and clefts were both decreased compared to normal. Inheritance The transmission pattern of CMS2C in the family reported by Quiram et al. (1999) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 sibs with CMS2C, Quiram et al. (1999) identified compound heterozygosity for 2 mutations in the CHRNB1 gene (100710.0003; 100710.0004). INHERITANCE \- Autosomal recessive RESPIRATORY \- Respiratory insufficiency, episodic ABDOMEN Gastrointestinal \- Feeding difficulties MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Muscle weakness \- Decremental response to repetitive nerve stimulation \- Decreased amplitude of the miniature endplate potential (MEPP) and current (MEPC) \- Endplate myopathy \- Decreased numbers of AChR MISCELLANEOUS \- Onset at birth \- May respond to cholinesterase inhibitors \- One family has been reported (last curated April 2015) MOLECULAR BASIS \- Caused by mutation in the cholinergic receptor, nicotinic, beta polypeptide 1 gene (CHRNB1, 100710.0003 ) ▲ 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MYASTHENIC SYNDROME, CONGENITAL, 2C, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY	c0751882	3,529	omim	https://www.omim.org/entry/616314	2019-09-22T15:49:13	{"doid": ["0110680"], "mesh": ["D020294"], "omim": ["616314"], "orphanet": ["98913", "590"], "synonyms": [], "genereviews": ["NBK1168"]}
Ludwig's angina Other namesAngina Ludovici Swelling in the submandibular area in a person with Ludwig's angina. SpecialtyOtorhinolaryngology, oral and maxillofacial surgery SymptomsFever, pain, a raised tongue, trouble swallowing, neck swelling[1] ComplicationsAirway compromise[1] Usual onsetRapid[1] Risk factorsDental infection[1] Diagnostic methodBased on symptoms and examination, CT scan[1] TreatmentAntibiotics, corticosteroids, endotracheal intubation, tracheostomy[1] Ludwig's angina (lat.: Angina ludovici) is a type of severe cellulitis involving the floor of the mouth.[2] Early on the floor of the mouth is raised and there is difficulty swallowing saliva, which may run from the person's mouth.[3] As the condition worsens, the airway may be compromised with hardening of the spaces on both sides of the tongue.[4] This condition has a rapid onset over hours. The majority of cases follow a dental infection.[3] Other causes include a parapharyngeal abscess, mandibular fracture, cut or piercing inside the mouth, or submandibular salivary stones.[5] It is a spreading infection of connective tissue through tissue spaces, normally with virulent and invasive organisms. It specifically involves the submandibular, submental, and sublingual spaces.[1] Prevention is by appropriate dental care including management of dental infections. Initial treatment is generally with broad-spectrum antibiotics and corticosteroids.[1] In more advanced cases endotracheal intubation or tracheostomy may be required.[1] With the advent of antibiotics in 1940s, improved oral and dental hygiene, and more aggressive surgical approach, the rates and risk of death among those infected has significantly reduced. It is named after a German physician, Wilhelm Frederick von Ludwig, who first described this condition in 1836.[6] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 3.1 Microbiology * 4 Treatment * 4.1 Airway management * 4.2 Antibiotics * 4.3 Incision and drainage * 4.4 Nutritional support * 4.5 Post-operative care * 5 Etymology * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Ludwig's angina is a form of severe diffuse cellulitis with bilateral involvement, primarily of the submandibular space with the sublingual and submental spaces also being involved. It presents with an acute onset and spreads very rapidly meaning early diagnosis and immediate treatment planning is key to saving lives.[7] The external signs may include bilateral lower facial swelling around the mandible and upper neck. Signs inside the mouth may include elevation of the floor of mouth due to sublingual space involvement and posterior displacement of the tongue, creating the potential for a compromised airway.[7] Additional symptoms may include painful neck swelling, tooth pain, dysphagia, shortness of breath, fever, and general malaise.[8] Stridor, trismus, and cyanosis may also be seen when an impending airway crisis is nearing.[8] ## Cause[edit] The most prevalent cause of Ludwig's angina is odontogenic,[9] accounting for approximately 75% to 90% of cases.[9][10][11][12] Infections of the lower second and third molars are usually implicated due to their roots extending inferiorly below the mylohyoid muscle.[9][13] Periapical abscesses of these teeth also result in lingual cortical penetration, leading to submandibular infection.[9] However, oral ulcerations, infections of oral malignancy, mandible fracture, bilateral sialolithiasis-related submandibular gland infection,[9] and penetrating injuries of the mouth floor[14] have also been reported as potential causes of Ludwig's angina. In fact, the same microorganisms responsible for less morbid head and neck infections are found in causing extensive infection throughout the floor of mouth and neck[14] when Ludwig's angina is critically reviewed.[9] Patients with systemic illness, such as diabetes mellitus, malnutrition, compromised immune system, and organ transplantation are also commonly predisposed to Ludwig's angina.[12] It is found that one third of the cases of Ludwig's angina are associated with systemic illness.[12] A review reporting the incidence of illnesses associated with Ludwig angina found that 18% of cases involved diabetes mellitus, 9% involved acquired immune deficiency syndrome, and another 5% were human immunodeficiency virus (HIV) positive.[15] ## Diagnosis[edit] Infections originating in the roots of teeth can be identified with a dental X-ray.[16][17] A CT scan of the neck with contrast material is used to identify deep neck space infections.[18] If there is suspicion of the infection of the chest cavity, a chest scan is sometimes done.[17] Angioneurotic oedema, lingual carcinoma and sublingual haematoma formation following anticoagulation should be ruled out as possible diagnoses.[18] ### Microbiology[edit] There are a few methods that can be used for determining the microbiology of Ludwig's angina. One of the traditionally used methods is taking culture samples although it has some limitations.[19][20] By taking pus samples from a patient with Ludwig's angina, the microbiology were found to be commonly polymicrobial and anaerobic.[21][22] Some of the commonly found microbes are Viridans Streptococci, Staphylococci, Peptostreptococci, Prevotella, Porphyromonas and Fusobacterium.[21][22] ## Treatment[edit] For each patient, the treatment plan should be done with consideration of each of the individual patient's differing factors. They are namely the stage of the disease and co-morbid conditions at the time of presentation, physician experience, available resources, and personnel are critical factors in formulation of a treatment plan.[23] There are four principles that guide the treatment of Ludwig's Angina:[24] Sufficient airway management, early and aggressive antibiotic therapy, incision and drainage for any who fail medical management or form localized abscesses, and adequate nutrition and hydration support. Each will be explained in detail below.[citation needed] ### Airway management[edit] Placement of an endotracheal tube to aid breathing. Airway management has been found to be the most important factor in treating patients with Ludwig's Angina,[19] i.e. it is the “primary therapeutic concern”.[25] Airway compromise is known to be the leading cause of death from Ludwig's Angina.[5] * The basic method to achieve this is to allow the patient to sit in an upright position, with supplemental oxygen provided by masks or nasal prongs.[19] Patients should never be left unattended, particularly if there is an absence of intubation or a surgical airway in place.[19] * Methods of airway management range from conservative airway management – consisting of close observation and intravenous antibiotics, to airway intervention with endotracheal intubation or tracheostomy.[19] * If the oxygen saturation levels are adequate and antimicrobials have been given, simple airway observation can be done.[19] This is a suitable method to adopt in the management of children, as a retrospective study described that only 10% of children required airway control. However, a tracheostomy was performed on 52% of those affected with Ludwig's Angina over 15 years old.[26] * Airway control is compulsory if a surgical procedure is required.[5] * Flexible nasotracheal intubation require skills and experience.[5] * If nasotracheal intubation is not possible, cricothyrotomy and tracheostomy under local anaesthetic can be done. This procedure is carried out on patients with advanced stage of Ludwig's Angina.[5] * Endotracheal intubation has been found to be in association with high failure rate with acute deterioration in respiratory status.[5] * Elective tracheostomy is described as a safer and more logical method of airway management in patients with fully developed Ludwig's Angina.[27] * Fibre-optic nasoendoscopy can also be used, especially for patients with floor of mouth swellings.[19] * It is important that incision and drainage are preceded by consulting the anaesthesiologist about possible airway problems at intubation.[19] A tracheostomy set should always be present in the operating room in case there is requirement for local tracheostomy or an emergency cricothyrotomy.[19] ### Antibiotics[edit] * Antibiotic therapy is empirical, it is given until culture and sensitivity results are obtained.[19] The empirical therapy should be effective against both aerobic and anaerobic bacteria species commonly involved in Ludwig's Angina.[19] Only when culture and sensitivity results return should therapy be tailored to the specific requirements of the patient.[19] * Empirical coverage should consist of either a penicillin with a B-lactamase inhibitor such as amoxicillin/ticarcillin with clavulanic acid or a Beta-lactamase resistant antibiotic such as cefoxitin, cefuroxime, imipenem or meropenem.[19] This should be given in combination with a drug effective against anaerobes such as clindamycin or metronidazole.[19] * Parenteral antibiotics are suggested until the patient is no longer febrile for at least 48 hours.[19] Oral therapy can then commence to last for 2 weeks, with amoxicillin with clavulanic acid, clindamycin, ciprofloxacin, trimethoprim-sulfamethoxazole, or metronidazole.[19] ### Incision and drainage[edit] * Surgical incision and drainage are the main methods in managing severe and complicated deep neck infections that fail to respond to medical management within 48 hours.[19] * It is indicated in cases of:[19] * Airway compromise * Septicaemia * Deteriorating condition * Descending infection * Diabetes mellitus * Palpable or radiographic evidence of abscess formation * Bilateral submandibular incisions should be carried out in addition to a midline submental incision. Access to the supramylohyoid spaces can be gained by blunt dissection through the mylohyoid muscle from below.[19] * Penrose drains are recommended in both supramylohyoid and inframylohyoid spaces bilaterally. In addition, through and through drains from the submandibular space to the submental space on both sides should be placed as well.[19] * The incision and drainage process is completed with the debridement of necrotic tissue and thorough irrigation.[19] * It is necessary to mark drains in order to identify their location. They should be sutured with loops as well so it will be possible to advance them without re-anaesthetizing the patient while drains are re-sutured to the skin.[19] * An absorbent dressing is then applied. A bandnet dressing retainer can be constructed so as to prevent the use of tape.[19] ### Nutritional support[edit] Adequate nutrition and hydration support is essential in deciding the outcomes in any patient following surgery, particularly young children.[24] In this case, pain and swelling in the neck region would usually cause difficulties in eating or swallowing, hence reducing patient's food and fluid intake. As a result, patients suffer from weight loss due to loss of fat, muscle and skin initially, followed by bone and internal organs in the late phase. Meanwhile, at the cellular level, the cells would be less able to maintain homeostasis in the presence of stressors such as infection and surgery. Patients must therefore be well-nourished and hydrated to promote wound healing and to fight off infection.[28] ### Post-operative care[edit] Extubation, which is the removal of endotracheal tube to liberate the patient from mechanical ventilation, should only be done when the patient's airway is proved to be patent, allowing adequate breathing. This is indicated by a decrease in swelling and patient's capability of breathing adequately around an uncuffed endotracheal tube with the lumen blocked.[28] During the hospital stay, patient's condition will be closely monitored by: * carrying out cultures and sensitivity tests to decide if any changes need to be made to patient's antibiotic course * observing patient's body temperature - a rise implies further infection * monitoring patient's white blood cell count - a decrease implies effective and sufficient drainage * repeating CT scans to prove patient's restored health status or if infection extends, the anatomical areas that are affected.[28] Moreover, it is advised to never leave young children with significant neck swelling unattended and they should always be seated to prevent suffocation.[24] ## Etymology[edit] The term “angina”, is derived from the Latin word “angere”, which means “choke”; and the Greek word “ankhone”, which means “strangle”. Placing it into context, Ludwig's angina refers to the feeling of strangling and choking, secondary to obstruction of the airway, which is the most serious potential complication of this condition.[22] ## See also[edit] * Anticor ## References[edit] 1. ^ a b c d e f g h i Gottlieb, M; Long, B; Koyfman, A (May 2018). "Clinical Mimics: An Emergency Medicine-Focused Review of Streptococcal Pharyngitis Mimics". The Journal of Emergency Medicine. 54 (5): 619–629. doi:10.1016/j.jemermed.2018.01.031. PMID 29523424. 2. ^ Candamourty R, Venkatachalam S, Babu MR, Kumar GS (July 2012). "Ludwig's Angina - An emergency: A case report with literature review". Journal of Natural Science, Biology, and Medicine. 3 (2): 206–8. doi:10.4103/0976-9668.101932. PMC 3510922. PMID 23225990. 3. ^ a b Coulthard P, Horner K, Sloan P, Theaker ED (2013-05-17). Master dentistry (3rd ed.). Edinburgh: Elsevier. ISBN 978-0-7020-4600-1. OCLC 786161764. 4. ^ Kremer MJ, Blair T (December 2006). "Ludwig angina: forewarned is forearmed". AANA Journal. 74 (6): 445–51. PMID 17236391. 5. ^ a b c d e f Saifeldeen K, Evans R (March 2004). "Ludwig's angina". Emergency Medicine Journal. 21 (2): 242–3. doi:10.1136/emj.2003.012336. PMC 1726306. PMID 14988363. 6. ^ Murphy SC (October 1996). "The person behind the eponym: Wilhelm Frederick von Ludwig (1790-1865)". Journal of Oral Pathology & Medicine. 25 (9): 513–5. doi:10.1111/j.1600-0714.1996.tb00307.x. PMID 8959561. 7. ^ a b Candamourty, Ramesh; Venkatachalam, Suresh; Babu, M. R. Ramesh; Kumar, G. Suresh (2012). "Ludwig's Angina – An emergency: A case report with literature review". Journal of Natural Science, Biology, and Medicine. 3 (2): 206–208. doi:10.4103/0976-9668.101932. ISSN 0976-9668. PMC 3510922. PMID 23225990. 8. ^ a b Saifeldeen, K.; Evans, R. (2004-03-01). "Ludwig's angina". Emergency Medicine Journal. 21 (2): 242–243. doi:10.1136/emj.2003.012336. ISSN 1472-0205. PMC 1726306. PMID 14988363. 9. ^ a b c d e f Current therapy in oral and maxillofacial surgery. Bagheri, Shahrokh C., Bell, R. Bryan., Khan, Husain Ali. Philadelphia: Elsevier Saunders. 2012. ISBN 9781416025276. OCLC 757994410.CS1 maint: others (link) 10. ^ Moreland, L. W.; Corey, J.; McKenzie, R. (February 1988). "Ludwig's angina. Report of a case and review of the literature". Archives of Internal Medicine. 148 (2): 461–466. doi:10.1001/archinte.1988.00380020205027. ISSN 0003-9926. PMID 3277567. 11. ^ Sethi, D. S.; Stanley, R. E. (February 1994). "Deep neck abscesses--changing trends". The Journal of Laryngology and Otology. 108 (2): 138–143. doi:10.1017/S0022215100126106. ISSN 0022-2151. PMID 8163915. 12. ^ a b c Chou, Yu-Kung; Lee, Chao-Yi; Chao, Hai-Hsuan (December 2007). "An upper airway obstruction emergency: Ludwig angina". Pediatric Emergency Care. 23 (12): 892–896. doi:10.1097/pec.0b013e31815c9d4a. ISSN 1535-1815. PMID 18091599. S2CID 2891390. 13. ^ Prince, Jim McMorran, Damian Crowther, Stew McMorran, Steve Youngmin, Ian Wacogne, Jon Pleat, Clive. "Ludwig's angina - General Practice Notebook". gpnotebook.co.uk. Retrieved 2018-02-17. 14. ^ a b "Peterson's Principles of Oral and Maxillofacial Surgery 2nd Ed 2004". Scribd. Retrieved 2018-02-17. 15. ^ Moreland, Larry W. (1988-02-01). "Ludwig's Angina". Archives of Internal Medicine. 148 (2): 461–6. doi:10.1001/archinte.1988.00380020205027. ISSN 0003-9926. PMID 3277567. 16. ^ Spitalnic SJ, Sucov A (July 1995). "Ludwig's angina: case report and review". The Journal of Emergency Medicine. 13 (4): 499–503. doi:10.1016/0736-4679(95)80007-7. PMID 7594369. 17. ^ a b Bagheri SC (2014). Clinical Review of Oral and Maxillofacial Surgery: A Case-Based Approach (Second ed.). St. Louis: Mosby Elsevier. pp. 95–118. ISBN 978-0-323-17127-4. 18. ^ a b Crespo AN, Chone CT, Fonseca AS, Montenegro MC, Pereira R, Milani JA (November 2004). "Clinical versus computed tomography evaluation in the diagnosis and management of deep neck infection". Sao Paulo Medical Journal. 122 (6): 259–63. doi:10.1590/S1516-31802004000600006. PMID 15692720. 19. ^ a b c d e f g h i j k l m n o p q r s t u v w Bagheri SC, Bell RB, Khan HA (2011). Current Therapy in Oral and Maxillofacial Surgery. Philadelphia: Elsevier. pp. 1092–1098. ISBN 978-1-4160-2527-6. 20. ^ Siqueira JF, Rôças IN (April 2013). "Microbiology and treatment of acute apical abscesses". Clinical Microbiology Reviews. 26 (2): 255–73. doi:10.1128/CMR.00082-12. PMC 3623375. PMID 23554416. 21. ^ a b Candamourty R, Venkatachalam S, Babu MR, Kumar GS (July 2012). "Ludwig's Angina - An emergency: A case report with literature review". Journal of Natural Science, Biology, and Medicine. 3 (2): 206–8. doi:10.4103/0976-9668.101932. PMC 3510922. PMID 23225990. 22. ^ a b c Costain N, Marrie TJ (February 2011). "Ludwig's Angina". The American Journal of Medicine. 124 (2): 115–7. doi:10.1016/j.amjmed.2010.08.004. PMID 20961522. 23. ^ Shockley WW (May 1999). "Ludwig angina: a review of current airway management". Archives of Otolaryngology–Head & Neck Surgery. 125 (5): 600. doi:10.1001/archotol.125.5.600. PMID 10326825. 24. ^ a b c Chou YK, Lee CY, Chao HH (December 2007). "An upper airway obstruction emergency: Ludwig angina". Pediatric Emergency Care. 23 (12): 892–6. doi:10.1097/pec.0b013e31815c9d4a. PMID 18091599. S2CID 2891390. 25. ^ Moreland LW, Corey J, McKenzie R (February 1988). "Ludwig's angina. Report of a case and review of the literature". Archives of Internal Medicine. 148 (2): 461–6. doi:10.1001/archinte.1988.00380020205027. PMID 3277567. 26. ^ Kurien M, Mathew J, Job A, Zachariah N (June 1997). "Ludwig's angina". Clinical Otolaryngology and Allied Sciences. 22 (3): 263–5. doi:10.1046/j.1365-2273.1997.00014.x. PMID 9222634. 27. ^ Parhiscar A, Har-El G (November 2001). "Deep neck abscess: a retrospective review of 210 cases". The Annals of Otology, Rhinology, and Laryngology. 110 (11): 1051–4. doi:10.1177/000348940111001111. PMID 11713917. S2CID 40027551. 28. ^ a b c Bagheri SC, Bell RB, Khan HA (2012). Current Therapy in Oral and Maxillofacial Surgery. Philadelphia: Elsevier Saunders. ISBN 978-1-4160-2527-6. OCLC 757994410. ## External links[edit] Classification D * ICD-10: K12.2 * ICD-9-CM: 528.3 * MeSH: D008158 * DiseasesDB: 29336 External resources * MedlinePlus: 001047 * v * t * e Proteobacteria-associated Gram-negative bacterial infections α Rickettsiales Rickettsiaceae/ (Rickettsioses) Typhus * Rickettsia typhi * Murine typhus * Rickettsia prowazekii * Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus Spotted fever Tick-borne * Rickettsia rickettsii * Rocky Mountain spotted fever * Rickettsia conorii * Boutonneuse fever * Rickettsia japonica * Japanese spotted fever * Rickettsia sibirica * North Asian tick typhus * Rickettsia australis * Queensland tick typhus * Rickettsia honei * Flinders Island spotted fever * Rickettsia africae * African tick bite fever * Rickettsia parkeri * American tick bite fever * Rickettsia aeschlimannii * Rickettsia aeschlimannii infection Mite-borne * Rickettsia akari * Rickettsialpox * Orientia tsutsugamushi * Scrub typhus Flea-borne * Rickettsia felis * Flea-borne spotted fever Anaplasmataceae * Ehrlichiosis: Anaplasma phagocytophilum * Human granulocytic anaplasmosis, Anaplasmosis * Ehrlichia chaffeensis * Human monocytotropic ehrlichiosis * Ehrlichia ewingii * Ehrlichiosis ewingii infection Rhizobiales Brucellaceae * Brucella abortus * Brucellosis Bartonellaceae * Bartonellosis: Bartonella henselae * Cat-scratch disease * Bartonella quintana * Trench fever * Either B. henselae or B. quintana * Bacillary angiomatosis * Bartonella bacilliformis * Carrion's disease, Verruga peruana β Neisseriales M+ * Neisseria meningitidis/meningococcus * Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia M− * Neisseria gonorrhoeae/gonococcus * Gonorrhea ungrouped: * Eikenella corrodens/Kingella kingae * HACEK * Chromobacterium violaceum * Chromobacteriosis infection Burkholderiales * Burkholderia pseudomallei * Melioidosis * Burkholderia mallei * Glanders * Burkholderia cepacia complex * Bordetella pertussis/Bordetella parapertussis * Pertussis γ Enterobacteriales (OX−) Lac+ * Klebsiella pneumoniae * Rhinoscleroma, Pneumonia * Klebsiella granulomatis * Granuloma inguinale * Klebsiella oxytoca * Escherichia coli: Enterotoxigenic * Enteroinvasive * Enterohemorrhagic * O157:H7 * O104:H4 * Hemolytic-uremic syndrome * Enterobacter aerogenes/Enterobacter cloacae Slow/weak * Serratia marcescens * Serratia infection * Citrobacter koseri/Citrobacter freundii Lac− H2S+ * Salmonella enterica * Typhoid fever, Paratyphoid fever, Salmonellosis H2S− * Shigella dysenteriae/sonnei/flexneri/boydii * Shigellosis, Bacillary dysentery * Proteus mirabilis/Proteus vulgaris * Yersinia pestis * Plague/Bubonic plague * Yersinia enterocolitica * Yersiniosis * Yersinia pseudotuberculosis * Far East scarlet-like fever Pasteurellales Haemophilus: * H. influenzae * Haemophilus meningitis * Brazilian purpuric fever * H. ducreyi * Chancroid * H. parainfluenzae * HACEK Pasteurella multocida * Pasteurellosis * Actinobacillus * Actinobacillosis Aggregatibacter actinomycetemcomitans * HACEK Legionellales * Legionella pneumophila/Legionella longbeachae * Legionnaires' disease * Coxiella burnetii * Q fever Thiotrichales * Francisella tularensis * Tularemia Vibrionaceae * Vibrio cholerae * Cholera * Vibrio vulnificus * Vibrio parahaemolyticus * Vibrio alginolyticus * Plesiomonas shigelloides Pseudomonadales * Pseudomonas aeruginosa * Pseudomonas infection * Moraxella catarrhalis * Acinetobacter baumannii Xanthomonadaceae * Stenotrophomonas maltophilia Cardiobacteriaceae * Cardiobacterium hominis * HACEK Aeromonadales * Aeromonas hydrophila/Aeromonas veronii * Aeromonas infection ε Campylobacterales * Campylobacter jejuni * Campylobacteriosis, Guillain–Barré syndrome * Helicobacter pylori * Peptic ulcer, MALT lymphoma, Gastric cancer * Helicobacter cinaedi * Helicobacter cellulitis * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Ludwig's angina	c0024081	3,530	wikipedia	https://en.wikipedia.org/wiki/Ludwig%27s_angina	2021-01-18T18:52:16	{"mesh": ["D008158"], "umls": ["C0024081"], "icd-9": ["528.3"], "icd-10": ["K12.2"], "wikidata": ["Q592804"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-44 (MRD44) is caused by heterozygous mutation in the TRIO gene (601893) on chromosome 5p15. Description Autosomal dominant mental retardation-44 is characterized by mildly delayed global development, resulting in variable intellectual deficits or learning difficulties, distinctive facial features, and abnormalities of the fingers, particularly brachydactyly, tapering fingers, and broad interphalangeal joints. Most patients also have microcephaly; additional features are highly variable (summary by Ba et al., 2016). Clinical Features Mercer et al. (2008) reported 2 brothers, their mother, and a maternal cousin who had a distinctive facial phenotype involving a straight pointed nose, micrognathia, and variable slanting of the palpebral fissures, mild brachydactyly with tapering fingers and distal phalangeal hypoplasia, and prominence of the interphalangeal joints. Microcephaly was present in 2, and there was evidence of hypodontia in 3 of the 4 affected individuals. One brother and the mother had multiple ventricular extrasystoles, but no syncope. Both brothers had mild learning disabilities and attended special schools; the mother had normal intelligence, but reported academic difficulties. Six other relatives over 4 generations were probably affected on the basis of history and family photographs. Pengelly et al. (2016) reported follow-up of this family. One of the affected brothers had a similarly affected daughter, who was the index case. She had mild global developmental delay with delayed speech. Dysmorphic features included microcephaly (-5 SD), short nose, long philtrum, thin upper lip, and epicanthal folds. Skeletal anomalies included right radial aplasia, rudimentary thumb, and absent first metacarpal. She also had several congenital cardiac septal defects that were clinically insignificant. Her father and his brother (the 2 brothers in the original report) had microcephaly (-3 and -5 SD, respectively) and the previously noted dysmorphic features, with the addition of low anterior hairline. Ba et al. (2016) reported 5 patients with a similar disorder. The patients included 7- and 10-year-old boys, a 35-year-old woman with no family history, and a 20-year-old man whose father was similarly affected. All patients had borderline to mild intellectual disability with delayed motor development or delay of fine motor skills and variable speech delay. The patients also had behavioral problems, including autistic-like features or attention deficit-hyperactivity disorder. Other common features in the index cases included small head circumference (range -1 to -2.5 SD), broad forehead, micrognathia with dental crowding, and minor hand anomalies, such as brachydactyly, tapering fingers, and broad interphalangeal joints. Additional features were highly variable: increased reflexes, hyperacusis, swallowing difficulties, facial asymmetry, full lips, high palate, kyphosis, pes planus, and pectus excavatum, among others. Three were noted to have recurrent infections. The 7-year-old boy, who had an intragenic deletion of the TRIO gene, had previously been reported by Vulto-van Silfhout et al. (2013) in a large study of 5,531 patients who underwent screening for copy number variations. Pengelly et al. (2016) reported 3 additional unrelated children with MRD44. All had global developmental delay and behavioral abnormalities, such as autistic features and obsessive-compulsive traits. Dysmorphic features and distal hand anomalies were more variable, but consistent with previous descriptions. Two patients had microcephaly; the third patient had nocturnal seizures and an ataxic gait. Inheritance The transmission pattern of MRD44 in the family reported by Mercer et al. (2008) and Pengelly et al. (2016) was consistent with autosomal dominant inheritance. Molecular Genetics In 4 patients from 3 unrelated families with MRD44, Ba et al. (2016) identified 3 different heterozygous truncating mutations in the TRIO gene (601893.0001-601893.0003). Two of the mutations occurred de novo. Studies of patient cells were not performed, but knockdown of the Trio gene in rat hippocampal cells resulted in an increase in dendrites and alterations in synaptic transmission, resulting in increased excitatory transmission during development (see ANIMAL MODEL). Ba et al. (2016) noted that premature maturation of excitatory synapses has been observed in several models of autism spectrum disorder, which was observed in these patients. By exome sequencing in 3 members of a family originally reported by Mercer et al. (2008), Pengelly et al. (2016) identified a heterozygous truncating mutation in the TRIO gene (601893.0004). One of the patients also had a pathogenic variant in the KCNJ2 gene (600681), which may have been responsible for the ectopic ventricular beats seen in this patient. Exome sequencing subsequently identified de novo heterozygous missense mutations in the TRIO gene in 3 additional unrelated patients with MRD44 (601893.0005-601893.0007). All mutations were confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the truncating mutation and 2 of the missense mutations affecting the GEFD1 domain resulted in decreased RAC1 (602048) activation. The last mutation (N1080I; 601893.0007), in a spectrin repeat domain, did not affect RAC1 activation; this patient had slightly different features with absence of microcephaly and presence of seizures. Animal Model Ba et al. (2016) found expression of the Trio gene during rat hippocampal development. It was expressed during the early postnatal period, but rapidly decreased after postnatal day 11, suggesting a role in early neuronal development. Knockdown of Trio using shRNA in dissociated rat hippocampal neurons resulted in an increase in primary dendrites and branch points during early neuronal development, suggesting that TRIO functions normally to limit dendrite formation. Knockdown of Trio in hippocampal slices resulted in increased AMPA receptor-mediated, but not NMDA receptor-mediated, transmission compared to controls, which was shown to result from a decrease in AMPA receptor endocytosis. These changes were associated with an increase in excitatory currents. These data suggested that Trio negatively regulates hippocampal synaptic strength during development. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly (in most patients, up to -5.4 SD) Face \- High forehead \- Pointed features \- Micrognathia \- Pointed jaw \- Asymmetric face Ears \- Large ears Eyes \- Upslanting palpebral fissures \- Downslanting palpebral fissures \- Synophrys \- Thick eyebrows Nose \- Straight nose \- Short nose Mouth \- High palate \- Full lips Teeth \- Dental crowding \- Hypodontia ABDOMEN Gastrointestinal \- Feeding difficulties (in some patients) SKELETAL Spine \- Kyphosis (in some patients) Hands \- Brachydactyly \- Tapering fingers \- Broad interphalangeal joints \- Clinodactyly Feet \- 2-3 toe syndactyly NEUROLOGIC Central Nervous System \- Intellectual disability, borderline to moderate \- Learning difficulties \- Delayed motor development, mild \- Delayed speech \- Poor speech \- Seizures (1 patient) Behavioral Psychiatric Manifestations \- Autistic-like features \- Attention deficit-hyperactivity disorder \- Aggressive behavior \- Obsessive-compulsive behavior IMMUNOLOGY \- Recurrent infections (in some patients) MISCELLANEOUS \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the triple functional domain gene (TRIO, 601893.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MENTAL RETARDATION, AUTOSOMAL DOMINANT 44	c4310740	3,531	omim	https://www.omim.org/entry/617061	2019-09-22T15:47:11	{"doid": ["0070074"], "omim": ["617061"], "orphanet": ["476126"], "synonyms": [], "genereviews": ["NBK447257"]}
Blepharophimosis-intellectual disability syndrome, Verloes type is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly, severe epilepsy with hypsarrhythmia, adducted thumbs, abnormal genitalia, and normal thyroid function. Hypotonia, moderate to severe psychomotor delay, and characteristic facial dysmorphism (including round face with prominent cheeks, blepharophimosis, large, bulbous nose with wide alae nasi, posteriorly rotated ears with dysplastic conchae, narrow mouth, cleft palate, and mild micrognathia) are additional characteristic features. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Blepharophimosis-intellectual disability syndrome, Verloes type	c1858538	3,532	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=293725	2021-01-23T18:46:48	{"mesh": ["C565797"], "omim": ["604314"], "umls": ["C1858538"], "icd-10": ["Q87.8"], "synonyms": ["BMRS type V", "BMRS, Verloes type", "Blepharophimosis-intellectual disability syndrome type V"]}
A rare hematologic disease characterized by increased levels of methemoglobin in the blood due to exposure to oxidizing agents like nitrates or nitrites, a variety of medications (most commonly local anesthetics), or aniline dyes, among others. Clinical manifestations include cyanosis, dizziness, headache, dyspnea, confusion, and coma. The severity of symptoms ranges from mild to life-threatening, depending on the percentage of methemoglobin. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Acquired methemoglobinemia	c0271905	3,533	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=464453	2021-01-23T18:49:32	{"icd-10": ["D74.8"], "synonyms": ["Drug-induced methemoglobinemia"]}
Uveal cancer that has material basis in uvea pigment cells Uveal melanoma Other namesOcular melanoma Iris melanoma SpecialtyOncology SymptomsA sensation of flashes or specks of dust (floaters); growing dark spot on the iris; change in the shape of the pupil; poor or blurry vision in one eye; loss of peripheral vision in one eye. ComplicationsRetinal detachment; Usual onsetVisual abnormalities Typeschoroid, iris, and ciliary body Diagnostic methodclinical examination by biomicroscopy and indirect ophthalmoscopy Differential diagnosisFor choroid: choroidal tumors, especially choroidal nevus, metastatic tumors, choroidal hemangioma, and osteoma; hemorrhagic conditions like AMD and hemorrhagic choroidal detachment; retinal tumors such as congenital retinal pigment epithelium hypertrophy and retinal pigment epithelium adenocarcinoma; and inflammatory lesions like posterior scleritis. For iris: iris nevus, iris pigment epithelial cyst, iris stromal cyst, metastatic tumor of the iris, melanocytoma, iris atrophy and Cogan-Reese syndrome. For ciliary body: staphyloma, medulloepithelioma and leiomyoma. PreventionReduce UV exposure to the eye. TreatmentBrachytherapy, enucleation, proton beam radiotherapy, transpupillary thermotherapy, photocoagulation, photodynamic therapy, and local resection. Frequency5 cases per million people per year [1] Uveal melanoma is a cancer (melanoma) of the eye involving the iris, ciliary body, or choroid (collectively referred to as the uvea). Tumors arise from the pigment cells (melanocytes) that reside within the uvea and give color to the eye. These melanocytes are distinct from the retinal pigment epithelium cells underlying the retina that do not form melanomas. When eye melanoma is spread to distant parts of the body, the five-year survival rate is about 15%.[2] ## Contents * 1 Signs and Symptoms * 2 Types * 2.1 Iris melanoma * 2.2 Posterior uveal melanoma * 3 Cause * 4 Metastasis * 5 Treatment * 6 Prognosis * 6.1 Surveillance * 7 Epidemiology * 8 History * 9 See also * 10 References * 11 External links ## Signs and Symptoms[edit] Ocular Melanoma may present without symptoms depending upon the location and size of the tumor. When symptoms do occur, they can include:[3] * blurred vision * double vision (diplopia) * irritation * pain * a perception of flashes of light in the eye (photopsia) * a reduction in the total field of vision * loss of vision * a sensation of a foreign body in the field of vision (floaters) * redness, bulging or displacement of the eye (proptosis), * a change in the shape of the pupil * pressure within the eye * metamorphopsia (a distortion of vision where, when a person looks at a grid of straight lines, the lines appear wavy and parts of the grid appears blank). ## Types[edit] Uveal melanomas, often referred to by the media and in the general population as ocular melanomas, may arise from any of the three parts of the uvea, and are sometimes referred to by their location, choroidal melanoma, ciliary body melanoma, or iris melanoma. Large tumors often encompass multiple parts of the uvea and can be named accordingly. True iris melanomas, originating from within the iris as opposed to originating elsewhere and invading the iris, are distinct in their etiology and prognosis, such that the other tumors are often referred to collectively as posterior uveal melanomas. ### Iris melanoma[edit] Uveal tumors can originate from melanocytes residing within the iris. Benign melanocytic tumors, such as iris freckles and moles (nevi), are common and pose no health risks, unless they show signs of malignancy, in which case they are classified as iris melanomas. Though derived from uveal melanocytes, iris melanomas share more in common with cutaneous (skin) melanomas in that they frequently harbor BRAF mutations associated with ultraviolet damage.[4][5] Iris melanomas are much less likely to metastasize than other uveal melanomas, and less likely to impair vision if detected and treated early. Approximately 5% of uveal melanomas involve the iris.[6] ### Posterior uveal melanoma[edit] Variably pigmented, mushroom-shaped choroidal tumor has ruptured the Bruch membrane and grown into the subretinal space. Benign melanocytic tumors of the choroid, such as choroidal freckles and nevi, are very common and pose no health risks, unless they show signs of malignancy, in which case they are considered melanomas.[7][8] Uveal melanoma is distinct from most skin melanomas associated with ultraviolet exposure; however, it shares several similarities with non-sun-exposed melanomas, such as acral melanomas and mucosal melanomas. BRAF mutations are extremely rare in posterior uveal melanomas;[9] instead, uveal melanomas frequently harbor GNAQ/GNA11 mutations, a trait shared with blue nevi, Nevus of Ota, and ocular melanosis.[10][11] As seen in BRAF, mutations in GNAQ/GNA11 are early events in tumorigenesis and are not prognostic for tumor stage or later metastatic spread.[12] In contrast, mutations in the gene BAP1 are strongly linked to metastatic spread and patient survival.[13] Incidence of posterior uveal melanoma is highest among people with light skin and blue eyes. Other risk factors, such as blue light exposure and arc welding, have been put forward, but are still debated in the field. Mobile phone use is not a risk factor for uveal melanoma.[14] Malignant melanoma of the choroid. ## Cause[edit] The cause of uveal melanoma is unclear. Uveal nevi are common (5% of Caucasians),[15] but rarely progress to melanoma. ## Metastasis[edit] Because there are no lymphatic channels to the uveal tract, metastasis occurs through local extension and/or blood-borne dissemination.[16] The most common site of metastasis for uveal melanoma is the liver;[17] the liver is the first site of metastasis for 80%-90% of ocular melanoma patients.[18] Other common sites of metastasis include the lung, bones, and just beneath the skin (subcutaneous). Approximately 50 percent of patients will develop metastases within 15 years after treatment of the primary tumor, and the liver will be involved 90% of the time.[19] Metastasis can occur more than 10 years after treatment of the primary tumor, and patients should not be considered cured even after a 10-year interval of monitoring.[20] Molecular features of the tumor, including chromosome 3 status, chromosome 6p status, and chromosome 8q status and gene expression profiling (such as the DecisionDx-UM test), can be used to adjust this likelihood of metastasis for an individual patient. The average survival time after diagnosis of liver metastases depends on the extent of systemic spread. The disease-free interval, the performance status, the liver substitution by metastases and the serum level of lactic dehydrogenase are the most important prognostic factors for metastatic uveal melanoma.[21] There is currently no cure for metastatic uveal melanoma. ## Treatment[edit] The treatment protocol for uveal melanoma has been directed by many clinical studies, the most important being The Collaborative Ocular Melanoma Study (COMS).[22] The treatment varies depending upon many factors, chief among them the size of the tumor and results from testing of biopsied material from the tumor. Primary treatment can involve removal of the affected eye (enucleation); however, this is now reserved for cases of extreme tumor burden or other secondary problems. Advances in radiation therapies have significantly decreased the number of patients treated by enucleation in developed countries. The most common radiation treatment is plaque brachytherapy, in which a small disc-shaped shield (plaque) encasing radioactive seeds (most often iodine-125, though ruthenium-106 and palladium-103 are also used) is attached to the outside surface of the eye, overlying the tumor. The plaque is left in place for a few days and then removed. The risk of metastasis after plaque radiotherapy is the same as that of enucleation, suggesting that micrometastatic spread occurs prior to treatment of the primary tumor. Other modalities of treatment include transpupillary thermotherapy, external beam proton therapy, resection of the tumor, gamma knife stereotactic radiosurgery, or a combination of different modalities. Different surgical resection techniques can include trans-scleral partial choroidectomy and transretinal endoresection. Recent analysis of genomic data led to a new analysis of clinical subtying in uveal melanoma.[23] Ocular melanoma expert Professor Sarah Coupland has recently suggested cautious optimism as new types of targeted therapeutics are tested and approved.[24] ## Prognosis[edit] When eye melanoma is spread to distant parts of the body, the five-year survival rate is about 15%.[2] Several clinical and pathological prognostic factors have been identified that are associated with higher risk of metastasis of uveal melanomas. These include large tumor size, ciliary body involvement, presence of orange pigment overlying the tumor, and older patient age.[25][26] Likewise several histological and cytological factors are associated with higher risk of metastasis, including presence and extent of cells with epithelioid morphology, presence of looping extracellular matrix patterns, increased infiltration of immune cells,[17] and staining with several immunohistochemical markers.[27] The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of BAP1, which most often occurs through mutation of one allele and subsequent loss of an entire copy of chromosome 3 (monosomy 3) to unmask the mutant copy.[13] Because of this function in inactivation of BAP1, monosomy 3 correlates strongly with metastatic spread[28] Where BAP1 mutation status is not available, gains on chromosomes 6 and 8 can be used to refine the predictive value of the monosomy 3 screen, with gain of 6p indicating a better prognosis and gain of 8q indicating a worse prognosis in disomy 3 tumors.[29] In rare instances, monosomy 3 tumors may duplicate the BAP1-mutant copy of the chromosome to return to a disomic state referred to as isodisomy.[30] Thus, isodisomy 3 is prognostically equivalent to monosomy 3, and both can be detected by tests for chromosome 3 loss of heterozygosity.[31] Monosomy 3, along with other chromosomal gains, losses, amplifications, and LOH, can be detected in fresh or paraffin-embedded samples by virtual karyotyping. The most accurate prognostic factor is molecular classification by gene expression profiling of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas: class 1 tumors that have a very low risk of metastasis, and class 2 tumors that have a very high risk of metastasis.[32][33] Gene expression profiling outperforms all of the above-mentioned factors at predicting metastatic spread of the primary tumor, including monosomy 3.[34][35][36] ### Surveillance[edit] Currently, there is no consensus regarding type or frequency of scans following diagnosis and treatment of the primary eye tumor. Of the 50% of patients who develop metastatic disease, more than 90% of patients will develop liver metastases. As such, the majority of surveillance techniques are focused on the liver. These include abdominal magnetic resonance imaging (MRI), abdominal ultrasound and liver function tests. The scientific community is currently working to develop guidelines, but until then, each patient must take into consideration their individual clinical situation and discuss appropriate surveillance with their doctors.[37] Some ophthalmologists have also found promise with the use of intravitreal avastin injections in patients suffering from radiation-induced retinopathy, a side effect of plaque brachytherapy treatment, as well as imaging surveillance with SD-OCT. ## Epidemiology[edit] Uveal melanomas are the most common primary intraocular tumor in adults.[17] Uveal melanoma is classified as a rare cancer with 5.1 cases per million people per year.[38] The incidence has remained stable for several years. In 2018, it was reported that two clusters of cases have been identified in Huntersville, NC and Auburn, AL. Cases involved alumni of Auburn University who were acquainted with each other. Health officials investigated and found that the "cluster" is an artifact of social networking.[39][40][41] There are ~2500 patients with UM diagnosed annually in the US.[42] ## History[edit] Uveal melanoma was first described in the literature in 1809-1812 by two Scottish surgeons, Allan Burns and James Wardrop.[43] ## See also[edit] * Melanoma * Eye cancer * DecisionDx-UM ## References[edit] 1. ^ Ocular Melanoma, National Organization for Rare Disorders, 2018 2. ^ a b Eye Cancer Survival Rates, American Cancer Society, Last Medical Review: December 9, 2014 Last Revised: February 5, 2016 3. ^ https://rarediseases.org/rare-diseases/ocular-melanoma/ 4. ^ Henriquez F, Janssen C, Kemp EG, Roberts F (2007). "The T1799A BRAF mutation is present in iris melanoma". Invest Ophthalmol Vis Sci. 48 (11): 4897–900. doi:10.1167/iovs.07-0440. PMID 17962436. 5. ^ Hocker T, Tsao H (2007). "Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants". Hum Mutat. 28 (6): 578–88. doi:10.1002/humu.20481. PMID 17295241. 6. ^ Damato B; Coupland S (2008). "Ocular melanoma". Melanoma Molecular Map Project. Retrieved 2013-02-02. 7. ^ Augsburger JJ (1993). "Is observation really appropriate for small choroidal melanomas". Trans Am Ophthalmol Soc. 91: 147–75. PMC 1298464. PMID 8140689. 8. ^ Shields CL, Demirci H, Materin MA, Marr BP, Mashayekhi A, Shields JA (2004). "Clinical factors in the identification of small choroidal melanoma". Can J Ophthalmol. 39 (4): 351–57. doi:10.1016/s0008-4182(04)80005-x. PMID 15327099. 9. ^ Malaponte G, Libra M, Gangemi P, Bevelacqua V, Mangano K, D'Amico F, Mazzarino MC, Stivala F, McCubrey JA, Travali S (2006). "Detection of BRAF gene mutation in primary choroidal melanoma tissue". Cancer Biol Ther. 5 (2): 225–27. doi:10.4161/cbt.5.2.2429. PMID 16410717. 10. ^ Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, Simpson EM, Barsh GS, Bastian BC (2009). "Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi". Nature. 457 (7229): 599–602. Bibcode:2009Natur.457..599V. doi:10.1038/nature07586. PMC 2696133. PMID 19078957. 11. ^ Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O'Brien J, Bastian BC (2010). "Mutations in GNA11 in uveal melanoma". N Engl J Med. 363 (23): 2191–99. doi:10.1056/NEJMoa1000584. PMC 3107972. PMID 21083380. 12. ^ Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, Harbour JW (2008). "Oncogenic mutations in GNAQ occur early in uveal melanoma". Invest Ophthalmol Vis Sci. 49 (12): 5230–34. doi:10.1167/iovs.08-2145. PMC 2634606. PMID 18719078. 13. ^ a b Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, Council ML, Matatall KA, Helms C, Bowcock AM (2010). "Frequent mutation of BAP1 in metastasizing uveal melanomas". Science. 330 (6009): 1410–13. Bibcode:2010Sci...330.1410H. doi:10.1126/science.1194472. PMC 3087380. PMID 21051595. 14. ^ Stang A, Schmidt-Pokrzywniak A, Lash TL, Lommatzsch PK, Taubert G, Bornfeld N, Jöckel KH (2009). "Mobile phone use and risk of uveal melanoma: results of the risk factors for uveal melanoma case-control study". J Natl Cancer Inst. 101 (2): 120–23. doi:10.1093/jnci/djn441. PMC 2639317. PMID 19141780. 15. ^ Chien JL, Sioufi K, Surakiatchanukul T, Shields JA, Shields CL (May 2017). "Choroidal nevus: a review of prevalence, features, genetics, risks, and outcomes". Curr Opin Ophthalmol. 28 (3): 228–37. doi:10.1097/ICU.0000000000000361. PMID 28141766. S2CID 19367181. 16. ^ "Classification and Stage Information for Intraocular (Uveal) Melanoma". National Cancer Institute. 1980-01-01. Retrieved 2013-07-04. 17. ^ a b c Kumar, Vinay (2009). "Uvea: Neoplasms". Robbins and Cotran Pathologic Basis of Disease, Professional Edition (8th ed.). Philadelphia, PA: Elsevier. ISBN 978-1-4377-0792-2. 18. ^ "Prognostic Indicators". Ocular Melanoma Foundation. 2012. Retrieved 2013-02-02. 19. ^ Spagnolo, Francesco; Graziano Caltabiano; Paola Queirolo (January 2012). "Uveal melanoma". Cancer Treatment Reviews. 38 (5): 549–53. doi:10.1016/j.ctrv.2012.01.002. PMID 22270078. Retrieved 24 November 2013. 20. ^ Kolandjian, NA; Wei C; Patel SP; Richard JL; Dett T; Papadopoulos NE; Bedikian AY (October 2013). "Delayed systemic recurrence of uveal melanoma". American Journal of Clinical Oncology. 36 (5): 443–49. doi:10.1097/COC.0b013e3182546a6b. PMC 4574291. PMID 22706174. 21. ^ Valpione Sara; et al. (Mar 2015). "Development and external validation of a prognostic nomogram for metastatic uveal melanoma". PLOS ONE. 10 (3): e0120181. Bibcode:2015PLoSO..1020181V. doi:10.1371/journal.pone.0120181. PMC 4363319. PMID 25780931. 22. ^ "The Collaborative Ocular Melanoma Study: An Overview". Medscape. Retrieved 27 December 2016. 23. ^ Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, Hess JM, Uzunangelov V, Walter V, Danilova L, Lichtenberg TM, Kucherlapati M, Kimes PK, Tang M, Penson A, Babur O, Akbani R, Bristow CA, Hoadley KA, Iype L, Chang MT, Cherniack AD, Benz C, Mills GB, Verhaak RG, Griewank KG, Felau I, Zenklusen JC, Gershenwald JE, Schoenfield L, Lazar AJ, Rahman MH, Roman S, Stern MH, Cebulla CM, Williams MD, Jager MJ, Coupland SE, Esmaeli B, Kandoth C, Woodman SE (2017). "Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma". Cancer Cell. 33 (1): 204–220. doi:10.1016/j.ccell.2017.12.013. PMID 29316429. 24. ^ Sacco JJ, Kalirai H, Kenyani J, Figueiredo CR, Coulson JM, Coupland SE (2018). "Recent breakthroughs in metastatic uveal melanoma: a cause for optimism?". Future Oncology. 14 (14): 1335–1338. doi:10.2217/fon-2018-0116. PMID 29741103. 25. ^ Augsburger JJ, Gamel JW (1990). "Clinical prognostic factors in patients with posterior uveal malignant melanoma". Cancer. 66 (7): 1596–600. doi:10.1002/1097-0142(19901001)66:7<1596::AID-CNCR2820660726>3.0.CO;2-6. PMID 2208011. 26. ^ "General Information About Intraocular (Uveal) Melanoma". National Institutes of Health. 1980-01-01. Retrieved 26 November 2013. 27. ^ Pardo M, Dwek RA, Zitzmann N (2007). "Proteomics in uveal melanoma research: opportunities and challenges in biomarker discovery". Expert Rev Proteomics. 4 (2): 273–86. doi:10.1586/14789450.4.2.273. PMID 17425462. S2CID 7269454. 28. ^ Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jöckel KH, Becher R (1996). "Prognostic implications of monosomy 3 in uveal melanoma". Lancet. 347 (9010): 1222–25. doi:10.1016/S0140-6736(96)90736-9. PMID 8622452. S2CID 44328116. 29. ^ Damato BE, Dopierala J, Klaasen A, van Dijk M, Sibbring J, Coupland S (2009). "Multiplex Ligation-Dependent Probe Amplification of Uveal Melanoma: Correlation with Metastatic Death". Invest Ophthalmol Vis Sci. 50 (7): 3048–55. doi:10.1167/iovs.08-3165. PMID 19182252. 30. ^ White VA, McNeil BK, Horsman DE (1998). "Acquired homozygosity (isodisomy) of chromosome 3 in uveal melanoma". Cancer Genet Cytogenet. 102 (1): 40–45. doi:10.1016/S0165-4608(97)00290-2. PMID 9530338. 31. ^ Onken MD, Worley LA, Person E, Char DH, Bowcock AM, Harbour JW (2007). "Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma". Clin Cancer Res. 13 (10): 2923–37. doi:10.1158/1078-0432.CCR-06-2383. PMID 17504992. 32. ^ Tschentscher F, Hüsing J, Hölter T, Kruse E, Dresen IG, Jöckel KH, Anastassiou G, Schilling H, Bornfeld N, Horsthemke B, Lohmann DR, Zeschnigk M (2003). "Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities". Cancer Res. 63 (10): 2578–84. PMID 12750282. 33. ^ Onken MD, Worley LA, Ehlers JP, Harbour JW (2004). "Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death". Cancer Res. 64 (20): 7205–09. doi:10.1158/0008-5472.CAN-04-1750. PMC 5407684. PMID 15492234. 34. ^ Petrausch U, Martus P, Tönnies H, Bechrakis NE, Lenze D, Wansel S, Hummel M, Bornfeld N, Thiel E, Foerster MH, Keilholz U (2008). "Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases". Eye. 22 (8): 997–1007. doi:10.1038/sj.eye.6702779. PMID 17384575. 35. ^ van Gils W, Lodder EM, Mensink HW, Kiliç E, Naus NC, Brüggenwirth HT, van Ijcken W, Paridaens D, Luyten GP, de Klein A (2008). "Gene expression profiling in uveal melanoma: two regions on 3p related to prognosis". Invest Ophthalmol Vis Sci. 49 (10): 4254–62. doi:10.1167/iovs.08-2033. PMID 18552379. 36. ^ Worley LA, Onken MD, Person E, Robirds D, Branson J, Char DH, Perry A, Harbour JW (2007). "Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma". Clin Cancer Res. 13 (5): 1466–71. doi:10.1158/1078-0432.CCR-06-2401. PMID 17332290. 37. ^ "MRF CURE OM". Melanoma Research Foundation. Retrieved 30 March 2012. 38. ^ Kaliki S, Shields CL (2017). "Uveal melanoma: relatively rare but deadly cancer". Eye (Lond). 31 (2): 241–57. doi:10.1038/eye.2016.275. PMC 5306463. PMID 27911450. 39. ^ https://www.alabamapublichealth.gov/news/2018/10/24.html 40. ^ "What is ocular melanoma? Medical mystery shines light on rare eye cancer". 41. ^ Rosenberg, Eli (30 April 2018). "A rare eye cancer showed up in three friends. Doctors want to know if the cases are connected". Washington Post. 42. ^ Masoomian B, Shields JA, Shields CL (2018) Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J Curr Ophthalmol 30(2):102-109 43. ^ Kivelä T (Aug 2017). "The first description of the complete natural history of uveal melanoma by two Scottish surgeons, Allan Burns and James Wardrop". Acta Ophthalmol. 95 (2): 203–214. doi:10.1111/aos.13535. PMID 28834323. ## External links[edit] Classification D * ICD-10: C69 * ICD-9-CM: 190 * ICD-O: M8720/3 * OMIM: 155720 * MeSH: D014604 * DiseasesDB: 2614 External resources * MedlinePlus: 001022 * eMedicine: oph/403 * All NCI-approved clinical trials for uveal melanoma that has spread to the liver * National Cancer Institute Clinical Trials Search Results * National Organization for Rare Diseases - Ocular Melanoma * Cancer Research UK * National Cancer Institute - Intraocular (Eye) Melanoma—Patient Version * Ocular Melanoma Foundation * A Cure In Sight * v * t * e Eye neoplasm Melanoma * Uveal melanoma * Ciliary body melanoma Other * Medulloepithelioma/Diktyoma * Intraocular lymphoma * Orbital lymphoma * Optic nerve sheath meningioma * Optic nerve tumor * Retinoblastoma * Schwannoma * Visual pathway glioma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Uveal melanoma	c0220633	3,534	wikipedia	https://en.wikipedia.org/wiki/Uveal_melanoma	2021-01-18T18:28:01	{"mesh": ["C536494"], "umls": ["C0220633"], "orphanet": ["39044"], "wikidata": ["Q356372"]}
Erythrokeratodermia variabilis et progressiva is a skin condition characterized by well-defined round or oval red scaly patches that may join together to form map-like patterns. Some patches are fixed, occurring most often on the outer surfaces of the arms and legs, while others are migratory - lasting for hours to days and then fading or moving to another location. Some skin lesions are accompanied by burning or itching sensations. Common triggers include emotional stress, temperature changes, mechanical friction and hot or cold weather. Skin lesions often occur during the fist year of life, gradually progress during childhood, and then stabilize during puberty. Treatment is aimed at alleviating symptoms and may include topical retinoids or antihistamines. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Erythrokeratodermia variabilis et progressiva	c1851479	3,535	gard	https://rarediseases.info.nih.gov/diseases/10923/erythrokeratodermia-variabilis-et-progressiva	2021-01-18T18:00:39	{"mesh": ["C536154"], "omim": ["133200"], "orphanet": ["308166"], "synonyms": ["Progressive symmetric erythrokeratodermia", "PSEK", "Erythrokeratodermia variabilis", "Darier-Gottron disease", "EKV", "Erythrokeratodermia, progressive symmetric", "Erythrokeratoderma variabilis progressiva", "EKVP", "Progressiva symmetrica erythrokeratodermia", "Erythrokeratodermia variabilis, Mendes da Costa type"]}
Insulinoma, arising from the beta cells of the pancreatic islet, is the most common pancreatic endocrine tumor, accounting for 70% of this type. Although only about 10% of insulinomas are malignant, determination of malignancy in these tumors by histopathology is occasionally very difficult, making genetic markers that could reliably indicate malignancy very valuable. Wild et al. (2001) performed a fine deletion mapping study of chromosome 22q with 8 microsatellite markers in 15 insulinomas (4 malignant and 11 benign). Fourteen of 15 (93%) insulinomas revealed loss of heterozygosity (LOH) on chromosome 22q, whereas the shortest region of overlap implicated a deletion of approximately 700 kb at 22q12.1-q12.2, with an LOH rate of up to 57% (8 of 14). Although the EST marker A006E25 that is localized in the SNF5/INI1 gene (601607) on 22q11.2 revealed LOH in 50% of informative cases (7 of 14), no alterations in this gene could be identified by SSCP analysis, direct DNA sequencing, or RNA expression analysis. Remarkably, the 4 malignant tumors showed a common deleted region between markers D22S345 and D22S1144 compared with none of the 11 benign insulinomas. The authors concluded that the observed high frequency of chromosome 22q12 deletions in insulinomas is suggestive for a region compatible with harboring a tumor suppressor gene. The SNF5/INI1 gene is most likely not the candidate gene, since no alterations were identified. The distinct pattern of allelic loss identified in this chromosomal region appears to be an attractive candidate marker for further evaluation with regard to the discrimination between benign and malignant insulinomas. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	INSULINOMA TUMOR SUPPRESSOR GENE LOCUS	c1847015	3,536	omim	https://www.omim.org/entry/606960	2019-09-22T16:09:48	{"omim": ["606960"]}
PARC syndrome is a rare genetic developmental defect during embryogenesis syndrome characterized by the association of congenital poikiloderma (P), generalized alopecia (A), retrognathism (R) and cleft palate (C). There have been no further descriptions in the literature since 1990. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PARC syndrome	c1838256	3,537	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2825	2021-01-23T17:55:03	{"gard": ["4223"], "mesh": ["C537174"], "omim": ["600331"], "umls": ["C1838256"], "icd-10": ["Q87.8"], "synonyms": ["Poikiloderma-alopecia-retrognathism-cleft palate syndrome"]}
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. (August 2018) 3-Hydroxyisobutyryl-CoA deacylase deficiency Autosomal recessive pattern is the inheritance manner of this condition SpecialtyMedical genetics 3-Hydroxyisobutyryl-CoA deacylase deficiency is a rare autosomal recessive condition that is associated with severely delayed psychomotor development, neurodegeneration, increased lactic acid and brain lesions in the basal ganglia.[1] Fewer than 10 patients have been described with this condition. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathogenesis * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 History * 7 References ## Signs and symptoms[edit] These include:[citation needed] * Delayed motor development * Hypotonia * Progressive neurodegeneration * Seizures ## Genetics[edit] This condition is caused by mutations in the HIBCH gene. This gene is located on the long arm of chromosome 2 (2q32).[citation needed] ## Pathogenesis[edit] This enzyme is involved in the metabolism of the amino acid valine. Mutations in this enzyme result in the accumulation of methacrylic acid. When this acid is acetylated, it is very reactive with free sulfhydryl groups. When the levels of this enzymes are too low valine levels increase, particularly in the mitochondria.[citation needed] How this produces the clinical picture is not yet clear. ## Diagnosis[edit] This is difficult on clinical grounds alone. It may be suspected by examination of the urine for conjugates of methacrylic acid. The diagnosis is made by sequencing the mutated gene.[citation needed] ### Differential diagnosis[edit] * Leigh syndrome ## Treatment[edit] There is currently no curative treatment for this condition.Supportive management is all that is currently available.[citation needed] ## History[edit] This condition was first described in 1982.[2] ## References[edit] 1. ^ Yamada, Kenichiro; Naiki, Misako; Hoshino, Shin; Kitaura, Yasuyuki; Kondo, Yusuke; Nomura, Noriko; Kimura, Reiko; Fukushi, Daisuke; Yamada, Yasukazu; Shimozawa, Nobuyuki; Yamaguchi, Seiji; Shimomura, Yoshiharu; Miura, Kiyokuni; Wakamatsu, Nobuaki (2014). "Clinical and biochemical characterization of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency that causes Leigh-like disease and ketoacidosis". Molecular Genetics and Metabolism Reports. 1: 455–460. doi:10.1016/j.ymgmr.2014.10.003. PMC 5121361. PMID 27896122. 2. ^ Brown, GK; Hunt, SM; Scholem, R; Fowler, K; Grimes, A; Mercer, JF; Truscott, RM; Cotton, RG; Rogers, JG; Danks, DM (October 1982). "Beta-hydroxyisobutyryl coenzyme A deacylase deficiency: a defect in valine metabolism associated with physical malformations". Pediatrics. 70 (4): 532–8. PMID 7122152. Classification D * OMIM: 250620 * MeSH: C562803 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	3-Hydroxyisobutyryl-CoA deacylase deficiency	c0342738	3,538	wikipedia	https://en.wikipedia.org/wiki/3-Hydroxyisobutyryl-CoA_deacylase_deficiency	2021-01-18T18:56:42	{"gard": ["13202"], "mesh": ["C562803"], "umls": ["C0342738"], "orphanet": ["88639"], "wikidata": ["Q2823334"]}
Dead arm of grapevine Common namesgrape canker Eutypa dieback Phomopsis leaf Cane spot Fruit rot disease Eutypiosis Causal agentsEutypa lata and Phomopsis viticola HostsVine, Prunus, apples, pears, walnuts, pistachios EPPO CodePHOPVI DistributionAustralia, North America Dead arm, sometimes grape canker, is a disease of grapes caused by a deep-seated wood rot of the arms or trunk of the grapevine. As the disease progresses over several years, one or more arms may die, hence the name "dead arm". Eventually the whole vine will die. In the 1970s, dead-arm was identified as really being two diseases, caused by two different fungi, Eutypa lata and Phomopsis viticola (syn. Cryptosporella viticola). ## Contents * 1 Hosts and symptoms * 2 Disease cycle * 3 Environment * 4 Use in wines * 5 Eutypa dieback * 6 Phomopsis leaf * 7 See also * 8 References ## Hosts and symptoms[edit] Dead arm is a disease that causes symptoms in the common grapevine species, vitis vinifera, in many regions of the world.[1] This disease is mainly caused by the fungal pathogen, Phomopsis viticola, and is known to affect many cultivars of table grapes, such as Thompson Seedless, Red Globe, and Flame Seedless.[2] Early in the growing season, the disease can delay the growth of the plant and cause leaves to turn yellow and curl. Small, brown spots on the shoots and leaf veins are very common first symptoms of this disease.[1] Soil moisture and temperature can impact the severity of symptoms, leading to a systemic infection in warm, wet conditions. As the name of this disease suggests, it also causes one or more arms of the grapevine to die, often leading to death of the entire vine.[1] ## Disease cycle[edit] Dead arm of grapevine is caused by an ascomycete fungal plant pathogen.[3] This pathogen produces sexual spores (ascospores) in the teleomorph stage and asexual spores (conidia) during the anamorph stage.[4] When the pathogen is in the teleomorph stage it is referred to as Cryptosporella viticola and during the anamorph stage is it called Phomopsis viticola.[4] The teleomorph stage of the disease cycle does not occur in nature and involves sexual combination of the antheridium with the ascogonium to produce ascospores, allowing for genetic variation.[5] The ascospores are encased in an ascus, which is further protected in a survival structure called the perithecium.[6] Ascospores can be dispersed over long distances in the wind, but can also be mechanically transmitted or disseminated in rain. The anamorph stage is known to occur in nature and produces the main inoculum associated with this plant pathogen.[5] During favorable conditions, conidia are released from infected lesions on the leaves or fruit and dispersed to other plants through rainfall or wind. Pre-existing wounds on the plant from annual pruning or insects allow the pathogen to gain entry into the next plant. However, if wounds are not present, the conidia can germinate to produce an appressorium to directly penetrate the plant.[6] Once new plants are infected, conidia are produced throughout the season as the secondary cycle of this polycyclic disease. Phomopsis viticola overwinters as pycnidia until favorable conditions arise again.[6] ## Environment[edit] The severity of dead arm in grapevine varies greatly between growing seasons. Fungal pathogens depend on moist conditions, causing the intensity of disease outbreaks to increase in wet environments. As the amount of rainfall changes between the seasons, so does the amount of pathogen present in the field. Prolonged rainfall early in the season has been correlated with greater disease outbreak.[6] Temperature has also been shown to influence the infection rate. It has been found that the pathogen experiences the fastest rate of reproduction between 23 °C and 25°.[6] Although temperature is important, the amount of rainfall has a greater impact on this pathogen because rainfall is an effective method of conidial dispersal. The conidia of Phomopsis viticola can also be dispersed through sprinkler irrigation and agricultural runoff.[7] It has not yet been determined if an insect vector for this pathogen exists.[7] ## Use in wines[edit] Although the dead-arm disease is usually looked upon as a malignant disease that often cripples one or more vines, some wine estates have discovered that the arms that are still alive when dead-arm has struck yield a very flavorful wine. One such vineyard belonging to Australian wine producer d'Arenberg have marketed this "Dead Arm" Shiraz, which has received high wine ratings among various wine critics. ## Eutypa dieback[edit] Eutypa dieback is caused by Eutypa lata (synonym: Eutypa armeniacae) which infects fresh pruning wounds when there is adequate moisture on the vine, such as just after a rain. The fungus also attacks many other hosts such as cherry trees, most other Prunus species, as well as apples, pears and walnuts. ## Phomopsis leaf[edit] Phomopsis leaf, also called cane spot or fruit rot disease, is caused by Phomopsis viticola. ## See also[edit] * List of apricot diseases * List of pistachio diseases ## References[edit] 1. ^ a b c Erincik, O.; Madden, L. V.; Ferree, D. C.; Ellis, M. A. (2001-05-01). "Effect of Growth Stage on Susceptibility of Grape Berry and Rachis Tissues to Infection by Phomopsis viticola". Plant Disease. 85 (5): 517–520. doi:10.1094/PDIS.2001.85.5.517. ISSN 0191-2917. PMID 30823128. 2. ^ Elsevier. "Postharvest Biology and Technology of Tropical and Subtropical Fruits - 1st Edition". www.elsevier.com. Retrieved 2017-12-10. 3. ^ Resources, Department of Economic Development, Jobs, Transport and. "Phomopsis Cane and Leaf Spot on Grapevines". agriculture.vic.gov.au. Retrieved 2017-12-10. 4. ^ a b Erincik, O.; Madden, L. V.; Ferree, D. C.; Ellis, M. A. (2003-07-01). "Temperature and Wetness-Duration Requirements for Grape Leaf and Cane Infection by Phomopsis viticola". Plant Disease. 87 (7): 832–840. doi:10.1094/PDIS.2003.87.7.832. ISSN 0191-2917. PMID 30812895. 5. ^ a b Merrin, S. J.; Nair, N. G.; Tarran, J. (1995-03-01). "Variation in Phomopsis recorded on grapevine in Australia and its taxonomic and biological implications". Australasian Plant Pathology. 24 (1): 44–56. doi:10.1071/APP9950044. ISSN 0156-0972. S2CID 40444413. 6. ^ a b c d e Phillips, Alan J. L. (1999). "The Relationship between Diaporthe perjuncta and Phomopsis viticola on Grapevines". Mycologia. 91 (6): 1001–1007. doi:10.1080/00275514.1999.12061110. JSTOR 3761631. 7. ^ a b Krol, Ewa (2005-01-01). "Influence of some chemicals on the viability of Phomopsis viticola Sacc. spores". Cite journal requires `\|journal=` (help) * Lecomte P, Péros JP, Blancard D, Bastien N, Délye C (October 2000). "PCR assays that identify the grapevine dieback fungus Eutypa lata". Appl. Environ. Microbiol. 66 (10): 4475–80. doi:10.1128/AEM.66.10.4475-4480.2000. PMC 92327. PMID 11010901. * "An Online Guide to Plant Disease Control: Grape: Eutypa Dieback" Oregon State University Extension; * Ramsdell DC (October 1994). "Common Diseases of the Grapevine in Michigan". MSUE Fruit IPM Extension Bulletin. E-1732. Archived from the original on 2006-12-01. * "Eutypa Dieback of Grape" Ohio State University Extension Fact Sheet HYG-3203-95; * Munkvold, G. P. (2001) "Eutypa dieback of grapevine and apricot" Plant Health Progress Online doi:10.1094/PHP-2001-0219-01-DG; * EPPO Standards: Good plant protection practice: Grapevine PP 2/23(1), 2002, Bulletin OEPP/EPPO Bulletin 32: pp. 367-392; * Winter, Mick, (July 2000). Wine Business Monthly "Eutypa Dieback: The Next Grapevine Threat is Already Here" * v * t * e Viticulture Biology and horticulture * Ampelography * Annual growth cycle of grapevines * Grape varieties * Grapes * Hybrid grape * International Grape Genome Program * Ripening (Veraison) * Rootstock * Vineyard * Vitis * Vitis vinifera Environmental variation * Climate categories * Diurnal temperature variation * Drainage * Microclimate * Regional climate levels * Soil types * Terroir * Topography * aspect * elevation * slope Vineyard planting * Grapevine planting * Propagation * Row orientation * Trellis design * Vine training * Yield Vineyard management * Canopy * Clos * Coulure * Erosion control * Fertilizer * Frost damage prevention * Green harvest (Vendange verte) * Integrated pest management * Irrigation * Klopotec * Millerandage * Pruning * Weed control Harvest * Brix * Festivals * Noble rot * Ripeness * Vintage * Weather Pests and diseases * Birds * Black rot * Botrytis bunch rot * Bot canker * Dead arm * Downy mildew * Grapevine yellows * Great French Wine Blight * Lepidoptera * Nematodes * Phylloxera * Pierce's disease * Powdery mildew * Uncinula necator * Red spider mite * Vine moth Approaches and issues * Adaptive management * Biodynamic wine * Effects of climate change on wine production * Environmental stewardship * Organic farming * Sustainable agriculture See also * Glossary of viticulture terms * Glossary of wine terms * Glossary of winemaking terms * Oenology * Outline of wine * Wine * Winemaking [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Dead arm of grapevine	None	3,539	wikipedia	https://en.wikipedia.org/wiki/Dead_arm_of_grapevine	2021-01-18T18:38:09	{"wikidata": ["Q1378999"]}
A number sign (#) is used with this entry because factor H deficiency is caused by homozygous mutation in the gene encoding complement factor H (CFH; 134370) on chromosome 1q31. Heterozygous mutation carriers may show milder manifestations. Description Complement factor H deficiency (CFHD) can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3 (120700), and a decrease in other alternative pathway components, indicating activation of the alternative complement pathway. Homozygotes and heterozygotes may show increased susceptibility to meningococcal infections. In addition, a number of renal diseases have been associated with factor H defect or deficiency, including atypical hemolytic-uremic syndrome (aHUS; 235400), membranoproliferative glomerulonephritis type II (MPGN II), and nonspecific hematuria or nephritis (Ault, 2000). See also complement factor I deficiency (610984), which shows phenotypic overlap with this disorder. Welch (2002) discussed the role of complement in renal disease. ### Membranoproliferative Glomerulonephritis type II Abrera-Abeleda et al. (2006) summarized features of MPGN relevant to the complement cascade. MPGN type II, also known as dense deposit disease, causes chronic renal dysfunction that progresses to end-stage renal disease in about half of patients within 10 years of diagnosis. MPGN types I and III are variants of immune complex-mediated disease; MPGN II, in contrast, has no known association with immune complexes (Appel et al., 2005). MPGN II accounts for less than 20% of cases of MPGN in children and only a fractional percentage of cases in adults. Both sexes are affected equally, with the diagnosis usually made in children between the ages of 5 and 15 years who present with nonspecific findings such as hematuria, proteinuria, acute nephritic syndrome, or nephrotic syndrome. More than 80% of patients with MPGN II are positive for serum C3 nephritic factor (C3NeF), an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. C3NeF prolongs the half-life of C3 convertase. Patients with MPGN type II without C3NeF often have mutations in the CFH gene, which also results in prolonged activation of C3 convertase. Clinical Features Wyatt et al. (1982) reported 2 families with partial factor H deficiency and glomerulonephritis. In 1 family, of Polish origin, a teenaged male had vasculitis, thrombocytopenia, proteinuria, and depressed levels of serum factor H and complement component C3. The mother, maternal uncle, and a cousin had depressed H levels. The second family was of English-Irish extraction living in Kentucky; 3 persons in 3 generations had H levels about half normal. The index case had depressed serum factors H and B levels and IgA nephropathy (161950) which progressed to renal failure. A sister also had IgA nephropathy and depressed serum H and C3 levels. Levy et al. (1986) reported a consanguineous Algerian family in which 2 brothers had early-onset glomerulonephritis with C3 deposits and low levels (less than 10% of normal) of complement factor H. The factor H deficiency was defined by undetectable complement hemolytic activity by the classic (CH50) and alternate (AP50) pathways, and low levels of C3 and factor B (138470). The unaffected first-cousin parents and 2 healthy sibs, presumed heterozygotes, had half-normal H values. Renal disease was discovered at 14 and 4 months of age in the elder and younger brother, respectively. The elder had recurrent episodes of macroscopic hematuria occurring during the course of infections but did not seem to have an excessive number of infections; the younger had repeated upper and lower respiratory tract infections and nearly persistent macroscopic hematuria. Electron microscopy of renal biopsies from both patients were typical for intramembranous dense deposit disease, but immunofluorescence microscopy showed an atypical pattern with abundant granular C3 deposits within the mesangium and along the capillary walls. Lopez-Larrea et al. (1987) studied a family in which 3 female sibs had undetectable levels of factor H and C3 nephritic factor, low levels of factor B, C3, and C5 (see 120500), and normal levels of C4-binding protein (120830), factor I (217030), and classic pathway factors. C4 (see 120810) levels were low in 1 patient. Two of the sibs had Neisseria meningitidis sepsis; all 3 developed membranoproliferative glomerulonephritis. Brai et al. (1988) and Misiano et al. (1993) described a consanguineous Italian family in which 3 sibs had deficiency of factor H and its spliced isoform FHL1. The proband had systemic lupus erythematosus (152700) with chronic renal failure and had highly reduced C3 serum levels and low concentrations of C5-C9. She had suffered from skin lesions (chronic discoid plaques on sun-exposed areas), with ulcerations and central nervous system involvement with psychosis. Her 2 affected brothers showed a similar serum complement profile. They had suffered from 3 and 1 episodes, respectively, of meningococcal meningitis, without autoimmune disease. Factor H was undetectable in all affected sibs, and both parents presented serum concentrations of factor H that were about 50% of normal. Western blot analysis showed the absence of both factor H and FHL1 in the affected sibs. The father and 2 of the H-deficient sibs, including the proband, also had a partial C2 deficiency (217000). Nielsen et al. (1989) described a 15-year-old girl with a complete deficiency of factor H. Both parents had half normal levels. The girl had 2 episodes of meningococcal disease. The degree of H reduction was sufficient to cause increased, spontaneous activation of the alternative complement pathway. Fijen et al. (1996) described a Dutch family in which both heterozygous and homozygous factor H deficiency was observed. The proband of the family suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis. Western blot analysis showed complete factor H deficiency. Among 21 relatives of the proband encompassing 3 generations, 10 had low factor H levels, including 2 children of the proband, indicating heterozygosity. Serum studies showed decreased levels of components of the alternative complement pathway. Vogt et al. (1995) reported a 6-year-old Native American (Sioux) boy who presented at age 13 months with hypocomplementemic hypertensive renal disease. Renal biopsy showed changes consistent with membranoproliferative glomerulonephritis, deposition of type III collagen (120180), and segmental complement C3 deposition in capillary loops. Decreased levels of serum C3 and factor B but normal levels of serum C4 and factor I were found; factor H was undetectable by radial immunodiffusion analysis. Slightly depressed levels of factor H were present in both parents; his sibs had normal levels. Ault et al. (1997) reported that the child originally described by Vogt et al. (1995) underwent renal transplantation at age 7; serum C3 concentrations remained low thereafter, as did factor H levels. Western blot analysis of the patient's plasma before and after renal transplantation showed slightly increased concentration of the 45-kD factor H and no detectable 150-kD factor H when compared with 7 normal plasma samples. Ault et al. (1997) demonstrated that the patient's fibroblasts retained 155-kD factor H protein, which was not degraded even after 12 hours, and showed that factor H was retained in the endoplasmic reticulum. Licht et al. (2006) reported 2 girls, born of consanguineous Turkish parents, with early onset of membranoproliferative glomerulonephritis type II. Renal biopsies showed thickening of the glomerular basement membrane caused by dense deposits in the lamina densa. Immunohistochemistry showed deposition of C3. Laboratory analysis showed activation of both the alternative and classical complement pathway, and both patients and their asymptomatic mother also had autoantibodies to C3 nephritic factor (C3Nef). Genetic analysis identified a homozygous mutation in the CFH gene (134370.0014) in the patients; both parents were heterozygous for the mutation. Servais et al. (2007) described a unique form of glomerulonephritis characterized by isolated mesangial C3 deposits without dense intramembranous deposits or mesangial proliferation, which the authors termed 'glomerulonephritis C3.' Heterozygous mutations in complement regulatory genes were identified in 4 of 6 unrelated patients with glomerulonephritis C3, including 2 patients each with mutations in the CFH (see, e.g., 134370.0017) and CFI genes (see, e.g., 217030.0007), respectively. In addition, 1 of 13 unrelated patients with glomerulonephritis with MPGN also had a heterozygous CFH mutation. The findings indicated that dysregulation of the complement alternative pathway is associated with a wide spectrum of diseases ranging from HUS to MPGN with C3 deposits. Pathogenesis Licht et al. (2006) noted that a defect in complement factor H results in continuous activation of the alternative complement pathway and continuous generation of the convertase C3BbB. This results in hypocomplementemia and activation of complement on tissue surfaces that lack endogenous regulators, such as the glomerular basement membrane. Continuous C3 deposition results in the formation of dense deposits, thickening of the basement membrane, impaired renal filtration, and progressive loss of renal function. Molecular Genetics In a Native American boy reported by Vogt et al. (1995) who had factor H deficiency and membranoproliferative glomerulonephritis, Ault et al. (1997) identified compound heterozygosity for 2 mutations (134370.0002 and 134370.0003) in the CFH gene. In 3 affected sibs of a consanguineous Italian family with complement factor H deficiency reported by Brai et al. (1988) and Misiano et al. (1993), Sanchez-Corral et al. (2000) identified a homozygous nonsense mutation in the CFH gene (134370.0006). In 1 of the brothers reported by Levy et al. (1986), Dragon-Durey et al. (2004) identified a homozygous mutation in the CFH gene (134370.0010). Dragon-Durey et al. (2004) identified homozygous mutations in the CFH gene in 3 additional patients with MPGN, including 2 Turkish brothers (134370.0013). Animal Model Hogasen et al. (1995) reported hereditary membranoproliferative glomerulonephritis type II caused by factor H deficiency in the Norwegian Yorkshire pig. Affected animals had excessive complement activation and massive deposits of complement in the renal glomeruli; they died of renal failure within 11 weeks of birth. Hegasy et al. (2002) identified mutations in the factor H gene as the basis for porcine factor H deficiency and membranoproliferative glomerulonephritis. Studies showed that the mutant factor H was not properly secreted from cells. Pickering et al. (2002) showed that mice deficient in factor H (Cfh -/- mice) develop membranoproliferative glomerulonephritis spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B (CFB; 138470), which prevents C3 turnover in vivo, prevented development of the phenotype of Cfh -/- mice. The authors concluded that uncontrolled C3 activation in vivo is essential for the development of membranoproliferative glomerulonephritis associated with deficiency of factor H. INHERITANCE \- Autosomal dominant \- Autosomal recessive GENITOURINARY Kidneys \- Progressive renal failure \- Membranoproliferative glomerulonephritis type II \- Thickening of the glomerular basement membrane on renal biopsy \- Deposition of complement component C3 in glomerular basement membrane \- Hematuria IMMUNOLOGY \- Continuous activation of the alternative complement pathway \- Hypocomplementemia \- Depletion of components of the alternative complement pathway \- Increased susceptibility to certain bacterial infections, especially Neisseria meningitidis LABORATORY ABNORMALITIES \- Decreased serum complement factor H \- Normal levels of complement factor H, but impaired function \- Hypocomplementemia MISCELLANEOUS \- Onset in infancy or childhood \- Variable phenotype \- Some patients may be asymptomatic MOLECULAR BASIS \- Caused by mutation in the complement factor H gene (CFH, 134370.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	COMPLEMENT FACTOR H DEFICIENCY	c0268743	3,540	omim	https://www.omim.org/entry/609814	2019-09-22T16:05:32	{"mesh": ["D015432"], "omim": ["609814"], "orphanet": ["93571", "200421", "329918", "54370", "2134", "544472"], "synonyms": ["Alternative titles", "FACTOR H DEFICIENCY", "CFH DEFICIENCY"], "genereviews": ["NBK1425"]}
Infantile-onset spinocerebellar ataxia (IOSCA) is a hereditary neurological disorder with early and severe involvement of both the peripheral and central nervous systems. It has only been described in Finnish families. ## Epidemiology So far, 24 cases have been reported. In Finland, IOSCA has a population carrier frequency of more than 1:230. ## Clinical description IOSCA is characterized by very early ataxia, athetosis and reduced tendon reflexes (between 9 and 18 months of age). Ophthalmoplegia and sensorineural hearing loss are diagnosed in childhood. Other features, such as optic atrophy and sensory neuropathy with progressive loss of myelinated fibers in the sural nerve, appear later in the disease course. Hypogonadism may occur in females. Some patients show intellectual deficit. Epilepsy is a late manifestation and seizures may be life-threatening. ## Etiology IOSCA is caused by mutations in the C10orf2 gene (10q24) encoding the mitochondrial helicase Twinkle. The c.1523A>G (p.Y508C) causative mutation has been postulated to be a founder mutation. Twenty-one of the reported patients were homozygous for this mutation, and three were compound heterozygotes: c.952G>A/c.1523A>G (two patients) and c.1523A>G/c.1287C>T (one patient). The mutations lead to mtDNA depletion in the brain and the liver, but not in the muscle. ## Diagnostic methods The diagnosis is based on clinical and pathological findings. Studies of sural nerve biopsies reveal an early and rapidly progressive axonal neuropathy. Neuroimaging studies revealing cerebellar atrophy and genetic testing for the c.1523A>G mutation may also help to confirm the diagnosis. ## Differential diagnosis Differential diagnoses include early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy, mitochondrial disorders with axonal neuropathy (such as Friedreich ataxia), progressive external ophthalmoplegia (PEO), juvenile- or adult-onset mitochondrial recessive ataxia syndrome (MIRAS), and POLG-related disorders (see theseterms). ## Antenatal diagnosis Prenatal testing may be available for families in which the disease-causing mutations have already been identified. ## Genetic counseling IOSCA is inherited in an autosomal recessive manner. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child: the risk of having an affected child in further pregnancies is 25%. ## Management and treatment IOSCA patients are often managed by a multidisciplinary team, involving a pediatrician, neurologist, psychiatrist, orthopedic surgeon, physical and occupational therapists, genetic counselor, and social worker. Treatment is symptomatic and may include: (1) hearing aids, speech therapy and sign language for deafness; (2) physical therapy, orthotic devices and orthopedic surgery for sensory axonal neuropathy; (3) walking aids, a wheelchair, physiotherapy and occupational therapy for ataxia; (4) antiepileptic drugs for seizures and (5) antipsychotics and antidepressants for psychiatric symptoms. ## Prognosis Prognosis is unfavorable. Patients are wheelchair-bound by adolescence. Early death is common due to severe seizures. The clinical course seems to be more rapid and severe (with death during infancy) in c.952G>A/ c.1523A>G compound heterozygotes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Infantile-onset spinocerebellar ataxia	c1849096	3,541	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1186	2021-01-23T18:17:25	{"gard": ["4062"], "mesh": ["C535523"], "omim": ["271245"], "umls": ["C1849096"], "icd-10": ["G11.1"], "synonyms": ["IOSCA", "Ohaha syndrome", "Ophthalmoplegia-hypotonia-ataxia-hypoacusis-athetosis syndrome"]}
Radiologically isolated syndrome (RIS) is a clinical situation in which a person has white matter lesions suggestive of multiple sclerosis (MS), as shown on an MRI scan that was done for reasons unrelated to MS symptoms. The nerve lesions in these people show dissemination in space with an otherwise normal neurological examination and without historical accounts of typical MS symptoms.[1] MRI findings that are consistent with multiple sclerosis have been observed in healthy people who underwent MRI scanning, and 50% go on to develop symptomatic MS, sometimes with a primary progressive course.[2][3] This condition was first characterized in 2009.[4] ## Contents * 1 Diagnosis * 1.1 Discovery * 2 Management * 3 Prognosis * 4 Epidemiology * 5 RIS in children * 6 Research directions * 7 Etymology * 8 References ## Diagnosis[edit] The criteria for an RIS diagnosis are as follows:[5][4][6] 1. The presence of incidental MRI findings in the CNS white matter: 1. Ovoid and well-circumscribed homogeneous foci, with or without involvement of the corpus callosum 2. T2 hyperintensities larger than 3 mm in diameter, which fulfill at least 3 of the 4 Barkhof MRI criteria[7] for DIS 3. The CNS abnormalities are not consistent with a vascular condition 2. No historical accounts of clinical symptoms consistent with neurological dysfunction. 3. MRI anomalies do not account for apparent impairment in social, occupational, or generalized areas of functioning. 4. MRI anomalies are not due to substance abuse, such as recreational drug use, toxic exposure, or a prior known medical condition. 5. Exclusion of a differential diagnosis of leukoaraiosis, or extensive white matter pathology excluding the corpus callosum. 6. MRI anomalies of the CNS are not accounted for by another disease. ### Discovery[edit] RIS is discovered when an MRI scan is performed for other reasons. The most common symptom that led to the incidental discovery of RIS is headache.[5] Other common reasons are trauma, psychiatric disorders, and endocrinological disorders.[5] ## Management[edit] Currently, routine clinical follow-up and MRI neuroimaging surveillance is the standard by which patients are observed.[4] While treatment of MS disease modifying therapies have been given to some individuals with RIS, the majority opt for active surveillance and the appearance of clinical symptoms before commencing treatment,[5] as treatment is considered controversial.[8] ## Prognosis[edit] In a 5 year study, clinical events, which refers to the first symptoms of exacerbations, clinical attacks, flare ups, or severe symptoms, indicative of MS, appeared in 34% of individuals.[9] Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive multiple sclerosis (PPMS).[9] ## Epidemiology[edit] Due to the incidental nature of RIS, exact figures on prevalence is unknown, though it has been suggested that RIS is the most common type of asymptomatic MS.[10] The prevalence may be higher in relatives of patients with MS.[11] One study, at a university hospital that is located in a high region of MS disease incidence, put the disease prevalence at approximately 1 in 2000.[12] An earlier study in 1961 of 15,644 autopsies found 12 cases (0.08%) of unexpected MS findings without a previous history of MS symptoms.[5][13] The mean age of first indication of RIS from 451 patients is 37.2 years.[9] ## RIS in children[edit] Though rare, some children that have had MRI scans for reasons unrelated to MS have shown signs of RIS. The most common reason for an initial MRI in these children was a headache. The first occurrence of a clinical event characteristic of MS in nearly half of the children examined was 2 years, though in a majority of cases, 'radiologic evolution', i.e. the increase in the number of size of lesions as detected in subsequent MRI, developed after one year. The presence of oligoclonal bands in the CSF and spinal cord lesions were associated with an increased risk of a first clinical event characteristic of MS. It was found that children with RIS had a substantial risk of subsequent clinical symptoms and/or radiologic evolution.[6] ## Research directions[edit] Current studies have been noted as being short in study duration; longer prospective studies, tracking the development of potential disease progression over a longer period of time are warranted. This will ensure the current criteria in RIS is satisfactory and whether consideration should be given to treating individuals with RIS on current MS medication.[5][7] ## Etymology[edit] The acronym RIS was coined in 2009 by Okuda and colleagues.[4] Siva and colleagues suggested an alternate name, radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD).[5][14] ## References[edit] 1. ^ Labiano-Fontcuberta, Andrés; Benito-León, Julián (October 2016). "Radiologically isolated syndrome: An update on a rare entity". Multiple Sclerosis (Houndmills, Basingstoke, England). 22 (12): 1514–1521. doi:10.1177/1352458516653666. ISSN 1477-0970. PMID 27288053. 2. ^ Reich, Daniel S; Lucchinetti, Claudia F.; Calabresi, Peter A (January 2018). "Multiple Sclerosis". The New England Journal of Medicine. 378 (2): 169–180. doi:10.1056/NEJMra1401483. PMC 6942519. PMID 29320652. 3. ^ Kantarci, Orhun H.; Lebrun, Christine; Siva, Aksel; Keegan, Mark B.; Azevedo, Christina J.; Inglese, Matilde; Tintoré, Mar; Newton, Braeden D.; Durand-Dubief, Francoise (February 2016). "Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome". Annals of Neurology. 79 (2): 288–294. doi:10.1002/ana.24564. ISSN 1531-8249. PMID 26599831. 4. ^ a b c d Okuda, D. T.; Mowry, E. M.; Beheshtian, A.; Waubant, E.; Baranzini, S. E.; Goodin, D. S.; Hauser, S. L.; Pelletier, D. (2009-03-03). "Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome". Neurology. 72 (9): 800–805. doi:10.1212/01.wnl.0000335764.14513.1a. ISSN 1526-632X. PMID 19073949. 5. ^ a b c d e f g Granberg, Tobias; Martola, Juha; Kristoffersen-Wiberg, Maria; Aspelin, Peter; Fredrikson, Sten (March 2013). "Radiologically isolated syndrome--incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review". Multiple Sclerosis. 19 (3): 271–280. doi:10.1177/1352458512451943. ISSN 1477-0970. PMID 22760099. 6. ^ a b Makhani, Naila; Lebrun, Christine; Siva, Aksel; Brassat, David; Dallière, Clarisse Carra; Seze, Jérôme de; Du, Wei; Dubief, Françoise Durand; Kantarci, Orhun (2017-11-01). "Radiologically isolated syndrome in children: Clinical and radiologic outcomes". Neurology: Neuroimmunology & Neuroinflammation. 4 (6): e395. doi:10.1212/NXI.0000000000000395. ISSN 2332-7812. PMC 5614726. 7. ^ a b Leahy, Hannah; Center, University of Massachusetts Memorial Medical; Garg, Neeta (2013). "Radiologically Isolated Syndrome: An Overview". Neurological Bulletin. 5 (1): 22–26. doi:10.7191/neurol_bull.2013.1044. 8. ^ Yamout, B.; Khawajah, M. Al (2017-10-01). "Radiologically isolated syndrome and multiple sclerosis". Multiple Sclerosis and Related Disorders. 17: 234–237. doi:10.1016/j.msard.2017.08.016. ISSN 2211-0348. PMID 29055465. 9. ^ a b c Okuda, Darin T.; Siva, Aksel; Kantarci, Orhun; Inglese, Matilde; Katz, Ilana; Tutuncu, Melih; Keegan, B. Mark; Donlon, Stacy; Hua, Le H. (2014-03-05). "Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event". PLOS ONE. 9 (3): e90509. doi:10.1371/journal.pone.0090509. ISSN 1932-6203. PMC 3943959. PMID 24598783. 10. ^ Siva, Aksel (2013-12-01). "Asymptomatic MS". Clinical Neurology and Neurosurgery. 115: S1–S5. doi:10.1016/j.clineuro.2013.09.012. ISSN 0303-8467. PMID 24321147. 11. ^ Gabelic, T.; Ramasamy, D. P.; Weinstock-Guttman, B.; Hagemeier, J.; Kennedy, C.; Melia, R.; Hojnacki, D.; Ramanathan, M.; Zivadinov, R. (2014-01-01). "Prevalence of Radiologically Isolated Syndrome and White Matter Signal Abnormalities in Healthy Relatives of Patients with Multiple Sclerosis". American Journal of Neuroradiology. 35 (1): 106–112. doi:10.3174/ajnr.A3653. ISSN 0195-6108. PMID 23886745. 12. ^ Granberg, Tobias; Martola, Juha; Aspelin, Peter; Kristoffersen-Wiberg, Maria; Fredrikson, Sten (2013-11-01). "Radiologically isolated syndrome: an uncommon finding at a university clinic in a high-prevalence region for multiple sclerosis". BMJ Open. 3 (11): e003531. doi:10.1136/bmjopen-2013-003531. ISSN 2044-6055. PMC 3822304. PMID 24189079. 13. ^ Georgi W. Multiple sclerosis. Anatomopathological findings of multiple sclerosis in diseases not clinically diagnosed. Schweiz Med Wochenschr 1961; 91: 605–607. (German) 14. ^ Siva, A.; Saip, S.; Altintas, A.; Jacob, A.; Keegan, B.M.; Kantarci, O.H. (2009). "Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease". Multiple Sclerosis Journal. 15 (8): 918–927. doi:10.1177/1352458509106214. PMID 19667020. * v * t * e Multiple sclerosis and other demyelinating diseases of the central nervous system Signs and symptoms * Ataxia * Depression * Diplopia * Dysarthria * Dysphagia * Fatigue * Incontinence * Nystagmus * Optic neuritis * Pain * Uhthoff's phenomenon Investigations and diagnosis * Multiple sclerosis diagnosis * McDonald criteria * Poser criteria * Clinical * Clinically isolated syndrome * Expanded Disability Status Scale * Serological and CSF * Oligoclonal bands * Radiological * Radiologically isolated syndrome * Lesional demyelinations of the central nervous system * Dawson's fingers Approved[by whom?] treatment * Management of multiple sclerosis * Alemtuzumab * Cladribine * Dimethyl fumarate * Fingolimod * Glatiramer acetate * Interferon beta-1a * Interferon beta-1b * Mitoxantrone * Natalizumab * Ocrelizumab * Ozanimod * Siponimod * Teriflunomide Other treatments * Former * Daclizumab * Multiple sclerosis research Demyleinating diseases Autoimmune * Multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis Inflammatory * Acute disseminated encephalomyelitis * MOG antibody disease * Balo concentric sclerosis * Marburg acute multiple sclerosis * Neuromyelitis optica * Diffuse myelinoclastic sclerosis * Tumefactive multiple sclerosis * Experimental autoimmune encephalomyelitis Hereditary * Adrenoleukodystrophy * Alexander disease * Canavan disease * Krabbe disease * Metachromatic leukodystrophy * Pelizaeus–Merzbacher disease * Leukoencephalopathy with vanishing white matter * Megalencephalic leukoencephalopathy with subcortical cysts * CAMFAK syndrome Other * Central pontine myelinolysis * Marchiafava–Bignami disease * Mitochondrial DNA depletion syndrome Other * List of multiple sclerosis organizations * List of people with multiple sclerosis * Multiple sclerosis drug pipeline * Pathophysiology [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Radiologically isolated syndrome	c4324721	3,542	wikipedia	https://en.wikipedia.org/wiki/Radiologically_isolated_syndrome	2021-01-18T18:30:50	{"umls": ["CL519501"], "wikidata": ["Q55631058"]}
Renin-angiotensin-aldosterone system (RAAS)-blocker induced angioedema (RAE) is a type of acquired angioedema (AAE, see this term) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway. ## Clinical description Like other forms of AAE it has a later onset than HAE (see this term) and occurs generally in adults. ## Etiology The main causative RAAS-blockers are the angiotensin-converting enzyme inhibitors (ACEIs) which increase levels of bradykinin leading to increased vascular permeability and vasodilation. Angioedema develops in 0.1%-0.5% of patients taking these drugs. Angioedema develops more often at an early phase of treatment, but may also occur with long-term treatment. The same side effect appears more rarely with angiotensin II receptor antagonists (ARAIIs) and direct renin inhibitors (DRIs). Co-administration of ACEI and an antidiabetic agent, dipeptidylptidase-4 (DPP-4) inhibitor, significantly increases the risk of angioedema. This reaction imposes the immediate cessation of these drugs. ## Management and treatment The orphan drug icatibant or C1-INH concentrate can be effective for acute attack treatment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Renin-angiotensin-aldosterone system-blocker-induced angioedema	c3806711	3,543	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100057	2021-01-23T18:55:57	{"omim": ["300909"], "icd-10": ["T78.3"], "synonyms": ["ACE inhibitor-related acquired angioedema", "ACEI-related acquired angioedema", "Acquired angioedema with normal C1 inhibitor", "Acquired angioedema with normal C1INH", "RAAS-blocker-induced angioedema", "RAAS-blocker-induced angioneurotic edema", "RAE", "Renin-angiotensin-aldosterone system-blocker-induced angioneurotic edema"]}
A number sign (#) is used with this entry because immunodeficiency-centromeric instability-facial anomalies syndrome-1 is caused by homozygous or compound heterozygous mutation in the gene encoding DNA methyltransferase-3B (DNMT3B; 602900) on chromosome 20q11. Description Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients that is explained by mutations in the DNMT3B gene in some, but not all, ICF patients (Hagleitner et al., 2008). ### Genetic Heterogeneity of Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome See also ICF2 (614069), caused by mutation in the ZBTB24 gene (614064) on chromosome 6q21; ICF3 (616910), caused by mutation in the CDCA7 gene (609937) on chromosome 2q31; and ICF4 (616911), caused by mutation in the HELLS gene (603946) on chromosome 10q23. Clinical Features Variable immune deficiency in association with centromeric instability of chromosomes 1, 9, 16, and, rarely, 2, with an increased frequency of somatic recombination of the arms of these chromosomes and a marked tendency to formation of multibranched configurations, has been reported by Hulten (1978), Tiepolo et al. (1979), Fryns et al. (1981), Howard et al. (1985), and Valkova et al. (1987). Three males and 2 females have been reported. The parents are clinically and cytogenetically normal. In 2 of the 5 families, those reported by Tiepolo et al. (1979) and Valkova et al. (1987), sibs were affected. The most frequent symptoms of the syndrome are facial dysmorphism, mental retardation, recurrent and prolonged respiratory infections, infections of the skin and digestive system, and variable immune deficiency with a constant decrease of IgA. Maraschio et al. (1988) described ICF syndrome in a 4-year-old girl. From the age of 2 years she had suffered from recurrent pulmonary infections and from diarrhea in the summertime. The face was described as dysmorphic with hypertelorism, flat nasal bridge, low-set ears, and protrusion of the tongue. Maraschio et al. (1989) reported further clinical data on this child, who had severe chronic bronchitis with bronchiectasis, maxillary sinusitis, and otitis media. They demonstrated that, unlike lymphocytes, fibroblasts showed no major chromosomal anomalies. Turleau et al. (1989) reported a patient with ICF syndrome. Haas (1990) pointed to 8 reports of variable immunodeficiency associated with instability of the centromeric regions of chromosomes 1, 9, and 16. The children suffered from a serious variable immunodeficiency, mild developmental delay, and facial abnormalities with hypertelorism, a flat nasal bridge, epicanthal folds, protrusion of the tongue, and mild micrognathia. The severity of the disorder was indicated by the fact that 3 children died at ages 14, 12.5, and 2.5 years. They showed absence or severe reduction of at least 2 immunoglobulin classes with or without a defective cell-mediated immunity. Although no cytogenetically documented familial cases were reported, a genetic trait was suggested by the retrospective recognition of similar symptoms in deceased sibs of 2 of the patients (Tiepolo et al., 1979; Valkova et al., 1987). Fasth et al. (1990) observed instability of the centromeric region of chromosome 1 and multibranched configurations formed by the short and long arms in a brother and sister with facial dysmorphism, mental retardation, and recurrent infections. The parents, who were first cousins, showed no chromosomal abnormalities. A combined immunodeficiency characterized by a lack of immunoglobulin production, low numbers of T cells, and lack of cells with NK (natural killer) cell markers was found. Gimelli et al. (1993) reported ICF syndrome in a 29-year-old woman and her 30-year-old brother. The proband showed mental retardation, facial anomalies, recurrent respiratory infections, combined deficit of IgM and IgE immunoglobulin classes, and paracentromeric heterochromatin instability of chromosomes 1, 9, and 16. Smeets et al. (1994) reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. Brown et al. (1995) described a 25-month-old girl with ICF syndrome. The proband's grandfathers were twin brothers and her grandmothers were sisters. Assuming that the twin grandfathers were monozygotic, the parents were related to each as half sibs, giving a coefficient of relationship of one-fourth; but they were also related to each other as first cousins, giving an additional coefficient of relatedness of one-eighth and a total coefficient of three-eighths. In other words, the parents were related as something half way between half sibs and full sibs. Brown et al. (1995) reviewed the features of the 15 published ICF cases. All but 1 had facial anomalies, most often hypertelorism, flat nasal bridge, epicanthic folds, protrusion of the tongue, and micrognathia. Mental retardation was variable, from severe neurodegeneration to special educational needs without any delay in motor function. Their patient was typical in that speech development was delayed. Follow-up information was provided on the published cases. Franceschini et al. (1995) reported 2 new patients and reviewed the literature. They commented on the marked phenotypic variability in the 15 affected individuals reported to that time. Both of their patients were boys found to have hypogammaglobulinemia. Both of them were described as having bipartite nipples. One had shawl scrotum and the other had cryptorchidism and hypospadias. The photographs showed striking similarity of facies in the 2 boys. They showed abnormal mitotic configurations, involving chromosomes 1, 16, and to a lesser extent, 9. De Ravel et al. (2001) found reports of 32 cases of this rare disorder. They reported findings in a young patient who received appropriate early therapy, with a good outcome. The published photograph showed hypertelorism, low-set ears, and high forehead as facial features. Starting at the age of 7 months, gammaglobulin was periodically administered intravenously, with no serious infections occurring. Despite nasogastric feeding, malnutrition was a problem, requiring continuous gastrostomy feeding from 19 to 28 months of age. A verbal IQ of 104 and a performance IQ of 90 was observed at 4 years of age. Hagleitner et al. (2008) reviewed the clinical features of 45 patients with ICF syndrome. Facial dysmorphism, including epicanthic folds, hypertelorism, flat nasal bridge, and low-set ears, was commonly present. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (39 of 44), and opportunistic infections were seen in several patients, indicating T-cell dysfunction. However, there was phenotypic variability in that not all patients had obvious facial dysmorphism, and 39% had normal intelligence. Life expectancy was poor: 17 (40.5%) patients died at a mean age of 8 years, predominantly due to severe respiratory tract infections, sepsis, and failure to thrive. Clinical Management Hagleitner et al. (2008) emphasized that early diagnosis of ICF syndrome is critical since early immunoglobulin supplementation can improve the course of disease. Allogeneic stem cell transplantation should also be considered as a therapeutic option in patients with severe infections or failure to thrive. Cytogenetics Haas (1990) noted that the chromosome alterations in ICF syndrome affected the heterochromatic regions of chromosomes 1, 9, and 16 and consisted of despiralization, chromatid and chromosome breaks, somatic pairing, and interchanges between homologous and nonhomologous chromosomes. In general, the abnormalities were restricted to peripheral blood lymphocytes. Haas (1990) suggested that instability of these chromosomes is a virus-induced effect appearing in genetically predisposed individuals. By nonisotopic in situ hybridization, using a satellite II-related probe, Maraschio et al. (1992) found evidence for interphase somatic pairing in ICF lymphocytes at a frequency higher than that found in normal cells. Lymphocytes of ICF patients showed nuclear protrusions and micronuclei and these nuclear abnormalities consistently involved a hybridization signal. Somatic pairing was also present in fibroblasts but with frequencies similar in normal and ICF subjects. Fibroblasts did not have the major chromosomal abnormalities found in lymphocytes. The degree of heterochromatin condensation in fibroblasts was lower than that in lymphocytes, prompting Maraschio et al. (1992) to postulate that the more decondensed state of chromocenters in the fibroblasts explains the absence of major chromosomal abnormalities. Smeets et al. (1994) reported an affected boy with ICF syndrome and reviewed the 14 previously reported cases. Their patient showed a normal male karyotype; however, half of his GTG-banded cells showed aberrations of chromosomes 1 and/or 16. These aberrations were recognized as breaks, deletions, isochromosomes, triradial figures, interchanges between pericentromeric regions of chromosomes 1 and 16, and multiradial configurations. In all aberrant cells, 2 short arms of both chromosomes 1 and chromosomes 16 were present, with a variable number of long arms of these 2 chromosomes, indicating that breaks occurred just below the centromere within the heterochromatin region on the proximal long arm. Smeets et al. (1994) could demonstrate no hypersensitivity to physical and/or chemical agents and no increased incidence of neoplasia and skin abnormalities, indicating that ICF syndrome is not a chromosome breakage syndrome. Sawyer et al. (1995) examined a patient with ICF syndrome and found through traditional cytogenetic methods that the chromosomal aberrations of ICF primarily involve the centromeric regions of chromosomes 1 and 16. Undercondensation of heterochromatic blocks of chromosomes 1, 9, and 16 are involved. The undercondensation of the heterochromatic blocks appears to be restricted to a portion of phytohemagglutinin-stimulated T cells. Patients with this syndrome also show an increase in micronucleus formation. Stacey et al. (1995) used dual-color fluorescence in situ hybridization to investigate the chromosomal content of these micronuclei in PHA-stimulated peripheral blood cultures, an EBV-transformed B-cell line, and also in micronuclei observed in vivo from peripheral blood smears. Chromosome 1 appeared to be present in a high proportion of micronuclei compared to chromosomes 9 and 16 in both a PHA-stimulated culture and an EBV-transformed cell line. An 18-centromeric probe showed no signal in any of the micronuclei observed. The implications of the findings were that the heterochromatic instability in ICF syndrome is manifested not only in T but also in B cells and that it is present in vivo. Brown et al. (1995) presented scanning electron micrographs of the heterochromatin abnormalities of an ICF patient's chromosomes 1, 9, and 16. Using fluorescence in situ hybridization analysis, Sumner et al. (1998) showed that it is always the paracentromeric heterochromatin of the relevant chromosomes that becomes decondensed and which fuses to produce multiradial configurations in ICF syndrome. The centromeric regions appear never to become decondensed and always remain outside the regions of chromosome fusion in the multiradials. Mapping Wijmenga et al. (1998) used DNA from 3 consanguineous families with a total of 4 ICF patients to localize the ICF syndrome gene by homozygosity mapping. One chromosomal region, 20q11-q13, was consistently found to be homozygous in ICF patients, whereas all healthy sibs showed heterozygosity. Comparison of the regions of homozygosity in the 4 patients localized the ICF locus to a 9-cM region between D20S477 and D20S850. Molecular Genetics Xu et al. (1999) demonstrated homozygous or compound heterozygous mutations in the DNMT3B gene (e.g., 602900.0001) in 5 unrelated ICF patients. All mutations affected residues invariant in DNMT3A (602769) and DNMT3B of mouse and human, and in an uncategorized zebrafish Dnmt3 family member. Okano et al. (1999) identified compound heterozygous mutations in the DNMT3B gene in DNA from a lymphoblastoid cell line derived from an individual with ICF syndrome and her parents. One of the 2 mutations was de novo (not present in the parents), and neither was found in 100 normal alleles. Genotype/Phenotype Correlations Among 44 patients with a clinical diagnosis of ICF, Weemaes et al. (2013) found that 23 (52%) had mutations in the DNMT3B gene and 13 (30%) had mutations in the ZBTB24 gene. A genetic defect was not identified in 8 patients. Although the phenotype was relatively homogeneous, systematic phenotypic evaluation showed that humoral immunodeficiency was generally more pronounced in ICF1 patients and that ICF2 patients had a significantly higher incidence of intellectual disability. Both T- and B-cell compartments were involved in ICF1 and ICF2. A few patients from both groups had congenital malformations including cardiac defects, cleft lip, clinodactyly, choanal stenosis, hip dislocation, and cerebral malformations. Pathogenesis Jeanpierre et al. (1993) reported undermethylation of classical satellite DNA, but not of alpha-satellite DNA, in 4 patients with ICF syndrome. Classical satellite DNA is located in the pericentromeric regions of chromosomes 1, 9, and 16, and on the distal long arm of the Y chromosome. Methylation of these sequences, normally almost complete in leukocyte DNA, is reduced or absent in ICF patients, thus mimicking the germinal and embryonic pattern of undermethylation. Why there are no abnormalities in the Y chromosome is not known. Further study of alpha-satellite DNA methylation at 10 sites in 4 ICF patients by Miniou et al. (1997) revealed undermethylation at all 10 sites in only 1 individual. In another patient, undermethylation was limited to only 2 alpha satellites, while in a third, alpha-satellite methylation was unchanged compared with controls. In the fourth patient, a 20-week fetus with ICF, alpha-satellite methylation was uninformative, as normal fetal tissue showed undermethylation of these satellites at this gestational age. Analysis of alpha-satellite methylation in normal somatic and fetal tissues revealed variable methylation, with the alpha satellites of chromosomes 13 and 21 being less methylated than those of metacentric and submetacentric chromosomes. In normal fetal tissue at 20 weeks gestation, alpha satellites were all undermethylated, while classical satellites showed the same methylation pattern as in normal somatic tissues, demonstrating asynchrony in timing of methylation during development. Kondo et al. (2000) investigated the methylation abnormalities in CpG islands of B cell lines from 4 ICF patients and their unaffected parents. Using CpG methylation-sensitive restriction digestion and 2-dimensional DNA gel electrophoresis, ICF DNA digests displayed multicopy fragments which were absent in controls. In particular, the nonsatellite repeats D4Z4 and NBL2 were strongly hypomethylated in all 4 patients, as compared with their unaffected parents. Deletion of D4Z4 has been implicated in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHMD1A; 158900), and the NBL2 locus had been previously shown to be demethylated in DNA from neuroblastoma cells (Thoraval et al., 1996). Hansen et al. (2000) reported several examples of extensive hypomethylation that were associated with advanced replication time, nuclease hypersensitivity, and a variable escape from silencing for genes on the inactive X and Y chromosomes of ICF cells. Their data suggested that all genes on the inactive X chromosome may be extremely hypomethylated at their 5-prime CpG islands. Abnormal escape from X chromosome inactivation of G6PD (305900) and SYBL1 (300053) was noted in untransformed female ICF fibroblasts. SYBL1 silencing was also disrupted on the Y chromosome in male ICF cells. Increased chromatin sensitivity to nuclease was found at all hypomethylated promoters examined, including those of silenced genes. The persistence of inactivation in these latter cases appeared to depend critically on delayed replication of DNA, since escape from silencing was only seen when replication was advanced to an active X-like pattern. Hendrich and Bickmore (2001) reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome, Rett syndrome (312750), Rubinstein-Taybi syndrome (180849), and Coffin-Lowry syndrome (303600). Ehrlich et al. (2001) performed microarray expression analysis on B-cell lymphoblastoid cell lines from 5 ICF patients with diverse DNMT3B mutations and on control lymphoblastoid cell lines. They employed oligonucleotide arrays for approximately 5,600 different genes, 510 of which showed a lymphoid lineage-restricted expression pattern among several different lineages tested. A set of 32 genes, half of which are thought to play a role in immune function, had consistent and significant ICF-specific changes in RNA levels. ICF-specific increases in immunoglobulin (Ig) heavy constant mu- and delta-RNA and cell surface IgM and IgD, decreases in Ig-gamma and Ig-alpha RNA, and surface IgG and IgA suggested inhibition of the later steps of lymphocyte maturation. ICF-specific increases were seen in RNA for RGS1 (600323), a B-cell specific inhibitor of G-protein signaling implicated in negative regulation of B-cell migration, and in RNA for the proapoptotic protein kinase C eta gene (605437). ICF-associated decreases were observed in RNAs encoding proteins involved in activation, migration, or survival of lymphoid cells, namely, transcription factor negative regulator ID3 (600277), the enhancer-binding MEF2C (600662), the iron regulatory TFRC (190010), integrin beta-7 (ITGB7; 147559), the stress protein heme oxygenase (HMOX1; 141250), and the lymphocyte-specific tumor necrosis factor receptor family members 7 and 17 (TNFRSF7, 186711; TNFRSF17, 109545). No differences in promoter methylation were seen between ICF and normal lymphoblastoid cell lines for 3 ICF upregulated genes and 1 downregulated gene by a quantitative methylation assay. The authors hypothesized that DNMT3B mutations in the ICF syndrome may cause lymphogenesis-associated gene dysregulation by indirect effects on gene expression that interfere with normal lymphocyte signaling, maturation, and migration. Using a model EBV-based system and 3 members of the unique cellular cancer-testis gene family, Tao et al. (2002) determined that de novo methylation of newly introduced viral sequences is defective in ICF cells. Limited de novo methylation capacity was retained in ICF cells, suggesting that the mutations in DNMT3B may not be complete loss-of-function mutations, or that other DNMTs may cooperate with DNMT3B. Analysis of 3 cancer-testis genes (2 on the X chromosome and 1 autosomal) revealed that loss of methylation from cellular gene sequences was heterogeneous, with both autosomal and X chromosome-based genes demonstrating sensitivity to mutations in DNMT3B. Aberrant hypomethylation at a number of loci examined correlated with altered gene expression levels. However, no consistent changes in the protein levels of the DNA methyltransferases were noted when normal and ICF cell lines were compared. In a review of genetic disorders associated with aberrant chromatin structure, Bickmore and van der Maarel (2003) discussed altered heterochromatin structure, DNA methylation, and gene expression in ICF syndrome. Jin et al. (2008) used global expression profiling to analyze and compare gene expression patterns in lymphoblastoid cell lines from 3 patients with ICF syndrome and 5 healthy controls. There were significant changes, both up- and downregulation, of genes involved in immune function, signal transduction, mRNA transcription, development, and neurogenesis between the 2 groups that were highly relevant to the ICF phenotype. Loss of DNMT3B function in ICF cells resulted in loss of methylation at promoter regions in several genes, such as LHX2 (603759), compared to normal cells. These changes were associated with histone modifications, particularly H3K27 trimethylation, and gains in transcriptionally active H3K9 acetylation and H3K4 trimethylation marks. There was a consistent loss of binding of the SUZ12 (606245) component of the PRC2 polycomb repression complex and DNMT3B to derepressed genes, including a number of homeobox genes critical for immune system, brain, and craniofacial development. The findings indicated that genes upregulated in ICF cells lose histone modifications characteristic of repressed chromatin and gain modifications characteristic of transcriptionally active chromatin. Jin et al. (2008) suggested that their results showed the interrelatedness of DNA methylation and histone modifications and the importance of DNMT3B in DNA methylation and repression of transcription. Heterogeneity Wijmenga et al. (2000) found mutations in the DNMT3B gene in only 9 of 14 ICF patients. Moreover, 2 ICF patients from consanguineous families who did not show homozygosity by descent for the DNMT3B locus did not have DNMT3B mutations, suggesting genetic heterogeneity for this disease. Kubota et al. (2004) described a 3-year-old girl with phenotypic and cytogenetic characteristics of ICF syndrome and DNA hypomethylation but without a detectable mutation in the DNMT3B gene. Indeed, from an analysis of 17 patients, Jiang et al. (2005) suggested that there are 2 types of clinically indistinguishable ICF syndrome: type 1 is characterized by DNMT3B mutations and normal methylation of alpha satellites; type 2 lacks DNMT3B mutations and shows hypomethylation of alpha satellites. Both show characteristic heterochromatin abnormalities and undermethylation of classic satellites 2 and 3. Kloeckener-Gruissem et al. (2005) reported a Turkish boy (patient 1), born of consanguineous parents, with ICF syndrome. He had hypertelorism, hypospadias, severe hypogammaglobulinemia with normal T-cell function, delayed speech development, and bilateral suspected focal cortical heterotopy. An affected brother had died at age 4.5 years. Cytogenetic and Southern blot analysis showed that the patient had hypomethylation and centromeric instability of chromosomes 1 and 16, although he did not have mutations in the DNMT3B gene or in genes encoding the DNMT3B-interacting proteins SUMO1 (601912) and UBC9 (UBE2I; 601661). Including this study, Kloeckener-Gruissem et al. (2005) estimated that approximately 40% of reported patients with ICF lack mutations in the DNMT3B coding region, suggesting genetic heterogeneity. A second patient reported by Kloeckener-Gruissem et al. (2005) (patient 2), previously reported by Braegger et al. (1991), was found by Thijssen et al. (2015) to have ICF3 (616910), caused by a homozygous mutation in the CDCA7 gene (609937.0001). Schuetz et al. (2007) described a brother and sister with ICF syndrome. The brother had a history of multiple infections, mild facial dysmorphism, delayed development, and hypogammaglobulinemia (absent IgM and low IgG). At age 7, the boy presented with hemiplegia secondary to tumorous invasion of the right brachial plexus. Immunohistochemistry confirmed the diagnosis of classic Hodgkin lymphoma of the lymphocyte depleted subtype. Following surgery, the boy had sudden cardiac arrest and died. The younger sister has similar dysmorphic features, hypogammaglobulinemia, and psychomotor retardation. No mutation was found in the DNMT3B gene. DNA of the affected sister was tested for the presence of hypomethylation of repetitive DNA by Southern blot analysis; hypomethylation of alpha-satellite DNA and classic satellite 2, characteristic of ICF type 2, was observed. Schuetz et al. (2007) suggested that clinical follow-up for children with ICF include surveillance for neoplasia. Hagleitner et al. (2008) identified DNMT3B mutations in only 20 (57%) of 34 ICF patients tested, suggesting genetic heterogeneity. No genotype/phenotype correlations were found between patients with and without DNMT3B mutations. INHERITANCE \- Autosomal recessive GROWTH Height \- Below the third percentile Weight \- Below the third percentile Other \- Head circumference below the third percentile \- Failure to thrive HEAD & NECK Head \- Sinusitis Face \- Flat face \- Epicanthal folds \- Hypertelorism Ears \- Low set ears Nose \- Flat nasal bridge \- Small upturned nose Mouth \- Micrognathia \- Tongue protrusion \- Macroglossia RESPIRATORY Airways \- Chronic bronchitis \- Bronchiectasis Lung \- Pneumonia ABDOMEN Gastrointestinal \- Diarrhea \- Malabsorption NEUROLOGIC Central Nervous System \- Variable mental retardation ranging from severe neurodegeneration to mild mental retardation IMMUNOLOGY \- Reduced number of T cells \- Reduced number of natural killer cells LABORATORY ABNORMALITIES \- Reduced IgA \- Increased IgM MISCELLANEOUS \- Centromeric instability of chromosomes 1, 9 and 16 with increased somatic recombination and formation of multibranched configurations MOLECULAR BASIS \- Caused by mutation in the DNA methyl-transferase 3B gene (DNMT3B, 602900.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1	c0398788	3,544	omim	https://www.omim.org/entry/242860	2019-09-22T16:26:22	{"doid": ["0090008"], "mesh": ["C537362"], "omim": ["242860"], "orphanet": ["2268"], "synonyms": ["IMMUNODEFICIENCY SYNDROME, VARIABLE", "IMMUNE DEFICIENCY, VARIABLE, WITH CENTROMERIC INSTABILITY OF CHROMOSOMES 1, 9, AND 16", "Alternative titles", "Immunodeficiency-centromeric instability-facial anomalies syndrome", "CENTROMERIC INSTABILITY, IMMUNODEFICIENCY SYNDROME"]}
Actinic keratosis Other namesSolar keratosis, senile keratosis (SK) Actinic keratosis seen on the back of the hands SpecialtyDermatology Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis,[1][2] is a pre-cancerous[3] area of thick, scaly, or crusty skin.[4][5] Actinic keratosis is a disorder (-osis) of epidermal keratinocytes that is induced by ultraviolet (UV) light exposure (actin-).[6] These growths are more common in fair-skinned people and those who are frequently in the sun.[7] They are believed to form when skin gets damaged by UV radiation from the sun or indoor tanning beds, usually over the course of decades. Given their pre-cancerous nature, if left untreated, they may turn into a type of skin cancer called squamous cell carcinoma.[5] Untreated lesions have up to a 20% risk of progression to squamous cell carcinoma,[8] so treatment by a dermatologist is recommended. Actinic keratoses characteristically appear as thick, scaly, or crusty areas that often feel dry or rough. Size commonly ranges between 2 and 6 millimeters, but they can grow to be several centimeters in diameter. Notably, AKs are often felt before they are seen, and the texture is sometimes compared to sandpaper.[9] They may be dark, light, tan, pink, red, a combination of all these, or have the same color as the surrounding skin. Given the causal relationship between sun exposure and AK growth, they often appear on a background of sun-damaged skin and in areas that are commonly sun-exposed, such as the face, ears, neck, scalp, chest, backs of hands, forearms, or lips. Because sun exposure is rarely limited to a small area, most people who have an AK have more than one.[10] If clinical examination findings are not typical of AK and the possibility of in situ or invasive squamous cell carcinoma (SCC) cannot be excluded based on clinical examination alone, a biopsy or excision can be considered for definitive diagnosis by histologic examination of the lesional tissue.[11] Multiple treatment options for AK are available. Photodynamic therapy (PDT) is one option the treatment of numerous AK lesions in a region of the skin, termed field cancerization.[12] It involves the application of a photosensitizer to the skin followed by illumination with a strong light source. Topical creams, such as 5-fluorouracil or imiquimod, may require daily application to affected skin areas over a typical time course of weeks.[13] Cryotherapy is frequently used for few and well-defined lesions,[14] but undesired skin lightening, or hypopigmentation, may occur at the treatment site.[15] By following up with a dermatologist, AKs can be treated before they progress to skin cancer. If cancer does develop from an AK lesion, it can be caught early with close monitoring, at a time when treatment is likely to have a high cure rate. ## Contents * 1 Signs and symptoms * 1.1 Variants * 2 Causes * 2.1 Ultraviolet radiation * 2.2 Skin pigmentation * 2.3 Other risk factors * 3 Diagnosis * 3.1 Biopsy * 3.1.1 Histopathology * 3.2 Dermoscopy * 4 Prevention * 5 Management * 5.1 Medication * 5.1.1 Fluorouracil cream * 5.1.2 Imiquimod cream * 5.1.3 Ingenol mebutate gel * 5.1.4 Diclofenac sodium gel * 5.1.5 Retinoids * 5.1.6 Tirbanibulin * 5.2 Procedures * 5.2.1 Cryotherapy * 5.2.2 Photodynamic therapy * 5.2.3 Surgical techniques * 5.2.4 Laser therapy * 5.2.5 Chemical peels * 6 Prognosis * 6.1 Clinical course * 7 Epidemiology * 8 Research * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Close-up view of an actinic keratosis lesion Multiple lesions of actinic keratosis on the scalp. Actinic keratoses (AKs) most commonly present as a white, scaly plaque of variable thickness with surrounding redness; they are most notable for having a sandpaper-like texture when felt with a gloved hand. Skin nearby the lesion often shows evidence of solar damage characterized by notable pigmentary alterations, being yellow or pale in color with areas of hyperpigmentation; deep wrinkles, coarse texture, purpura and ecchymoses, dry skin, and scattered telangiectasias are also characteristic.[16] Photoaging leads to an accumulation of oncogenic changes, resulting in a proliferation of mutated keratinocytes that can manifest as AKs or other neoplastic growths.[17] With years of sun damage, it is possible to develop multiple AKs in a single area on the skin. This condition is termed field cancerization. The lesions are usually asymptomatic, but can be tender, itch, bleed, or produce a stinging or burning sensation.[18] AKs are typically graded in accordance with their clinical presentation: Grade I (easily visible, slightly palpable), Grade II (easily visible, palpable), and Grade III (frankly visible and hyperkeratotic).[19] ### Variants[edit] Hyperkeratotic actinic keratosis on lip ("cutaneous horn") Actinic keratoses can have various clinical presentations, often characterized as follows: * Classic (or common): Classic AKs present as white, scaly macules, papules or plaques of various thickness, often with surrounding erythema. They are usually 2–6mm in diameter but can sometimes reach several centimeters in diameter.[18] * Hypertrophic (or hyperkeratotic): Hypertrophic AKs (HAKs) appear as a thicker scale or rough papule or plaque, often adherent to an erythematous base. Classic AKs can progress to become HAKs, and HAKs themselves can be difficult to distinguish from malignant lesions. * Atrophic: Atrophic AKs lack an overlying scale, and therefore appear as a nonpalpable change in color (or macule). They are often smooth and red, and are less than 10mm in diameter. * AK with cutaneous horn: A cutaneous horn is a keratinic projection with its height at least one-half of its diameter, often conical in shape. They can be seen in the setting of actinic keratosis as a progression of an HAK, but are also present in other skin conditions.[18] 38–40% of cutaneous horns represent AKs.[20] * Pigmented AK: Pigmented AKs are rare variants that often present as macules or plaques that are tan to brown in color. They can be difficult to distinguish from a solar lentigo or lentigo maligna.[21] * Actinic cheilitis: When an AK forms on the lip, it is called actinic cheilitis. This usually presents as a rough, scaly patch on the lip, often accompanied by the sensation of dry mouth and symptomatic splitting of the lips. * Bowenoid AK: Usually presents as a solitary, erythematous, scaly patch or plaque with well-defined borders. Bowenoid AKs are differentiated from Bowen's disease by degree of epithelial involvement as seen on histology.[22] The presence of ulceration, nodularity, or bleeding should raise concern for malignancy.[citation needed] Specifically, clinical findings suggesting an increased risk of progression to squamous cell carcinoma can be recognized as "IDRBEU": I (induration/inflammation), D (diameter > 1 cm), R (rapid enlargement), B (bleeding), E (erythema), and U (ulceration).[23] AKs are usually diagnosed clinically, but because they are difficult to clinically differentiate from squamous cell carcinoma, any concerning features warrant biopsy for diagnostic confirmation.[24] ## Causes[edit] The most important cause of AK formation is solar radiation, through a variety of mechanisms. Mutation of the p53 tumor suppressor gene, induced by UV radiation, has been identified as a crucial step in AK formation.[25] This tumor suppressor gene, located on chromosome 17p132, allows for cell cycle arrest when DNA or RNA is damaged. Dysregulation of the p53 pathway can thus result in unchecked replication of dysplastic keratinocytes, thereby serving as a source of neoplastic growth and the development of AK, as well as possible progression from AK to skin cancer.[26] Other molecular markers that have been associated with the development of AK include the expression of p16ink4, p14, the CD95 ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors, and loss of heterozygosity.[27][26] Evidence also suggests that the human papillomavirus (HPV) plays a role in the development of AKs. The HPV virus has been detected in AKs, with measurable HPV viral loads (one HPV-DNA copy per less than 50 cells) measured in 40% of AKs.[28] Similar to UV radiation, higher levels of HPV found in AKs reflect enhanced viral DNA replication. This is suspected to be related to the abnormal keratinocyte proliferation and differentiation in AKs, which facilitate an environment for HPV replication. This in turn may further stimulate the abnormal proliferation that contributes to the development of AKs and carcinogenesis. ### Ultraviolet radiation[edit] It is thought that ultraviolet (UV) radiation induces mutations in the keratinocytes of the epidermis, promoting the survival and proliferation of these atypical cells. Both UV-A and UV-B radiation have been implicated as causes of AKs. UV-A radiation (wavelength 320–400 nm) reaches more deeply into the skin and can lead to the generation of reactive oxygen species, which in turn can damage cell membranes, signaling proteins, and nucleic acids. UV-B radiation (wavelength 290–320 nm) causes thymidine dimer formation in DNA and RNA, leading to significant cellular mutations.[29] In particular, mutations in the p53 tumor suppressor gene have been found in 30–50% of AK lesion skin samples.[25][27] UV radiation has also been shown to cause elevated inflammatory markers such as arachidonic acid, as well as other molecules associated with inflammation.[26] Eventually, over time these changes lead to the formation of AKs. Several predictors for increased AK risk from UV radiation have been identified: * Extent of sun exposure: Cumulative sun exposure leads to an increased risk for development of AKs. In one U.S. study, AKs were found in 55% of fair-skinned men with high cumulative sun exposure, and in only 19% of fair-skinned men with low cumulative sun exposure in an age-matched cohort (the percents for women in this same study were 37% and 12% respectively).[30] Furthermore, the use of sunscreen (SPF 17 or higher) has been found to significantly reduce the development of AK lesions, and also promotes the regression of existing lesions.[31] * History of sunburn: Studies show that even a single episode of painful sunburn as a child can increase an individual's risk of developing AK as an adult.[32] Six or more painful sunburns over the course of a lifetime was found to be significantly associated with the likelihood of developing AK.[32] ### Skin pigmentation[edit] Actinic keratoses on the forehead of a male Melanin is a pigment in the epidermis that functions to protect keratinocytes from the damage caused by UV radiation; it is found in higher concentration in the epidermis of darker-skinned individuals, affording them protection against the development of AKs. Fair-skinned individuals have a significantly increased risk of developing AKs when compared to olive-skinned individuals (odds ratios of 14.1 and 6.5, respectively),[32] and AKs are uncommon in dark-skinned people of African descent.[33] Other phenotypic features seen in fair-skinned individuals that are associated with an increased propensity to develop AKs include:[33] * Freckling * Light hair and eye color * Propensity to sunburn * Inability to tan ### Other risk factors[edit] * Immunosuppression: People with a compromised immune system from medical conditions (such as AIDS) or immunosuppressive therapy (such as chronic immunosuppression after organ transplantation, or chemotherapy for cancer) are at increased risk for developing AKs.[34] They may develop AK at an earlier age or have an increased number of AK lesions compared to immunocompetent people.[citation needed] * Human papillomavirus (HPV): The role of HPV in the development of AK remains unclear, but evidence suggests that infection with the betapapillomavirus type of HPV may be associated with an increased likelihood of AK.[35] * Genodermatoses: Certain genetic disorders interfere with DNA repair after sun exposure, thereby putting these individuals at higher risk for the development of AKs. Examples of such genetic disorders include xeroderma pigmentosum and Bloom syndrome. * Balding: AKs are commonly found on the scalps of balding men. Degree of baldness seems to be a risk factor for lesion development, as men with severe baldness were found to be seven times more likely to have 10 or more AKs when compared to men with minimal or no baldness.[36] This observation can be explained by an absence of hair causing a larger proportion of scalp to be exposed to UV radiation if other sun protection measures are not taken. ## Diagnosis[edit] Physicians usually diagnose actinic keratosis by doing a thorough physical examination, through a combination of visual observation and touch. However a biopsy may be necessary when the keratosis is large in diameter, thick, or bleeding, in order to make sure that the lesion is not a skin cancer. Actinic keratosis may progress to invasive squamous cell carcinoma (SCC) but both diseases can present similarly upon physical exam and can be difficult to distinguish clinically.[6] Histological examination of the lesion from a biopsy or excision may be necessary to definitively distinguish AK from in situ or invasive SCC.[6] In addition to SCCs, AKs can be mistaken for other cutaneous lesions including seborrheic keratoses, basal cell carcinoma, lichenoid keratosis, porokeratosis, viral warts, erosive pustular dermatosis of the scalp, pemphigus foliaceus, inflammatory dermatoses like psoriasis, or melanoma.[37] ### Biopsy[edit] Actinic keratosis, atrophic form A lesion biopsy is performed if the diagnosis remains uncertain after a clinical physical exam, or if there is suspicion that the AK might have progressed to squamous cell carcinoma. The most common tissue sampling techniques include shave or punch biopsy. When only a portion of the lesion can be removed due to its size or location, the biopsy should sample tissue from the thickest area of the lesion, as SCCs are most likely to be detected in that area. If a shave biopsy is performed, it should extend through to the level of the dermis in order to provide sufficient tissue for diagnosis; ideally, it would extend to the mid-reticular dermis. Punch biopsy usually extends to the subcutaneous fat when the entire length of the punch blade is utilized. #### Histopathology[edit] On histologic examination, actinic keratoses usually show a collection of atypical keratinocytes with hyperpigmented or pleomorphic nuclei, extending to the basal layer of the epidermis. A "flag sign" is often described, referring to alternating areas of orthokeratosis and parakeratosis. Epidermal thickening and surrounding areas of sun-damaged skin are often seen.[38] The normal ordered maturation of the keratinocytes is disordered to varying degrees: there may be widening of the intracellular spaces, cytologic atypia such as abnormally large nuclei, and a mild chronic inflammatory infiltrate.[39] Specific findings depend on the clinical variant and particular lesion characteristics. The seven major histopathologic variants are all characterized by atypical keratinocytic proliferation beginning in the basal layer and confined to the epidermis; they include:[38] * Hypertrophic: Notable for marked hyperkeratosis, often with evident parakeratosis.[38] Keratinocytes in the stratum malphigii may show a loss of polarity, pleomorphism, and anaplasia.[24] Some irregular downward proliferation into the uppermost dermis may be observed, but does not represent frank invasion.[24] * Atrophic: With slight hyperkeratosis and overall atrophic changes to the epidermis; the basal layer shows cells with large, hyperchromatic nuclei in close proximity to each other. These cells have been observed to proliferate into the dermis as buds and duct-like structures.[24] * Lichenoid: Demonstrate a band-like lymphocytic infiltrate in the papillary dermis, directly beneath the dermal-epidermal junction.[38] * Achantholytic: Intercellular clefts or lacunae in the lowermost epidermal layer that result from anaplastic changes; these produce dyskeratotic cells with disrupted intercellular bridges. * Bowenoid: This term is controversial and usually refers to full-thickness atypia, microscopically indistinguishable from Bowen's Disease.[24] However most dermatologists and pathologists will use it in reference to tissue samples that are notable for small foci of atypia that involve the full thickness of the epidermis, in the background of a lesion that is otherwise consistent with an AK.[38] * Epidermolytic: With granular degeneration.[24] * Pigmented: Show pigmentation in the basal layer of the epidermis, similar to a solar lentigo.[38] ### Dermoscopy[edit] Dermoscopy is a noninvasive technique utilizing a handheld magnifying device coupled with a transilluminating lift. It is often used in the evaluation of cutaneous lesions, but lacks the definitive diagnostic ability of biopsy-based tissue diagnosis. Histopathologic exam remains the gold standard Polarized contact dermoscopy of AKs occasionally reveals a "rosette sign," described as four white points arranged in a clover pattern, often localized to within a follicular opening.[40] It is hypothesized that the "rosette sign" corresponds histologically to the changes of orthokeratosis and parakeratosis known as the "flag sign."[40] * Non-pigmented AKs: linear or wavy vascular patterning, or a "strawberry pattern," described as unfocused vessels between hair follicles, with white-haloed follicular openings.[41] * Pigmented AKs: gray to brown dots or globules surrounding follicular openings, and annular-granular rhomboidal structures; often difficult to differentiate from lentigo maligna.[42] ## Prevention[edit] Ultraviolet radiation is believed to contribute to the development of actinic keratoses by inducing mutations in epidermal keratinocytes, leading to proliferation of atypical cells.[43] Therefore, preventive measures for AKs are targeted at limiting exposure to solar radiation, including: * Limiting extent of sun exposure * Avoid sun exposure during noontime hours between 10:00 AM and 2:00 PM when UV light is most powerful * Minimize all time in the sun, since UV exposure occurs even in the winter and on cloudy days[44] * Using sun protection * Applying sunscreens with SPF ratings 30 or greater that also block both UVA and UVB light, at least every 2 hours and after swimming or sweating[44] * Applying sunscreen at least 15 minutes before going outside, as this allows time for the sunscreen to be absorbed appropriately by the skin[44] * Wearing sun protective clothing such as hats, sunglasses, long-sleeved shirts, long skirts, or trousers Recent research implicating human papillomavirus (HPV) in the development of AKs suggests that HPV prevention might in turn help prevent development of AKs, as UV-induced mutations and oncogenic transformation are likely facilitated in cases of active HPV infection.[28] A key component of HPV prevention includes vaccination, and the CDC currently recommends routine vaccination in all children at age 11 or 12.[45] There is some data that in individuals with a history of non-melanoma skin cancer, a low-fat diet can serve as a preventative measure against future actinic keratoses.[37] ## Management[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: "Actinic keratosis" – news · newspapers · books · scholar · JSTOR (November 2017) There are a variety of treatment options for AK depending on the patient and the clinical characteristics of the lesion. AKs show a wide range of features, which guide decision-making in choosing treatment. As there are multiple effective treatments, patient preference and lifestyle are also factors that physicians consider when determining the management plan for actinic keratosis. Although overall cure rates are high, experts agree that the best treatment for AK is prevention.[46] Regular follow-up is advisable after any treatment to make sure no new lesions have developed and that old ones are not progressing. Adding topical treatment after a procedure may improve outcomes.[47] ### Medication[edit] Topical medications are often recommended for areas where multiple or ill-defined AKs are present, as the medication can easily be used to treat a relatively large area.[46] #### Fluorouracil cream[edit] Topical fluorouracil (5-FU) destroys AKs by blocking methylation of thymidylate synthetase, thereby interrupting DNA and RNA synthesis.[48] This in turn prevents the proliferation of dysplastic cells in AK. Topical 5-FU is the most utilized treatment for AK, and often results in effective removal of the lesion.[49] Overall, there is a 50% efficacy rate resulting in 100% clearance of AKs treated with topical 5-FU.[50][51] 5-FU may be up to 90% effective in treating non-hyperkeratotic lesions.[52] While topical 5-FU is a widely used and cost-effective treatment for AKs and is generally well tolerated, its potential side-effects can include: pain, crusting, redness, and local swelling.[53] These adverse effects can be mitigated or minimized by reducing the frequency of application or taking breaks between uses.[53] The most commonly used application regimen consists of applying a layer of topical cream to the lesion twice a day after washing; duration of treatment is typically 2–4 weeks to thinner skin like the cheeks and up to 8 weeks for the arms; treatment of up to 8 weeks has demonstrated a higher cure rate.[54][55] #### Imiquimod cream[edit] Imiquimod is a topical immune-enhancing agent licensed for the treatment of genital warts.[24] Imiquimod stimulates the immune system through the release and up-regulation of cytokines.[54] Treatment with Imiquimod cream applied 2–3 times per week for 12 to 16 weeks was found to result in complete resolution of AKs in 50% of people, compared to 5% of controls.[56] The Imiquimod 3.75% cream has been validated in a treatment regimen consisting of daily application to entire face and scalp for two 2-week treatment cycles, with a complete clearance rate of 36%.[57] While the clearance rate observed with the Imiquimod 3.75% cream was lower than that observed with the 5% cream (36 and 50 percent, respectively), there are lower reported rates of adverse reactions with the 3.75% cream: 19% of individuals using Imiquimod 3.75% cream reported adverse reactions including local erythema, scabbing, and flaking at the application site, while nearly a third of individuals using the 5% cream reported the same types of reactions with Imiquimod treatment.[56][57] However, it is ultimately difficult to compare the efficacy of the different strength creams directly, as current study data varies in methodology (e.g. duration and frequency of treatment, and amount of skin surface area covered). #### Ingenol mebutate gel[edit] Ingenol mebutate is a newer treatment for AK used in Europe and the United States. It works in two ways, first by disrupting cell membranes and mitochondria resulting cell death, and then by inducing antibody-dependent cellular cytotoxicity to eliminate remaining tumor cells.[58] A 3-day treatment course with the 0.015% gel is recommended for the scalp and face, while a 2-day treatment course with the 0.05% gel is recommended for the trunk and extremities.[59] Treatment with the 0.015% gel was found to completely clear 57% of AK, while the 0.05% gel had a 34% clearance rate.[60] Advantages of ingenol mebutate treatment include the short duration of therapy and a low recurrence rate.[61] Local skin reactions including pain, itching and redness can be expected during treatment with ingenol mebutate. This treatment was derived from the petty spurge, Euphorbia peplus which has been used as a traditional remedy for keratosis. #### Diclofenac sodium gel[edit] Topical diclofenac sodium gel is a nonsteroidal anti-inflammatory drug that is thought to work in the treatment of AK through its inhibition of the arachidonic acid pathway, thereby limiting the production of prostaglandins which are thought to be involved in the development of UVB-induced skin cancers.[39] Recommended duration of therapy is 60 to 90 days with twice daily application. Treatment of facial AK with diclofenac gel led to complete lesion resolution in 40% of cases.[62] Common side effects include dryness, itching, redness, and rash at the site of application.[62] #### Retinoids[edit] Topical retinoids have been studied in the treatment of AK with modest results, and the American Academy of Dermatology does not currently recommend this as a first-line therapy.[63] Treatment with adapalene gel daily for 4 weeks, and then twice daily thereafter for a total of nine months led to a significant but modest reduction in the number AKs compared to placebo; it demonstrated the additional advantage of improving the appearance of photodamaged skin.[64] Topical tretinoin is ineffective as treatment for reducing the number of AKs.[24] For secondary prevention of AK, systemic, low-dose acitretin was found to be safe, well tolerated and moderately effective in chemoprophylaxis for skin cancers in kidney transplant patients.[65] Acitretin is a viable treatment option for organ transplant patients according to expert opinion.[46] #### Tirbanibulin[edit] Tirbanibulin (Klisyri) was approved for medical use in the United States in December 2020, for the treatment of actinic keratosis on the face or scalp.[66][67][68][69] ### Procedures[edit] #### Cryotherapy[edit] Cryosurgery instrument used to treat actinic keratoses Liquid nitrogen (−195.8 °C) is the most commonly used destructive therapy for the treatment of AK in the United States.[70] It is a well-tolerated office procedure that does not require anesthesia.[71] Cryotherapy is particularly indicated for cases where there are fewer than 15 thin, well-demarcated lesions.[70] Caution is encouraged for thicker, more hyperkeratotic lesions, as dysplastic cells may evade treatment.[55] Treatment with both cryotherapy and field treatment can be considered for these more advanced lesions.[55] Cryotherapy is generally performed using an open-spray technique, wherein the AK is sprayed for several seconds.[24] The process can be repeated multiple times in one office visit, as tolerated. Cure rates from 67 to 99 percent have been reported,[72][15] depending on freeze time and lesion characteristics. Disadvantages include discomfort during and after the procedure; blistering, scarring and redness; hypo- or hyperpigmentation; and destruction of healthy tissue.[73] #### Photodynamic therapy[edit] Interim result of phototherapy for actinic keratosis with methyl aminolevulinate one week after exposure. Patient has light skin, blue eyes. AKs are one of the most common dermatologic lesions for which photodynamic therapy, including topical methyl aminolevulinate (MAL) or 5-aminolevulinic acid (5-ALA), is indicated.[74] Treatment begins with preparation of the lesion, which includes scraping away scales and crusts using a dermal curette. A thick layer of topical MAL or 5-ALA cream is applied to the lesion and a small area surrounding the lesion, which is then covered with an occlusive dressing and left for a period of time. During this time the photosensitizer accumulates in the target cells within the AK lesion. The dressings are then removed and the lesion is treated with light at a specified wavelength. Multiple treatment regimens using different photosensitizers, incubation times, light sources, and pretreatment regimens have been studied and suggest that longer incubation times lead to higher rates of lesion clearance.[75] Photodynamic therapy is gaining in popularity. It has been found to have a 14% higher likelihood of achieving complete lesion clearance at 3 months compared to cryotherapy,[76] and seems to result in superior cosmetic outcomes when compared to cryotherapy or 5-FU treatment.[77] Photodynamic therapy can be particularly effective in treating areas with multiple AK lesions.[78] #### Surgical techniques[edit] * Surgical excision: Excision should be reserved for cases when the AK is a thick, horny papule, or when deeper invasion is suspected and histopathologic diagnosis is necessary.[24] It is a rarely utilized technique for AK treatment. * Shave excision and curettage (sometimes followed by electrodesiccation when deemed appropriate by the physician[79][70]): This technique is often used for treatment of AKs, and particularly for lesions appearing more similar to squamous cell carcinoma, or those that are unresponsive to other treatments.[70] The surface of the lesion can be scraped away using a scalpel, or the base can be removed with a curette. Tissue can be evaluated histopathologically under the microscope, but specimens acquired using this technique are not often adequate to determine whether a lesion is invasive or intraepidermal. * Dermabrasion: Dermabrasion is useful in the treatment of large areas with multiple AK lesions. The process involves using a hand-held instrument to "sand" the skin, removing the stratum corneum layer of the epidermis. Diamond fraises or wire brushes revolving at high speeds are used.[24] The procedure can be quite painful and requires procedural sedation and anesthetic, necessitating a hospital stay. One-year clearance rates with dermabrasion treatment are as high as 96%, but diminish drastically to 54% at five years.[80] #### Laser therapy[edit] Laser therapy using carbon dioxide (CO 2) or erbium:yttrium aluminum garnet (Er:YAG) lasers is a treatment approach being utilized with increased frequency, and sometimes in conjunction with computer scanning technology.[81] Laser therapy has not been extensively studied, but current evidence suggests it may be effective in cases involving multiple AKs refractive to medical therapy, or AKs located in cosmetically sensitive locations such as the face.[82] The CO 2 laser has been recommended for extensive actinic cheilitis that has not responded to 5-FU.[55] #### Chemical peels[edit] A chemical peel is a topically applied agent that wounds the outermost layer of the skin, promoting organized repair, exfoliation, and eventually the development of smooth and rejuvenated skin. Multiple therapies have been studied. A medium-depth peel may effectively treat multiple non-hyperkeratotic AKs.[83] It can be achieved with 35% to 50% trichloroacetic acid (TCA) alone or at 35% in combination with Jessner's solution in a once-daily application for a minimum of 3 weeks; 70% glycolic acid (α-hydroxy acid); or solid CO 2.[84] When compared to treatment with 5-FU, chemical peels have demonstrated similar efficacy and increased ease of use with similar morbidity.[85] Chemical peels must be performed in a controlled clinic environment and are recommended only for individuals who are able to comply with follow-up precautions, including avoidance of sun exposure. Furthermore, they should be avoided in individuals with a history of HSV infection or keloids, and in those who are immunosuppressed or who are taking photosensitizing medications. ## Prognosis[edit] Squamous cell carcinoma of the nose. This skin cancer can develop from actinic keratoses if they are not treated. Untreated AKs follow one of three paths: they can either persist as AKs, regress, or progress to invasive skin cancer, as AK lesions are considered to be on the same continuum with squamous cell carcinoma (SCC).[17] AK lesions that regress also have the potential to recur. * Progression: The overall risk of an AK turning into invasive cancer is low. In average-risk individuals, likelihood of an AK lesion progressing to SCC is less than 1% per year.[86][87] Despite this low rate of progression, studies suggest that a full 60% of SCCs arise from pre-existing AKs, reinforcing the idea that these lesions are closely related.[86][87] * Regression: Reported regression rates for single AK lesions have ranged between 15–63% after one year.[88] * Recurrence: Recurrence rates after 1 year for single AK lesions that have regressed range between 15–53%.[88] ### Clinical course[edit] Given the aforementioned differering clinical outcomes, it is difficult to predict the clinical course of any given actinic keratosis. AK lesions may also come and go—in a cycle of appearing on the skin, remaining for months, and then disappearing. Often they will reappear in a few weeks or months, particularly after unprotected sun exposure. Left untreated, there is a chance that the lesion will advance to become invasive. Although it is difficult to predict whether an AK will advance to become squamous cell carcinoma, it has been noted that squamous cell carcinomas originate in lesions formerly diagnosed as AKs with frequencies reported between 65 and 97%.[17] ## Epidemiology[edit] Actinic keratosis is very common, with an estimated 14% of dermatology visits related to AKs.[89] It is seen more often in fair-skinned individuals,[32] and rates vary with geographical location and age.[90] Other factors such as exposure to ultraviolet (UV) radiation,[91] certain phenotypic features, and immunosuppression can also contribute to the development of AKs. Men are more likely to develop AK than women, and the risk of developing AK lesions increases with age. These findings have been observed in multiple studies, with numbers from one study suggesting that approximately 5% of women ages 20–29 develop AK compared to 68% of women ages 60–69, and 10% of men ages 20–29 develop AK compared to 79% of men ages 60–69.[92] Geography seems to play a role in the sense that individuals living in locations where they are exposed to more UV radiation throughout their lifetime have a significantly higher risk of developing AK. Much of the literature on AK comes from Australia, where prevalence of AK is estimated at 40–50% in adults over 40,[92] as compared to the United States and Europe, where prevalence is estimated at under 11–38% in adults.[36][91] One study found that those who immigrated to Australia after age 20 had fewer AKs than native Australians in all age groups.[93] ## Research[edit] Diagnostically, researchers are investigating the role of novel biomarkers to assist in determining which AKs are more likely to develop into cutaneous or metastatic SCC. Upregulation of matrix metalloproteinases (MMP) is seen in many different types of cancers, and the expression and production of MMP-7 in particular has been found to be elevated in SCC specifically.[94] The role of serin peptidase inhibitors (Serpins) is also being investigated. SerpinA1 was found to be elevated in the keratinocytes of SCC cell lines, and SerpinA1 upregulation was correlated with SCC tumor progression in vivo.[94] Further investigation into specific biomarkers could help providers better assess prognosis and determine best treatment approaches for particular lesions. In terms of treatment, a number of medications are being studied. Resiquimod is a TLR 7/8 agonist that works similarly to imiquimod, but is 10 to 100 times more potent; when used to treat AK lesions, complete response rates have range from 40 to 74%.[95] Afamelanotide is a drug that induces the production of melanin by melanocytes to act as a protective factor against UVB radiation.[96] It is being studied to determine its efficacy in preventing AKs in organ transplant patients who are on immunosuppressive therapy. Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib, and anti-EGFR antibodies such as cetuximab are used in the treatment of various types of cancers, and are currently being investigated for potential use in the treatment and prevention of AKs.[97] ## See also[edit] * Age spot * Freckle * Lentigo * Squamous cell carcinoma * List of cutaneous conditions ## References[edit] 1. ^ Rapini RP, Bolognia J, Jorizzo JL (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. Chapter 108. ISBN 978-1-4160-2999-1. 2. ^ Logan CM, Rice MK (1987). Logan's Medical and Scientific Abbreviations. J. B. Lippincott and Company. p. 512. ISBN 0-397-54589-4. 3. ^ Prajapati V, Barankin B (May 2008). "Dermacase. Actinic keratosis". Canadian Family Physician. 54 (5): 691, 699. PMC 2377206. PMID 18474700. 4. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 5. ^ a b Quaedvlieg PJ, Tirsi E, Thissen MR, Krekels GA (2006). 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"Effective photodynamic therapy of actinic keratoses on the head and face with a novel, self-adhesive 5-aminolaevulinic acid patch". Experimental Dermatology. 18 (2): 116–21. doi:10.1111/j.1600-0625.2008.00770.x. PMID 18643849. 76. ^ Patel G, Armstrong AW, Eisen DB (December 2014). "Efficacy of photodynamic therapy vs other interventions in randomized clinical trials for the treatment of actinic keratoses: a systematic review and meta-analysis". JAMA Dermatology. 150 (12): 1281–8. doi:10.1001/jamadermatol.2014.1253. PMID 25162181. 77. ^ Gupta AK, Paquet M, Villanueva E, Brintnell W (December 2012). "Interventions for actinic keratoses". The Cochrane Database of Systematic Reviews. 12: CD004415. doi:10.1002/14651858.CD004415.pub2. PMC 6599879. PMID 23235610. 78. ^ Kaufmann R, Spelman L, Weightman W, Reifenberger J, Szeimies RM, Verhaeghe E, Kerrouche N, Sorba V, Villemagne H, Rhodes LE (May 2008). 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PMID 20725548. ## External links[edit] Classification D * ICD-10: L57.0 * ICD-9-CM: 702.0 * MeSH: D055623 * DiseasesDB: 29438 External resources * MedlinePlus: 000827 * Patient UK: Actinic keratosis * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e 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 * t * e Skin cancer of the epidermis Tumor Carcinoma BCC * Forms * Aberrant * Cicatricial * Cystic * Fibroepithelioma of Pinkus * Infltrative * Micronodular * Nodular * Pigmented * Polypoid * Pore-like * Rodent ulcer * Superficial * Nevoid basal cell carcinoma syndrome SCC * Forms * Adenoid * Basaloid * Clear cell * Signet-ring-cell * Spindle-cell * Marjolin's ulcer * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Actinic keratosis Adenocarcinoma * Aggressive digital papillary adenocarcinoma * Extramammary Paget's disease Ungrouped * Merkel cell carcinoma * Microcystic adnexal carcinoma * Mucinous carcinoma * Primary cutaneous adenoid cystic carcinoma * Verrucous carcinoma * Malignant mixed tumor Benign tumors Acanthoma * Forms * Large cell * Fissuring * Clear cell * Epidermolytic * Melanoacanthoma * Pilar sheath acanthoma * Seboacanthoma * Seborrheic keratosis * Warty dyskeratoma Keratoacanthoma * Generalized eruptive * Keratoacanthoma centrifugum marginatum * Multiple * Solitary Wart * Verruca vulgaris * Verruca plana * Plantar wart * Periungual wart Other Epidermal nevus * Syndromes * Epidermal nevus syndrome * Schimmelpenning syndrome * Nevus comedonicus syndrome * Nevus comedonicus * Inflammatory linear verrucous epidermal nevus * Linear verrucous epidermal nevus * Pigmented hairy epidermal nevus syndrome * Systematized epidermal nevus * Phakomatosis pigmentokeratotica Other nevus * Nevus unius lateris * Patch blue nevus * Unilateral palmoplantar verrucous nevus * Zosteriform speckled lentiginous nevus Ungrouped * Cutaneous horn * Medicine portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Actinic keratosis	c0022602	3,545	wikipedia	https://en.wikipedia.org/wiki/Actinic_keratosis	2021-01-18T18:39:33	{"mesh": ["D055623"], "umls": ["C0022602"], "wikidata": ["Q422225"]}
Morvan's syndrome SpecialtyNeurology SymptomsMorvan's fibrillary chorea Morvan's syndrome is a rare, life-threatening autoimmune disease named after the nineteenth century French physician Augustin Marie Morvan. "La chorée fibrillaire" was first coined by Morvan in 1890 when describing patients with multiple, irregular contractions of the long muscles, cramping, weakness, pruritus, hyperhidrosis, insomnia, and delirium.[1] It normally presents with a slow insidious onset over months to years.[2] Approximately 90% of cases spontaneously go into remission, while the other 10% of cases lead to death.[3] In 1890, Morvan described a patient with myokymia (muscle twitching) associated with muscle pain, excessive sweating, and disordered sleep.[4] This rare disorder is characterized by severe insomnia, amounting to no less than complete lack of sleep (agrypnia) for weeks or months in a row, and associated with autonomic alterations consisting of profuse perspiration with characteristic skin miliaria (also known as sweat rash), tachycardia, increased body temperature, and hypertension. Patients display a remarkable hallucinatory behavior, and peculiar motor disturbances, which Morvan reported under the term “fibrillary chorea” but which are best described in modern terms as neuromyotonic discharges.[5] The association of the disease with thymoma, tumour, autoimmune diseases, and autoantibodies suggests an autoimmune or paraneoplastic aetiology.[1] Besides an immune-mediated etiology, it is also believed to occur in gold, mercury, or manganese poisoning.[6] ## Contents * 1 Signs and symptoms * 1.1 Insomnia * 1.2 Neuromyotonia * 1.3 Other symptoms * 1.4 Comorbid conditions * 2 Mechanism * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 Epidemiology * 6 References * 7 External links ## Signs and symptoms[edit] In one of the few reported cases, the subject presented with muscle weakness and fatigue, muscle twitching, excessive sweating and salivation, small joint pain, itching and weight loss. The subject also developed confusional episodes with spatial and temporal disorientation, visual and auditory hallucinations, complex behavior during sleep and progressive nocturnal insomnia associated with diurnal drowsiness. There was also severe constipation, urinary incontinence, and excessive lacrimation. When left alone, the subject would slowly lapse into a stuporous state with dreamlike episodes characterized by complex and quasi-purposeful gestures and movements (enacted dreams). Marked hyperhidrosis and excessive salivation were evident. Neurological examination disclosed diffuse muscle twitching and spontaneous and reflex myoclonus, slight muscle atrophy in the limbs, absence of tendon reflexes in the lower limbs and diffuse erythema especially on the trunk with scratching lesions of the skin.[4] Compulsive behaviours, stereotypies and reduplicative paramnesias can be part of the CNS spectrum.[7] ### Insomnia[edit] In all of the reported cases, the need for sleep was severely reduced and in some cases not necessary. The duration of sleep in one case decreased to about 2–4 hours per 24-hour period.[8] Clinical features pertaining to insomnia include daytime drowsiness associated with a loss of ability to sleep, intermingled with confusional oneiric status, and the emergence of atypical REM sleep from wakefulness. The polysomnogram (PSG) picture of this disease is characterized by an inability to generate physiological sleep (key features are the suppression of the hallmarks of stage 2 non-REM sleep: spindles and K complexes) and by the emergence of REM sleep without atonia. The involvement of the thalamus and connected limbic structures in the pathology indicate the prominent role that the limbic thalamus plays in the pathophysiology of sleep.[3] In a case documented in 1974, PSG findings documented the sustained absence of all sleep rhythms for up to a period of 4 months.[5] Electroencephalography (EEG) in one case was dominated by "wakefulness" and “subwakefulness” states alternating or intermingled with short (< 1 min) atypical REM sleep phases, characterized by a loss of muscle atonia. The “subwakefulness” state was characterized by 4–6 Hz theta activity intermingled with fast activity and desynchronized lower voltage theta activity, behaviourally associated with sleep-like somatic and autonomic behavior. The subject was said to suffer from “agrypnia excitata”, which consists of severe total insomnia of long duration associated with decreased vigilance, mental confusion, hallucinations, motor agitation, and complex motor behavior mimicking dreams, and autonomic activation. CNS and autonomic symptoms were caused by impaired corticolimbic control of the subcortical structures regulating the sleep-wake and autonomic functions.[4] ### Neuromyotonia[edit] Neuromyotonia refers to muscle twitching and cramping at rest that is exacerbated with exercise. It is caused by sustained or repetitive spontaneous muscle activity of peripheral nerve origin. Myokymia, or spontaneous rippling and twitching movements of muscles, is a visible component of neuromyotonia. Electromyography (EMG) discloses spontaneous, repetitive motor unit or single fiber discharges firing in irregular rhythmic bursts at high intraburst frequencies.[1] Some of the muscles exhibiting twitching include the bilateral gastrocnemii, quadriceps femoris, biceps brachii, and right masseter.[8] In vivo electrophysiological studies suggest at least some dysfunction of the muscle cell membrane.[6] In the examined muscles, no abnormal insertional activity or fibrillation potentials were noted. Nerve conduction studies were normal.[4] ### Other symptoms[edit] Breathing difficulties can occur, resulting from neuromyotonic activity of the laryngeal muscles. Laryngeal spasm possibly resulting from neuromyotonia has been described previously, and this highlights that, in patients with unexplained laryngospasm, neuromytonia should be added to the list of differential diagnoses.[6] Studies have shown subtly decreased metabolism on positron emission tomography (PET) and single photon emission computed tomography (SPECT) in the left inferior frontal and left temporal lobes.[8] and or basal ganglia hypermetabolism.[7] Ancillary laboratory tests including MRI and brain biopsy have confirmed temporal lobe involvement. Cranial MRI shows increased signal in the hippocampus.[9] Cerebral spinal fluid (CSF) shows normal protein, glucose, white blood cell, and immunoglobulin G (IgG) levels, but there are weak oligoclonal bands, which are absent in the blood serum. Marked changes in circadian serum levels of neurohormones and increased levels of peripheral neurotransmitters were also observed. The absence of morphological alterations of the brain pathology, the suggestion of diffusion of IgG into the thalamus and striatum, more marked than in the cortex (consistent with effects on the thalamolimbic system) the oligoclonal bands in the CSF and the amelioration after PE all strongly support an antibody-mediated basis for the condition.[4] Raised CSF IgG concentrations and oligoclonal bands have been reported in patients with psychosis. Anti-acetylcholine receptors (anti-AChR) antibodies have also been detected in patients with thymoma, but without clinical manifestations of myasthenia gravis.[1] There have also been reports of non-paraneoplastic limbic encephalitis associated with raised serum VGKC suggesting that these antibodies may give rise to a spectrum of neurological disease presenting with symptoms arising peripherally, centrally, or both. Yet, in two cases, oligoclonal bands were absent in the CSF and serum, and CSF immunoglobulin profiles were unremarkable.[2] ### Comorbid conditions[edit] In one case, a patient was diagnosed with both Morvan's syndrome and pulmonary hyalinizing granulomas (PHG). PHG are rare fibrosing lesions of the lung, which have central whorled deposits of lamellar collagen. How these two diseases relate to one another is still unclear.[10] Thymoma, prostate adenoma, and in situ carcinoma of the sigmoid colon have also been found in patients with Morvan's Syndrome.[1] ## Mechanism[edit] Antibodies against voltage-gated potassium channels (VGKC), which are detectable in about 40% of patients with acquired neuromytonia, have been implicated in Morvan's pathophysiology. Raised serum levels of antibodies to VGKCs have been reported in three patients with Morvan's Syndrome. Binding of serum from a patient with Morvan's Syndrome to the hippocampus in a similar pattern of antibodies to known VGKC suggest that these antibodies can also cause CNS dysfunction. Additional antibodies against neuromuscular junction channels and receptors have also been described. Experimental evidence exists that these anti-VGKC antibodies cause nerve hyperexcitability by suppression of voltage gated K+ outward currents, whereas other, yet undefined humoral factors have been implicated in anti-VGKC antibody negative neuromyotonia.[6] It is believed that antibodies to the Shaker-type K+ channels (the Kv1 family) are the type of potassium channel most strongly associated with acquired neuromyotonia and Morvan's Syndrome.[11] Whether VGKC antibodies play a pathogenic role in the encephalopathy as they do in the peripheral nervous system is as yet unclear. It has been suggested that the VGKC antibodies may cross the blood–brain barrier and act centrally, binding predominantly to thalamic and striatal neurons causing encephalopathic and autonomic features.[2] ## Diagnosis[edit] ### Differential diagnosis[edit] The symptoms of Morvan's Syndrome have been noted to bear a striking similarity to limbic encephalitis (LE). These include the CNS symptoms consisting of insomnia, hallucinations, and disorientation, as well as dementia and psychosis. Both entities can be paraneoplastic and associated with thymoma. Recently, VGKC antibodies were found in patients with LE, strengthening the hypothesis that LE and Morvan's Syndrome may be closely connected.[9] Varying symptoms may be used to determine which of the two diseases the subject has. Amnesia, seizures, and mesial temporal lobe structural abnormalities are features of LE, whereas myokymia, hyperhydrosis, and insomnia favor Morvan's Syndrome.[8] ## Treatment[edit] In most of the reported cases, the treatment options were very similar. Plasmapheresis alone or in combination with steroids, sometimes also with thymectomy and azathioprine, have been the most frequently used therapeutic approach in treating Morvan's Syndrome. However, this does not always work, as failed response to steroids and to subsequently added plasmapheresis have been reported. Intravenous immunoglobulin was effective in one case.[9] In one case, the dramatic response to high-dose oral prednisolone together with pulse methylprednisolone with almost complete disappearance of the symptoms within a short period should induce consideration of corticosteroids.[9] In another case, the subject was treated with haloperidol (6 mg/day) with some improvement in the psychomotor agitation and hallucinations, but even high doses of carbamazepine given to the subject failed to improve the spontaneous muscle activity. Plasma Exchange (PE) was initiated, and after the third such session, the itching, sweating, mental disturbances, and complex nocturnal behavior improved and these symptoms completely disappeared after the sixth session, with improvement in insomnia and reduced muscle twitching. However, one month after the sixth PE session, there was a progressive worsening of insomnia and diurnal drowsiness, which promptly disappeared after another two PE sessions.[4] In one case, high dose steroid treatment resulted in a transient improvement, but aggressive immuno-suppressive therapy with cyclophosphamide was necessary to control the disease and result in a dramatic clinical improvement.[7] In another case, the subject was treated with prednisolone (1 mg/kg body weight) with carbamazepine, propranolol, and amitriptyline. After two weeks, improvement with decreased stiffness and spontaneous muscle activity and improved sleep was observed. After another 7–10 days, the abnormal sleep behavior disappeared completely.[8] In another case, symptomatic improvement with plasmapheresis, thymectomy, and chronic immunosuppression provide further support for an autoimmune or paraneoplastic basis.[1] Although thymectomy is believed to be a key element in the proposed treatment, there is a reported case of Morvan's Syndrome presenting itself post-thymectomy.[2] ## Epidemiology[edit] There are only about 14 reported cases of Morvan's syndrome in the English literature.[8] With only a limited number of reported cases, the complete spectrum of the central nervous system (CNS) symptomatology has not been well established.[9] The natural history of Morvan's is highly variable. Two cases have been reported to remit spontaneously. Others have required a combination of plasmapheresis and long term immunosuppression, although in one of these cases the patient died shortly after receiving plasma exchange (PE). Other fatalities without remission have been described by, amongst others, Morvan himself.[2] ## References[edit] 1. ^ a b c d e f Lee, E K; R A Maselli; W G Ellis; M A Agius (1998-06-15). "Morvan's fibrillary chorea: a paraneoplastic manifestation of thymoma". Journal of Neurology, Neurosurgery, and Psychiatry. 65 (6): 857–862. doi:10.1136/jnnp.65.6.857. PMC 2170383. PMID 9854961. 2. ^ a b c d e Cottrell, D A; K J Blackmore; P R W Fawcett; et al. (2004). "Sub-acute presentation of Morvan's syndrome after thymectomy". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (10): 1504–1509. doi:10.1136/jnnp.2003.031401. PMC 1738744. PMID 15377711. 3. ^ a b Plazzi, Giuseppe; Pasquale Montagna; Stefano Meletti; Elio Lugaresi (2001-10-25). "Polysomnographic study of sleeplessness and oneiricisms in the alcohol withdrawal syndrome". Sleep Medicine. 3 (3): 279–282. doi:10.1016/S1389-9457(02)00014-X. PMID 14592220. 4. ^ a b c d e f Liguori, R.; A. Vincent; L. Clover; et al. (2001-08-07). "Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels". Brain. 124 (Pt 12): 2417–2426. doi:10.1093/brain/124.12.2417. PMID 11701596. 5. ^ a b Montagna, P.; E. Lugaresi (2002-01-23). "Agrypnia Excitata: a generalized overactivity syndrome and a useful concept in the neurophysiopathology of sleep". Clinical Neurophysiology. 113 (4): 552–560. doi:10.1016/S1388-2457(02)00022-6. PMID 11956000. 6. ^ a b c d Loscher, Wolfgang N.; Julia Wanschitz; Karlheinz Reiners; Stefan Quasthoff (2004-03-24). "Morvan's Syndrome: Clinical, Laboratory, and in vitro Electrophysiological Studies". Muscle Nerve. 30 (2): 157–163. doi:10.1002/mus.20081. PMID 15266630. 7. ^ a b c Spinazzi M, Argentiero V, Zuliani L, Palmieri A, Tavolato B, Vincent A. Immunotherapy-reversed compulsive, monoaminergic, circadian rhythm disorder in Morvan syndrome. Neurology. 2008 9;71:2008-10. 8. ^ a b c d e f Bajaj, B.K.; S. Shrestha (2006-10-07). "An interesting case report of Morvan's syndrome from the Indian subcontinent". Neurology India. 55 (1): 67–69. doi:10.4103/0028-3886.30432. PMID 17272905. 9. ^ a b c d e Deymeer, Feza; Sukriye Akca; Gulsen Kocaman; et al. (2005-10-25). "Fasciculations, Autonomic Symptoms and Limbic Encephalitis: A Thymoma-Associated Morvan's-Like Syndrome". European Neurology. 54 (4): 235–237. doi:10.1159/000090719. PMID 16401901. 10. ^ Winger, David I.; Peter Spiegler; Terence K. Trow; et al. (2007-03-26). "Radiology-Pathology Conference: pulmonary hyalinizing granuloma associated with lupus-like anticoagulant and Morvan's Syndrome". Clinical Imaging. 31 (4): 264–268. doi:10.1016/j.clinimag.2007.03.007. PMID 17599621. 11. ^ Kleopa, Kleopas A.; Lauren B. Elman; Bethan Lang; et al. (2006-03-13). "Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations". Brain. 129 (Pt 6): 1570–1584. doi:10.1093/brain/awl084. PMID 16613892. ## External links[edit] Classification D * ICD-10: G60.8 * ICD-9-CM: 336.0 * MeSH: D013595 * DiseasesDB: 12769 * v * t * e Focal lesions of the spinal cord General * Myelopathy * Myelitis * Spinal cord compression By location * Brown-Séquard syndrome * Posterior cord syndrome * Anterior cord syndrome * Central cord syndrome * Cauda equina syndrome Other * Polio * Demyelinating disease * Transverse myelitis * Tropical spastic paraparesis * Epidural abscess * Syringomyelia * Syringobulbia * Morvan's syndrome * Sensory ataxia * Tabes dorsalis * Abadie's sign * Subacute combined degeneration of spinal cord * Vascular myelopathy * Anterior spinal artery syndrome * Foix–Alajouanine syndrome * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Morvan's syndrome	c0751540	3,546	wikipedia	https://en.wikipedia.org/wiki/Morvan%27s_syndrome	2021-01-18T19:09:34	{"gard": ["9766"], "mesh": ["D013595"], "umls": ["C0751540"], "icd-9": ["336.0"], "icd-10": ["G60.8"], "orphanet": ["83467"], "wikidata": ["Q2964544"]}
Gorham's disease is a rare bone disorder characterized by bone loss (osteolysis), often associated abnormal blood vessel growth (angiomatous proliferation). Bone loss can occur in just one bone, or spread to soft tissue and adjacent bones. Symtoms may include pain, swelling, and increased risk of fracture. It may affect any part of the skeleton, but most commonly involves the skull, collarbone (clavicle), pelvis, ribs, spine, and/or jaw. Depending on the bones affected, various complications may occur. The cause of Gorham's disease is currently unknown. Most cases occur sporadically. Treatment is based on the signs and symptoms in each affected person, and most commonly involves surgery and/or radiation therapy. In some cases, Gorham's disease improves without treatment (spontaneous remission). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Gorham's disease	c0029438	3,547	gard	https://rarediseases.info.nih.gov/diseases/6542/gorhams-disease	2021-01-18T18:00:13	{"mesh": ["D010015"], "omim": ["123880"], "umls": ["C0029438"], "orphanet": ["73"], "synonyms": ["Cystic angiomatosis of bone diffuse", "Gorham-Stout syndrome", "Gorham-Stout disease", "Osteolysis massive", "Vanishing bone disease"]}
## Description In humans and primates, NR1H5P is a pseudogene. However, in other mammals, it encodes a functional nuclear hormone receptor that appears to be involved in cholesterol biosynthesis (Otte et al., 2003). Cloning and Expression By database analysis, Otte et al. (2003) identified human NR1H5P, which they called FXRB. They found that human FXRB contains several stop codons and frameshifts. RT-PCR showed extremely low expression for human FXRB, indicating that it is a pseudogene. Similar results were found in primates. However, in all other mammals, Fxrb contains a continuous ORF, suggesting that it encodes a functional protein. RT-PCR and RACE revealed several splice variants of mouse Fxrb, including a full-length variant encoding a 505-amino acid protein containing a conserved DNA-binding domain and a conserved ligand-binding domain. RT-PCR revealed ubiquitous and strong expression during mouse embryonic development. In adult mouse, Fxrb expression was more tissue specific and was restricted mainly to liver, reproductive tissue, and heart. Coexpression with Fxr (NR1H4; 603826) was observed in liver and intestine, but not in kidney. Gene Function Otte et al. (2003) found that mouse Fxrb heterodimerized with Rxra (180245) and stimulated transcription through specific DNA response elements. The authors identified lanosterol as a candidate endogenous ligand for Fxrb that induced coactivator recruitment and transcriptional activation by Fxrb. Otte et al. (2003) concluded that Fxrb is a functional receptor that controls cholesterol biosynthesis in nonprimate animals. Gene Structure Otte et al. (2003) determined that human NR1H5P contains 11 exons. NR1H5P has 2 stop codons in exon 11 and 3 frameshifts at exon-intron junctions, indicating that it is likely a nonfunctional pseudogene. Mapping Gross (2017) mapped the NR1H5P pseudogene to chromosome 1p13.2 based on an alignment of the NR1H5P sequence (GenBank NG_007471) with the genomic sequence (GRCh38). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NUCLEAR RECEPTOR SUBFAMILY 1, GROUP H, MEMBER 5, PSEUDOGENE	None	3,548	omim	https://www.omim.org/entry/617386	2019-09-22T15:45:57	{"omim": ["617386"], "synonyms": ["Alternative titles", "FARNESOID X-ACTIVATED RECEPTOR, BETA, PSEUDOGENE"]}
Colorado tick fever Other namesMountain tick fever, American tick fever, American mountain tick fever SpecialtyInfectious disease Colorado tick fever (CTF) is a viral infection (Coltivirus) transmitted from the bite of an infected Rocky Mountain wood tick (Dermacentor andersoni). It should not be confused with the bacterial tick-borne infection, Rocky Mountain spotted fever. Colorado tick fever is probably the same disease that American pioneers referred to as "mountain fever".[1][2] The type species of the genus Coltivirus, Colorado tick fever virus (CTFV) infects haemopoietic cells, particularly erythrocytes, which explains how the virus is transmitted by ticks and also accounts for the incidence of transmission by blood transfusion. ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Virology * 2.2 Tick * 2.3 Transmission * 3 Diagnosis * 4 Prevention * 5 Treatment * 5.1 Tick removal * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] First signs or symptoms can occur about three to six days after the initial tick bite, although it can have incubation periods of up to 20 days. Patients usually experience a two-staged fever and illness which can continue for three days, diminish, and then return for another episode of one to three days. The virus has the ability to live in the bloodstream for up to 120 days; therefore, coming in contact without proper precautions and the donation of blood are prohibited. Initial symptoms include fever, chills, headaches, pain behind the eyes, light sensitivity, muscle pain, generalized malaise, abdominal pain, hepatosplenomegaly, nausea and vomiting, and a flat or pimply rash.[3] During the second phase of the virus, a high fever can return with an increase in symptoms. CTF can be very severe in cases involving children and can even require hospitalization. Complications with this disease have included aseptic meningitis, encephalitis, and hemorrhagic fever, but these are rare. CTF is seasonal, mostly occurring in the Rocky Mountain region of the United States and usually in altitudes from 4,000 to 10,000 feet (1.600 to 3.000 meters).[3] Patients with CTF are mostly campers and young males, who most likely have been bitten because of their activities. ## Cause[edit] ### Virology[edit] Colorado tick fever coltivirus Virus classification (unranked): Virus Realm: Riboviria Kingdom: Orthornavirae Phylum: Duplornaviricota Class: Resentoviricetes Order: Reovirales Family: Reoviridae Genus: Coltivirus Species: Colorado tick fever coltivirus The virus particle, like other coltiviruses, is about 80 nm in diameter and is generally not enveloped. The double-stranded RNA viral genome is about 20,000 bp long and is divided into 12 segments, which are termed Seg-1 to Seg-12. Viral replication in infected cells is associated with characteristic cytoplasmic granular matrices. Evidence suggests the viral presence in mature erythrocytes is a result of replication of the virus in hematopoitic erythrocyte precursor cells and simultaneous maturation of the infected immature cells rather than of direct entry and replication of CTFV in mature erythrocytes.[4] ### Tick[edit] The Rocky Mountain wood tick is usually found attached to a host, but when it is without a host, it hides in cracks and crevices, as well as soil. If for some reason the tick is not able to find a host before the winter, it will stay under groundcover until spring, when it can resume its search. The wood tick does not typically seek hosts in the hottest summer months. Adult ticks tend to climb to the tops of grasses or low shrubs, attaching themselves to a host wandering by. They secure the attachment by secreting a cement-like substance from their mouths, inserting it into the host.[5] ### Transmission[edit] Colorado tick fever is acquired by tick bite. No evidence of natural person-to-person transmission has been found. However, rare cases of transmission from blood transfusions have been reported. The virus which causes Colorado tick fever may stay in the blood for as long as four months after onset of the illness. ## Diagnosis[edit] A combination of clinical signs, symptoms, and laboratory tests can confirm the likelihood of having CTF. Some tests include complement fixation to Colorado tick virus, immunofluorescence for Colorado tick fever, and some other common laboratory findings suggestive of CTF, including leucopenia, thrombocytopenia, and mildly elevated liver enzyme levels. Detection of viral antibodies on red blood cells is possible.[6] ## Prevention[edit] To avoid tick bites and infection, experts advise: * Avoid tick-infested areas, especially during the warmer months. * Wear light-colored clothing so ticks can be easily seen. Wear a long sleeved shirt, hat, long pants, and tuck pant legs into socks. * Walk in the center of trails to avoid overhanging grass and brush. * Clothing and body parts should be checked every few hours for ticks when spending time outdoors in tick-infested areas. Ticks are most often found on the thigh, arms, underarms, and legs. Ticks can be very small (no bigger than a pinhead). Look carefully for new "freckles". * The use of insect repellents containing DEET on skin or permethrin on clothing can be effective. Follow the directions on the container and wash off repellents when going indoors. * Remove attached ticks immediately. Contracting the CTF virus is thought to provide long-lasting immunity against reinfection. However, it is always wise to be on the safe side and try to prevent tick bites.[3] ## Treatment[edit] No specific treatment for CTF is yet available. The first action is to make sure the tick is fully removed from the skin, then acetaminophen and analgesics can be used to help relieve the fever and pain. Aspirin is not recommended for children, as it has been linked to Reye’s syndrome in some viral illnesses. Salicylates should not be used because of thrombocytopenia, and the rare occurrence of bleeding disorders. People who suspect they have been bitten by a tick or are starting to show signs of CTF should contact their physicians immediately.[7] ### Tick removal[edit] Ticks should be removed promptly and carefully with tweezers and by applying gentle, steady traction. The tick's body should not be crushed when it is removed and the tweezers should be placed as close to the skin as possible to avoid leaving tick mouthparts in the skin. Mouthparts left in the skin can allow secondary infections. Ticks should not be removed with bare hands. Hands should be protected by gloves or tissues and thoroughly washed with soap and water after the removal process. A match or flame should not be used to remove a tick. This method, once thought safe, can cause the tick to regurgitate expelling any disease it may be carrying into the bite wound.[8] ## Epidemiology[edit] The disease develops from March to September, with the highest infections occurring in June.[7] The disease is found almost exclusively in the western United States and Canada, mostly in high mountain areas such as Colorado and Idaho. The CTFV was first isolated from human blood in 1944.[3] ## References[edit] 1. ^ Aldous JA, Nicholes PS. (1997). "What Is Mountain Fever?". Overland Journal. 15 (Spring): 18–23.CS1 maint: uses authors parameter (link) 2. ^ Aldous JA. (1997). "Mountain Fever in the 1847 Mormon Pioneer Companies" (PDF). Nauvoo Journal. 9 (Fall): 52–59. 3. ^ a b c d "Colorado Tick Fever". Retrieved 2009-01-20. 4. ^ Philipp CS, Callaway C, Chu MC, et al. (1 April 1993). "Replication of Colorado tick fever virus within human hematopoietic progenitor cells". J. Virol. 67 (4): 2389–95. doi:10.1128/JVI.67.4.2389-2395.1993. PMC 240408. PMID 8445735. 5. ^ "Rocky Mountain wood tick: Information from Answers.com". Retrieved 2009-01-20.[unreliable source?] 6. ^ Mohd Jaafar F, Attoui H, Gallian P, et al. (May 2003). "Recombinant VP7-based enzyme-linked immunosorbent assay for detection of immunoglobulin G antibodies to Colorado tick fever virus". J. Clin. Microbiol. 41 (5): 2102–5. doi:10.1128/JCM.41.5.2102-2105.2003. PMC 154693. PMID 12734255. 7. ^ a b "Colorado tick fever". MedlinePlus. Retrieved 2017-07-10. 8. ^ O'Connor, Anahad (2005-07-05). "The Claim: Remove a Tick From Your Skin by Burning It". The New York Times. Retrieved 2009-01-20. ## External links[edit] Classification D * ICD-10: A93.2 * ICD-9-CM: 066.1 * MeSH: D003121 * DiseasesDB: 31134 External resources * MedlinePlus: 000675 * eMedicine: emerg/586 * Orphanet: 83595 * 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 * t * e Zoonotic viral diseases (A80–B34, 042–079) Arthropod -borne Mosquito -borne Bunyavirales * Arbovirus encephalitides: La Crosse encephalitis * LACV * Batai virus * BATV * Bwamba Fever * BWAV * California encephalitis * CEV * Jamestown Canyon encephalitis * Tete virus * Tahyna virus * TAHV * Viral hemorrhagic fevers: Rift Valley fever * RVFV * Bunyamwera fever * BUNV * Ngari virus * NRIV Flaviviridae * Arbovirus encephalitides: Japanese encephalitis * JEV * Australian encephalitis * MVEV * KUNV * Saint Louis encephalitis * SLEV * Usutu virus * West Nile fever * WNV * Viral hemorrhagic fevers: Dengue fever * DENV-1-4 * Yellow fever * YFV * Zika fever * Zika virus Togaviridae * Arbovirus encephalitides: Eastern equine encephalomyelitis * EEEV * Western equine encephalomyelitis * WEEV * Venezuelan equine encephalomyelitis * VEEV * Chikungunya * CHIKV * O'nyong'nyong fever * ONNV * Pogosta disease * Sindbis virus * Ross River fever * RRV * Semliki Forest virus Reoviridae * Banna virus encephalitis Tick -borne Bunyavirales * Viral hemorrhagic fevers: Bhanja virus * Crimean–Congo hemorrhagic fever (CCHFV) * Heartland virus * Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus) * Tete virus Flaviviridae * Arbovirus encephalitides: Tick-borne encephalitis * TBEV * Powassan encephalitis * POWV * Viral hemorrhagic fevers: Omsk hemorrhagic fever * OHFV * Kyasanur Forest disease * KFDV * AHFV * Langat virus * LGTV Orthomyxoviridae * Bourbon virus Reoviridae * Colorado tick fever * CTFV * Kemerovo tickborne viral fever Sandfly -borne Bunyavirales * Adria virus (ADRV) * Oropouche fever * Oropouche virus * Pappataci fever * Toscana virus * Sandfly fever Naples virus Rhabdoviridae * Chandipura virus Mammal -borne Rodent -borne Arenaviridae * Viral hemorrhagic fevers: Lassa fever * LASV * Venezuelan hemorrhagic fever * GTOV * Argentine hemorrhagic fever * JUNV * Brazilian hemorrhagic fever * SABV * Bolivian hemorrhagic fever * MACV * LUJV * CHPV Bunyavirales * Hemorrhagic fever with renal syndrome * DOBV * HTNV * PUUV * SEOV * AMRV * THAIV * Hantavirus pulmonary syndrome * ANDV * SNV Herpesviridae * Murid gammaherpesvirus 4 Bat -borne Filoviridae * BDBV * SUDV * TAFV * Marburg virus disease * MARV * RAVV Rhabdoviridae * Rabies * ABLV * MOKV * DUVV * LBV * CHPV Paramyxoviridae * Henipavirus encephalitis * HeV * NiV Coronaviridae * SARS-related coronavirus * SARS-CoV * MERS-CoV * SARS-CoV-2 Primate -borne Herpesviridae * Macacine alphaherpesvirus 1 Retroviridae * Simian foamy virus * HTLV-1 * HTLV-2 Poxviridae * Tanapox * Yaba monkey tumor virus Multiple vectors Rhabdoviridae * Rabies * RABV * Mokola virus Poxviridae * Monkeypox [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Colorado tick fever	c0009400	3,549	wikipedia	https://en.wikipedia.org/wiki/Colorado_tick_fever	2021-01-18T19:00:38	{"mesh": ["D003121"], "umls": ["C0009400"], "icd-9": ["066.1"], "orphanet": ["83595"], "wikidata": ["Q319315"]}
Idiopathic macular telangiectasia type 1 is a rare, acquired, eye disease characterized by unilateral (rarely bilateral) abnormally dilated and tortuous capillaries around the fovea, associated with multiple arteriolar and venular aneurysms, lipid depositions, and intra-retinal cystoid degeneration. It leads to vision loss due to macular edema with hard exudates. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Idiopathic macular telangiectasia type 1	None	3,550	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353344	2021-01-23T18:20:10	{"icd-10": ["H35.5"], "synonyms": ["Aneurysmal telangiectasia", "Visible and exudative idiopathic juxtafoveolar retinal telangiectasis"]}
## Clinical Features Diphenylhydantoin is poorly excreted by the kidney. Removal from the body depends on its hydroxylation. Kutt et al. (1964) found a family in which 3 members had reduced ability to hydroxylate diphenylhydantoin. The proband, who developed toxicity on usual doses of the drug, showed accumulation of the drug and much less hydroxylated derivative than normal in the urine. A defect in the hydroxylation of diphenylhydantoin can be produced by simultaneous administration of isoniazid (INH) which inhibits hydroxylation by liver microsomes (Kutt et al., 1968). Patients who show intolerance to diphenylhydantoin when receiving INH at the same time are patients who are the slow acetylators (243400) of INH (Kutt et al., 1970; Brennan et al., 1970). The family reported by Kutt et al. (1964) had a mother and 2 sons with inadequate hydroxylation. The proband was one of the sons, a 24-year-old male without liver disease, who consulted the authors 3 weeks after he had been given a daily dosage of 300 mg diphenylhydantoin and 90 mg phenobarbital for control of seizures after head injury. He showed marked nystagmus, ataxia and mental blunting, which disappeared when diphenylhydantoin was discontinued and reappeared when it was given again. Barbiturates alone produced no toxicity. Vasko et al. (1977) reported a family with phenytoin hypometabolism. The proband was a 32-year-old epileptic who developed high blood levels and toxicity on a moderate dose. The 24-hour urinary output of 5-(p-hydroxyphenyl)-5-phenylhydantoin was only 50% of the ingested drug. The half-life of the drug was 32 hours. At least one child had a prolonged half-life. Spielberg et al. (1981) studied individual susceptibility to toxicity from phenytoin metabolites by exposing human lymphocytes to metabolites generated by a murine hepatic microsomal system. Cells from 17 controls showed no toxicity at concentrations of phenytoin from 31 to 125 micromoles. Cells from 3 patients with phenytoin hepatotoxicity manifested dose-dependent toxicity from the metabolites. Phenytoin alone was not toxic to cells. The patients' dose-response curves resembled the response of control cells in which epoxide hydrolase, a detoxification enzyme for arene oxides, was inhibited. Detoxification of non-arene oxide metabolites (e.g., of acetaminophen) was normal in patients' cells. Cells from parents of 2 patients had intermediate responses. Cells from a sib of 1 patient showed no toxicity. A sib of another patient had a response similar to that of the patient. Strickler et al. (1985) hypothesized a mutant form of microsomal epoxide hydrolase (EPHX1; 132810) as the molecular basis for abnormal reactions to phenytoin and some other drugs. Phenytoin (diphenylhydantoin, dilantin) is metabolized by cytochrome P-450 monooxygenases to several oxidized products, including parahydroxylated and dihydrodiol metabolites (see 124020). Arene oxides, which are reactive electrophilic compounds, are intermediates in these oxidative reactions. If not detoxified, arene oxide metabolites can covalently bind to cell macromolecules, resulting in cell death, mutation, tumors, birth defects, and, by acting as haptens, can lead to secondary immune phenomena. In animals, toxic effects of phenytoin, including gingival hyperplasia and teratogenicity, have been attributed to the arene oxide metabolites. Presumably the defect in hydroxylation of diphenylhydantoin is unrelated to the mephenytoin-metabolizing P450 system (124020) (Spielberg, 1988). Gennis et al. (1991) described 3 sibs out of 12 who developed hypersensitivity reactions to phenytoin characterized by fever, rash, lymphadenopathy, and anicteric hepatitis. All recovered completely after discontinuation of treatment. One sib tolerated phenobarbital without toxic sequelae. Peripheral blood monocytes from the 3 patients and from 5 additional sibs who had never taken anticonvulsants were exposed to oxidative metabolites of phenytoin, phenobarbital, and carbamazepine. The cells from each of the 3 patients demonstrated increased toxicity from metabolites of phenytoin and carbamazepine, while the cellular response to metabolites of phenobarbital was within normal limits. Cells from 4 of the 5 other sibs showed an abnormal response to phenytoin metabolites, while cells from the fifth sib detoxified phenytoin metabolites normally. ### Fetal Hydantoin Syndrome Phelan et al. (1981) observed dizygotic twins in whom the evidence of diandric origin through superfecundation was strong (about 150 to 1). One suspected father was black, the other white. Throughout pregnancy the mother had taken phenobarbital and dilantin. Only 1 of the twins had signs of the fetal hydantoin syndrome (FHS). Strickler et al. (1985) presented evidence suggesting a genetic predisposition to phenytoin-induced birth defects. Lymphocytes from 24 children exposed to phenytoin throughout gestation and from their families were challenged with phenytoin metabolites generated by a mouse hepatic microsomal drug-metabolizing system. Fourteen of the children had a positive assay result, i.e., a significant increase in cell death associated with phenytoin metabolites. Each of these 14 children had 1 parent whose cells were also positive. A positive in vitro challenge was highly correlated with major birth defects including congenital heart disease, cleft lip/palate, microcephaly, and major genitourinary, eye, and limb defects. There was no difference between children with positive and negative results in the number or distribution of minor birth defects and even features that have been thought to be pathognomonic of the fetal hydantoin syndrome, such as distal digital hypoplasia, were distributed evenly among children with positive and negative assays. Some have questioned whether the epilepsy rather than the drug used in its treatment is responsible for the clinical abnormalities observed in the children of epileptic women treated with hydantoin. Chodirker et al. (1987) presented instructive observations of the hydantoin effect in a child born of a nonepileptic mother who had been given the drug during pregnancy for seizure prophylaxis after brain surgery. Goldman et al. (1987) found that children with the fetal hydantoin syndrome had glucocorticoid receptor (138040) levels in circulating lymphocytes significantly higher than those of unaffected children with similar exposure to phenytoin. The receptor level of affected children was also significantly elevated above that of fathers of children with FHS and of fathers and mothers of control children. Buehler et al. (1990) appeared to have demonstrated that low epoxide hydrolase activity in amniocytes is a risk factor for congenital malformations in the infants of mothers receiving phenytoin. In a random sample of amniocytes from 100 pregnant women, thin-layer chromatography showed an apparently trimodal distribution, suggesting that the level of the enzyme was controlled by a single gene with 2 allelic forms. In a prospective study of 19 pregnancies monitored by amniocentesis, an adverse outcome was predicted for 4 fetuses on the basis of low enzyme activity (less than 30% of the standard). In all 4 cases, the mother was receiving phenytoin monotherapy, and, after birth, the infants had clinical findings compatible with the fetal hydantoin syndrome. The 15 fetuses with enzyme activity above 30% of the standard were not considered to be at risk, and all 15 neonates lacked any characteristics of the fetal hydantoin syndrome. Sabry and Farag (1996) suggested that hand anomaly in the fetal hydantoin syndrome can be unilateral acheiria at one extreme with nail/phalangeal hypoplasia at the other extreme. They reported the case of a baby born with absence of the right hand with rudimentary tags at the distal end of the right forearm. The infant was born of a nonepileptic mother who had a history of first trimester prophylactic anticonvulsant therapy after surgical excision of a meningioma. The status of the nails and phalanges in the left hand was not stated. De Smet and Debeer (2002) described 2 children whose mother had been treated with phenylhydantoin for epilepsy that developed after surgery for a brain tumor. The first son had hypoplasia of the terminal phalanx of the fifth finger of the left hand. The second son was born with severe malformation of the right hand consistent with vascular disruption. He had facial dysmorphism with ocular hypertelorism, a small triangular shaped skull, and a depressed nasal bridge. Inheritance Dominant inheritance of phenytoin toxicity was proposed by Vesell (1979). Vasko et al. (1980) observed phenytoin hypometabolism in 4 members of 4 generations of a kindred. Vermeij et al. (1988) studied the inheritance of deficient phenytoin p-hydroxylation in the family of a patient who had previously suffered from phenytoin intoxication caused by insufficient metabolism of this drug (de Wolff et al., 1983). The rate of phenytoin metabolism was derived from the phenytoin/metabolite ratio in serum 6 hours after an oral test dose of 300 mg phenytoin. The propositus, a brother, and a sister were very slow metabolizers of phenytoin, with a metabolic ratio of approximately 20. All 22 children of these 3 individuals showed a mean metabolic ratio of 6.6 (SD = 1.7), whereas a control group of 37 individuals showed a mean metabolic ratio of 3.7 (SD = 1.8). The fetal hydantoin syndrome has been observed in multiple sibs (e.g., Hanson et al., 1976). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PHENYTOIN TOXICITY	c0149969	3,551	omim	https://www.omim.org/entry/617955	2019-09-22T15:44:13	{"omim": ["617955"], "icd-10": ["Q86.1"], "synonyms": ["Alternative titles", "ARENE OXIDE DETOXIFICATION DEFECT", "DIPHENYLHYDANTOIN, DEFECT IN HYDROXYLATION OF"]}
A rare genetic developmental and epileptic encephalopathy (DEE) characterized by developmental delay, generalized epilepsy consisting of eyelid myoclonia with absences and myoclonic-atonic seizures, intellectual disability and autism spectrum disorder (ASD). ## Epidemiology This disorder has an estimated prevalence of <1/1 000 000. ## Clinical description Presentation is of developmental delay, identified in the first months of life, associated with hypotonia and subsequent neurodevelopmental plateauing or regression. Generalized epilepsy is present in most with seizure onset typically at 2-3 years (ranges from 4 months to 7 years) with a distinctive epilepsy syndrome, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Drop attacks due to eyelid myoclonia evolving to myoclonic-atonic or atonic seizure can be present. Other generalized seizure types, variably combined, and reflex seizures triggered by eating or eyes closure may occur. The spectrum of seizure severity varies, with drug-resistant seizures in about half of patients. Moderate to severe intellectual disability becomes progressively evident in most, associated with ASD in about half of the patients. Behavioral disorders, including oppositional and defiant behavior with aggression, self-injury, and temper tantrums, are seen in most. Subtle dysmorphic facial features may be present in some, including slightly prominent eyebrows with medial flaring, hypertelorism, full nasal tip, slightly upturned nasal tip, short philtrum, cupid bow upper lip, broad mouth with diastemata of the upper teeth, and small pointed chin. Other associated features comprise high pain threshold, eating and sleeping problems, ataxia or gait abnormalities, and orthopedic abnormalities. Brain imaging is usually normal with possible nonspecific findings. ## Etiology The SYNGAP1 gene (6p21.32) encodes the synaptic Ras-GTPase-activating protein 1, mainly expressed in the synapses of excitatory neurons. Loss of function mutations in SYNGAP1 impairs neuronal homeostasis and development. This disorder is caused by heterozygous pathogenc SYNGAP1 variants or chromosome 6p21.32 microdeletions encompassing the SYNGAP1 gene. ## Diagnostic methods The diagnosis is suspected in a patient with developmental delay or intellectual disability, ASD and generalized epilepsy with generalized epileptiform abnormalities on EEG. The genetic identification of pathogenic SYNGAP1 variants (next generation sequencing) or chromosome 6p21.32 microdeletions (aCGH ) confirms the diagnosis. ## Differential diagnosis The phenotype of SYNPAG1-related encephalopathy might overlap with that of other neurodevelopmental disorders and DEEs. Seizures semiology, trigger factors and EEG patterns can help to differentiate this syndrome and orient the genetic testing. ## Antenatal diagnosis Once a pathogenic SYNGAP1 variant has been identified, prenatal testing is possible for a pregnancy at increased risk. ## Genetic counseling The pattern of inheritance is autosomal dominant. Whilst pathogenic variants occur de novo in almost all cases, parental mosaicism is possible. In such cases, genetic counseling is recommended as the risk of recurrence in affected families is higher than the general population. ## Management and treatment Management requires a multidisciplinary approach and tailored treatments addressing the specific symptoms. Anti-seizure medications and ketogenic diet are used for the management of seizures. Non-pharmacological interventions comprise physical, occupational, speech, and feeding therapy, as well as individualized educational plans. ## Prognosis Life expectancy is unknown due to under diagnosis in adult age. However, adult patients are known, demonstrating that survival into adulthood is possible. Prognosis is poor, resulting in severe cognitive deficits in most, associated with behavioral disorders of variable degree, and persisting seizures in half of the cases. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SYNGAP1-related developmental and epileptic encephalopathy	None	3,552	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=544254	2021-01-23T16:53:30	{"icd-10": ["G40.4"], "synonyms": ["SYNGAP1-related DEE"]}
The topic of this article may not meet Wikipedia's general notability guideline. Please help to demonstrate the notability of the topic by citing reliable secondary sources that are independent of the topic and provide significant coverage of it beyond a mere trivial mention. If notability cannot be shown, the article is likely to be merged, redirected, or deleted. Find sources: "Neuropathia mucinosa cutanea" – news · newspapers · books · scholar · JSTOR (May 2011) (Learn how and when to remove this template message) Neuropathia mucinosa cutanea SpecialtyDermatology Neuropathia mucinosa cutanea is a cutaneous condition characterized by livedo reticularis on the legs and hyperesthesia.[1] ## See also[edit] * Nodular lichen myxedematosus * 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 1-4160-2999-0. 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Neuropathia mucinosa cutanea	None	3,553	wikipedia	https://en.wikipedia.org/wiki/Neuropathia_mucinosa_cutanea	2021-01-18T18:50:24	{"wikidata": ["Q16901107"]}
In 4 sibs (one named Nathalie) of a Dutch family reported by Cremers et al. (1975), deafness and cataract were associated with muscular atrophy, retardation in growth and sexual development, and electrocardiographic abnormalities. One was male and 3 female. One had Perthes disease and one had Scheuermann disease. Two were young adults at the time of study. GU \- Sexual development retarded Inheritance \- Autosomal recessive Growth \- Growth retardation Cardiac \- Abnormal EKG HEENT \- Deafness \- Cataract Muscle \- Muscular atrophy ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NATHALIE SYNDROME	c1850626	3,554	omim	https://www.omim.org/entry/255990	2019-09-22T16:24:27	{"mesh": ["C538342"], "omim": ["255990"], "orphanet": ["2663"]}
Brain ischemia Other namesWatershed infarct T1 MRI of an ischemic stroke in the brain without (left) and with (right) contrast. SpecialtyNeurology A watershed stroke is defined as a brain ischemia that is localized to the vulnerable border zones between the tissues supplied by the anterior, posterior and middle cerebral arteries. [1] The actual blood stream blockage/restriction site can be located far away from the infarcts. Watershed locations are those border-zone regions in the brain supplied by the major cerebral arteries where blood supply is decreased. Watershed strokes are a concern because they comprise approximately 10% of all ischemic stroke cases.[2] The watershed zones themselves are particularly susceptible to infarction from global ischemia as the distal nature of the vasculature predisposes these areas to be most sensitive to profound hypoperfusion.[1] Watershed strokes are localized to two primary regions of the brain, and are termed cortical watersheds (CWS) and internal watersheds (IWS).[3] Patients with many different cardiovascular diseases have a higher likelihood of experiencing a blood clot or loss of blood flow in border-zone regions of the brain. The resulting symptoms differ based on the affected area of the brain. A CT scan and MRI are used for diagnosis, and afterward several treatment options are available, including the removal of atherosclerotic plaque and a physical widening of the clogged blood vessel. Long-term care is focused around three areas: rehabilitative therapy, surgical interventions, and prevention of future watershed strokes. Going forward, research to combat watershed strokes is focusing on various topics, such as stem cell research.[citation needed] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathogenesis * 3.1 Anatomy * 3.2 Hypotension * 3.3 Microemboli * 3.4 ICA occlusions * 4 Diagnosis * 4.1 Classification systems * 5 Treatment * 5.1 Carotid endarterectomy * 5.2 Percutaneous treatments of carotid stenosis * 5.2.1 Carotid angioplasty * 5.2.2 Carotid stenting * 6 Prognosis * 6.1 Rehabilitative therapies * 6.2 Surgical interventions * 6.3 Prevention of future strokes * 7 Research * 7.1 Stem cell transplantation * 7.2 Strokes after cardiac surgery * 7.3 Deep watershed infarcts * 7.4 Basilar artery (BA) stenting * 7.5 Penumbra imaging * 7.5.1 CLEVSRKNC peptide * 7.5.2 Liposomal drug delivery * 8 Terminology * 9 References ## Signs and symptoms[edit] Watershed stroke symptoms are due to the reduced blood flow to all parts of the body, specifically the brain, thus leading to brain damage. Initial symptoms, as promoted by the American Stroke Association, are FAST, representing F = Facial weakness (droop), A = Arm weakness (drift), S = Speech difficulty (slur), and T = Time to act (priority of intervention).[4] All strokes are considered a medical emergency. Any one of these symptoms, whether seen alone or in combination, should be assumed to be stroke until proven otherwise. Emergency medical help should be sought IMMEDIATELY if any or all of these symptoms are seen or experienced. Early diagnosis and timely medical intervention can drastically reduce the severity of a stroke, limit damage to the brain, improve the chances of a full recovery and reduce recovery times massively. After the initial stroke, other symptoms depend on the area of the brain affected. If one of the three central nervous system pathways is affected, symptoms can include numbness, reduced sensation, and hyperreflexia. Most often, the side of the brain damaged results in body defects on the opposite side. Since the cranial nerves originate from the brainstem, damage to this area can lead to defects in the function of these nerves. Symptoms can include altered breathing, problems with balance, drooping of eyelids, and decreased sensation in the face.[5] Damage to the cerebral cortex may lead to aphasia or confusion and damage to the cerebellum may lead to lack of motor movement.[5] Stroke presentations which are particularly suggestive of a watershed stroke include bilateral visual loss, stupor, and weakness of the proximal limbs, sparing the face, hands and feet. ## Causes[edit] Watershed strokes are caused by ischemia or a lack of blood flow to the brain.[2] There are several causes of ischemia, including embolism and atherosclerosis. There are several conditions that can predispose someone to watershed stroke by increasing the likelihood that insufficient blood supply will be able to reach the brain. People with many different cardiovascular diseases have a higher likelihood of experiencing a clot or a plaque that impedes flow through a blood vessel.[3] Cardiovascular diseases that increase the risk of ischemia include: * Congestive heart failure, which can lead to an inability to pump sufficient amounts of blood to the brain * Atherosclerosis, which can cause a buildup of cholesterol plaques in the blood vessels, thereby decreasing the volume of blood that can flow through the vessel and reach the brain[3] * Angiopathy, a disease of the blood vessels[6] * Arterial hypotension, or low blood pressure in the arteries[2] * Hypertension, or high blood pressure[7] * Hyperlipidemia, or excessive cholesterol buildup in the blood vessels[7] * Diseases such as sickle cell anemia, which can lead to deformed red blood cells clogging blood vessels and impeding blood flow[8] * Carotid artery stenosis, or narrowing of the carotid artery which can decrease the volume of blood flow to the brain[7] ## Pathogenesis[edit] Although many imaging techniques are used to document watershed strokes, their pathogenesis remains controversial. It may involve various mechanisms such as systemic hypotension, microemboli, severe arterial stenosis, ICA occlusion or a combination of these.[3] ### Anatomy[edit] Outer surface of cerebral hemisphere, showing areas supplied by cerebral arteries. Pink is the region supplied by the middle cerebral artery, blue is supplied by the anterior cerebral artery and yellow is supplied by the posterior cerebral artery. Cortical watershed strokes occur at the borders between those areas. These events are localized to two primary regions of the brain: 1. Cortical watershed strokes (CWS), or outer brain infarcts, are located between the cortical territories of the anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA).[3] 2. Internal watershed strokes (IWS), or subcortical brain infarcts, are located in the white matter along and slightly above the lateral ventricle, between the deep and the superficial arterial systems of the MCA, or between the superficial systems of the MCA and ACA.[3] Nonetheless, within the literature itself, there exists confusion over the terminology used to describe cortical (outer brain) infarcts and subcortical (inner brain) infarcts. Besides watershed, border-zone is another common term used to refer to areas of the brain between the ends of two adjacent arteries. Other less used terms include: borderland, end zone, boundary zone, and terminal zone. These varying terms have arisen from the considerable anatomic variability both in the cerebral vascular structure and the territories of the brain that they supply.[9] ### Hypotension[edit] A sharp drop in blood pressure is the most frequent cause of watershed infarcts. The most frequent location for a watershed stroke is the region between the anterior cerebral artery and middle cerebral artery. These events caused by hypotension do not usually cause the blood vessel to rupture.[2] ### Microemboli[edit] Microemboli have not been experimentally proven to cause watershed strokes. It is unclear whether they are a cause or an effect of a watershed stroke.[10] With watershed strokes, platelet aggregates block the small meningeal arteries in watershed regions creating a microembolism. Microemboli usually form as thrombi, and can block arteries outright. On the other hand, they often detach, move into blood circulation, and eventually block smaller downstream branches of arteries causing a thromboembolism. Generally, emboli travel as far outward as their size permits along the vascular branches of the brain. Using this hypothesis, microemboli are viewed as the cause of the infarct rather than secondary events. Nevertheless, secondary thrombi do form after infarcts, and therefore it has been difficult to distinguish between emboli and thrombi in watershed locations.[2] The best supporting evidence is correlative; patients display subcortical abnormalities on CT scans and present more microembolic signals during a carotid endarterectomy.[10] Microemboli can be common in some high-risk patients, such as those with carotid stenosis. However, in healthier patients strokes do not usually result from microemboli.[10] ### ICA occlusions[edit] Internal carotid artery Arteries of the neck. The internal carotid arteries arise from the common carotid arteries \- labeled Common caroti on the figure. Anatomical terminology [edit on Wikidata] Thrombi at the split of the internal carotid artery in the neck may cause watershed infarcts between the territories of the anterior cerebral artery and the middle cerebral artery. The resulting watershed infarcts in carotid artery blockages have mostly been considered to be due to a reduced blood flow, similar to that of hypotension.[2] Imaging studies in severe internal carotid artery (ICA) disease report an incidence of watershed stroke ranging from 19% to 64%.[3] Almost 40% of these watershed infarcts are attributed to narrowing of the carotid artery, which produces the reduced blood flow.[3] However, a different possible explanation has emerged. Alternatively, the vascular occlusion could be the result of microemboli from the carotid thrombi before the lumen becomes completely blocked.[2] In this scenario, the clotting becomes too severe and the clot breaks free. The resulting traveling clot is known as an embolus (plural emboli). The wall of internal carotid artery just distal to the bifurcation (split) is a common site of atherosclerosis because of the unique hemodynamic effects caused by the blood flow divider. As a result, thrombi formation is more prevalent there.[10] In general, researches have observed that this microembolization is a frequent phenomenon during the build-up of cerebral thrombi.[2] The resulting emboli are pieces of calcified plaque. If these microemboli are 0.1 mm in diameter, they might pass into the small branches of the vascular system. There they may be destroyed by protective cellular defenses, or they may cause a stroke.[10] Altogether, these considerations suggest that the watershed infarcts in carotid thrombosis are caused by microembolization from mural thrombi, thrombi adherent to the vessel wall, rather than by blood flow disturbances.[2] ## Diagnosis[edit] Diagnosis of a cerebral vascular accident begins with a general neurological examination, used to identify specific areas of resulting injury. A CT scan of the brain is then used to identify any cerebral hemorrhaging. An MRI with special sequences called diffusion-weighted MR imaging (DWI), is very sensitive for locating areas of an ischemic based stroke, such as a watershed stroke. Further diagnosis and evaluation of a stroke includes evaluation of the blood vessels in the neck using either Doppler ultrasound, MR-angiography or CT-angiography, or formal angiography. An echocardiogram may be performed looking for a cardiac source of emboli. Blood tests for risk factors also may be ordered, including cholesterol levels, triglyceride levels, homocysteine levels, and blood coagulation tests. ### Classification systems[edit] * The Oxfordshire Community Stroke Project classification (OCSP, also known as the Bamford or Oxford classification) relies primarily on the patient's initial symptoms. Based on the extent of the symptoms, the stroke episode is classified as total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) or posterior circulation infarct (POCI). These four entities predict the extent of the stroke, the area of the brain affected, the underlying cause, and the prognosis.[11][12] * The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification is based on clinical symptoms as well as results of further investigations. In this diagnostic system, a stroke is classified as being due to 1. Thrombosis or embolism due to atherosclerosis of a large artery 2. Embolism of cardiac origin 3. Occlusion of a small blood vessel[13] ## Treatment[edit] ### Carotid endarterectomy[edit] Often considered one of the safest ways to treat symptomatic carotid stenosis, carotid endarterectomy is a procedure by which a surgeon gently removes atherosclerotic plaque. Blood flow hopefully then returns to normal, increasing oxygen concentration to normal amounts in watershed areas of the brain. There is the potential for complications, including disturbing portions of the plaque leading to a stroke or heart attack during or after surgery. Small risks of bleeding and infection exist as well.[14] ### Percutaneous treatments of carotid stenosis[edit] In this type of procedure, a narrowed blood vessel is expanded via angioplasty or stenting. A thin angiography catheter is inserted in a large groin blood vessel and advanced to the stenosis. Percutaneous treatment is less invasive than endarterectomy, usually requiring only local anesthesia. Endarterectomy is still considered safer though, as percutaneous treatments can lead to accidental dislodging of plaque or even arterial rupturing.[14] #### Carotid angioplasty[edit] During carotid angioplasty, an angiography cather with a small deflated balloon attached on the tip is advanced to a carotid stenosis. The ballon is then inflated slowly, forcing the narrowed portion of the vessel to expand. #### Carotid stenting[edit] Carotid stenting follows a similar procedure. Rather than using a balloon, a stent (metal mesh-like tube) is placed over the atherosclerotic plaque in the hopes of stabilizing it and allowing for increased blood flow to watershed portions of the brain. ## Prognosis[edit] Watershed strokes are seldom fatal, but they can lead to neuromuscular degeneration, as well as dementia.[3] This degeneration at the watershed regions of the brain can lead to difficulties with movement and motor coordination, as well as speech. Long-term care is focused around three areas: rehabilitative therapy, surgical interventions, and prevention of future watershed strokes. ### Rehabilitative therapies[edit] Long-term rehabilitative therapy for watershed stroke patients involves physical, occupational, and speech and language therapies. Physical therapy can be used to enhance motor function in the legs and arms that has been impacted by stroke.[15] Occupational therapies can be provided to help to alleviate cognitive impairments that result from watershed stroke,[16] as well as to improve fine motor function that was damaged as a result of the stroke.[17] Stroke can also cause impairments in speech production secondary to neurocognitive and neuromuscular impairments, and therefore speech and language therapies are often a component of long-term care for stroke patients. Intensive speech and language therapy has been shown to improve speech deficits associated with aphasia resulting from stroke.[18] ### Surgical interventions[edit] Endovascular interventions, including surgical revascularization, can increase blood flow in the area of the stroke, thereby decreasing the likelihood that insufficient blood flow to the watershed regions of the brain will result in subsequent strokes.[14] Neuroscientists are currently researching stem cell transplantation therapies to improve recovery of cebreral tissue in affected areas of the brain post-stroke. Should this intervention be proven effective, it will greatly increase the number of neurons in the brain that can recover from a stroke.[19] ### Prevention of future strokes[edit] There are several interventions that are often used to help prevent the recurrence of a watershed stroke; namely, nutritional interventions, as well as antiplatelet, anticoagulant, and statin drug use. Nutritional interventions, including increased consumption of certain amino acids, antioxidants, B-group vitamins, and zinc, have been shown to increase the recovery of neurocognitive function after a stroke.[20] Antiplatelet drugs, such as aspirin, as well as anticoagulants, are used to help prevent blood clots and therefore embolisms, which can cause watershed strokes. Statin drugs are also used to control hyperlipidemia, another risk factor for watershed stroke. ## Research[edit] ### Stem cell transplantation[edit] Ischemic stroke is still a major health concern and studies are being conducted to determine the pathway in which brain damage occurs to identify targets for intervention. Stem cell transplantation may help in intervention to improve cell recovery and regeneration.[19] ### Strokes after cardiac surgery[edit] Although the mechanism is not entirely understood, the likelihood of a watershed stroke increases after cardiac surgery. An experiment conducted in a five-year span studied the diagnosis, etiology, and outcome of these postoperative strokes. It was observed that intraoperative decrease in blood pressure may lead to these strokes and patients who have undergone aortic procedures are more likely to have bilateral watershed infarcts. Furthermore, bilateral watershed strokes are associated with poor short-term outcomes and are most reliably observed by diffusion-weighted imaging MRI. Thus future clinical research and practice should focus on the identification of bilateral stroke characteristics. This identification can help discover affected areas and increase correct diagnosis.[21] ### Deep watershed infarcts[edit] Hemodynamic impairment is thought to be the cause of deep watershed infarcts, characterized by a rosary-like pattern. However new studies have shown that microembolism might also contribute to the development of deep watershed infarcts. The dual contribution of hemodynamic impairment and microembolism would result in different treatment for patients with these specific infarcts.[22] ### Basilar artery (BA) stenting[edit] While intracranial artery stenting is used for same side stroke prevention, basilar artery stenting may help to improve parallel, accessory blood flow. The stent may also lead to termination of recurrent middle cerebral artery (MCA) strokes.[23] ### Penumbra imaging[edit] The area around the damaged ischemia is known as the penumbra. This viable area has the ability to regenerate with the help of pharmacological treatment however most patients with penumbra are left untreated. New research is being conducted in metabolic suppression, direct energy delivery, and selective drug delivery to help salvage this area of the brain after a stroke.[24] #### CLEVSRKNC peptide[edit] This new drug has been shown to home to ischemic stroke tissue as well as apoptotic neuronal cells of the penumbra region. This discovery may help in creating selective drug delivery for stroke patients.[25] #### Liposomal drug delivery[edit] Nanoliposomes are currently being researched for specific drug delivery due to their ph-sensitive and high blood–brain barrier diffusion characteristics. Many advantages of these drugs include: 1. Drugs can be maintained in the active state while encapsulated. 2. Being encapsulated provides direct access to target tissue 3. Prevention of non-specific binding 4. Allows for a high concentration of drug Due to the fact that acidic environment and low blood flow are prominent characteristic of the penumbra area, liposomal drugs seem to be well suited.[24] ## Terminology[edit] Watershed strokes are named because they affect the distal watershed areas of the brain. The original terminology came from the German literature, which used the analogy of an irrigation system. The German scholars compared the blood flow in distal arterial territories of the brain to the last field on a farm, which was the area with the least supply of water and therefore most vulnerable to any reduction in flow.[9] In a medical context, the term "watershed" refers to those areas of the brain that receive dual blood supply from the branching ends of two large arteries.[9] ## References[edit] 1. ^ a b Porth, C.M. (2009). Pathophysiology: Concepts of Altered Health States (Eighth Edition). Philadelphia: Wolters Kluwer Health \| Lippincott Williams & Wilkins. p. 1301. ISBN 978-16054-7390-1. 2. ^ a b c d e f g h i Torvik, A. (1984). "The pathogenesis of watershed infarcts in the brain". Stroke. 15 (2): 221–3. doi:10.1161/01.STR.15.2.221. PMID 6701929. 3. ^ a b c d e f g h i Momjian-Mayor, I; Baron, J.C. (2005). "The Pathophysiology of Watershed Infarction in Internal Carotid Artery Disease: Review of Cerebral Perfusion Studies". Stroke. 36 (3): 567–77. doi:10.1161/01.STR.0000155727.82242.e1. PMID 15692123. 4. ^ Harbison, J.; Massey, A.; Barnett, L.; Hodge, D.; Ford, G. A. (1999). "Rapid ambulance protocol for acute stroke". The Lancet. 353 (9168): 1935. doi:10.1016/S0140-6736(99)00966-6. PMID 10371574. 5. ^ a b Martini, F, Nath, J, Bartholomew, E 2012. "Fundamentals of Anatomy & Physiology.", p. 742-43. Pearson Education Inc, San Francisco. ISBN 9780321709332. 6. ^ Miklossy, J. (2003). "Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease". Neurological Research. 25 (6): 605–10. doi:10.1179/016164103101202048. PMID 14503014. 7. ^ a b c Donnan, G.A.; Fisher, M; MacLeod, M.; Davis, S. M. (2008). "Stroke". The Lancet. 371 (9624): 1612–23. doi:10.1016/S0140-6736(08)60694-7. PMID 18468545. 8. ^ Verduzco, L. A.; Nathan, D. G. (2009). "Sickle cell disease and stroke". Blood. 114 (25): 5117–25. doi:10.1182/blood-2009-05-220921. PMID 19797523. 9. ^ a b c Bladin, C. F.; Chambers, B. R.; Donnan, G. A. (1993). "Confusing stroke terminology: Watershed or borderzone infarction?". Stroke. 24 (3): 477–8. doi:10.1161/01.STR.24.3.477. PMID 8446987. 10. ^ a b c d e Grotta, JC; Alexandrov, AV (2001). "Preventing stroke: Is preventing microemboli enough?". Circulation. 103 (19): 2321–2. doi:10.1161/01.CIR.103.19.2321. PMID 11352876. 11. ^ Bamford, J.; Sandercock, P.; Dennis, M.; Warlow, C.; Burn, J. (1991). "Classification and natural history of clinically identifiable subtypes of cerebral infarction". The Lancet. 337 (8756): 1521–6. doi:10.1016/0140-6736(91)93206-O. PMID 1675378. Later publications distinguish between "syndrome" and "infarct", based on evidence from imaging. "Syndrome" may be replaced by "hemorrhage" if imaging demonstrates a bleed. See Internet Stroke Center. "Oxford Stroke Scale". Retrieved 2008-11-14. 12. ^ Bamford, J.M. (2000). "The Role of the Clinical Examination in the Subclassification of Stroke". Cerebrovascular Diseases. 10 (4): 2–4. doi:10.1159/000047582. PMID 11070389. 13. ^ Adams, H. P.; Bendixen, B. H.; Kappelle, L. J.; Biller, J.; Love, B. B.; Gordon, D. L.; Marsh, E. E. (1993). "Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment". Stroke. 24 (1): 35–41. doi:10.1161/01.STR.24.1.35. PMID 7678184. 14. ^ a b c Mathews, Marlon S.; Sharma, J.; Snyder, K. V.; Natarajan, S. K.; Siddiqui, A. H.; Hopkins, L. N.; Levy, E. I. (2009). "Safety, Effectiveness, and Practicality of Endovascular Therapy Within the First 3 Hours of Acute Ischemic Stroke Onset". Neurosurgery. 65 (5): 860–5, discussion 865. doi:10.1227/01.NEU.0000358953.19069.E5. PMID 19834397. 15. ^ Winter, Jackie; Hunter, S.; Sim, J.; Crome, P. (2011). Winter, Jackie (ed.). "Hands-on therapy interventions for upper limb motor dysfunction following stroke". Cochrane Database of Systematic Reviews (6): CD006609. doi:10.1002/14651858.CD006609.pub2. PMC 6464865. PMID 21678359. 16. ^ Hoffmann, Tammy; Bennett, S.; Koh, C. L.; McKenna, K. T. (2010). Hoffmann, Tammy (ed.). "Occupational therapy for cognitive impairment in stroke patients" (PDF). Cochrane Database of Systematic Reviews (9): CD006430. doi:10.1002/14651858.CD006430.pub2. PMC 6464961. PMID 20824849. 17. ^ Legg, L.; Drummond, A.; Leonardi-Bee, J.; Gladman, J R F; Corr, S.; Donkervoort, M.; Edmans, J.; Gilbertson, L.; et al. (2007). "Occupational therapy for patients with problems in personal activities of daily living after stroke: Systematic review of randomised trials". BMJ. 335 (7626): 922. doi:10.1136/bmj.39343.466863.55. PMC 2048861. PMID 17901469. 18. ^ Brady, Marian C; Kelly, H.; Godwin, J.; Enderby, P.; Campbell, P. (2016). Brady, Marian C (ed.). "Speech and language therapy for language problems after a stroke". Cochrane Database Syst Rev (6): 1–4. doi:10.1002/14651858.CD000425.pub4. hdl:1893/26112. PMID 27245310. 19. ^ a b Jablonska, A.; Lukomska, B. (2011). "Stroke induced brain changes: Implications for stem cell transplantation". Acta Neurobiologiae Experimentalis. 71 (1): 74–85. PMID 21499328. 20. ^ Aquilani, R.; Sessarego, P.; Iadarola, P.; Barbieri, A.; Boschi, F. (2011). "Nutrition for Brain Recovery After Ischemic Stroke: An Added Value to Rehabilitation". Nutrition in Clinical Practice. 26 (3): 339–45. doi:10.1177/0884533611405793. PMID 21586419. 21. ^ Gottesman, R. F.; Sherman, P. M.; Grega, M. A.; Yousem, D. M.; Borowicz Jr, L. M.; Selnes, O. A.; Baumgartner, W. A.; McKhann, G. M. (2006). "Watershed Strokes After Cardiac Surgery: Diagnosis, Etiology, and Outcome". Stroke. 37 (9): 2306–11. doi:10.1161/01.STR.0000236024.68020.3a. PMID 16857947. 22. ^ Moustafa, R. R.; Momjian-Mayor, I.; Jones, P. S.; Morbelli, S.; Day, D.; Aigbirhio, F.; Fryer, T.; Warburton, E.; Baron, J. (2011). "Microembolism Versus Hemodynamic Impairment in Rosary-Like Deep Watershed Infarcts: A Combined Positron Emission Tomography and Transcranial Doppler Study". Stroke. 42 (11): 3138–43. doi:10.1161/STROKEAHA.111.616334. PMID 21852602. 23. ^ Titsworth, W; Civelek, A; Abou-Chebl, A (2010). "Use of far field basilar artery stenting for recurrent middle cerebral artery ischemia". Journal of NeuroInterventional Surgery. 3 (1): 57–61. doi:10.1136/jnis.2009.001958. PMID 21990791. 24. ^ a b Liu, S; Levine, S; Winn, H (2010). "Targeting ischemic penumbra: Part I - from pathophysiology to therapeutic strategy". Journal of Experimental Stroke & Translational Medicine. 3 (1): 47–55. doi:10.6030/1939-067x-3.1.47. PMC 2896002. PMID 20607107. 25. ^ Hong, H; Choi, J; Kim, Y; Lee, H; Kwak, W; Yoo, J; Lee, J; Kwon, T; et al. (2008). "Detection of apoptosis in a rat model of focal cerebral ischemia using a homing peptide selected from in vivo phage display". Journal of Controlled Release. 131 (3): 167–72. doi:10.1016/j.jconrel.2008.07.020. PMID 18692101. * v * t * e Cerebrovascular diseases including stroke Ischaemic stroke Brain * Anterior cerebral artery syndrome * Middle cerebral artery syndrome * Posterior cerebral artery syndrome * Amaurosis fugax * Moyamoya disease * Dejerine–Roussy syndrome * Watershed stroke * Lacunar stroke Brain stem * Brainstem stroke syndrome * Medulla * Medial medullary syndrome * Lateral medullary syndrome * Pons * Medial pontine syndrome / Foville's * Lateral pontine syndrome / Millard-Gubler * Midbrain * Weber's syndrome * Benedikt syndrome * Claude's syndrome Cerebellum * Cerebellar stroke syndrome Extracranial arteries * Carotid artery stenosis * precerebral * Anterior spinal artery syndrome * Vertebrobasilar insufficiency * Subclavian steal syndrome Classification * Brain ischemia * Cerebral infarction * Classification * Transient ischemic attack * Total anterior circulation infarct * Partial anterior circulation infarct Other * CADASIL * Binswanger's disease * Transient global amnesia Haemorrhagic stroke Extra-axial * Epidural * Subdural * Subarachnoid Cerebral/Intra-axial * Intraventricular Brainstem * Duret haemorrhages General * Intracranial hemorrhage Aneurysm * Intracranial aneurysm * Charcot–Bouchard aneurysm Other * Cerebral vasculitis * Cerebral venous sinus thrombosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Watershed stroke	None	3,555	wikipedia	https://en.wikipedia.org/wiki/Watershed_stroke	2021-01-18T18:28:53	{"wikidata": ["Q7974427"]}
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. (February 2017) Nasal septal abscess Nasal septum(normal) SpecialtyENT surgery Nasal septal abscess is a condition of the nasal septum[1] in which there is a collection of pus between the mucoperichondrium and septal cartilage. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Cause * 3 Treatment * 4 References ## Signs and symptoms[edit] Individuals with this condition may also have fever, general malaise and nasal pain, including tenderness over the dorsum of the nose. A bilateral persistent nasal obstruction may also be present.[citation needed] ### Complications[edit] Potential complications of a nasal septal abscess include cavernous sinus thrombophlebitis, septal perforation, or saddle deformity due to cartilage necrosis.[citation needed] ## Cause[edit] A nasal septal abscess is frequently a result of a secondary bacterial infection of a nasal septal hematoma.[citation needed] ## Treatment[edit] Treatment for a nasal septal abscess is similar to that of other bacterial infections. Aggressive broad spectrum antibiotics may be used after the infected area has been drained of fluids. ## References[edit] 1. ^ Ginsburg CM (April 1998). "Nasal septal hematoma". Pediatr Rev. 19 (4): 142–3. doi:10.1542/pir.19-4-142. PMID 9557069. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Nasal septal abscess	c0264264	3,556	wikipedia	https://en.wikipedia.org/wiki/Nasal_septal_abscess	2021-01-18T18:51:19	{"icd-10": ["J34.0"], "wikidata": ["Q6966584"]}
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). Clinical Features Valente et al. (2002) reported an Italian family in which 10 members in 3 consecutive generations had spastic paraplegia. Mean age of onset was 47 years (range, 36-55) and clinical findings included lower limb hyperreflexia, progressive spastic gait abnormality, extensor plantar responses, ankle or knee clonus, and urinary urgency. Spasticity was exacerbated by stress, anxiety, and walking after rest. Nerve conduction studies on some of the individuals revealed slowing of motor and sensory conduction velocities localized to the lower limbs. In general, however, the disorder followed a slow progression and was relatively benign, with only 1 patient confined to a wheelchair. Inheritance Valente et al. (2002) reported an autosomal dominant form of SPG in a family with affected members spanning 3 consecutive generations. Mapping In a large family segregating SPG, Valente et al. (2002) excluded linkage to known autosomal dominant hereditary SPG loci and found a maximum lod score of 3.31 with markers on 9q. Haplotype analysis showed a common area between D9S1776 and D9S1826, which allowed identification of a 36-cM interval containing the disease locus, designated SPG19. INHERITANCE \- Autosomal dominant GENITOURINARY Bladder \- Urinary urgency \- Urinary incontinence \- Sphincter disturbances NEUROLOGIC Central Nervous System \- Lower limb spasticity \- Lower limb weakness \- Spastic gait \- Hyperreflexia \- Extensor plantar responses \- Pyramidal signs \- Ankle or knee clonus \- Decreased vibratory sense in the lower limbs MISCELLANEOUS \- Age of onset 36 to 55 years (mean 47) \- Slow progression \- Genetic heterogeneity, see SPG3A ( 182600 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPASTIC PARAPLEGIA 19, AUTOSOMAL DOMINANT	c1846685	3,557	omim	https://www.omim.org/entry/607152	2019-09-22T16:09:34	{"doid": ["0110772"], "mesh": ["C536856"], "omim": ["607152"], "orphanet": ["100999"]}
## Clinical Features Cumming et al. (1986) described a stillborn male infant, born at 27 weeks' gestation of an Egyptian couple related as first cousins once removed, who had bowed limbs, marked cervical lymphocele (a term the authors preferred to cystic hygroma), polycystic dysplasia of the kidneys, pancreas, and liver, short gut, and polysplenia. Two apparently identically affected stillborn infants, a male and a female, had been born previously at 28 weeks' gestation. Urioste et al. (1991) described 2 female sibs, the offspring of healthy nonconsanguineous parents, who died shortly after birth. They showed generalized lymphedema, cervical lymphocele, shortness of limbs, bowed long bones, and multicystic kidneys with fibrotic liver or pancreas. Ming et al. (1997) described a fetus with tetramelic campomelia, polysplenia, multicystic dysplastic kidneys, and cervical lymphocele. In addition, there were anomalies not previously described in this condition, including abnormal lung lobation with bilateral left bronchial morphology, dextrocardia, total anomalous pulmonary venous return, left superior vena cava, and right aortic arch. The pancreas was short, with absence of the body and tail. Ming et al. (1997) suggested that the syndrome reported by Cumming et al. (1986) could be expanded to include polysplenia with heterotaxia and that Cumming syndrome may be considered another autosomal recessive condition associated with a laterality defect. Perez del Rio et al. (1999) reported the cases of 2 sisters born to young parents of unknown consanguinity. The clinical and autopsy findings were considered to be consistent with the diagnosis of Cumming syndrome. The first fetus was stillborn at 36 weeks and showed hydrops, cloverleaf skull, and a severely deformed face, with a considerable amount of redundant subcutaneous tissue, massive cervical edema, and microphthalmia. The facial appearance was said to be similar to that of a 40-day embryo. The chest was narrow and the abdomen swollen with mild ascites. All 4 limbs were short and bowed. Autopsy revealed lung hypoplasia, enlarged cystic kidneys, and hepatomegaly. The second fetus, delivered by cesarean section at 31 weeks, died within minutes after delivery. The external appearance was similar to that of her sister, with cloverleaf skull and redundant soft tissue in the occipital and facial regions. Again, lung hypoplasia and enlarged cystic kidneys were found. The liver likewise showed polycystic dysplasia. Watiker et al. (2005) reported 2 patients originally diagnosed as having Cumming syndrome who were subsequently found to have mutations in the SOX9 gene, prompting reassessment of the cases and reclassification as campomelic dysplasia (114290). Features consistent with Cumming syndrome included campomelia of prenatal onset, cystic hygroma, and a small chest; 1 patient also had a cleft palate and multicystic kidneys, and the other had a complex congenital heart defect. The patients also had short, irregular chondrocyte columns, whereas chondroosseous morphology appears normal in campomelic dysplasia except at the diaphyseal bend. Watiker et al. (2005) concluded that the presence of a narrow, tall pelvis, hypoplastic scapulae, and sex reversal are key findings in campomelic dysplasia that allow it to be differentiated from Cumming syndrome. Inheritance Consanguinity in the families with Cumming syndrome reported by Cumming et al. (1986) and Perez del Rio et al. (1999) is consistent with autosomal recessive inheritance. Inheritance \- Autosomal recessive Limbs \- Bowed \- Short Neck \- Cervical lymphocele (cystic hygroma) Liver \- Polycystic dysplasia Spleen \- Polysplenia Pancreas \- Polycystic dysplasia Skin \- Generalized lymphedema GI \- Short gut Renal \- Polycystic kidney dysplasia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	CAMPOMELIA, CUMMING TYPE	c1859371	3,558	omim	https://www.omim.org/entry/211890	2019-09-22T16:30:15	{"mesh": ["C537966"], "omim": ["211890"], "orphanet": ["1318"], "synonyms": ["Alternative titles", "CERVICAL LYMPHOCELE WITH BOWED LONG BONES", "CUMMING SYNDROME"]}
A rare, genetic, spondyloepimetaphyseal dysplasia disease characterized by short-limbed short stature (more pronounced in lower limbs) associated with characterisitic facial dysmorphism (i.e. relative macrocephaly, frontal bossing, midface hypoplasia, depressed nasal root, small upturned nose, prognathism) and abnormal radiological findings, which include abnormal vertebral bodies (particularly in the lumbar region), striated metaphyses, generalized mild osteoporosis, and delayed ossification of the carpal bones. Progressive coxa vara, short dental roots, hypogammaglobulinemia and cataracts may be occasionally associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPONASTRIME dysplasia	c1300260	3,559	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93357	2021-01-23T16:59:18	{"gard": ["4970"], "mesh": ["C535786"], "omim": ["271510"], "umls": ["C1300260"], "icd-10": ["Q77.7"], "synonyms": ["Spondylar and nasal changes with striations of the metaphyses (SPONASTRIME) dysplasia", "Spondyloepimetaphyseal dysplasia, Sponastrime type"]}
"CRSD" redirects here. For the Oracle Cluster Ready Services daemon (CRSd), see Oracle Clusterware. For the school district in Alaska, see Copper River School District. Family of sleep disorders which affect the timing of sleep Circadian rhythm sleep disorder Other namesCircadian rhythm sleep-wake disorders SpecialtyNeurology, Chronobiology Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be caused either by dysfunction in one's biological clock system, or by misalignment between one's endogenous oscillator and externally imposed cues. As a result of this mismatch, those affected by circadian rhythm sleep disorders have a tendency to fall asleep at unconventional time points in the day. These occurrences often lead to recurring instances of disturbed rest, where individuals affected by the disorder are unable to go to sleep and awaken at "normal" times for work, school, and other social obligations. Humans, like most living organisms, have various biological rhythms. These biological clocks control processes that fluctuate daily (e.g. body temperature, alertness, hormone secretion), generating circadian rhythms. Among these physiological characteristics, our sleep-wake propensity can also be considered one of the daily rhythms regulated by the biological clock system. Our sleeping cycles are tightly regulated by a series of circadian processes working in tandem, which allow us to experience moments of consolidated sleep during the night and a long wakeful moment during the day. Conversely, disruptions to these processes and the communication pathways between them can lead to problems in sleeping patterns, which are collectively referred to as circadian rhythm sleep disorders. ## Contents * 1 Normal rhythm * 2 Diagnosis * 3 Types * 3.1 Intrinsic * 3.2 Extrinsic * 4 Alzheimer's disease * 5 Treatment * 6 See also * 7 References * 8 External links ## Normal rhythm[edit] A circadian rhythm is an entrainable, endogenous, biological activity that has a period of roughly twenty-four hours. This internal time-keeping mechanism is centralized in the suprachiasmatic nucleus (SCN) of humans and allows for the internal physiological mechanisms underlying sleep and alertness to become synchronized to external environmental cues, like the light-dark cycle.[1] The SCN also sends signals to peripheral clocks in other organs, like the liver, to control processes such as glucose metabolism.[2] Although these rhythms will persist in constant light or dark conditions, different Zeitgebers (time givers such as the light-dark cycle) give context to the clock and allow it to entrain and regulate expression of physiological processes to adjust to the changing environment. Genes that help control light-induced entrainment include positive regulators BMAL1 and CLOCK and negative regulators PER1 and CRY.[3] A full circadian cycle can be described as a twenty-four hour circadian day, where circadian time zero (CT 0) marks the beginning of a subjective day for an organism and CT 12 marks the start of subjective night.[4] Humans with regular circadian function have been shown to maintain regular sleep schedules, regulate daily rhythms in hormone secretion, and sustain oscillations in core body temperature.[5] Even in the absence of Zeitgebers, humans will continue to maintain a roughly 24-hour rhythm in these biological activities. Regarding sleep, normal circadian function allows people to maintain balance rest and wakefulness that allows people to work and maintain alertness during the day's activities, and rest at night.[6] Some misconceptions regarding circadian rhythms and sleep commonly mislabel irregular sleep as a circadian rhythm sleep disorder. In order to be diagnosed with CRSD, there must be either a misalignment between the timing of the circadian oscillator and the surrounding environment, or failure in the clock entrainment pathway.[7] Among people with typical circadian clock function, there is variation in chronotypes, or preferred wake and sleep times, of individuals. Although chronotype varies from individual to individual, as determined by rhythmic expression of clock genes, people with typical circadian clock function will be able to entrain to environmental cues. For example, if a person wishes to shift the onset of a biological activity, like waking time, light exposure during the late subjective night or early subjective morning can help advance one's circadian cycle earlier in the day, leading to an earlier wake time.[8] ## Diagnosis[edit] The International Classification of Sleep Disorders classifies Circadian Rhythm Sleep Disorder as a type of sleep dyssomnia. Although studies suggest that 3% of the adult population suffers from a CRSD, many people are often misdiagnosed with insomnia instead of a CRSD. Of adults diagnosed with sleep disorders, an estimated 10% have a CRSD and of adolescents with sleep disorders, an estimated 16% may have a CRSD.[9] Patients diagnosed with circadian rhythm sleep disorders typically express a pattern of disturbed sleep, whether that be excessive sleep that intrudes on working schedules and daily functions, or insomnia at desired times of sleep. Note that having a preference for extreme early or late wake times are not related to a circadian rhythm sleep disorder diagnosis. There must be distinct impairment of biological rhythms that affects the person's desired work and daily behavior. For a CRSD diagnosis, a sleep specialist gathers the history of a patient's sleep and wake habits, body temperature patterns, and dim-light melatonin onset (DLMO).[9] Gathering this data gives insight into the patient's current schedule as well as the physiological phase markers of the patient's biological clock.[citation needed] The start of the CRSD diagnostic process is a thorough sleep history assessment. A standard questionnaire is used to record the sleep habits of the patient, including typical bedtime, sleep duration, sleep latency, and instances of waking up. The professional will further inquire about other external factors that may impact sleep. Prescription drugs that treat mood disorders like tricyclic antidepressants, selective serotonin reuptake inhibitors and other antidepressants are associated with abnormal sleep behaviors. Other daily habits like work schedule and timing of exercise are also recorded because they may impact an individual's sleep and wake patterns. To measure sleep variables candidly, patients wear actigraphy watches that record sleep onset, wake time, and many other physiological variables. Patients are similarly asked to self-report their sleep habits with a week-long sleep diary to document when they go to bed, when they wake up, etc. to supplement the actigraphy data. Collecting this data allows sleep professionals to carefully document and measure patient's sleep habits and confirm patterns described in their sleep history.[9] Other additional ways to classify the nature of a patient's sleep and biological clock are the morningness-eveningness questionnaire (MEQ) and the Munich ChronoType Questionnaire, both of which have fairly strong correlations with accurately reporting phase advanced or delayed sleep.[8] Questionnaires like the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) help gauge the severity of sleep disruption. Specifically, these questionnaires can help the professional assess the patient's problems with sleep latency, undesired early-morning wakefulness, and problems with falling or staying asleep.[9] ## Types[edit] Currently, the International Classification of Sleep Disorders (ICSD-3) lists 6 disorders under the category of circadian rhythm sleep disorders.[10] CRSDs can be categorized into two groups based on their underlying mechanisms: The first category is composed of disorders where the endogenous oscillator has been altered, known as intrinsic type disorders. This category will be referred to as the intrinsic disorder type. The second category consists of disorders in which the external environment and the endogenous circadian clock are misaligned, called extrinsic type CRSDs.[citation needed] ### Intrinsic[edit] * Delayed sleep phase disorder (DSPD): Individuals who have been diagnosed with delayed sleep phase disorder have sleep-wake times which are delayed when compared to normal functioning individuals. People with DSPD typically have very long periods of sleep latency when they attempt to go to sleep during conventional sleeping times. Similarly, they also have trouble waking up at conventional times.[citation needed] * Advanced sleep phase disorder (ASPD): People with advanced sleep phase disorder exhibit characteristics opposite to those with delayed sleep phase disorder. These individuals have advanced sleep wake times, so they tend to go to bed and wake up much earlier as compared to normal individuals. ASPD is less common than DSPD, and is most prevalent within older populations.[citation needed] * Familial Advanced Sleep Phase Syndrome (FASPS) is linked to an autosomal dominant mode of inheritance. It is associated with a missense mutation in human PER2 that replaces Serine for a Glycine at position 662 (S662G).[11] Families that have this mutation in PER2 experience extreme phase advances in sleep, waking up around 2 AM and going to bed around 7 PM. * Irregular sleep–wake rhythm disorder (ISWRD) is characterized by a normal 24-hr sleeping period. However, individuals with this disorder experience fragmented and highly disorganized sleep that can manifest in the form of waking frequently during the night and taking naps during the day, yet still maintaining sufficient total time asleep. People with ISWRD often experience a range of symptoms from insomnia to excessive daytime sleepiness.[citation needed] * Most common in individuals that are blind and unable to detect light, Non-24-hour sleep–wake disorder (N24SWD) is characterized by chronic patterns of sleep/wake cycles which are not entrained to the 24-hr light-dark environmental cycle. As a result of this, individuals with this disorder will usually experience a gradual yet predictable delay of sleep onset and waking times. Patients with DSPD may develop this disorder if their condition is untreated.[citation needed] ### Extrinsic[edit] * Shift work sleep disorder (SWSD): Approximately 9% of Americans who work night or irregular work shifts are believed to experience Shift work sleep disorder.[12] Night shift work directly opposes the environmental cues that entrain our biological clock, so this disorder arises when an individual's clock is unable to adjust to the socially imposed work schedule. Shift work sleep disorder can lead to severe cases of insomnia as well as excessive daytime sleepiness.[citation needed] * Jet lag: Jet lag is best characterized by difficulty falling asleep or staying asleep as a result of misalignment between one's internal circadian system and external, or environmental cues. It is typically associated with rapid travel across multiple time zones.[10] ## Alzheimer's disease[edit] CRSD has been frequently associated with excessive daytime sleepiness and nighttime insomnia in patients diagnosed with Alzheimer's disease (AD), representing a common characteristic among AD patients as well as a risk factor of progressive functional impairments.[13][14][15] On one hand, it has been stated that people with AD have melatonin alteration and high irregularity in their circadian rhythm that lead to a disrupted sleep-wake cycle, probably due to damage on hypothalamic SCN regions typically observed in AD.[14][15] On the other hand, disturbed sleep and wakefulness states have been related to worsening of an AD patient's cognitive abilities, emotional state and quality of life.[13][14][15] Moreover, the abnormal behavioural symptoms of the disease negatively contribute to overwhelming patient's relatives and caregivers as well.[13][14] However, the impact of sleep-wake disturbances on the subjective experience of a person with AD is not yet fully understood.[14] Therefore, further studies exploring this field have been highly recommended, mainly considering the increasing life expectancy and significance of neurodegenerative diseases in clinical practices.[15] ## Treatment[edit] Possible treatments for circadian rhythm sleep disorders include: * Chronotherapy, best shown to effectively treat delayed sleep phase disorder, acts by systematically delaying an individual's bedtime until their sleep-wake times coincide with the conventional 24-hr day.[citation needed] * Light therapy utilizes bright light exposure to induce phase advances and delays in sleep and wake times. This therapy requires 30–60 minutes of exposure to a bright (5,000-10,000 lux) white, blue, or natural light at a set time until the circadian clock is aligned with the desired schedule.[7][16] Treatment is initially administered either upon awakening or before sleeping, and if successful may be continued indefinitely or performed less frequently.[17] Though proven very effective in the treatment of individuals with DSPD and ASPD, the benefits of light therapy on N24SWD, shift work disorder, and jet lag have not been studied as extensively. * Hypnotics have also been used clinically alongside bright light exposure therapy and pharmacotherapy for the treatment of CRSDs such as Advanced Sleep Phase Disorder.[18] Additionally, in conjunction with cognitive behavioral therapy, short-acting hypnotics also present an avenue for treating co-morbid insomnia in patients suffering from circadian sleep disorders.[citation needed] * Melatonin, a naturally occurring biological hormone with circadian rhythmicity, has been shown to promote sleep and entrainment to external cues when administered in drug form (0.5-5.0 mg). Melatonin administered in the evening causes phase advances in sleep-wake times while maintaining duration and quality of sleep. Similarly, when administered in the early morning, melatonin can cause phase delays. It has been shown most effective in cases of shift work sleep disorder and delayed phase sleep disorder, but has not been proven particularly useful in cases of jet lag.[16] * Dark therapy, for example, the use of blue-blocking goggles, is used to block blue and blue-green wavelength light from reaching the eye during evening hours so as not to hinder melatonin production.[19] ## See also[edit] * Chronobiology * Light effects on circadian rhythm * Phase response curve * Sleep diary * Sleep medicine ## References[edit] 1. ^ Toh KL (August 2008). "Basic science review on circadian rhythm biology and circadian sleep disorders". Annals of the Academy of Medicine, Singapore. 37 (8): 662–8. PMID 18797559. 2. ^ Dibner C, Schibler U, Albrecht U (2010-03-17). "The mammalian circadian timing system: organization and coordination of central and peripheral clocks" (PDF). Annual Review of Physiology. 72 (1): 517–49. doi:10.1146/annurev-physiol-021909-135821. PMID 20148687. 3. ^ Dunlap JC (January 1999). "Molecular bases for circadian clocks". Cell. 96 (2): 271–90. doi:10.1016/s0092-8674(00)80566-8. PMID 9988221. S2CID 14991100. 4. ^ Vitaterna MH, Takahashi JS, Turek FW (December 2001). "Overview of circadian rhythms". Alcohol Research & Health. 25 (2): 85–93. PMC 6707128. PMID 11584554. 5. ^ Farhud D, Aryan Z (August 2018). "Circadian Rhythm, Lifestyle and Health: A Narrative Review". Iranian Journal of Public Health. 47 (8): 1068–1076. PMC 6123576. PMID 30186777. 6. ^ "Body Clock & Sleep - National Sleep Foundation". www.sleepfoundation.org. Retrieved 2019-04-10. 7. ^ a b Dodson ER, Zee PC (December 2010). "Therapeutics for Circadian Rhythm Sleep Disorders". Sleep Medicine Clinics. 5 (4): 701–715. doi:10.1016/j.jsmc.2010.08.001. PMC 3020104. PMID 21243069. 8. ^ a b Zhu L, Zee PC (November 2012). "Circadian rhythm sleep disorders". Neurologic Clinics. 30 (4): 1167–91. doi:10.1016/j.ncl.2012.08.011. PMC 3523094. PMID 23099133. 9. ^ a b c d Kim MJ, Lee JH, Duffy JF (November 2013). "Circadian Rhythm Sleep Disorders". Journal of Clinical Outcomes Management. 20 (11): 513–528. PMC 4212693. PMID 25368503. 10. ^ a b Sateia MJ (November 2014). "International classification of sleep disorders-third edition: highlights and modifications". Chest. 146 (5): 1387–1394. doi:10.1378/chest.14-0970. PMID 25367475. 11. ^ Jones CR, Huang AL, Ptáček LJ, Fu YH (May 2013). "Genetic basis of human circadian rhythm disorders". Experimental Neurology. 243: 28–33. doi:10.1016/j.expneurol.2012.07.012. PMC 3514403. PMID 22849821. 12. ^ Di Milia L, Waage S, Pallesen S, Bjorvatn B (2013-01-25). Gamble KL (ed.). "Shift work disorder in a random population sample--prevalence and comorbidities". PLOS ONE. 8 (1): e55306. Bibcode:2013PLoSO...855306D. doi:10.1371/journal.pone.0055306. PMC 3555931. PMID 23372847. 13. ^ a b c Malkani, R., & Attarian, H. (2015). Sleep in Neurodegenerative Disorders. Current Sleep Medicine Reports, 1(2), 81-90. 14. ^ a b c d e Dick-Muehlke, C. (2015). Psychosocial studies of the individual's changing perspectives in Alzheimer's disease (Premier Reference Source). Hershey, PA: Medical Information Science Reference. 15. ^ a b c d Zhong G, Naismith SL, Rogers NL, Lewis SJG (2011). "Sleep–wake disturbances in common neurodegenerative diseases: A closer look at selected aspects of the neural circuitry". Journal of the Neurological Sciences. 307 (1–2): 9–14. doi:10.1016/j.jns.2011.04.020. PMID 21570695. S2CID 44744844.CS1 maint: multiple names: authors list (link) 16. ^ a b Dagan Y (February 2002). "Circadian rhythm sleep disorders (CRSD)". Sleep Medicine Reviews. 6 (1): 45–54. doi:10.1053/smrv.2001.0190. PMID 12531141. S2CID 45059503. 17. ^ Dijk DJ, Boulos Z, Eastman CI, Lewy AJ, Campbell SS, Terman M (June 1995). "Light treatment for sleep disorders: consensus report. II. Basic properties of circadian physiology and sleep regulation". Journal of Biological Rhythms. 10 (2): 113–25. doi:10.1177/074873049501000204. PMID 7632985. S2CID 9788704. 18. ^ Barion A, Zee PC (September 2007). "A clinical approach to circadian rhythm sleep disorders". Sleep Medicine. 8 (6): 566–77. doi:10.1016/j.sleep.2006.11.017. PMC 2679862. PMID 17395535. 19. ^ "Blue light has a dark side". Harvard Health Letter. May 2012. ## External links[edit] Classification D * ICD-10: F51.2, G47.2 * ICD-9-CM: 327.3, 780.55 * MeSH: D021081 * Circadian Sleep Disorders Network * An American Academy of Sleep Medicine Review: Circadian Rhythm Sleep Disorders: Part I, Basic Principles, Shift Work and Jet Lag Disorders. PDF, 24 pages. November 2007. * An American Academy of Sleep Medicine Review: Circadian Rhythm Sleep Disorders: Part II, Advanced Sleep Phase Disorder, Delayed Sleep Phase Disorder, Free-Running Disorder, and Irregular Sleep–Wake Rhythm. PDF, 18 pages. November 2007. * An American Academy of Sleep Medicine Report: Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders, November 1, 2007 * NASA Sleep–Wake Actigraphy and Light Exposure During Spaceflight-Long Experiment * v * t * e Sleep and sleep disorders Stages of sleep cycles * Rapid eye movement (REM) * Non-rapid eye movement * Slow-wave Brain waves * Alpha wave * Beta wave * Delta wave * Gamma wave * K-complex * Mu rhythm * PGO waves * Sensorimotor rhythm * Sleep spindle * Theta wave Sleep disorders Dyssomnia * Excessive daytime sleepiness * Hypersomnia * Insomnia * Kleine–Levin syndrome * Narcolepsy * Night eating syndrome * Nocturia * Sleep apnea * Catathrenia * Central hypoventilation syndrome * Obesity hypoventilation syndrome * Obstructive sleep apnea * Periodic breathing * Sleep state misperception Circadian rhythm disorders * Advanced sleep phase disorder * Cyclic alternating pattern * Delayed sleep phase disorder * Irregular sleep–wake rhythm * Jet lag * Non-24-hour sleep–wake disorder * Shift work sleep disorder Parasomnia * Bruxism * Nightmare disorder * Night terror * Periodic limb movement disorder * Rapid eye movement sleep behavior disorder * Sleepwalking * Somniloquy Benign phenomena * Dreams * Exploding head syndrome * Hypnic jerk * Hypnagogia / Sleep onset * Hypnopompic state * Sleep paralysis * Sleep inertia * Somnolence * Nocturnal clitoral tumescence * Nocturnal penile tumescence * Nocturnal emission Treatment * Sleep diary * Sleep hygiene * Sleep induction * Hypnosis * Lullaby * Somnology * Polysomnography Other * Sleep medicine * Behavioral sleep medicine * Sleep study Daily life * Bed * Bunk bed * Daybed * Four-poster bed * Futon * Hammock * Mattress * Sleeping bag * Bed bug * Bedding * Bedroom * Bedtime * Bedtime story * Bedtime toy * Biphasic and polyphasic sleep * Chronotype * Dream diary * Microsleep * Mouth breathing * Nap * Nightwear * Power nap * Second wind * Siesta * Sleep and creativity * Sleep and learning * Sleep deprivation / Sleep debt * Sleeping while on duty * Sleepover * Snoring [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Circadian rhythm sleep disorder	c0236811	3,560	wikipedia	https://en.wikipedia.org/wiki/Circadian_rhythm_sleep_disorder	2021-01-18T18:39:11	{"mesh": ["D021081", "D020178"], "umls": ["C0236811"], "icd-9": ["780.55", "327.3"], "icd-10": ["G47.2"], "wikidata": ["Q2712607"]}
Tietz syndrome is a rare condition characterized by hearing loss, fair skin, and light-colored hair. The hearing loss in affected individuals is caused by abnormalities of the inner ear (sensorineural hearing loss) and is present from birth. People with Tietz syndrome are born with white hair and very pale skin but their hair color often darkens over time; The colored part of the eye (the iris) is blue. It is caused by changes (mutations) in the MITF gene which affects the development of melanocytes. The inheritance is autosomal dominant. The goal of treatment is to improve hearing; cochlear implantation may be considered. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Tietz syndrome	c0391816	3,561	gard	https://rarediseases.info.nih.gov/diseases/7772/tietz-syndrome	2021-01-18T17:57:21	{"mesh": ["C536919"], "omim": ["103500"], "umls": ["C0391816"], "orphanet": ["42665"], "synonyms": ["Albinism-deafness of Tietz", "Hypopigmentation/deafness of Tietz", "Tietz albinism-deafness syndrome"]}
Distal hereditary motor neuropathy, type II is a progressive disorder that affects nerve cells in the spinal cord. It results in muscle weakness and affects movement, primarily in the legs. Onset of distal hereditary motor neuropathy, type II ranges from the teenage years through mid-adulthood. The initial symptoms of the disorder are cramps or weakness in the muscles of the big toe and later, the entire foot. Over a period of approximately 5 to 10 years, affected individuals experience a gradual loss of muscle tissue (atrophy) in the lower legs. They begin to have trouble walking and running, and eventually may have complete paralysis of the lower legs. The thigh muscles may also be affected, although generally this occurs later and is less severe. Some individuals with distal hereditary motor neuropathy, type II have weakening of the muscles in the hands and forearms. This weakening is less pronounced than in the lower limbs and does not usually result in paralysis. ## Frequency The prevalence of distal hereditary motor neuropathy, type II is unknown. At least 25 affected families have been identified worldwide. ## Causes Mutations in the HSPB1 and HSPB8 genes cause distal hereditary motor neuropathy, type II. These genes provide instructions for making proteins called heat shock protein beta-1 and heat shock protein beta-8. Heat shock proteins help protect cells under adverse conditions such as infection, inflammation, exposure to toxins, elevated temperature, injury, and disease. They block signals that lead to programmed cell death. In addition, they appear to be involved in activities such as cell movement (motility), stabilizing the cell's structural framework (the cytoskeleton), folding and stabilizing newly produced proteins, and repairing damaged proteins. Heat shock proteins also appear to play a role in the tensing of muscle fibers (muscle contraction). Heat shock protein beta-1 and heat shock protein beta-8 are found in cells throughout the body and are abundant in nerve cells. In nerve cells, heat shock protein beta-1 helps to organize a network of molecular threads called neurofilaments that maintain the diameter of specialized extensions called axons. Maintaining proper axon diameter is essential for the efficient transmission of nerve impulses. The function of heat shock protein beta-8 is not well understood, but studies have shown that it interacts with heat shock protein beta-1. The HSPB1 and HSPB8 gene mutations that cause distal hereditary motor neuropathy, type II change single protein building blocks (amino acids) in the protein sequence. If either protein is altered, they may be more likely to cluster together and form clumps (aggregates). Aggregates of heat shock proteins may block the transport of substances that are essential for the proper function of nerve axons. The disruption of other cell functions in which these proteins are involved may also contribute to the signs and symptoms of distal hereditary motor neuropathy, type II. ### Learn more about the genes associated with Distal hereditary motor neuropathy, type II * HSPB1 * HSPB8 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Distal hereditary motor neuropathy, type II	c1834692	3,562	medlineplus	https://medlineplus.gov/genetics/condition/distal-hereditary-motor-neuropathy-type-ii/	2021-01-27T08:24:55	{"mesh": ["C563561"], "omim": ["158590", "608634"], "synonyms": []}
Paraneoplastic syndromes are a group of rare disorders that include paraneoplastic cerebellar degeneration (PCD). Paraneoplastic syndromes are thought to result from an abnormal immune response to an underlying (and often undetected) malignant tumor. PCD is a rare, non-metastatic complication of cancer. PCD is typically thought to be caused by antibodies generated against tumor cells. Instead of just attacking the cancer cells, the cancer-fighting antibodies also attack normal cells in the cerebellum. PCD occurs most often in individuals with the following cancers: ovarian cancer, cancer of the uterus, breast cancer, small-cell lung cancer, and Hodgkin lymphoma. Symptoms of PCD may include dizziness, loss of coordination, blurred vision, nystagmus, ataxia, and speech difficulties. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Paraneoplastic cerebellar degeneration	c0393534	3,563	gard	https://rarediseases.info.nih.gov/diseases/7326/paraneoplastic-cerebellar-degeneration	2021-01-18T17:58:26	{"mesh": ["D020362"], "umls": ["C0393534"], "synonyms": []}
## Summary ### Clinical characteristics. The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM. ### Diagnosis/testing. The diagnosis of a dystrophinopathy is established in a proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic variant in DMD on molecular genetic testing in a male and of a heterozygous pathogenic variant in DMD on molecular genetic testing in a female. Females may present with a classic dystrophinopathy or may be asymptomatic carriers. ### Management. Treatment of manifestations: ACE inhibitors are used with or without beta blockers for cardiomyopathy in both DMD and BMD phenotypes. Congestive heart failure is treated with diuretics and oxygen as needed; cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. Scoliosis is treated with bracing and surgery. Corticosteroid therapy improves muscle strength and function for individuals with DMD between ages five and 15 years; the same treatment is used in BMD, although the efficacy is less clear. Prevention of secondary complications: Evaluation by a pulmonologist and cardiologist before surgeries; pneumococcal and influenza immunizations annually; nutrition assessment; physical therapy to promote mobility and prevent contractures; sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures; weight control to avoid obesity. Surveillance: For males with DMD or BMD: annual or biannual evaluation by a cardiologist beginning at the time of diagnosis; monitoring for scoliosis; baseline pulmonary function testing before wheelchair dependence; frequent evaluations by a pediatric pulmonologist. For heterozygous females: cardiac evaluation at least once after the teenage years. Agents/circumstances to avoid: Botulinum toxin injections; succinylcholine and inhalational anesthetics because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions. Evaluation of relatives at risk: Early identification of heterozygous females who are at increased risk for cardiomyopathy and, thus, need routine cardiac surveillance and prompt treatment. ### Genetic counseling. The dystrophinopathies are inherited in an X-linked manner. The risk to the sibs of a proband depends on the genetic status of the mother. Heterozygous females have a 50% chance of transmitting the DMD pathogenic variant in each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant are heterozygous and may have a range of clinical manifestations. Males with DMD usually do not reproduce. Males with BMD or DMD-associated DCM may reproduce: all of their daughters are heterozygotes; none of their sons inherit their father's DMD pathogenic variant. Carrier testing for at-risk females and prenatal testing or preimplantation genetic diagnosis for pregnancies at increased risk are possible if the DMD pathogenic variant in the family is known. ## Diagnosis The dystrophinopathies cover a spectrum of X-linked muscle disease that ranges from mild to severe and includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). ### Suggestive Findings A dystrophinopathy should be suspected in an individual with the following clinical and laboratory test findings that support the diagnosis of Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or DMD-associated dilated cardiomyopathy (DCM) – especially when they occur in addition to a positive family history compatible with X-linked inheritance. Findings are most commonly noted in males, but females may also be affected. #### Clinical Findings Duchenne muscular dystrophy (DMD) * Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy * Symptoms present before age five years * Wheelchair dependency before age 13 years Becker muscular dystrophy (BMD) * Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign * Activity-induced cramping (present in some individuals) * Flexion contractures of the elbows (if present, late in the course) * Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond * Preservation of neck flexor muscle strength (differentiates BMD from DMD) Note: The presence of fasciculations or loss of sensory modalities excludes a suspected diagnosis of a dystrophinopathy. Individuals with an intermediate phenotype (outliers) have symptoms of intermediate severity and become wheelchair dependent between ages 13 and 16 years. DMD-associated dilated cardiomyopathy (DCM) * Dilated cardiomyopathy (DCM) with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life * Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD * Rapid progression to death in several years in males and slower progression over a decade or more in females [Beggs 1997] See also Dilated Cardiomyopathy Overview. #### Laboratory Testing Serum creatine phosphokinase (CK) concentration (Table 1) ### Table 1. Serum Creatine Phosphokinase (CK) Concentration in the Dystrophinopathies View in own window Phenotype% of Affected IndividualsSerum CK Concentration MalesDMD100% 1>10x normal BMD100% 1>5x normal DMD-associated DCMMost individuals 2"Increased" Female carriersDMD~50% 3, 42-10x normal BMD~30% 3, 42-10x normal 1\. Serum CK concentration gradually decreases with advancing age as a result of the progressive elimination of dystrophic muscle fibers that are the source of the elevated serum CK concentration [Hoffman et al 1988, Zatz et al 1991]. 2\. Serum CK concentrations are usually increased, but normal concentrations have been reported in DMD-associated DCM [Mestroni et al 1999]. 3\. Hoogerwaard et al [1999b] 4\. Other investigations have confirmed a wide variability in serum CK concentration among DMD/BMD carriers with the mean serum CK concentration significantly higher in carriers age <20 years than in those age >20 years [Sumita et al 1998]. ### Establishing the Diagnosis Male proband. The diagnosis of a dystrophinopathy is established in a male proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic variant in DMD on molecular genetic testing (see Table 1). Female proband. The diagnosis of a dystrophinopathy is usually established in a female proband with characteristic clinical findings and elevated CK concentration and/or by identification of a heterozygous pathogenic variant in DMD on molecular genetic testing (see Table 1). Females may present with a classic dystrophinopathy or may be asymptomatic carriers. * Females with a classic dystrophinopathy. The genetic mechanisms that can explain this rare occurrence (and testing to identify the cause) include the following: * A deletion involving Xp21.2 (microarray [CMA] studies) * An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) * Uniparental disomy (UPD) of the X chromosome (UPD studies) * Compound heterozygosity for two DMD pathogenic variants [Soltanzadeh et al 2010] (deletion/duplication analysis and/or sequence analysis) * Nonrandom X-chromosome inactivation (XCI). See Genotype-Phenotype Correlations. * Carrier testing for at-risk female relatives. Note: Carriers are heterozygotes for this X-linked disorder and may later develop clinical findings related to the disorder (see Clinical Characteristics and Management, Evaluation of Relatives at Risk for testing recommendations). Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Because the majority of pathogenic variants involve deletions of one or more exons, gene-targeted deletion/duplication analysis of DMD is performed first and followed by sequence analysis if no pathogenic variant is found. * A multigene panel that includes DMD and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Note: (1) A multigene panel may be most appropriate for individuals with less severe clinical presentations. Men with the BMD phenotype and most women may not have findings clinically distinct enough to suggest single-gene testing of DMD as the initial test. (2) Chromosomal microarray analysis (CMA) may: * Be appropriate if not already performed, to identify multiple gene deletions/duplications (including DMD); * Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as retinitis pigmentosa, chronic granulomatous disease, and McLeod red cell phenotype (see McLeod neuroacanthocytosis syndrome) [Francke et al 1985] or glycerol kinase deficiency and adrenal hypoplasia [Darras & Francke 1988] to suggest a contiguous gene disorder; * Detect an unexpected or incidental DMD deletion/duplication in an asymptomatic individual. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered, particularly if the presentation is atypical. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic given the frequency of DMD deletions or duplications associated with dystrophinopathy. ### Table 2. Molecular Genetic Testing Used in Dystrophinopathies View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method DMDSequence analysis 3, 420%-35% Gene-targeted deletion/duplication analysis 5, 665%-80% 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Chromosomal microarray analysis (CMA) may detect DMD deletions or duplications either as part of a contiguous gene deletion syndrome or as an incidental or unexpected intragenic finding. Given that the sensitivity of CMA is not sufficient to detect all exon-level DMD deletions and duplications, CMA is not recommended as a primary assay for dystrophinopathies. Note: If no DMD pathogenic variant is identified, skeletal muscle biopsy of individuals with suspected DMD or BMD is warranted for western blot and immunohistochemistry studies of dystrophin. Skeletal muscle biopsy continues to be used only rarely in the diagnosis of dystrophinopathies. * Muscle histology early in the disease shows nonspecific dystrophic changes, including variation in fiber size, foci of necrosis and regeneration, hyalinization, increased internal nuclei, fiber splitting, inflammatory changes, and, later in the disease, deposition of fat and connective tissue. * Western blot and immunohistochemistry are summarized in Table 3. ### Table 3. Findings in the Dystrophin Protein from Skeletal Muscle Biopsy View in own window PhenotypeWestern BlotImmunohistochemistry 3 Dystrophin Mol Wt 1Dystrophin Quantity 2 MalesDMDUndetectable0%-5%Complete or almost complete absence IntermediateNormal/ abnormal5%-20% BMDNormal20%-50%Normal appearing or reduced intensity ± patchy staining Abnormal20%-100% Heterozygous FemalesDMD random XCI 4Normal/ abnormal>60% 5, 6 (70%±9%)Normal or minor changes or mosaic pattern; dystrophin-negative fibers (9%±2%) 5 DMD skewed XCI 7Normal/ abnormal<30% on average (29%±25%) 5Mosaic pattern; dystrophin-negative fibers (44%±33%) 5 Mol Wt = molecular weight; XCI = X-chromosome inactivation 1\. Normal molecular mass is 427 kb. 2\. The quantity of dystrophin is expressed in percent of control values. The reference ranges shown in this table are the ones currently used by clinical laboratories and reflect approximate and reconciled data from the literature. 3\. Uses monoclonal antibodies to the C terminus, N terminus, and rod domain of dystrophin [Hoffman et al 1988] 4\. Asymptomatic to mild disability 5\. Pegoraro et al [1995] 6\. Quantitative analysis of dystrophin in female carriers is not useful in clinical practice because of the wide range of values and the significant overlap with normal values. 7\. Mild, intermediate, severe symptoms. Carriers with mild disease were young (age 5-10 years) [Pegoraro et al 1995]. ## Clinical Characteristics ### Clinical Description #### Males The dystrophinopathies cover a spectrum of muscle disease that ranges from mild to severe. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of CK and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) when skeletal muscle is primarily affected and as DMD-associated dilated cardiomyopathy (DCM) when the heart is primarily affected [Beggs 1997, Cox & Kunkel 1997, Muntoni et al 2003]. DMD vs BMD vs DMD-associated DCM. The distinction between DMD and BMD is based on the age of wheelchair dependency: before age 13 years in DMD and after age 16 years in BMD. An intermediate group of individuals who become wheelchair bound between ages 13 and 16 years is also recognized. Additionally, some investigators have extended the mild end of the BMD spectrum to include individuals with elevated serum CK concentration and abnormal dystrophin on muscle biopsy, but with "subclinical" skeletal muscle involvement [Melacini et al 1996]. When these individuals with atypical disease develop severe cardiomyopathy, it is not possible to distinguish between BMD and DMD-associated DCM [Cox & Kunkel 1997]. Cardiac involvement is usually asymptomatic in the early stages of the disease, although sinus tachycardia and various ECG abnormalities may be noted. Echocardiography is normal or shows only regional abnormalities. Pericardial effusion with cardiac tamponade and myocardial inflammation precipitating heart failure has been described in people with DMD [Lin et al 2009, Mavrogeni et al 2010]. Subclinical or clinical cardiac involvement is present in approximately 90% of individuals with DMD or BMD; however, cardiac involvement is the cause of death in only 20% of individuals with DMD and 50% of those with BMD [Hermans et al 2010]. DMD-associated DCM generally presents with congestive heart failure secondary to an increase in ventricular size and impairment of ventricular function. In males, DCM is rapidly progressive with onset in teenage years, leading to death from heart failure within one to two years after the diagnosis [Finsterer & Stollberger 2003]. Individuals with DCM may or may not have clinical evidence of skeletal muscle disease [Neri et al 2007]. DMD Motor development. DMD usually presents in early childhood with delayed motor milestones, including delays in walking independently and standing up from the floor. The mean age of walking is approximately 18 months (range 12-24 months). The first symptoms of DMD as identified by parents are typically: general motor delays (42%); gait problems including persistent toe-walking and flat-footedness (30%); delay in walking (20%); learning difficulties (5%); and speech problems (3%). The mean age of diagnosis of boys with DMD without a family history of DMD is approximately four years ten months (range: 16 months - 8 years) [Bushby 1999, Zalaudek et al 1999]. A recent study reported a mean age of 41 months at diagnosis of DMD [D'Amico et al 2017]. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position [Li et al 2012, Liang et al 2018]. Boys use the Gower maneuver to rise from a supine position, using the arms to supplement weak pelvic girdle muscles. The calf muscles are hypertrophic and firm to palpation. Occasionally there is calf pain. DMD is rapidly progressive, with affected children being wheelchair bound by age 12 years [Darras et al 2015]. Cardiomyopathy. Among children with DMD, the incidence of cardiomyopathy increases steadily in the teenage years, with approximately one third of individuals being affected by age 14 years, one half by age 18 years, and all individuals after age 18 years [Nigro et al 1990]. Cognitive abilities. Some degree of non-progressive cognitive impairment in boys with DMD has long been known. This was initially described as a general "leftward shift" in the spectrum of IQ scores of a population with DMD compared to the population at large. Earlier reports had suggested that verbal IQ was more affected than performance IQ on the Wechsler Intelligence Scales. A retrospective study by Banihani et al [2015] demonstrated that in their sample, 27% of the boys had IQ <70, with 19% overall fulfilling all criteria for intellectual disability (ID). A learning disability was present in 44%, attention-deficit hyperactivity disorder (ADHD) in 32%, autism spectrum disorder (ASD) in 15%, and anxiety in 27%. No significant correlation was seen between these neuropsychiatric conditions and dystrophin isoforms. Ricotti et al [2016] accessed 130 males with DMD from four European centers and reviewed IQ assessment and a screening questionnaire. Of the original 130, 87 then underwent more extensive testing. Comparable rates of ID, ASD, ADHD, learning disability, and anxiety were observed. These retrospective studies thus suggest increased rates of ID, ASD, ADHD, and learning disability in boys with DMD compared to the population at large. Battini et al [2018] engaged in a prospective assessment of 40 boys with DMD. Their work showed that in boys without frank ID, executive functions such as multitasking, problem solving, inhibition, and working memory were affected out of proportion to overall cognitive function. They suggested that DMD was therefore associated with deficits in "executive function" in boys who did not demonstrate ID. This confirms the retrospective work of Wicksell et al [2004], who demonstrated that boys with DMD who did not have ID showed deficits in active working memory in both verbal and visuospatial domains. It also confirms the retrospective study of Hinton et al [2001], who demonstrated short-term verbal memory issues in boys with DMD who did not have ID. All of these studies thus suggest that the earlier allegation of poorer verbal function in boys with DMD and without ID was better explained by deficits in executive function, which could also lead to visuospatial difficulties in certain settings. Mobility. DMD is associated with reduced mobility. Thus, boys with DMD have decreased bone density and are at increased risk for fractures. Corticosteroids further increase the risk of vertebral compression fractures, many of which are asymptomatic. Life span. Despite improvement of survival, few affected individuals survive beyond the third decade [Passamano et al 2012]. Respiratory complications and progressive cardiomyopathy are common causes of death. A study of individuals with molecularly confirmed diagnoses has determined a median survival of 24 years, with ventilated patients reaching a median survival of 27 years [Rall & Grimm 2012]. In a cohort of affected individuals having both spinal surgery and nocturnal ventilation, the median survival was 30 years [Eagle et al 2007]. Because death frequently occurs outside the hospital setting, the cause of death is often difficult to determine [Parker et al 2005]. BMD Motor development. BMD is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s [Yazaki et al 1999]. Mildly affected individuals with confirmatory DMD molecular genetic studies and/or dystrophin studies on muscle biopsy have been classified as having either of the following [Melacini et al 1996]: * BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria * "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle Cardiomyopathy. While skeletal muscle involvement is milder in BMD, heart failure from DCM is a common cause of morbidity and the most common cause of death [Cox & Kunkel 1997]. Mean age at cardiomyopathy diagnosis is 14.6 years, similar to that in DMD (14.4 years) [Connuck et al 2008]. Heart transplantation rate in BMD is high within five years after the diagnosis of cardiomyopathy [Connuck et al 2008, Kamdar & Garry 2016]. Mean age of death is in the mid-40s [Bushby 1999]. Cognitive abilities. Cognitive impairment is not as common or as severe in BMD as in DMD. DMD-associated DCM In 1987, a five-generation, 63-member family with DCM but no evidence of skeletal myopathy was reported. Males present in their teens and twenties; the disease course is rapidly progressive and associated ventricular arrhythmias are common. Heterozygous females develop mild dilated cardiomyopathy in the fourth or fifth decade, with slow progression. The only biochemical abnormality is elevation in serum CK concentration. Towbin et al [1993] demonstrated linkage to the dystrophin locus in this family and one other. Subsequent study demonstrated that in individuals with the most severe cardiac phenotype the cardiac muscle is usually unable to produce functional dystrophin in the heart, while in skeletal muscle reduced levels of virtually normal dystrophin transcript and protein are present [Ferlini et al 1999, Neri et al 2007, Neri et al 2012]; see Molecular Genetics. DMD-associated DCM may be the presenting finding in individuals with BMD who have little or no clinical evidence of skeletal muscle disease. Some investigators classify such individuals as having subclinical or benign BMD, whereas others may classify such individuals as having DCM with increased serum CK concentration [Towbin 1998]. In one study of 28 individuals with subclinical and benign BMD between ages six and 48 years, 19 (68%) had myocardial involvement, although only two were symptomatic [Melacini et al 1996]. In another study of 21 individuals ranging from age three to 63 years (mean age 40 years), 33% had cardiac failure despite relatively mild skeletal muscle findings [Saito et al 1996]. DMD is a relatively infrequent cause of DCM. In a cohort of 99 Japanese unrelated adult males and females with familial and sporadic DCM, DMD pathogenic variants were identified in only three males [Shimizu et al 2005]. #### Females In some instances females can have classic DMD (see Establishing the Diagnosis). Signs and symptoms of DMD and BMD were studied among confirmed heterozygous females [Hoogerwaard et al 1999a, Hoogerwaard et al 1999b] (Table 4). In contrast, Nolan et al [2003] found no cardiac abnormalities in 23 proven heterozygotes age 6.2 to 15.9 years (see Penetrance). The prevalence of cardiomyopathy depends on its definition and can vary from 3% to 33% [Mccaffrey et al 2017]. No correlation of phenotype (DMD vs BMD), age, CK level, or muscle symptoms was noted. In another study, however, DCM was more common in functionally symptomatic heterozygous females [Schade van Westrum et al 2011]. ### Table 4. Signs and Symptoms in Females Heterozygous for a DMD Pathogenic Variant View in own window Signs/SymptomsIn Families with DMDIn Families with BMD None76%81% Muscle weakness 119%14% Myalgia/cramps5%5% Left-ventricle dilation19%16% Dilated cardiomyopathy8%0 From Hoogerwaard et al [1999b] 1\. Mild to moderate weakness ### Genotype-Phenotype Correlations If a pathogenic variant is identified, the diagnosis of a dystrophinopathy is established, but the distinction between DMD and BMD can be difficult in some cases. For example, deletion of exons 3-7, the most extensively investigated deletion associated with both phenotypes, has been found in males with DMD and also with BMD [Aartsma-Rus et al 2006]. Reading frame rule. This "rule" states that pathogenic variants that do not alter the reading frame (in-frame deletions/duplications) generally correlate with the milder BMD phenotype, whereas those that alter the reading frame (out-of-frame) generally correlate with the more severe DMD phenotype [Monaco et al 1988]. Therefore, the type of deletion/duplication can distinguish between the DMD and BMD phenotypes with 91%-92% accuracy in young children who represent simplex cases (i.e., a single occurrence in a family) [Aartsma-Rus et al 2006], and in many cases a muscle biopsy is not needed to address the issue of BMD vs DMD. Although exceptions to the "reading frame rule" have been documented to occur at a rate below 10% [Aartsma-Rus et al 2006], more recent studies suggest that this may only hold true for the DMD phenotype, and that the rate of exception may be higher with the BMD phenotype for both deletions and duplications [Kesari et al 2008, Takeshima et al 2010]. Correlation of clinical features with molecular test results is thus very important. In males with DMD and BMD, phenotypes are best correlated with the degree of expression of dystrophin, which is largely determined by the reading frame of the spliced message obtained from the deleted allele [Monaco et al 1988, Koenig et al 1989]. * DMD. Very large deletions may lead to absence of dystrophin expression. Pathogenic variants that disrupt the reading frame include stop variants, some splicing variants, and deletions or duplications. They produce a severely truncated dystrophin protein molecule that is degraded, leading to the more severe DMD phenotype. Exceptions to this "reading frame rule": deletions in protein-binding domains that may severely affect function even when in-frame [Hoffman et al 1991]; and exon-skipping events in which apparently out-of-frame deletions behave as in-frame deletions or vice versa [Chelly et al 1990]. The accuracy of phenotype prediction using this rule is in the range of 91%-92% [Aartsma-Rus et al 2006]. More recent studies suggest that duplications, which occur more commonly in BMD, may result in exceptions to the reading frame rule in a higher proportion of cases, perhaps up to 30% [Kesari et al 2008, Takeshima et al 2010]. Correlation of clinical features with molecular test results is thus very important. Wingeier et al [2011] showed that there was no clear relationship between pathogenic variants seen in males with DMD and specific aspects of cognitive function, or overall performance on standard measures of cognitive abilities. They did note, however, that the lack of the dystrophin isoform Dp140 was associated with greater impairments overall; this observation confirms the findings of a previous study that suggested that dystrophin deletions involving the brain distal isoform Dp140 are associated with intellectual impairment [Felisari et al 2000]. Mild intellectual disability is significantly more common in males with pathogenic variants affecting Dp140; also, most males with pathogenic variants involving the Dp71 isoform are cognitively disabled [Daoud et al 2009, Taylor et al 2010]. Recent work from the French Neuromuscular Network suggests that pathogenic variants in the distal parts of the dystrophin gene are more likely to be associated with cognitive impairment [Mercier et al 2013]. Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain with gradual increase from the embryonic stage to adult. Dp71 is very abundant in the hippocampus and some layers of the cerebral cortex with sublocalization in synaptic membranes, microsomes, synaptic vesicles, and mitochondria. The location of the pathogenic variant appears to correlate with full-scale IQ (FSIQ) values (e.g., pathogenic variants affecting the Dp140 isoform 5' UTR affect FSIQ less than those affecting the Dp140 promoter or coding region) [Taylor et al 2010]. Further, the cumulative loss of isoforms expressed in the central nervous system increases the risk of cognitive deficit [Taylor et al 2010]. * BMD. The BMD phenotype occurs when some dystrophin is produced, usually resulting from deletions or duplications that juxtapose in-frame exons, some splicing variants, and most non-truncating single-base changes that result in translation of a protein product with intact N and C termini. The shorter-than-normal dystrophin protein molecule, which retains partial function, produces the milder BMD phenotype [Deburgrave et al 2007]. Exceptions to the reading frame rule occur more commonly in BMD than in DMD. In one large cohort, a BMD phenotype failed to follow the reading frame rule in approximately 15% of cases caused by deletion, and approximately 34% of cases caused by duplication [Takeshima et al 2010]. Another study also reported exceptions to the reading frame rule in 30% of males with BMD with a duplication [Kesari et al 2008]. Correlation of clinical features with molecular test results is crucial; affected males and their families should be informed that using this rule, phenotype prediction may be less accurate. In men with BMD, deletions involving the amino-terminal domain correlate with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions affecting part of the rod domain and hinge 3 result in a later-onset DCM (mid-40s) [Kaspar et al 2009]. DMD-associated DCM is caused by pathogenic variants in DMD that affect the muscle promoter (PM) and the first exon (E1), resulting in no dystrophin transcripts being produced in cardiac muscle; however, two alternative promoters that are normally only active in the brain (PB) and Purkinje cells (PP) are active in the skeletal muscle, resulting in dystrophin expression sufficient to prevent manifestation of skeletal muscle symptoms [Beggs 1997, Towbin 1998, Yoshida et al 1998]. Other types of pathogenic variants including a novel rod domain duplication of exons 13-16 [Chamberlain et al 2015], missense variants, and deletions in the exon 45-53 region of DMD [Shimizu et al 2005] have been reported in DMD-associated DCM. DMD-associated DCM may also be caused by alteration of epitopes in a region of the protein of particular functional importance to cardiac muscle [Ortiz-Lopez et al 1997] or possibly by pathogenic variants in hypothetic cardiac-specific exons. Abnormalities in cardiac conduction noted in persons with dystrophinopathies may be related to reduced expression of cardiac sodium channel NA(v)1.5 secondary to dystrophin deficiency [Gavillet et al 2006]. See also Dilated Cardiomyopathy Overview. The occurrence of either cardiomyopathy or BMD in the same family raises the possibility of modification of the phenotypic expression of a specific pathogenic variant by epigenetic factors [Palmucci et al 2000]. ### Penetrance Penetrance of dystrophinopathies is complete in males. Penetrance in heterozygous females varies, and may depend in part on patterns of X-chromosome inactivation (XCI). * Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in XCI studies in leukocytes and serum CK concentration, clinical signs, or the proportion of dystrophin-negative fibers observed on muscle biopsy [Sumita et al 1998]. * In another study of seven symptomatic heterozygous females, the XCI pattern was skewed toward non-random in the four with deletions or duplications but was random in the three with pathogenic nonsense variants [Soltanzadeh et al 2010]. * In contrast, Pegoraro et al [1995] showed that more than 90% of heterozygous females with skewed XCI (defined as ≥75% of nuclei harboring the DMD pathogenic variant on the active X-chromosome) as demonstrated from a blood sample develop mild, moderate, or severe muscular dystrophy. Heterozygous females with a mild phenotype were young (i.e., age 5-10 years). * Direct correlation with a skewed XCI pattern was also observed recently in cohorts of symptomatic and asymptomatic DMD/BMD carriers [Giliberto et al 2014, Viggiano et al 2016, Viggiano et al 2017]. However, because the methylation status of the androgen receptor (AR) gene in white blood cells or muscle may not always reflect the methylation status of DMD, the use of the AR methylation assay has limited prognostic value in clinical practice [Juan-Mateu et al 2012]. ### Nomenclature The term "pseudohypertrophic muscular dystrophy" was used in the past; however, it is not used currently because pseudohypertrophy is not unique to the DMD or BMD phenotype. ### Prevalence Prevalence data are not available. The overall incidence of DMD in Canada (Nova Scotia) is one in 4,700 live male births and has remained stable from 1969 to 2008 [Dooley et al 2010a]. The incidence of BMD in northern England is 1:18,450 live male births [Bushby et al 1991]. During the years 1968 to 1978, the incidence of DMD in southeast Norway was 1:3,917 live male births [Tangsrud & Halvorsen 1989]. ## Differential Diagnosis Limb-girdle muscular dystrophy (LGMD) is a group of autosomal recessive and autosomal dominant disorders that are clinically similar to DMD but occur in both sexes. Limb-girdle dystrophies are caused by mutation of genes that encode sarcoglycans and other proteins associated with the muscle cell membrane that interact with dystrophin [Mohassel & Bönnemann 2015]. Testing for deficiency of proteins from the transmembrane sarcoglycan complex and of other proteins is indicated in individuals with dystrophin-positive dystrophies. LGMD type 2I phenotypically resembles DMD and BMD and is caused by biallelic pathogenic variants in FKRP (encoding fukutin-related protein). Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles, and cardiac involvement that may include palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure. Age of onset, severity, and progression of the muscle and cardiac involvement show intra- and interfamilial variation. Clinical variability ranges from early and severe presentation in childhood to a late onset and slowly progressive course. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade. Pathogenic variants in three genes are known to cause EDMD: EMD and FHL1, which cause X-linked EDMD; and LMNA, which causes autosomal dominant EDMD and autosomal recessive EDMD. Spinal muscular atrophy (SMA) is suspected in individuals with poor muscle tone, muscle weakness that spares the face and ocular muscles, and evidence of anterior horn cell involvement, including fasciculations of the tongue and absence of deep tendon reflexes. The onset of weakness ranges from before birth to adolescence or young adulthood. The weakness is symmetric, proximal > distal, and progressive. Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications. SMA is caused by pathogenic variants in SMN1 and inherited in an autosomal recessive manner. Dilated cardiomyopathy (DCM) can be familial or nonfamilial. In a large series in which family studies were performed, one third to one half of individuals had nonfamilial DCM and two thirds had familial DCM. Familial DCM may be inherited in an autosomal dominant, an autosomal recessive, or an X-linked manner. Most familial DCM (probably 80%-90%) appears to be autosomal dominant; X-linked and autosomal recessive forms are less common [Watkins et al 2011]. Barth syndrome, an X-linked disorder caused by mutation of TAZ, is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected individual. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular non-compaction. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. The non-progressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a dystrophinopathy, the following evaluations are recommended if they have not already been completed: * Physical therapy assessment * Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary * At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI [Towbin 2003, Bushby et al 2010b] * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Appropriate management of individuals with a dystrophinopathy can prolong survival and improve quality of life. #### DMD/BMD Phenotypes Cardiomyopathy. Recommendations are based on an American Academy of Pediatrics policy statement and various additional publications [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005, Jefferies et al 2005, Viollet et al 2012] and apply to patients with the DMD or BMD phenotype. * The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. * When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [Viollet et al 2012]. * The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [Jefferies et al 2005, Viollet et al 2012]. * Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [Allen et al 2013]. * In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. * Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. Scoliosis treatment as needed is appropriate. The management of scoliosis involves bracing and surgery. Most patients end up getting a spinal fusion. The use of rods is not contraindicated; therefore, rod and bone grafts are used to fuse the spine. A minority of patients do not develop significant scoliosis and may not require a spinal fusion. Corticosteroid therapy. Studies have shown that corticosteroids improve the muscle strength and function of individuals with DMD (see Corticosteroid Therapy in DMD). This therapy remains the treatment of choice for affected individuals between ages five and 15 years. Corticosteroid therapy is not recommended in children before age two years [Bushby et al 2010a]. This treatment is also used in BMD, although the efficacy is less clear (see BMD below). The following published recommendations for corticosteroid therapy are in accordance with the national practice parameters developed by the American Academy of Neurology and the Child Neurology Society [Moxley et al 2005] (full text), as well as the DMD Care Considerations Working Group [Bushby et al 2010a]. * Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. * To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. * To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [King et al 2007]. * The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). * If excessive weight gain occurs (>20% over estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. * If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. BMD. Information about the efficacy of prednisone in treating individuals with BMD is limited. Many clinicians continue treatment with glucocorticoids after loss of ambulation for the purpose of maintaining upper limb strength, delaying the progressive decline of respiratory and cardiac function, and decreasing the risk of scoliosis. Retrospective data suggest that the progression of scoliosis can be reduced by long-term daily corticosteroid treatment; however, an increased risk for vertebral and lower-limb fractures has been documented [King et al 2007]. Men on steroid therapy were less likely to require spinal surgery [Dooley et al 2010b]. The dose is allowed to drift down to 0.3-0.6 mg/kg/day of prednisone or deflazacort, which is still effective [Bushby et al 2010a]. #### DMD-Related DCM Phenotype Cardiomyopathy management is similar to the management of DMD- or BMD-associated cardiomyopathy. ### Prevention of Secondary Complications Cardiorespiratory * Evaluation by pulmonary and cardiac specialists before surgeries [Finder et al 2004] * Administration of pneumococcal vaccine and annual influenza vaccination [Finder et al 2004] Nutritional. Assessment if: * Planning to commence steroids [Davidson & Truby 2009] * Dysphagia is present * Patient is chronically constipated * Major surgery has been planned * Patient is malnourished Muscular * Physical therapy to promote mobility and prevent contractures * Exercise * All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. * Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. * If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. Bone health. Assessments [Bushby et al 2010b, Darras 2018]: * Blood * Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase * 25-hydroxyvitamin D (25-OHD) level in springtime or biannually * Consideration of magnesium and parathyroid hormone levels * Urine (calcium, sodium, creatinine) * Dual energy x-ray absorptiometry (DEXA) scanning * At baseline (age ≥3 years) or at start of corticosteroid therapy * Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DEXA Z score <-2 * Spine radiograph * If back pain is present * To exclude vertebral compression fracture * To assess degree of kyphoscoliosis if present on physical examination * Bone age if growth failure occurs (height for age <5th percentile or if linear growth is faltering) in persons on or off corticosteroids Interventions: * Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures. Supplementation should be carried out in consultation with a dietician. * Vitamin D supplementation should be initiated if the vitamin D serum concentration is <20 ng/mL [Bachrach 2005, Biggar et al 2005, Quinlivan et al 2005] and should be considered in all children if levels cannot be maintained [Bushby et al 2010b]. Supplementation should be carried out in consultation with an endocrinologist and in accordance with country-specific pediatric guidelines. * Intravenous bisphosphonates; recommended in persons with symptomatic vertebral fracture(s). A bone health expert should be consulted. * Note: Use of oral biphosphonates for prophylaxis or treatment remains controversial. ### Surveillance #### Cardiac The American Academy of Pediatrics (AAP) has published recommendations for optimal cardiac care in persons with dystrophinopathy [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005] (full text) and consensus guidelines [Bushby et al 2010b]. DMD * Complete cardiac evaluation at least every two years, beginning at the time of diagnosis Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. * At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. * If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [Bushby et al 2010a] BMD. Complete cardiac evaluation at least every two years, beginning at the time of diagnosis. Evaluations should continue at least every two years. DMD-related DCM. There are no consensus guidelines regarding the optimal cardiac care of patients with DMD-related DCM. However, once the diagnosis of DCM is made, patients will need complete cardiac evaluations at intervals defined by experienced cardiac specialists. Asymptomatic females. The AAP recommendations for optimal cardiac care of asymptomatic females with a heterozygous DMD pathogenic variant [American Academy of Pediatrics Section on Cardiology and Cardiac Surgery 2005] include the following: * Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure * Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms * Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years * Treatment of cardiac disease similar to that for boys with dystrophinopathy #### Pulmonary Perform baseline pulmonary function testing before confinement to a wheelchair (usually age ~9-10 years) Twice-yearly evaluation by a pediatric pulmonologist is indicated after ANY of the following [Finder et al 2004]: * Confinement to a wheelchair * Reduction in vital capacity below 80% predicted * Age 12 years The 2010 consensus guidelines [Bushby et al 2010b] make detailed recommendations regarding pulmonary care, including: * Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; * Manual and mechanically assisted cough techniques; * Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. #### Orthopedic Monitor for orthopedic complications, especially contractures and scoliosis in those with DMD and BMD phenotypes. Evaluate for surgical interventions as needed. ### Agents/Circumstances to Avoid Individuals with dystrophinopathy should avoid botulinum toxin injections. Although it is recommended that triggering agents like succinylcholine and inhalational anesthetics be avoided in patients with dystrophinopathy because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions (rhabdomyolysis, cardiac complications, hyperkalemia), it should be noted that an extensive literature search did not find an increased risk for malignant hyperthermia susceptibility in individuals with dystrophinopathy when compared with the general population [Gurnaney et al 2009]. However, individuals with DMD have been reported to have severe reactions to anesthesia (malignant hyperthermia-like) that did not meet the criteria for true malignant hyperthermia [Bamaga et al 2016]. ### Evaluation of Relatives at Risk It is appropriate to evaluate at-risk female family members (i.e., the sisters or maternal female relatives of an affected male and first-degree relatives of a known or possible heterozygous female) in order to identify as early as possible heterozygous females who would benefit from cardiac surveillance (see Surveillance). Evaluations can include the following: * Molecular genetic testing if the DMD pathogenic variant in the family is known * Serum CK testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative. * Molecular genetic testing of the at-risk female if an affected male is not available for testing: * By deletion/duplication analysis first * If no pathogenic variant is identified, by sequence analysis * Linkage analysis to determine carrier status in at-risk females if (1) the DMD pathogenic variant in the proband is not known, (2) no DMD pathogenic variant or serum CK elevation is identified in a carrier female, and (3) the family has more than one affected male with the unequivocal diagnosis of DMD/BMD/DMD-associated DCM * Linkage studies are based on accurate clinical diagnosis of DMD/BMD/DMD-associated DCM in the affected family members and accurate understanding of the genetic relationships in the family. * Linkage analysis relies on the availability and willingness of family members to be tested. * Because the markers used for linkage in DMD/BMD/DMD-associated DCM are highly informative and lie both within and flanking the DMD locus, they can be used in most families with DMD/BMD/DMD-associated DCM [Kim et al 2002]. Note: (1) The large size of DMD leads to an appreciable risk of recombination. It has been estimated that the gene itself spans a genetic distance of 12 centimorgans [Abbs et al 1990]; thus, multiple recombination events among different members of a family may complicate the interpretation of a linkage study. (2)Testing by linkage analysis is not possible for families in which there is a single affected male. (3) Testing by linkage analysis may not be widely available on a clinical basis. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management for Heterozygous Females Symptomatic heterozygous women should undergo an evaluation for dilated cardiomyopathy ideally prior to conceiving a pregnancy or as soon as the pregnancy is recognized. Asymptomatic heterozygous women should consider undergoing a cardiac evaluation prior to conception or when a pregnancy is recognized. Those with evidence of dilated cardiomyopathy should be treated and/or monitored by a cardiologist and a high-risk obstetrician. ### Therapies Under Investigation Gene therapy. Clinical studies in gene therapy currently focus on restoring dystrophin expression by administering recombinant adeno-associated virus vectors that deliver either functional dystrophin transgene (micro- or minidystrophin genes) [Mendell et al 2010, Konieczny et al 2013, Bengtsson et al 2016] or gene-editing components [Calos 2016, Long et al 2016, Nelson et al 2016, Tabebordbar et al 2016]. Gene repair. CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (CRISPR/Cas9)-mediated genome editing in mdx mice has been shown to partially restore dystrophin protein expression in cardiac and skeletal muscle by cutting the noncoding introns that flank the mutated sequence-containing exon 23 [Long et al 2016, Nelson et al 2016, Tabebordbar et al 2016]. Eteplirsen. Another investigational approach uses antisense oligonucleotides, such as eteplirsen, to induce specific exon skipping during pre-messenger RNA splicing, correcting the DMD open reading frame and restoring dystrophin expression [Goemans et al 2011, Lu et al 2011, Konieczny et al 2013, Jacobson & Feldman 2016]. Eteplirsen skips exon 51, inducing a dose-related increase in dystrophin production without drug-related adverse effects [Cirak et al 2011]. Affected individuals taking eteplirsen at a dose of 50 mg/kg showed a 23% increase in dystrophin-positive fibers at 24 weeks and walked a significantly greater distance in the six-minute walk test compared with placebo or delayed-administration groups at 48 weeks [Mendell et al 2013]. At 36 months, those treated with eteplirsen had continued benefit on the six-minute walk test and a lower rate of loss of ambulation [Mendell et al 2016]. The FDA granted accelerated approval for eteplirsen infusion in September 2016, making it the first drug approved to treat individuals with DMD; however, the manufacturer is required to conduct a trial to determine whether eteplirsen improves motor function of individuals with DMD with an amenable dystrophin gene pathogenic variant (see FDA news release). The FDA may withdraw approval if this trial fails to show clinical benefit. Ataluren. Ten to 15 percent of individuals with DMD harbor nonsense (stop) pathogenic variants, which the investigational drug ataluren may treat by promoting ribosomal read-through, allowing bypass of the pathogenic variant and continuation of the translation process to production of a functioning protein [Finkel 2010]. Preclinical efficacy studies showed production of dystrophin in primary muscle cells from humans and mdx mice [Welch et al 2007]. Studies in humans have shown increased full-length dystrophin expression in vitro and in vivo, and decreased serum muscle enzyme levels within 28 days of treatment [Bönnemann et al 2007]. Affected individuals on low doses of ataluren had a 30-meter lower decline in the six-minute walk distance than those on high doses or placebo [Bushby et al 2014]. Based on these results, the drug TranslarnaTM was granted conditional approval from the European Medicines Agency in August 2014 to treat DMD caused by a nonsense variant; TranslarnaTM is not approved for treating DMD in the US. A Phase III multicenter 48-week double-blind placebo-controlled trial (ACT DMD) showed no significant benefit of ataluren for the primary endpoint (i.e., change from baseline in the 6-minute walk test), though there was benefit for some secondary endpoints [McDonald et al 2017]. Myostatin inactivation. The protein myostatin has an inhibitory effect on muscle growth; without it, mice that would otherwise express the DMD phenotype have increased muscle mass compared with those with a wild type myostatin gene [Wagner et al 2002]. Animals treated with antibodies to myostatin have increased muscle mass and strength, lower serum creatine kinase, and less histologic evidence of muscle damage [Bogdanovich et al 2002], suggesting a potential therapeutic target to increase muscle bulk and strength in humans with DMD [McNally 2004]. Wagner et al [2008] conducted a double-blind placebo-controlled multinational randomized study of 116 subjects to test the safety of a neutralizing antibody to myostatin, MYO-029. Campbell et al [2017] found that ACE-031, a fusion protein that binds myostatin and related ligands, noted a trend toward maintenance of the six-minute walk test compared with a decline in the placebo group (not statistically significant), as well as a trend toward increased lean body mass and bone mineral density and reduced fat mass; however, the study was stopped due to non-muscle-related adverse effects. Cell therapy. Skeletal muscle progenitors continue to be investigated in the treatment of DMD. A promising technique in mice isolates and transplants muscle satellite cells, a natural source of cells for muscle regeneration [Blau 2008, Cerletti et al 2008]. Idebenone. A randomized controlled trial of the antioxidant idebenone showed significantly reduced decline in respiratory function as measured by peak expiratory flow and other pulmonary function tests [Buyse et al 2015]. Nearly all of the 64 individuals with DMD (age 10-18 years) were nonambulatory at baseline. Further study is needed to determine if idebenone treatment improves outcomes such as the time to assisted ventilation or to death. Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Dystrophinopathies	None	3,564	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1119/	2021-01-18T21:29:45	{"synonyms": []}
A very rare, malignant, epithelial tumor of the pancreas composed of cystic structures lined by glycogen-rich clear cells, associated with local invasiveness often involving the spleen, duodenum and/or stomach and metastatic spread to the liver, peritoneum and/or lymph nodes. Presenting symptoms are variable and usually non-specific and include abdominal and/or flank pain, palpable abdominal mass, upper gastrointestinal bleeding, jaundice or abnormal serum liver enzymes, vomiting, anorexia and/or 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Serous cystadenocarcinoma of pancreas	c1335315	3,565	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=424073	2021-01-23T18:04:05	{"umls": ["C1335315"], "icd-10": ["C25.0", "C25.1", "C25.2", "C25.7", "C25.8"], "synonyms": ["Pancreatic serous cystadenocarcinoma"]}
A number sign (#) is used with this entry because autosomal recessive adult-onset spinal muscular atrophy type IV (SMA4) is caused by mutation or deletion in the SMN1 gene (600354) on chromosome 5q13. Allelic disorders with overlapping phenotypes of differing severity and age at onset include SMA type I (253300), SMA type II (253550), and SMA type III (253400). Clinical Features Pearn et al. (1978) described 9 patients from 6 families with adult-onset spinal muscular atrophy. The median age at onset was 35 years, and the mean age at initial medical presentation was 37 years. The condition was relatively benign, with symmetrical proximal muscle involvement and preservation of the distal musculature. Family studies suggested autosomal recessive inheritance. Brahe et al. (1995) reported 6 patients from 4 families with autosomal recessive adult-onset SMA. Age at onset ranged from 20 to 32 years, and symptoms included tongue fasciculations, hand tremor, symmetrical weakness of the proximal muscles that was more severe in the lower limbs, and atrophy of the quadriceps muscle. Three patients had bilateral hypertrophy of the calves. One patient was very mildly affected; 3 patients had done military service, apparently without problems. In a letter, Zerres et al. (1995) noted that they defined SMA type IV as onset after age 30; patients with onset before age 30 years who retained the ability to walk were defined as having SMA type III. Clermont et al. (1995) reported a 73-year-old woman who developed type IV SMA at age 47, with proximal muscle weakness, muscular atrophy, and patellar areflexia. Three of her 5 children had SMA type II, and all died before age 15 years. Molecular analysis showed that the mother had deletion of SMN exons 7 and 8 on both chromosomes, but no DNA from the children was available. Clermont et al. (1995) concluded that adult and childhood SMA are allelic disorders, emphasizing the continuum of clinical phenotypes caused by SMN gene mutations and deletions. Clinical Management Weihl et al. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 (601627) gene transcription and result in increased production of full-length SMN protein. Molecular Genetics In 6 patients with SMA4, Brahe et al. (1995) identified deletion of exons 7 and 8 of the SMN1 gene, indicating that autosomal recessive adult SMA is allelic to the childhood forms of SMA. Mazzei et al. (2004) found evidence for a gene conversion event in SMN1 in 3 patients with SMA4, supporting the notion that a gene conversion event is usually associated with a milder SMA phenotype and a later age at disease onset. ### Modifying Factors Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis. ### Heterogeneity Hahnen et al. (1995) reported 4 patients with onset of SMA after age 30 who showed no homozygous deletion of exons 7 and 8 of the SMN1 gene, suggesting genetic heterogeneity. However, the 4 patients with presumed SMA IV had no family history, and spontaneous autosomal dominant mutation at a different locus could not be excluded. Animal Model Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease. INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Hypertrophy of calves (in 3 of 6 patients) NEUROLOGIC Central Nervous System \- Muscle weakness, proximal, symmetric (lower limbs more affected than upper limbs) due to motor neuronopathy \- Muscle atrophy, proximal \- Tongue fasciculations \- Hand tremor \- EMG shows neurogenic abnormalities \- Degeneration of spinal cord anterior horn cells \- Areflexia in lower limbs MISCELLANEOUS \- Mean age at onset 35 years (range 20-60) \- Slow disease progression \- Allelic disorder to spinal muscular atrophy type I ( 253300 ) MOLECULAR BASIS \- Caused by mutations in the survival of motor neuron 1 gene (SMN1, 600354.0011 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPINAL MUSCULAR ATROPHY, TYPE IV	c1838230	3,566	omim	https://www.omim.org/entry/271150	2019-09-22T16:22:12	{"doid": ["0050529"], "mesh": ["C563948"], "omim": ["271150"], "icd-10": ["G12.1"], "orphanet": ["83420", "70"], "synonyms": ["Alternative titles", "SPINAL MUSCULAR ATROPHY, ADULT FORM", "SPINAL MUSCULAR ATROPHY, PROXIMAL, ADULT, AUTOSOMAL RECESSIVE"], "genereviews": ["NBK1352"]}
Idiopathic macular telangiectasia type 3 is a rare, acquired, eye disease characterized by progressive visual loss, due to bilateral juxtafoveolar capillary occlusions, capillary telangiectasia, and minimal exudation. It is associated with systemic or cerebral vascular occlusive disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Idiopathic macular telangiectasia type 3	None	3,567	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353351	2021-01-23T18:27:45	{"icd-10": ["H35.5"], "synonyms": ["Occlusive idiopathic juxtafoveolar retinal telangiectasis"]}
Tooth ankylosis SpecialtyDentistry Tooth ankylosis is the pathological fusion between alveolar bone and the cementum of teeth, which is a rare phenomenon in the deciduous dentition and even more uncommon in permanent teeth.[1][2][3] Ankylosis occurs when partial root resorption is followed by repair with either cementum or dentine that unites the tooth root with the alveolar bone, usually after trauma.[4] However, root resorption does not necessarily lead to tooth ankylosis and the causes of tooth ankylosis remain uncertain to a large extent.[4] However, it is evident that the incident rate of ankylosis in deciduous teeth is much higher than that of permanent teeth.[5] Risk factors of tooth ankylosis can be generally classified into genetic factors and dental trauma. Diagnostic methods of tooth ankylosis include the use of clinical examinations, x-ray and cone beam computerized tomography (CBCT).[6][4] Tooth ankylosis could have several symptoms, with decreased tooth count being the most prominent one.[3] Factors like gender and sex may also lead to the incidence of certain signs, yet the full mechanisms have not been well evaluated. In general, the non-growing subjects and growing subjects would exhibit different signs and symptoms.[3] The individuals suffering from ankylosis of deciduous teeth would experience the risk of losing the teeth in the end due to the failure of the tooth eruption during facial growth and would lead to a series of functional and aesthetical problems.[citation needed] After diagnosed with clinical examination or CBCT image, tooth ankylosis is often treated by removing the crown of the affected tooth.[4] Early orthodontic interception is also confirmed to be effective in promoting the recovery of the lost space as well as allowing the eruption of the teeth. It is current under the investigation of its probability being used as a prevention of tooth ankylosis.[7] ## Contents * 1 Prevention and management * 2 Signs and symptoms * 3 Causes * 3.1 Deciduous (baby) teeth * 3.2 Permanent (adult) teeth * 4 Risk factors * 5 Pathophysiology * 6 Diagnosis * 7 Treatment * 8 Epidemiology * 9 References ## Prevention and management[edit] Since ankylosis may hinder the normal development of teeth, early diagnosis and intercession is important to avoid further progression and deterioration of the situation.[3] In particular, when such an abnormality is found in deciduous teeth among children and adolescents, it would often result in the infraocclusion of the ankylosed tooth, inclination of the teeth adjacent to the space.[7] Subsequently, impaction of the permanent successor tooth would result. In light of the situation, early interceptive orthodontic treatment is confirmed to be effective in promoting the recovery of the lost space as well as allowing the eruption of the teeth. According to a reported case, this method provided positive results and ameliorated the situation of the patient.[7] ## Signs and symptoms[edit] Tooth ankylosis can be recognised clinically by the loss of physiological mobility, and a high P note. It may also be detected radiographically, loss of periodontal ligament space and evidence of replacement resorption. Ankylosis usually initially occurs on the labial and lingual root surfaces making radiographic detection in the early stages difficult. Early diagnosis allows the practitioner to plan for future complications. curving of the pinkie finger, one of the symptoms observed in tooth ankylosis The signs and symptoms for patients can be varied mainly depending on the growing state of teeth (permanent or deciduous). Other factors, such as age, sex, site of infection may also lead to the occurrence of specific signs and symptoms, but their roles are not well-studied and evaluated. General symptoms include decreased tooth count, abnormal tooth enamel, curving of the fifth digit, enlarged lower jaw and abnormal dentition, with decreased tooth count as the most frequent symptom.[3] For non-growing subjects who possess fully developed permanent teeth, there may not be any observable symptoms. The alveolar support of the affected tooth will be lowered due to continuous replacement resorption of the root. This process will stop with the appearance of root fractures and shed crown, and changes in dentition, especially the anterior teeth, can be observed in this stage. Symptoms such as infraocclusion and asymmetry in the smile arc may be developed.[citation needed] However, for ankylosis in posterior teeth happening in non-growing subjects, it may be completely asymptomatic because the slow change in height of the affected teeth may not be noticeable to both the patient and the doctor, compared to that happened in anterior teeth.[8] For growing subjects, symptoms can also be varied as different growth aspects of teeth including the vertical, sagittal and transverse growth are different in children and adolescents.[citation needed] Generally, symptoms are more severe for earlier occurrence of the disease. Most ankyloses occurring in children are trauma-induced, which can lead to malposition of the affected teeth as the major symptom.[citation needed] For moderate and severe conditions in growing subjects, symptoms such as functional impairment due to loss of occlusal contacts which results from the reduced vertical distance of the ankylosed teeth, and shift in dental midline associated with tipping of adjacent teeth towards the affected tooth, are likely to be developed.[8] Alternatively, open bite and supra-eruption of opposing teeth may also be noticed. ## Causes[edit] Diagram of a healthy human molar showing the enamel, cementum, pulp, and dentin which make up the structure, as well as the surrounding tissues The causes of ankylosis of teeth is uncertain. One common belief is the role of genetic factors with an autosomal dominant inheritance pattern, evidenced by the appearance of family occurrence in several families. Trauma, inflammation and infection may also be responsible for causing the disease.[3][4] The frequency for ankylosis to happen in deciduous teeth is far more frequent than that in permanent teeth, with a ratio of about 10 to 1, and the majority of[3] the ankylosed teeth occur in lower teeth, about twice as often as in the upper teeth.[5] Therefore, it is strongly believed that their incidence may be due to different causes. For ankylosis in permanent teeth, with the first molar being the most common affected teeth, it is hard to find a precise cause because of the complicated nature which is believed to be linked to several different factors and the difficulty in diagnosis as many cases are asymptomatic.[citation needed] For other cases, there are several theories explaining the cause. Dental trauma may be a major cause for the disease since it can lead to luxation, reported in 30 to 44% of all dental trauma cases, and hence replacement resorption, which is the situation in ankylosis of teeth.[9] The association between tooth ankylosis and orthodontic treatment are also observed in some cases, in which the leakage of etchant to the junction between cementum and enamel during the surgery, damage to the junction or tilting of the tooth may be some possible mechanisms to relate the disease to the treatment.[citation needed] Genetic factors may also be involved in causing the disease, which is supported by the occurrence of ankylosed molars, either in primary or permanent dentition, in close relatives.[citation needed] The possible explanation is the inheritance of a gene which might be a process imitator of ankylosis in the periodontal ligament. This gene can then be transferred from parents to offsprings and lead to ankylosis of teeth.[10] ### Deciduous (baby) teeth[edit] Ankylosis of deciduous teeth may rarely occur. The most commonly affected tooth is the mandibular (lower) second deciduous molar. Partial root resorption first occurs and then the tooth fuses to the bone. This prevents normal exfoliation of the deciduous tooth and typically causes impaction of the permanent successor tooth. As growth of the alveolar bone continues and the adjacent permanent teeth erupt, the ankylosed deciduous tooth appears to submerge into the bone, although in reality it has not changed position. Treatment is by extraction of the involved tooth, to prevent malocclusion, periodontal disturbance or dental caries.[2] ### Permanent (adult) teeth[edit] In healthy teeth, the periodontal ligament (PDL) fibroblasts block osteogenic cells within the periodontium by releasing locally acting regulators. This separates the tooth root from alveolar bone.[11] Damage to the PDL disrupts this process resulting bone growth across the periodontal space and fusion with the root. It may occur following dental trauma, especially re-implanted or severely intruded teeth.[12][13] Increasing the extra oral dry time increases the likelihood of ankylosis[14] The probability also increases with the severity of intrusion. There is no known treatment to arrest the process. Ankylosis itself is not a reason to remove a permanent tooth, however teeth which must be removed for other reasons are made significantly more difficult to remove if they are ankylosed.[2] Ankylosis in growing patients can result in infra occlusion of teeth, this can lead to an aesthetic and functional deficit. ## Risk factors[edit] As ankylosis of teeth is often associated with metabolic abnormalities and deficiencies in vertical-bone growth, positive family history with the occurrence of dental ankylosis cases would be a prominent risk factor since such pathological condition could be inherited.[7] Furthermore, other factors or activities that would contribute to injuries, inflammations or infections would also increase the risk of developing ankylosis of teeth. ## Pathophysiology[edit] Ankylosis initiates with extensive necrosis of the periodontal ligament with formation of bone which will invade the denuded root surface area. Trauma is believed to be the cause of ankylosis, causing cell death on the root surface. Ankylosis may happen once the injured surface area has reached more than 20%.[citation needed] Damage to the root surface area will trigger an inflammatory response, migration and repopulation of faster bone forming cells, instead of slower periodontal ligament fibroblasts or cementoblasts, occurring in the teeth root surface.[4] In this stage, the teeth are termed to be ankylosed. This migration and repopulation process, termed replacement resorption, will continue and thus the teeth root will become fused with the bone tissue adjacent to it.[4] ## Diagnosis[edit] Diagnostic methods of tooth ankylosis include the use of clinical examinations and x-ray.[3][4] The feasibility of using cone beam computed tomography to diagnose ankylosed teeth is also explored and discussed in a recent research article.[6] Examinations of teeth are carried out to identify typical features of ankylosis, these features include varying percussion sound with adjacent normal teeth and a lack of mobility.[4] However, these examinations are not always reliable. Although a metal sound on examination of percussion is usually used to indicate the presence of ankylosis, it is found that only one-third of ankylosed teeth give a metal sound in percussion test[citation needed]. In addition, a lack of mobility is not a definitive sign of ankylosis as the tooth can still be mobile if less than 20% of root surface is ankylosed[citation needed]. A definitive diagnosis of ankylosis is believed to be given by checking the mobility of the targeted tooth after applying orthodontic force, an ankylosed tooth will show no mobility[citation needed]. In early detection of ankylosis, radiographic examination is not effective because it only produces 2-dimensional graphic.[4] This means that the ankylosed site would not be apparent if it is not perpendicular to the x-ray beam.[4] Therefore, it is impossible to identify ankylosis in some areas using x-ray, for instance, buccal or lingual root surface[citation needed]. To overcome such difficulty, cone beam computerized tomography (CBCT) is adopted to provide a 3-dimensional image for better clinical inspection of ankylosis.[6] In a recent research article, a retrospective cohort study was conducted where a wide range of teeth clinically diagnosed as ankylosed were collected and analyzed.[6] The histological sections of each tooth obtained from the CBCT scan were then evaluated by two specialists blinded to the details of the research to ensure the fairness and objectivity of the result.[6] As a result, all histologically established ankylosed teeth were identified by both observers provided with the CBCT image but some false positive results were obtained. It is concluded that CBCT scan can be used as a feasible and effective diagnostic method when it comes to the detection of tooth ankylosis. However, it is not recommended to treat CBCT image as the sole model in the identification of ankylosed teeth unless the false positive results are being eliminated.[6] Ankylosis and primary fail of eruption (PFE) give similar symptoms, since in both cases a targeted tooth is positioned not vertically and unresponsive to orthodontic force applied[citation needed]. Therefore, ankylosis should be differentiated from primary fail of eruption. For an ankylosed molar, distal teeth can respond to orthodontic force normally and thus can be used as substitute if the ankylosed tooth is extracted[citation needed]. Surgical luxation is sometimes used to break the ankylosis bridge to restore occlusion[citation needed]. For a case of PFE, the targeted molar can only be treated by osteotomy to restore its occlusion. ## Treatment[edit] Surgical extraction of an impacted molar Growing state of patient is one of the factors when deciding what treatment is going to be used. For growing patients, decoronation is used. Decoronation is the removal of tooth crown.[4] It serves as an alternative surgery for tooth extraction.It is recommended over extraction because it limits bone resorption and therefore maintains a sufficient growth of alveolar bone to enable tooth implantation[citation needed]. Decoronation can be carried out on both deciduous and permanent teeth. However, if the patient is too young and not close to puberty, decoronation should be postponed[citation needed]. In order to maximize the benefits of decoronation, regular monitoring and intervention are needed[10] For non-growing patients, decoronation is generally not recommended because the growth of alveolar bone may be inadequate for a future tooth implant[citation needed], and therefore is said to not give ideal treatment outcomes.[10] As a result, other methods are considered when treating non-growing patients. Follow-ups are often being adopted in the cases of late onset tooth ankylosis. As tooth growth is insignificant, no surgical procedures are needed to treat the ankylosed tooth as long as its height difference with adjacent teeth is small.[4] In some cases where the height difference is more significant, tooth crown build-up is recommended to restore occlusion.[4] In addition to tooth crown build-up, ankylosed teeth repositioning is another conservative method. In surgical luxation, after the bridge of ankylosis is broken mechanically, the tooth is positioned slightly away from its original site and allowed to erupt with a temporary insertion of a splint or an orthodontic appliance.[4] Tooth repositioning can also be performed by osteotomy and distraction osteogenesis in cases where surgical luxation fails, or as alternatives.[4] Extraction of an ankylosed tooth can be considered in both growing and non-growing patients. This method usually serves as a last resort when other methods such as osteotomy and distraction osteogenesis fail to treat ankylosis.[4] Growing state of patient is not the sole factor when deciding the treatment for an ankylosed tooth. Infraocclusion severity, bone resorption, location of the target tooth as well as dentist's preference all affect the option for treatment.[4][5] Therefore, treatment for an ankylosed tooth is case-specific. ## Epidemiology[edit] The prevalence of tooth ankylosis is still unknown. Individuals of both genders regarless of the ethnic groups may be affected due to inheritance or sporadic traumatic injuries.[citation needed] ## References[edit] 1. ^ Andersson, L; Blomlof, L; Lindskog, S; Feiglin, B; Hammarstrom, L (1984). "Tooth ankylosis: clinical, radiographic and histological assessments". International Journal of Oral Surgery. 13 (5): 423–31. doi:10.1016/S0300-9785(84)80069-1. PMID 6438004. 2. ^ a b c Rajendran A; Sundaram S (10 February 2014). Shafer's Textbook of Oral Pathology (7th ed.). Elsevier Health Sciences APAC. pp. 63, 528. ISBN 978-81-312-3800-4. 3. ^ a b c d e f g h "Ankylosis of teeth". Genetic and Rare Diseases Information Center. Retrieved 20 March 2019. 4. ^ a b c d e f g h i j k l m n o p q r de Souza, Raphael Freitas; Travess, Helen; Newton, Tim; Marchesan, Melissa A (2015-12-16). Cochrane Oral Health Group (ed.). "Interventions for treating traumatised ankylosed permanent front teeth". Cochrane Database of Systematic Reviews (12): CD007820. doi:10.1002/14651858.CD007820.pub3. PMC 7197413. PMID 26677103. 5. ^ a b c Biederman, William (September 1962). "Etiology and treatment of tooth ankylosis". American Journal of Orthodontics. 48 (9): 670–684. doi:10.1016/0002-9416(62)90034-9. 6. ^ a b c d e f Ducommun, F.; Bornstein, M. M.; Bosshardt, D.; Katsaros, C.; Dula, K. (2018). "Diagnosis of tooth ankylosis using panoramic views, cone beam computed tomography, and histological data: a retrospective observational case series study". European Journal of Orthodontics. 40 (3): 231–238. doi:10.1093/ejo/cjx063. PMID 29016762. 7. ^ a b c d Guimarães, C. H.; Henriques, J.; Janson, G.; Moura, W. S. (2015). "Stability of interceptive/corrective orthodontic treatment for tooth ankylosis and Class II mandibular deficiency: A case report with 10 years follow-up". Indian Journal of Dental Research. 26 (3): 315–9. doi:10.4103/0970-9290.162886. PMID 26275202. 8. ^ a b Rosner, D; Becker, A; Casap, N; Chaushu, S (December 2010). "Orthosurgical treatment including anchorage from a palatal implant to correct an infraoccluded maxillary first molar in a young adult". American Journal of Orthodontics and Dentofacial Orthopedics. 138 (6): 804–9. doi:10.1016/j.ajodo.2008.09.039. PMID 21130340. 9. ^ Humphrey, Janice M.; Kenny, David J.; Barrett, Edward J. (2003). "Clinical outcomes for permanent incisor luxations in a pediatric population. I. Intrusions". Dental Traumatology. 19 (5): 266–273. doi:10.1034/j.1600-9657.2003.00207.x. ISSN 1600-9657. PMID 14708651. 10. ^ a b c Mohadeb, Jhassu Varsha Naveena; Somar, Mirinal; He, Hong (August 2016). "Effectiveness of decoronation technique in the treatment of ankylosis: A systematic review". Dental Traumatology. 32 (4): 255–263. doi:10.1111/edt.12247. ISSN 1600-9657. PMID 26663218. 11. ^ McCulloch, C, A (1995). "Origins and functions of cells essential for periodontal repair: the role of fibroblasts in tissue homeostasis". Oral Disease. 1 (4): 271–278. doi:10.1111/j.1601-0825.1995.tb00193.x. PMID 8705836. 12. ^ Barrett, E, J; Kenny, D, J (1997). "Survival of avulsed permanent maxillary incisors in children following delayed replantation". Ended Dent Traumatol. 13 (6): 269–75. doi:10.1111/j.1600-9657.1997.tb00054.x. PMID 9558508. 13. ^ Humphrey, J, M; Kenny, D, J; Barrett, E, J (2003). "Clinical outcomes for permanent incisor laxations in a paediatric population". Dental Traumatology. 19 (5): 266–73. doi:10.1034/j.1600-9657.2003.00207.x. PMID 14708651. 14. ^ Andreasen, J, O; Borum, M, K; Jacobsen, H, L; Andreasen, F, M (1995). "Replantation of 400 avulsed permanent incisors". Endod Dent Tramatol. 11 (2): 76–89. doi:10.1111/j.1600-9657.1995.tb00464.x. PMID 7641622. Classification D * ICD-10: K03.5 * MeSH: D020254 * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Tooth ankylosis	c2931182	3,568	wikipedia	https://en.wikipedia.org/wiki/Tooth_ankylosis	2021-01-18T18:51:10	{"gard": ["701"], "mesh": ["D020254", "C536375"], "umls": ["C2931182"], "orphanet": ["1077"], "wikidata": ["Q2188219"]}
For other uses, see Shock. Shock Other namesCirculatory shock Play media Video explanation SpecialtyCritical care medicine SymptomsInitial: Weakness, fast heart rate, fast breathing, sweating, anxiety, increased thirst[1] Later: Confusion, unconsciousness, cardiac arrest[1] TypesLow volume, cardiogenic, obstructive, distributive[2] CausesLow volume: Bleeding, vomiting, pancreatitis[1] Cardiogenic: heart attack, cardiac contusion[1] Obstructive: Cardiac tamponade, tension pneumothorax[1] Distributive: Sepsis, spinal cord injury, certain overdoses[1] Diagnostic methodBased on symptoms, physical exam, laboratory tests[2] TreatmentBased on the underlying cause[2] MedicationIntravenous fluid, vasopressors[2] PrognosisRisk of death 20 to 50%[3] Frequency1.2 million per year (USA)[3] Shock is the state of insufficient blood flow to the tissues of the body as a result of problems with the circulatory system.[1][2] Initial symptoms of shock may include weakness, fast heart rate, fast breathing, sweating, anxiety, and increased thirst.[1] This may be followed by confusion, unconsciousness, or cardiac arrest, as complications worsen.[1] Shock is divided into four main types based on the underlying cause: low volume, cardiogenic, obstructive, and distributive shock.[2] Low volume shock, also known as hypovolemic shock, may be from bleeding, diarrhea, or vomiting.[1] Cardiogenic shock may be due to a heart attack or cardiac contusion.[1] Obstructive shock may be due to cardiac tamponade or a tension pneumothorax.[1] Distributive shock may be due to sepsis, anaphylaxis, injury to the upper spinal cord, or certain overdoses.[1][4] The diagnosis is generally based on a combination of symptoms, physical examination, and laboratory tests.[2] A decreased pulse pressure (systolic blood pressure minus diastolic blood pressure) or a fast heart rate raises concerns.[1] The heart rate divided by systolic blood pressure, known as the shock index (SI), of greater than 0.8 supports the diagnosis more than low blood pressure or a fast heart rate in isolation.[5][6] Treatment of shock is based on the likely underlying cause.[2] An open airway and sufficient breathing should be established.[2] Any ongoing bleeding should be stopped, which may require surgery or embolization.[2] Intravenous fluid, such as Ringer's lactate or packed red blood cells, is often given.[2] Efforts to maintain a normal body temperature are also important.[2] Vasopressors may be useful in certain cases.[2] Shock is both common and has a high risk of death.[3] In the United States about 1.2 million people present to the emergency room each year with shock and their risk of death is between 20 and 50%.[3] ## Contents * 1 Signs and symptoms * 1.1 Low volume * 1.2 Cardiogenic * 1.3 Obstructive * 1.4 Distributive * 1.4.1 Endocrine * 2 Cause * 3 Pathophysiology * 3.1 Initial * 3.2 Compensatory * 3.3 Progressive * 3.4 Refractory * 4 Diagnosis * 5 Management * 5.1 Fluids * 5.2 Medications * 5.3 Mechanical support * 5.4 Treatment goals * 6 Epidemiology * 7 Prognosis * 8 History * 9 References * 10 External links ## Signs and symptoms[edit] The presentation of shock is variable, with some people having only minimal symptoms such as confusion and weakness.[7] While the general signs for all types of shock are low blood pressure, decreased urine output, and confusion, these may not always be present.[7] While a fast heart rate is common, those on β-blockers, those who are athletic, and in 30% of cases of those with shock due to intra abdominal bleeding may have a normal or slow heart rate.[8] Specific subtypes of shock may have additional symptoms. Dry mucous membrane, reduced skin turgor, prolonged capillary refill time, weak peripheral pulses and cold extremities can be early signs of shock.[9] ### Low volume[edit] Main articles: Hypovolemia and Hypovolemic shock Hypovolemic shock is the most common type of shock and is caused by insufficient circulating volume.[7] The most common cause of hypovolemic shock is hemorrhage (internal or external); however, vomiting and diarrhea are the most common cause in children.[10] Other causes include burns, as well as excess urine loss due to diabetic ketoacidosis and diabetes insipidus.[10] Hemorrhage classes[11] Class Blood loss Response Treatment I <15 %(0.75 l) min. fast heart rate, normal blood pressure minimal II 15-30 %(0.75-1.5 l) fast heart rate, min. low blood pressure intravenous fluids III 30-40 %(1.5-2 l) very fast heart rate, low blood pressure, confusion fluids and packed RBCs IV >40 %(>2 l) critical blood pressure and heart rate aggressive interventions Signs and symptoms of hypovolemic shock include: * A rapid, weak, thready pulse due to decreased blood flow combined with tachycardia * Cool skin due to vasoconstriction and stimulation of vasoconstriction * Rapid and shallow breathing due to sympathetic nervous system stimulation and acidosis * Hypothermia due to decreased perfusion and evaporation of sweat * Thirst and dry mouth, due to fluid depletion * Cold and mottled skin (Livedo reticularis), especially extremities, due to insufficient perfusion of the skin The severity of hemorrhagic shock can be graded on a 1–4 scale on the physical signs. The shock index (heart rate divided by systolic blood pressure) is a stronger predictor of the impact of blood loss than heart rate and blood pressure alone.[5] This relationship has not been well established in pregnancy-related bleeding.[12] ### Cardiogenic[edit] Main article: Cardiogenic shock Cardiogenic shock is caused by the failure of the heart to pump effectively.[7] This can be due to damage to the heart muscle, most often from a large myocardial infarction. Other causes of cardiogenic shock include dysrhythmias, cardiomyopathy/myocarditis, congestive heart failure (CHF), myocardial contusion, or valvular heart disease problems.[10] Symptoms of cardiogenic shock include: * Distended jugular veins due to increased jugular venous pressure * Weak or absent pulse * Abnormal heart rhythms, often a fast heart rate * Pulsus paradoxus in case of tamponade * Reduced blood pressure * Shortness of breath, due to pulmonary congestion ### Obstructive[edit] Main article: Obstructive shock Obstructive shock is a form of shock associated with physical obstruction of the great vessels of the systemic or pulmonary circulation.[13] Several conditions can result in this form of shock. * Cardiac tamponade[10] in which fluid in the pericardium prevents inflow of blood into the heart (venous return). Constrictive pericarditis, in which the pericardium shrinks and hardens, is similar in presentation. * Tension pneumothorax[10] Through increased intrathoracic pressure, bloodflow to the heart is prevented (venous return). * Pulmonary embolism is the result of a thromboembolic incident in the blood vessels of the lungs and hinders the return of blood to the heart. * Aortic stenosis hinders circulation by obstructing the ventricular outflow tract * Hypertrophic sub-aortic stenosis is overly thick ventricular muscle that dynamically occludes the ventricular outflow tract. * Abdominal compartment syndrome defined as an increase in intra-abdominal pressure to > 20 mmHg with organ dysfunction.[14] Increased intraabdominal pressure can be due to sepsis and severe abdominal trauma. This increased pressure reduced blood flow back to the heart, thereby reducing blood flow to the body and resulting in signs and symptoms of shock.[15] Many of the signs of obstructive shock are similar to cardiogenic shock, however treatments differ. Symptoms of obstructive shock include: * Abnormal heart rhythms, often a fast heart rate. * Reduced blood pressure. * Cool, clammy, mottled skin, often due to low blood pressure and vasoconstriction. * Decreased urine output. ### Distributive[edit] Main article: Distributive shock Systemic inflammatory response syndrome[16] Finding Value Temperature <36 °C (96.8 °F) or >38 °C (100.4 °F) Heart rate >90/min Respiratory rate >20/min or PaCO2<32 mmHg (4.3 kPa) WBC <4x109/L (<4000/mm³), >12x109/L (>12,000/mm³), or ≥10% bands Distributive shock is low blood pressure due to a dilation of blood vessels within the body.[7][17] This can be caused by systemic infection (septic shock), a severe allergic reaction (anaphylaxis), or spinal cord injury (neurogenic shock). Main article: Septic shock * Septic shock is the most common cause of distributive shock.[10] It is caused by an overwhelming systemic infection resulting in vasodilation leading to hypotension. Septic shock can be caused by Gram negative bacteria such as (among others) Escherichia coli, Proteus species, Klebsiella pneumoniae which have an endotoxin on their surface which produces adverse biochemical, immunological and occasionally neurological effects which are harmful to the body, and other Gram-positive cocci, such as pneumococci and streptococci, and certain fungi as well as Gram-positive bacterial toxins. Septic shock also includes some elements of cardiogenic shock. In 1992, the ACCP/SCCM Consensus Conference Committee defined septic shock: ". . .sepsis-induced hypotension (systolic blood pressure < 90 mmHg or a reduction of 40 mmHg from baseline) despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may have a normalized blood pressure at the time that perfusion abnormalities are identified. The pathophysiology behind septic shock is as follows: 1) Systemic leukocyte adhesion to endothelial cells[18] 2) Reduced contractility of the heart[18] 3) Activation of the coagulation pathways, resulting in disseminated intravascular coagulation[18] 4). Increased levels of neutrophils[18] * The main manifestations of septic shock are due to the massive release of histamine which causes intense dilation of the blood vessels. People with septic shock will also likely be positive for SIRS criteria. The most generally accepted treatment for these patients is early recognition of symptoms, and early administration of broad spectrum and organism specific antibiotics.[19] * Signs of septic shock include: * Abnormal heart rhythms, often a fast heart rate * Reduced blood pressure * Decreased urine output * Altered mental status * Anaphylactic shock is caused by a severe anaphylactic reaction to an allergen, antigen, drug or foreign protein causing the release of histamine which causes widespread vasodilation, leading to hypotension and increased capillary permeability. Signs of anaphylaxis Signs typically occur after exposure to an allergen and may include: * Skin changes, such as hives, itching, flushing and swelling. * Wheezing and shortness of breath. * Abdominal pain, diarrhea, and vomiting. * Lightheadedness, confusion, headaches, loss of consciousness. * High spinal injuries may cause neurogenic shock, which is commonly classified as a subset of distributive shock.[20] The classic symptoms include a slow heart rate due to loss of cardiac sympathetic tone and warm skin due to dilation of the peripheral blood vessels.[20] (This term can be confused with spinal shock which is a recoverable loss of function of the spinal cord after injury and does not refer to the hemodynamic instability.) #### Endocrine[edit] Although not officially classified as a subcategory of shock, many endocrinology disturbances in their severe form can result in shock. * Hypothyroidism (can be considered a form of cardiogenic shock) in people who are critically ill patients, reduces cardiac output and can lead to hypotension and respiratory insufficiency. * Thyrotoxicosis (cardiogenic shock) may induce a reversible cardiomyopathy. * Acute adrenal insufficiency (distributive shock) is frequently the result of discontinuing corticosteroid treatment without tapering the dosage. However, surgery and intercurrent disease in patients on corticosteroid therapy without adjusting the dosage to accommodate for increased requirements may also result in this condition. * Relative adrenal insufficiency (distributive shock) in critically ill patients where present hormone levels are insufficient to meet the higher demands ## Cause[edit] Type Cause Low volume Fluid loss such as bleeding or diarrhea Heart Ineffective pumping due to heart damage Obstructive Blood flow to or from the heart is blocked Distributive Due to abnormal flow within the small blood vessels[21] Shock is a common end point of many medical conditions.[10] Shock itself is a life-threatening condition as a result of compromised body circulation.[22] It can be divided into four main types based on the underlying cause: hypovolemic, distributive, cardiogenic, and obstructive.[23] A few additional classifications are occasionally used, such as endocrinologic shock.[10] ## Pathophysiology[edit] Effects of inadequate perfusion on cell function. There are four stages of shock. Shock is a complex and continuous condition, and there is no sudden transition from one stage to the next.[24] At a cellular level, shock is the process of oxygen demand becoming greater than oxygen supply.[7] One of the key dangers of shock is that it progresses by a positive feedback mechanism. Poor blood supply leads to cellular damage, which results in an inflammatory response to increase blood flow to the affected area. In this manner, the blood supply level is matched with tissue demand for nutrients. However, if there is enough increased demand in some areas, it can deprive other areas of sufficient supply. Due to this chain of events, immediate treatment of shock is critical for survival.[6] ### Initial[edit] During this stage, the state of hypoperfusion causes hypoxia. Due to the lack of oxygen, the cells perform lactic acid fermentation. Since oxygen, the terminal electron acceptor in the electron transport chain, is not abundant, this slows down entry of pyruvate into the Krebs cycle, resulting in its accumulation. The accumulating pyruvate is converted to lactate by lactate dehydrogenase. The accumulating lactate causes lactic acidosis. ### Compensatory[edit] This stage is characterised by the body employing physiological mechanisms, including neural, hormonal and bio-chemical mechanisms, in an attempt to reverse the condition. As a result of the acidosis, the person will begin to hyperventilate in order to rid the body of carbon dioxide (CO2). CO2 indirectly acts to acidify the blood, so the body attempts to return to acid–base homeostasis by removing that acidifying agent. The baroreceptors in the arteries detect the hypotension resulting from large amounts of blood being redirected to distant tissues, and cause the release of epinephrine and norepinephrine. Norepinephrine causes predominately vasoconstriction with a mild increase in heart rate, whereas epinephrine predominately causes an increase in heart rate with a small effect on the vascular tone; the combined effect results in an increase in blood pressure. The renin–angiotensin axis is activated, and arginine vasopressin (anti-diuretic hormone) is released to conserve fluid by reducing its excretion via the renal system. These hormones cause the vasoconstriction of the kidneys, gastrointestinal tract, and other organs to divert blood to the heart, lungs and brain. The lack of blood to the renal system causes the characteristic low urine production. However the effects of the renin–angiotensin axis take time and are of little importance to the immediate homeostatic mediation of shock.[citation needed] ### Progressive[edit] In the absence of successful treatment of the underlying cause, shock will proceed to the progressive stage. During this stage, compensatory mechanisms begin to fail. Due to the decreased perfusion of the cells in the body, sodium ions build up within the intracellular space while potassium ions leak out. Due to lack of oxygen, cellular respiration diminishes and anaerobic metabolism predominates. As anaerobic metabolism continues, a metabolic acidosis, the arteriolar smooth muscle and precapillary sphincters relax such that blood remains in the capillaries.[18] Due to this, the hydrostatic pressure will increase and, combined with histamine release, this will lead to leakage of fluid and protein into the surrounding tissues. As this fluid is lost, the blood concentration and viscosity increase, causing sludging of the micro-circulation. The prolonged vasoconstriction will also cause the vital organs to be compromised due to reduced perfusion.[18] If the bowel becomes sufficiently ischemic, bacteria may enter the blood stream, resulting in the increased complication of endotoxic shock.[6][18] ### Refractory[edit] At this stage, the vital organs have failed and the shock can no longer be reversed. Brain damage and cell death are occurring, and death will occur imminently. One of the primary reasons that shock is irreversible at this point is that much cellular ATP has been degraded into adenosine in the absence of oxygen as an electron receptor in the mitochondrial matrix. Adenosine easily perfuses out of cellular membranes into extracellular fluid, furthering capillary vasodilation, and then is transformed into uric acid. Because cells can only produce adenosine at a rate of about 2% of the cell's total need per hour, even restoring oxygen is futile at this point because there is no adenosine to phosphorylate into ATP.[6] ## Diagnosis[edit] The diagnosis of shock is commonly based on a combination of symptoms, physical examination, and laboratory tests. Many signs and symptoms are not sensitive or specific for shock, and as such many clinical decision making tools have been developed to identify shock at an early stage.[25] A high degree of suspicion is necessary for the proper diagnosis of shock. The first change seen in shock is increased cardiac output followed by a decrease in mixed venous oxygen saturation (SmvO2) as measured in the pulmonary artery via a pulmonary artery catheter.[26] Central venous oxygen saturation (ScvO2) as measured via a central line correlates well with SmvO2 and are easier to acquire. If shock progresses anaerobic metabolism will begin to occur with an increased blood lactic acid as the result. While many laboratory tests are typically performed, there is no test that either makes or excludes the diagnosis. A chest X-ray or emergency department ultrasound may be useful to determine volume status.[7][8] ## Management[edit] The best evidence exists for the treatment of septic shock in adults. However, the pathophysiology of shock appears similar in children, and treatment methodologies have been extrapolated to children.[10] Management may include securing the airway via intubation if necessary to decrease the work of breathing and for guarding against respiratory arrest. Oxygen supplementation, intravenous fluids, passive leg raising (not Trendelenburg position) should be started and blood transfusions added if blood loss is severe.[7] It is important to keep the person warm to avoid hypothermia[27] as well as adequately manage pain and anxiety as these can increase oxygen consumption.[7] Negative impact by shock is reversible if it's recognized and treated early in time.[22] ### Fluids[edit] Aggressive intravenous fluids are recommended in most types of shock (e.g. 1–2 liter normal saline bolus over 10 minutes or 20 ml/kg in a child) which is usually instituted as the person is being further evaluated.[28] Colloids and crystalloids appear to be similar with respect to outcomes.,[29] Balanced crystalloids and normal saline also appear to be similar in critically ill patients.[30] If the person remains in shock after initial resuscitation, packed red blood cells should be administered to keep the hemoglobin greater than 100 g/l.[7] For those with hemorrhagic shock, the current evidence supports limiting the use of fluids for penetrating thorax and abdominal injuries allowing mild hypotension to persist (known as permissive hypotension).[31] Targets include a mean arterial pressure of 60 mmHg, a systolic blood pressure of 70–90 mmHg,[7][32] or until their adequate mentation and peripheral pulses.[32] Hypertonic fluid may also be an option in this group.[33] ### Medications[edit] Epinephrine auto-injector Vasopressors may be used if blood pressure does not improve with fluids. Common vasopressors used in shock include: norepinephrine, phenylephrine, dopamine, dobutamine. There is no evidence of substantial benefit of one vasopressor over another;[34] however, using dopamine leads to an increased risk of arrhythmia when compared with norepinephrine.[35] Vasopressors have not been found to improve outcomes when used for hemorrhagic shock from trauma[36] but may be of use in neurogenic shock.[20] Activated protein C (Xigris) while once aggressively promoted for the management of septic shock has been found not to improve survival and is associated with a number of complications.[37] Activated protein C was withdrawn from the market in 2011, and clinical trials were discontinued.[37] The use of sodium bicarbonate is controversial as it has not been shown to improve outcomes.[38] If used at all it should only be considered if the pH is less than 7.0.[38] People with anaphylactic shock are commonly treated with epinephrine. Antihistamines, such as benadryl, diphenhydramine and ranitidine are also commonly administered. Albuterol, normal saline, and steroids are also commonly given. ### Mechanical support[edit] * Intra-aortic balloon pump (IABP) - a device inserted into the aorta that mechanically raises the blood pressure. Use of Intra-aortic balloon pumps is not recommended in cardiogenic shock.[39] * Ventricular assist device (VAD) - A mechanical pump that helps pump blood throughout the body. Commonly used in short term cases of refractory primary cardiogenic shock. * Artificial heart (TAH) * Extracorporeal membrane oxygenation (ECMO) - an external device that completely replaces the work of the heart. ### Treatment goals[edit] The goal of treatment is to achieve a urine output of greater than 0.5 ml/kg/h, a central venous pressure of 8–12 mmHg and a mean arterial pressure of 65–95 mmHg. In trauma the goal is to stop the bleeding which in many cases requires surgical interventions. A good urine output indicates that the kidneys are getting enough blood flow. ## Epidemiology[edit] Septic shock (a form of distributive shock), is the most common form of shock. Shock from blood loss occurs in about 1–2% of trauma cases.[32] Up to one-third of people admitted to the intensive care unit (ICU) are in circulatory shock.[40] Of these, cardiogenic shock accounts for approximately 20%, hypovolemic about 20%, and septic shock about 60% of cases.[41] ## Prognosis[edit] Sepsis mortality The prognosis of shock depends on the underlying cause and the nature and extent of concurrent problems. Low volume, anaphylactic, and neurogenic shock are readily treatable and respond well to medical therapy. Septic shock, however has a mortality rate between 30% and 80% while cardiogenic shock has a mortality rate between 70% and 90%.[42] ## History[edit] There is no evidence of the word shock being used in its modern-day form prior to 1743. However, there is evidence that Hippocrates used the word exemia to signify a state of being “drained of blood".[43] Shock or "choc" was first described in a trauma victim in the English translation of Henri-François LeDran's 1740 text, Traité ou Reflexions Tire'es de la Pratique sur les Playes d'armes à feu (A treatise, or reflections, drawn from practice on gun-shot wounds.)[44] In this text he describes "choc" as a reaction to the sudden impact of a missile. However, the first English writer to use the word shock in its modern-day connotation was James Latta, in 1795. Prior to World War I, there were several competing hypotheses behind the pathophysiology of shock. Of the various theories, the most well regarded was a theory penned by George W. Crile who in 1899 suggested in his monograph, "An Experimental Research into Surgical Shock", that shock was quintessentially defined as a state of circulatory collapse (vasodilation) due to excessive nervous stimulation. Other competing theories around the turn of the century included one penned by Malcolm in 1905, in which the assertion was that prolonged vasoconstriction led to the pathophysiological signs and symptoms of shock. In the following World War I, research around shock resulted in experiments by Walter B. Cannon of Harvard and William M. Bayliss of London in 1919 that showed that an increase in permeability of the capillaries in response to trauma or toxins was responsible for many clinical manifestations of shock. In 1972 Hinshaw and Cox suggested the classification system for shock which is still used today.[42] ## References[edit] 1. ^ a b c d e f g h i j k l m n International Trauma Life Support for Emergency Care Providers (8 ed.). Pearson Education Limited. 2018. pp. 172–173. ISBN 978-1292-17084-8. 2. ^ a b c d e f g h i j k l m ATLS - Advanced Trauma Life Support - Student Course Manual (10 ed.). American College of Surgeons. 2018. pp. 43–52, 135. ISBN 978-78-0-9968267. 3. ^ a b c d Tabas, Jeffrey; Reynolds, Teri (2010). High Risk Emergencies, An Issue of Emergency Medicine Clinics - E-Book. Elsevier Health Sciences. p. 58. ISBN 978-1455700257. 4. ^ Smith, N; Lopez, RA; Silberman, M (January 2019). "Distributive Shock". PMID 29261964. Cite journal requires `\|journal=` (help) 5. ^ a b Olaussen A, Blackburn T, Mitra B, Fitzgerald M (June 2014). "Review article: shock index for prediction of critical bleeding post-trauma: a systematic review". Emergency Medicine Australasia. 26 (3): 223–8. doi:10.1111/1742-6723.12232. PMID 24712642. S2CID 19881753. 6. ^ a b c d Guyton, Arthur; Hall, John (2006). "Chapter 24: Circulatory Shock and Physiology of Its Treatment". In Gruliow, Rebecca (ed.). Textbook of Medical Physiology (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc. pp. 278–288. ISBN 978-0-7216-0240-0. 7. ^ a b c d e f g h i j k Tintinalli, Judith E. (2010). Emergency Medicine: A Comprehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. pp. 165–172. ISBN 978-0-07-148480-0. 8. ^ a b Tintinalli, Judith E. (2010). Emergency Medicine: A Comprehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. pp. 174–175. ISBN 978-0-07-148480-0. 9. ^ Assessing dehydration and shock. NCBI Bookshelf. National Collaborating Centre for Women's and Children's Health (UK). Retrieved 2019-05-09. 10. ^ a b c d e f g h i Silverman, Adam (Oct 2005). "Shock: A Common Pathway For Life-Threatening Pediatric Illnesses And Injuries". Pediatric Emergency Medicine Practice. 2 (10). 11. ^ Tintinalli, Judith E. (2010). Emergency Medicine: A Comprehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. ISBN 978-0-07-148480-0. 12. ^ Pacagnella RC, Souza JP, Durocher J, Perel P, Blum J, Winikoff B, Gülmezoglu AM (2013). "A systematic review of the relationship between blood loss and clinical signs". PLOS ONE. 8 (3): e57594. Bibcode:2013PLoSO...857594P. doi:10.1371/journal.pone.0057594. PMC 3590203. PMID 23483915. 13. ^ Pich, H.; Heller, A.R. (May 2015). "Obstruktiver Schock". Der Anaesthesist (in German). 64 (5): 403–419. doi:10.1007/s00101-015-0031-9. ISSN 0003-2417. PMID 25994928. S2CID 39461027. 14. ^ Cheatham, Michael Lee (April 2009). "Abdominal compartment syndrome". Current Opinion in Critical Care. 15 (2): 154–162. doi:10.1097/MCC.0b013e3283297934. ISSN 1531-7072. PMID 19276799. S2CID 42407737. 15. ^ Cheatham, Michael L.; Malbrain, Manu L. N. G.; Kirkpatrick, Andrew; Sugrue, Michael; Parr, Michael; De Waele, Jan; Balogh, Zsolt; Leppäniemi, Ari; Olvera, Claudia; Ivatury, Rao; D'Amours, Scott (June 2007). "Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. II. Recommendations". Intensive Care Medicine. 33 (6): 951–962. doi:10.1007/s00134-007-0592-4. ISSN 0342-4642. PMID 17377769. S2CID 10770608. 16. ^ Bone RC, Balk RA, et al. (The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine) (June 1992). "Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis". Chest. 101 (6): 1644–55. doi:10.1378/chest.101.6.1644. PMID 1303622. 17. ^ Isaac, Jeff. (2013). Wilderness and rescue medicine. Jones & Bartlett Learning. ISBN 9780763789206. OCLC 785442005. 18. ^ a b c d e f g Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 102–103 ISBN 978-1-4160-2973-1 19. ^ "Surviving Sepsis Campaign Responds to ProCESS Trial" (PDF). Surviving Sepsis Campaign. Survivingsepsis.org. Retrieved 2015-03-25. 20. ^ a b c Cocchi MN, Kimlin E, Walsh M, Donnino MW (August 2007). "Identification and resuscitation of the trauma patient in shock". Emergency Medicine Clinics of North America. 25 (3): 623–42, vii. CiteSeerX 10.1.1.688.9838. doi:10.1016/j.emc.2007.06.001. PMID 17826209. 21. ^ Elbers PW, Ince C (2006). "Mechanisms of critical illness--classifying microcirculatory flow abnormalities in distributive shock". Critical Care. 10 (4): 221. doi:10.1186/cc4969. PMC 1750971. PMID 16879732. 22. ^ a b "Definition, classification, etiology, and pathophysiology of shock in adults". UpToDate. Retrieved 2019-02-22. 23. ^ Tintinalli, Judith E. (2010). Emergency Medicine: A Comprehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. p. 168. ISBN 978-0-07-148480-0. 24. ^ Armstrong, D.J. (2004). Shock. In: Alexander, M.F., Fawcett, J.N., Runciman, P.J. Nursing Practice. Hospital and Home. The Adult.(2nd edition): Edinburgh: Churchill Livingstone.CS1 maint: location (link) 25. ^ Lembke, Kelly; Parashar, Sanjay; Simpson, Steven (2017-10-01). "Sensitivity and Specificity of SIRS, qSOFA and Severe Sepsis for Mortality of Patients Presenting to the Emergency Department With Suspected Infection". Chest. 152 (4): A401. doi:10.1016/j.chest.2017.08.427. ISSN 0012-3692. 26. ^ Shoemaker, W. C. (May 1996). "Temporal physiologic patterns of shock and circulatory dysfunction based on early descriptions by invasive and noninvasive monitoring". New Horizons (Baltimore, Md.). 4 (2): 300–318. ISSN 1063-7389. PMID 8774804. 27. ^ Nolan JP, Pullinger R (March 2014). "Hypovolaemic shock". BMJ. 348 (mar07 1): g1139. doi:10.1136/bmj.g1139. PMID 24609389. S2CID 45691590. 28. ^ American College of Surgeons (2008). Atls, Advanced Trauma Life Support Program for Doctors. Amer College of Surgeons. p. 58. ISBN 978-1-880696-31-6. 29. ^ Lewis SR, Pritchard MW, Evans DJ, Butler AR, Alderson P, Smith AF, Roberts I (August 2018). "Colloids versus crystalloids for fluid resuscitation in critically ill people". The Cochrane Database of Systematic Reviews. 8: CD000567. doi:10.1002/14651858.CD000567.pub7. PMC 6513027. PMID 30073665. 30. ^ Liu, C; Lu, G; Wang, D; Lei, Y; Mao, Z; Hu, P; Hu, J; Liu, R; Han, D; Zhou, F (November 2019). "Balanced crystalloids versus normal saline for fluid resuscitation in critically ill patients: A systematic review and meta-analysis with trial sequential analysis". The American Journal of Emergency Medicine. 37 (11): 2072–2078. doi:10.1016/j.ajem.2019.02.045. PMID 30852043. 31. ^ Marx, J (2010). Rosen's emergency medicine: concepts and clinical practice 7th edition. Philadelphia, PA: Mosby/Elsevier. p. 2467. ISBN 978-0-323-05472-0. 32. ^ a b c Cherkas, David (Nov 2011). "Traumatic Hemorrhagic Shock: Advances In Fluid Management". Emergency Medicine Practice. 13 (11): 1–19, quiz 19-20. PMID 22164397. Archived from the original on 2012-01-18. 33. ^ Wu MC, Liao TY, Lee EM, Chen YS, Hsu WT, Lee MG, Tsou PY, Chen SC, Lee CC (November 2017). "Administration of Hypertonic Solutions for Hemorrhagic Shock: A Systematic Review and Meta-analysis of Clinical Trials". Anesthesia and Analgesia. 125 (5): 1549–1557. doi:10.1213/ANE.0000000000002451. PMID 28930937. S2CID 39310937. 34. ^ Gamper, Gunnar; Havel, Christof; Arrich, Jasmin; Losert, Heidrun; Pace, Nathan Leon; Müllner, Marcus; Herkner, Harald (2016-02-15). "Vasopressors for hypotensive shock". The Cochrane Database of Systematic Reviews. 2: CD003709. doi:10.1002/14651858.CD003709.pub4. ISSN 1469-493X. PMC 6516856. PMID 26878401. 35. ^ Gamper G, Havel C, Arrich J, Losert H, Pace NL, Müllner M, Herkner H (February 2016). "Vasopressors for hypotensive shock". The Cochrane Database of Systematic Reviews. 2: CD003709. doi:10.1002/14651858.CD003709.pub4. PMC 6516856. PMID 26878401. 36. ^ Diez C, Varon AJ (December 2009). "Airway management and initial resuscitation of the trauma patient". Current Opinion in Critical Care. 15 (6): 542–7. doi:10.1097/MCC.0b013e328331a8a7. PMID 19713836. S2CID 19918811. 37. ^ a b Martí-Carvajal AJ, Solà I, Gluud C, Lathyris D, Cardona AF (December 2012). "Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients". The Cochrane Database of Systematic Reviews. 12: CD004388. doi:10.1002/14651858.CD004388.pub6. PMC 6464614. PMID 23235609. 38. ^ a b Boyd JH, Walley KR (August 2008). "Is there a role for sodium bicarbonate in treating lactic acidosis from shock?". Current Opinion in Critical Care. 14 (4): 379–83. doi:10.1097/MCC.0b013e3283069d5c. PMID 18614899. S2CID 22613993. 39. ^ Vincent, Jean-Louis; De Backer, Daniel (2013-10-31). Finfer, Simon R.; Vincent, Jean-Louis (eds.). "Circulatory Shock". New England Journal of Medicine. 369 (18): 1726–1734. doi:10.1056/NEJMra1208943. ISSN 0028-4793. PMID 24171518. S2CID 6900105. 40. ^ Vincent JL, De Backer D (October 2013). "Circulatory shock". The New England Journal of Medicine. 369 (18): 1726–34. doi:10.1056/NEJMra1208943. PMID 24171518. S2CID 6900105. 41. ^ Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A (December 2014). "Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine". Intensive Care Medicine. 40 (12): 1795–815. doi:10.1007/s00134-014-3525-z. PMC 4239778. PMID 25392034. 42. ^ a b Irwin, Richard S.; Rippe, James M. (January 2003). Intensive Care Medicine. Lippincott Williams & Wilkins, Philadelphia & London. ISBN 978-0-7817-3548-3. Archived from the original on 2005-11-07. 43. ^ Cannon, Walter Bradford (1918). The Nature and Treatment of Wound Shock and Allied Conditions. American Medical Association. 44. ^ BLOCH, JACK H.; DIETZMAN, RONALD H.; PIERCE, CHARLES H.; LILLEHEI, RICHARD C. (April 1966). "Theories of the Production of Shock". British Journal of Anaesthesia. 38 (4): 234–249. doi:10.1093/bja/38.4.234. ISSN 0007-0912. PMID 5328405. ## External links[edit] Classification D * ICD-10: R57 * ICD-9-CM: 785.50 * MeSH: D012769 * DiseasesDB: 12013 External resources * MedlinePlus: 000039 * eMedicine: emerg/531 med/285 emerg/533 * v * t * e Shock Distributive * Septic shock * Neurogenic shock * Anaphylactic shock * Toxic shock syndrome Obstructive * Abdominal compartment syndrome Low volume * Hemorrhage * Hypovolemia * Osmotic shock Other * Spinal shock * Cryptic shock * Vasodilatory shock * v * t * e Intensive care medicine * Health science * Medicine * Medical specialities * Respiratory therapy General terms * Intensive care unit (ICU) * Neonatal intensive care unit (NICU) * Pediatric intensive care unit (PICU) * Coronary care unit (CCU) * Critical illness insurance Conditions Organ system failure Shock sequence SIRS Sepsis Severe sepsis Septic shock Multiple organ dysfunction syndrome Other shock Cardiogenic shock Distributive shock Anaphylaxis Obstructive shock Neurogenic shock Spinal shock Vasodilatory shock Organ failure Acute renal failure Acute respiratory distress syndrome Acute liver failure Respiratory failure Multiple organ dysfunction syndrome * Neonatal infection * Polytrauma * Coma Complications * Critical illness polyneuropathy / myopathy * Critical illness–related corticosteroid insufficiency * Decubitus ulcers * Fungemia * Stress hyperglycemia * Stress ulcer Iatrogenesis * Methicillin-resistant Staphylococcus aureus * Oxygen toxicity * Refeeding syndrome * Ventilator-associated lung injury * Ventilator-associated pneumonia * Dialytrauma Diagnosis * Arterial blood gas * Catheter * Arterial line * Central venous catheter * Pulmonary artery catheter * Blood cultures * Screening cultures Life-supporting treatments * Airway management * Chest tube * Dialysis * Enteral feeding * Goal-directed therapy * Induced coma * Mechanical ventilation * Therapeutic hypothermia * Total parenteral nutrition * Tracheal intubation Drugs * Analgesics * Antibiotics * Antithrombotics * Inotropes * Intravenous fluids * Neuromuscular-blocking drugs * Recombinant activated protein C * Sedatives * Stress ulcer prevention drugs * Vasopressors ICU scoring systems * APACHE II * Glasgow Coma Scale * PIM2 * SAPS II * SAPS III * SOFA Physiology * Hemodynamics * Hypotension * Level of consciousness * Acid–base imbalance * Water-electrolyte imbalance Organisations * Society of Critical Care Medicine * Surviving Sepsis Campaign * European Society of Paediatric and Neonatal Intensive Care Related specialties * Anesthesiology * Cardiology * Internal medicine * Neurology * Pediatrics * Pulmonology * Surgery * Traumatology * v * t * e Symptoms and signs relating to the circulatory system Chest pain * Referred pain * Angina * Levine's sign Auscultation * Heart sounds * Split S2 * S3 * S4 * Gallop rhythm * Heart murmur * Systolic * Functional murmur * Still's murmur * Diastolic * Pulmonary insufficiency * Graham Steell murmur * Continuous * Carey Coombs murmur * Mitral insufficiency * Presystolic murmur * Pericardial friction rub * Heart click * Bruit * carotid Pulse * Tachycardia * Bradycardia * Pulsus paradoxus * doubled * Pulsus bisferiens * Pulsus bigeminus * Pulsus alternans Other * Palpitations * Apex beat * Cœur en sabot * Jugular venous pressure * Cannon A waves * Hyperaemia * Shock * Cardiogenic * Obstructive * Hypovolemic * Distributive * See further Template:Shock Cardiovascular disease Aortic insufficiency * Collapsing pulse * De Musset's sign * Duroziez's sign * Müller's sign * Austin Flint murmur * Mayne's sign Other endocardium * endocarditis: Roth's spot * Janeway lesion/Osler's node * Bracht–Wachter bodies Pericardium * Cardiac tamponade/Pericardial effusion: Beck's triad * Ewart's sign Other * rheumatic fever: * Anitschkow cell * Aschoff body * EKG * J wave * Gallavardin phenomenon Vascular disease Arterial * aortic aneurysm * Cardarelli's sign * Oliver's sign * pulmonary embolism * Right heart strain * radial artery sufficiency * Allen's test * pseudohypertension * thrombus * Lines of Zahn * Adson's sign * arteriovenous fistula * Nicoladoni sign Venous * Friedreich's sign * Caput medusae * Kussmaul's sign * Trendelenburg test * superior vena cava syndrome * Pemberton's sign Authority control * NDL: 00572106 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Shock (circulatory)	c0036974	3,569	wikipedia	https://en.wikipedia.org/wiki/Shock_(circulatory)	2021-01-18T18:45:27	{"mesh": ["D012769"], "icd-9": ["785.50"], "icd-10": ["R57"], "wikidata": ["Q178061"]}
A number sign (#) is used with this entry because of evidence that frontonasal dysplasia-3 (FND3) is caused by homozygous mutation in the ALX1 gene (601527) on chromosome 12q21. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of frontonasal dysplasia, see FND1 (136760). Clinical Features Uz et al. (2010) described 3 Turkish sibs, born of consanguineous parents, with severe facial clefting and extreme microphthalmia. The male proband was born with hypertelorism, bilateral extreme microphthalmia, upper eyelid colobomata, sparse eyelashes, absence of eyebrows, wide nasal base, hypoplasia of the ala nasi, bilateral nonmidline cleft lip with a prominent glabella, complete cleft palate, and low-set posteriorly rotated ears. The only extracranial finding was a caudal appendage in the sacral region. Orbital and brain MRI showed brachycephaly, bilateral extreme microphthalmia, and a large midline bone defect of the cranium. At 11 years of age, the proband had mild mental retardation but followed commands well and his hearing was normal; however, his facial anatomy prevented sufficient expressive speech and he was only able to say 'mama.' Motor development milestones were normal. The mother had 2 consecutive pregnancies with affected female fetuses that were diagnosed prenatally. Uz et al. (2010) also reported an unrelated Turkish girl with an almost identical phenotype, who had hypertelorism, extreme microphthalmia of the right eye and microphthalmia of the left eye, upper eyelid colobomata, lack of eyelashes and eyebrows, and palpable midline cranial cleft with a soft tissue mass in the left frontal area. She also had a wide nasal bridge with hypoplasia of the ala nasi, bilateral nonmidline cleft lip, very prominent glabella, complete cleft palate, and low-set posteriorly rotated ears. Brain MRI at 4 months of age showed severely delayed myelinization, thin corpus callosum, and asymmetric cerebellar vermis configuration on the left side. Motor development was delayed. She underwent reconstructive surgery but died in infancy from a pulmonary infection. Uz et al. (2010) stated that the phenotype in these patients was borderline between frontofacionasal dysplasia (229400) and Fryns microphthalmia syndrome (600776). Mapping Uz et al. (2010) performed genomewide homozygosity mapping of 3 affected sibs with severe frontonasal dysplasia and their unaffected consanguineous parents and identified a single large homozygous stretch spanning approximately 27 Mb on chromosome 12q21.3. Molecular Genetics In 3 affected sibs from a consanguineous Turkish family with severe frontonasal dysplasia mapping to chromosome 12q21.3, Uz et al. (2010) detected a mendelian segregation error within a region of homozygosity; analysis of SNP array data revealed a homozygous deletion of the entire region in all affected offspring. The unaffected parents were heterozygous carriers of the deletion, which encompassed 7 genes, including a highly relevant candidate, ALX1. In an unrelated Turkish girl with a nearly identical phenotype, Uz et al. (2010) identified homozygosity at the ALX1 region on 12q21; sequencing ALX1 revealed a homozygous splice site mutation (601527.0001) that was found in heterozygosity in her unaffected parents and was not detected in 171 Turkish controls. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	FRONTONASAL DYSPLASIA 3	c3150706	3,570	omim	https://www.omim.org/entry/613456	2019-09-22T15:58:36	{"omim": ["613456"], "orphanet": ["306542"], "synonyms": ["ALX1-related frontonasal dysplasia", "Frontonasal dysplasia type 3"]}
Pycnodysostosis impacts bone growth and is present from birth. Symptoms include a large head and high forehead, undeveloped facial bones, and short fingers and toes. People with pycnodysostosis may have short stature, dental abnormalities, brittle bones, and delayed closure of the skull bones. Bones may become more brittle with age. Other complications like trouble breathing during sleep (sleep apnea) and bone infections may occur. Pycnodysostosis is caused by a CTSK gene that is not working correctly and inherited in an autosomal recessive pattern. The diagnosis of pycnodysostosis is based on clinical examination and X-ray findings, and is confirmed by genetic testing. Treatment is based on managing the symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pycnodysostosis	c0238402	3,571	gard	https://rarediseases.info.nih.gov/diseases/4611/pycnodysostosis	2021-01-18T17:58:02	{"mesh": ["D058631"], "omim": ["265800"], "umls": ["C0238402"], "orphanet": ["763"], "synonyms": ["Pyknodysostosis", "PKND", "PYCD"]}
Organic personality disorder (OPD) is not included in the wide variety of group of personality disorders. For this reason, the symptoms and diagnostic criteria of the organic personality disorder are different from those of the mental health disorders, which are included in this various group of personality disorders. According to the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems ICD-10, it defines the organic personality disorder as the personality change, which can be caused by traumatic brain injury (TBI) that means there are specific brain areas of patients, which have been injured after a very strong accident. Moreover, according to the ICD-10, the organic personality disorder is associated with a "significant alteration of the habitual patterns of premorbid behaviour".[1] Furthermore, organic personality disorder is associated with "personality change due to general medical condition".[2] There are crucial influences on emotions, impulses and personal needs because of this disorder. Thus, all these definitions about the organic personality disorder support that this type of disorder is associated with changes in personality and behaviour. ## Contents * 1 Causes * 2 Diagnosis and symptoms * 3 Treatment * 4 References ## Causes[edit] The organic personality disorder is included in a wide group of personality and behavioural disorders. This mental health disorder can be caused by disease, brain damages or dysfunctions in specific brain areas in frontal lobe. The most common reason for this profound change in personality is the traumatic brain injury (TBI).[1] Children, whose brain areas have been injured or damaged, may present attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and organic personality disorder.[3] Moreover, this disorder is characterised as "frontal lobe syndrome". This characteristic name shows that the organic personality disorder can usually be caused by lesions in three brain areas of frontal lobe. Specifically, the symptoms of organic personality disorder can also be caused by traumatic brain injuries in orbitofrontal cortex, anterior cingulate cortex and dorsolateral prefrontal cortex. It is worth mention that organic personality disorder may also be caused by lesions in other circumscribed brain areas.[4] ## Diagnosis and symptoms[edit] The ICD-10 includes a diagnostic guideline for the wide group of personality and behavioural disorders. However, every disorder has its own diagnostic criteria. In case of the organic personality disorder, patient has to show at least three of the following diagnostic criteria over a six or more months period. Organic personality disorder is associated with a large variety of symptoms, such as deficits in cognitive function, dysfunctional behaviours, psychosis, neurosis, emotional changes, alterations in expression function and irritability.[5] Patients with organic personality disorder can present emotional lability that means their emotional expressions are unstable and fluctuating. In addition, patients show reduction in ability of perseverance with their goals and they express disinhibited behaviours, which are characterised by inappropriate sexual and antisocial actions. For instance, patients can show dissocial behaviours, like stealing. Moreover, according to diagnostic guideline of ICD-10, patients can suffer from cognitive disturbances and they present signs of suspiciousness and paranoid ideas. Additionally, patients may present alteration in process of language production that means there are changes in language rate and flow. Furthermore, patients may show changes in their sexual preference and hyposexuality symptoms.[6] Another common feature of personality of patients with organic personality disorder is their dysfunctional and maladaptive behaviour that causes serious problems in these patients, because they face problems with pursuit and achievement of their goals. It is worth to be mentioned that patients with organic personality disorder express a feeling of unreasonable satisfaction and euphoria. Also, the patients show aggressive behaviours sometimes and these serious dysfunctions in their behaviour can have effects on their life and their relationships with other people.[7] Specifically patients show intense signs of anger and aggression because of their inability to handle their impulses. The type of this aggression is called "impulsive aggression".[1] Furthermore, it is worth to be mentioned that the pattern of organic personality disorder presents some similarities with pattern of temporal lobe epilepsy (TLE). Specifically patients who suffer from this chronic disorder type of epilepsy, express aggressive behaviours, likewise it happens to patients with organic personality disorder.[1] Another similar symptom between Temporal lobe epilepsy and organic personality disorder is the epileptic seizure. The symptom of epileptic seizure has influence on patients' personality that means it causes behavioural alterations".[8] The Temporal lobe epilepsy (TLE) is associated with the hyperexcitability of the medial temporal lobe (MTL) of patients.[1] Finally, patients with organic personality disorder may present similar symptoms with patients, who suffer from the Huntington's disease as well. The symptoms of apathy and irritability are common between these two groups of patients.[9] ## Treatment[edit] As it has already been mentioned, patients with organic personality disorder show a wide variety of sudden behavioural changes and dysfunctions. There are not a lot of information about the treatment of this mental health disorder. The pharmacological approach is the most common therapy among patients with organic personality disorder. However, the choice of drug therapy relies on the seriousness of patient's situation and what symptoms are shown. The choice and administration of specific drugs contribute to the reduction of symptoms of organic personality disorder. For this reason, it is crucial for patients' treatment to be assessed by clinical psychologists and psychiatrists before the administration of drugs. Additionally, the dysfunctions in expression of behaviour of patients with organic personality disorder and the development of symptom of irritability, which are caused by aggressive and self-injurious behaviours, can be dealt with the administration of carbamazepine. Moreover, the symptoms of this disorder can be decreased by the administration of valproic acid. Also, emotional irritability and signs of depression can be dealt with the use of nortriptyline and low-dose thioridazine. Except from the symptom of irritability, patients express aggressive behaviours. At the onset of drug therapy for effective treatment of anger and aggression, the drug of carbamazepine, phenobarbital, benztropine and haloperidol can be administrated in order to reduce the symptoms of patients with organic personality disorder. In addition, the use of propranolol may decrease the frequent behaviours of rage attacks.[10] Finally, it is important for patients to take part in psychotherapy during drug therapy. In this way, many of the adverse effects of the medications, both physiological and behavioural, can be lessened or avoided entirely. Furthermore, the clinicians can provide useful and helpful support to patients during these psychotherapy sessions. Thus, the combination of drug therapy with psychotherapy can lead to the reduction of symptoms of this disorder and the improvement of patients' situation. ## References[edit] 1. ^ a b c d e Linden, David (2011-11-23). The Biology of Psychological Disorders. Palgrave Macmillan. ISBN 9780230358089. 2. ^ Widiger, Thomas, A. The Oxford Handbook of Personality Disorders. Oxford Library of Psychology. p. 21. 3. ^ Barkley, Russell, A. (2015). Attention-Deficit Hyperactivity Disorder. A Handbook for Diagnosis and Treatment (4th ed.). The Guilford Press. p. 374. ISBN 9781462517855. 4. ^ World Health Organization. "The ICD-10 Classification of Mental and Behavioural Disorders" (PDF). World Health Organization Institutional Repository for Information Sharing. Geneva : World Health Organization. 5. ^ Franulic, Alexei; et al. (2009). "Organic personality disorder after traumatic brain injury: cognitive, anatomic and psychosocial factors. A 6 month follow-up". Brain Injury. 14 (5): 431–439. doi:10.1080/026990500120538. 6. ^ "The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic criteria for research" (PDF). World Health Organization. Geneva: WHO. 7. ^ Dowson, Jonathan, H.; Grounds, Adrian, T. (1995). Personality Disorders: Recognition and Clinical Management. Cambridge University Press. p. 126. ISBN 9780521029032. 8. ^ Kaufman, David, Myland (2007). Clinical Neurology for Psychiatrists (6th ed.). SAUNDERS ELSEVIER. 9. ^ Stein, George; Wilkinson, Greg (April 2007). Seminars in General Adult Psychiatry (2nd ed.). Royal College of Psychiatrists. p. 491. ISBN 9781904671442. 10. ^ Stark, Jack, A.; Menolascino, Frank, J.; Albarelli, Michael, H.; Gray, Vincent, C. (1988). Mental Retardation and Mental Health: Classification, Diagnosis, Treatment, Services (1st ed.). Springer-Verlag New York Inc. Classification D * ICD-10: F07.0 * v * t * e Personality disorders Schizotypal * Schizotypal Specific * Anankastic * Anxious (avoidant) * Dependent * Dissocial * Emotionally unstable * Histrionic * Paranoid * Schizoid * Other * Eccentric * Haltlose * Immature * Narcissistic * Passive–aggressive * Psychoneurotic Organic * Organic Unspecified * Unspecified [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Organic personality disorder	c0029233	3,572	wikipedia	https://en.wikipedia.org/wiki/Organic_personality_disorder	2021-01-18T18:47:49	{"umls": ["C0029233"], "icd-10": ["F07.0"], "wikidata": ["Q3449191"]}
A number sign (#) is used with this entry because of evidence that primary avascular necrosis of the femoral head-2 (ANFH2) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24. One such family has been reported. For a phenotypic description and discussion of genetic heterogeneity of primary avascular necrosis of the femoral head, see ANFH1 (608805). Clinical Features Mah et al. (2016) studied 3 affected sisters and 1 affected brother from a Greek family with bilateral avascular necrosis of the femoral head. The 3 older sibs developed hip pain at approximately 30 years of age and were diagnosed in their late 30s to mid-40s. The proband, however, developed hip pain at age 20 years and was diagnosed at age 21; he underwent hip core decompressions and bone grafting at age 28. The affected sibs were negative for osteonecrosis-associated thrombophilia markers, and they did not harbor other risk factors for osteonecrosis. Their parents and grandparents were deceased, but the sibs recalled symptoms of joint pain in their father that were never evaluated. Molecular Genetics In 4 affected sibs from a Greek family with avascular necrosis of the femoral head who were negative for mutation in the COL2A1 gene (120140), Mah et al. (2016) performed exome sequencing and identified heterozygosity for a truncating mutation in the TRPV4 gene (605427.0034). The mutation was not present in an unaffected brother or in public variant databases; DNA was not available from their deceased parents. Screening of 49 sporadic patients with ANFH showed that they did not carry the TRPV4 truncating mutation. Complete physical examination by a medical geneticist with experience in skeletal dysplasias, as well as neurologic examination by a neurologist with expertise in polyneuropathy, did not reveal any evidence for previously reported TRPV4-associated skeletal dysplasias or neuropathies in the affected sibs. INHERITANCE \- Autosomal dominant SKELETAL Pelvis \- Degenerative changes in hip joints \- Narrowing of joint space \- Osteophytes at acetabulum Limbs \- Avascular necrosis of the femoral head, bilateral \- Patchy cystic changes of femoral head \- Patchy sclerosis of femoral head \- Collapse of femoral head MISCELLANEOUS \- Based on report of 4 sibs in 1 family (last curated February 2017) \- Onset of hip pain in third to fourth decade of life MOLECULAR BASIS \- Caused by mutation in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4, 605427.0034 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	AVASCULAR NECROSIS OF FEMORAL HEAD, PRIMARY, 2	c0410480	3,573	omim	https://www.omim.org/entry/617383	2019-09-22T15:46:04	{"mesh": ["D005271"], "omim": ["608805", "617383"], "orphanet": ["86820"], "synonyms": ["Familial osteonecrosis of the femoral head"]}
"Android porn" redirects here. For pornography on Android OS, see Mobile porn. An Actroid manufactured by Kokoro Company Ltd. Robot fetishism (also ASFR, technosexuality[1] and robophilia) is a fetishistic attraction to humanoid robots; also to people acting like robots or people dressed in robot costumes. A less common fantasy involves transformation into a robot. In these ways it is similar to agalmatophilia, which involves attraction to or transformation into statues or mannequins.[1] Robot fetishism can be viewed as a form of erotic anthropomorphism.[1] When transformation or roleplaying is involved it can be thought of as a form of erotic objectification.[1][2] ## Contents * 1 ASFR * 2 In popular culture * 3 See also * 4 References * 5 External links ## ASFR[edit] By its enthusiasts, robot fetishism is more commonly referred to by the initials "ASFR". This initialism stems from the now-defunct Usenet newsgroup alt.sex.fetish.robots. Many devotees of this fetish refer to themselves as technosexual,[2][3] or as "ASFRians".[1] ASFR can be divided into two distinct but sometimes overlapping types of fantasies.[2][3][4] An example of ASFR art. The first of these is simply a desire to have a ready-made android partner. This partner can be desired for sex, companionship, or any combination of the two. The main distinguishing feature of this fantasy is that the android is a completely artificial construct, often manufactured solely to fulfil the wishes of its owner. This type of fantasy or situation is referred to as "built".[1][3][5] The second type of fantasy prevalent within ASFR is referred to as "transformation". This involves a human who has been either willingly or unwillingly turned into an android. That person can be either oneself or one's partner, or both. It is usually the process of transformation (through whatever means it is achieved) that is the focus of this fantasy.[1][3][5] Many people in the ASFR community prefer either one or the other.[2][3][5] In some cases this preference is very strong, and people can be as equally repelled by one type as they are attracted to the other. In other cases, there is as much appreciation for built as there is for transformation.[4] A recent informal survey of ASFR community members found that two thirds prefer built while the remainder prefer transformation or some combination of both.[6] The aspects of this fetish that are most appreciated by members of the ASFR community are greatly varied. For some, things like robotic appearance, motion, or sound are important for arousal.[2] For others, these are not, and a completely lifelike android that appears to be human is desired.[4] This holds true for other aspects, such as sentience or self-awareness. The ability of the android to remove parts of its skin or other bodily appendages in order to reveal its circuitry is quite pleasing to some, but distasteful to others.[4] There is a further divide between those who prefer an android to appear human-like and those who would prefer a more mechanical looking robot, i.e. with a metallic surface. As realistic androids and humanoid robots do not currently exist in a form readily available to the consumer,[2] this fetish can only be acted upon in a limited number of ways. Primarily this is done through fantasy, involving either self stimulation or sexual roleplaying with a partner.[4] ASFR art is therefore important to aid in the reinforcement of imagination.[1] Art with ASFR content includes but is not limited to science fiction movies, music videos,[7] television shows, novels, short stories, illustrations, manipulated photographs, songs and even television commercials.[8] Such works are sought after by technosexuals since economically viable androids are not yet available. Realistic sex dolls such as the RealDoll may provide a way to explore this fetish with existing technology. Recent developments in robotics and artificial intelligence, such as those seen in the Actroid or EveR-1 may lead to the production of more advanced synthetic partners.[1][2] Some ASFRians do not use synthetic partners, and instead prefer human partners to participate in forms of fantasy play.[4] ## In popular culture[edit] * In the animated adult cartoon series Futurama, set in the 31st century, "robosexuality" refers to sexual relations between a human and a robot, notably in the episode "Proposition Infinity" (season 6, episode 4), after Amy Wong and Bender the Bending Robot start an affair. Their boss, Professor Farnsworth, objects on moral grounds, and two competing propositions are advanced, one to outlaw robosexuality, and the other to legalize it. The Professor drops his opposition when he reveals that his animus stems from his being jilted by a robot lover when he was younger. Robosexuality had been referred to in two earlier episodes, "Space Pilot 3000", the pilot for the series, and "I Dated a Robot" (season 3, episode 15), in which Fry dates a robot which has been downloaded with Lucy Liu's image and personality. In this episode, as opposed to "Opposition Infinity", Bender opposes robot-human relationships. ## See also[edit] * Doll fetish * Gynoid * Sex robot * Sexual objectification * Uncanny valley ## References[edit] 1. ^ a b c d e f g h i "ASFR", documentary short by filmmaker Allison de Fren, 2004 (streaming video) 2. ^ a b c d e f g "Let's mech love", by Lisa Scott, Metro daily paper, 7 February 2007 (web page) 3. ^ a b c d e "Acting Like a Sex Machine", by Kate Hodges, Bizarre Magazine, October 2004 4. ^ a b c d e f "Deviant Desires: Incredibly Strange Sex", by Katharine Gates, Juno Books (October 1999), ISBN 1-890451-03-7 (web page) 5. ^ a b c "Remote Control: Romancing the Robot" (clip only), SexTV documentary episode featuring interviews with members of the ASFR community (streaming video) 6. ^ "Transformation vs. Built Poll", Fembot Central Message Board, Sept. 26, 2006 (web page) 7. ^ Electrosexual Fetish (ASFR) Video Directed by Mashyno 8. ^ "Wrong Turns Down The Sex-Info-Highway 5.07", by Martine Duplessis, Exotic Magazine, 1996 (web page) ## External links[edit] * Fetish (ASFR) Music video by french electronic music musician Electrosexual, directed by Mashyno, dedicated to the ASFRians * The Technosexuality, Pygmalionist & Mind Control Fetish FAQ 3.0 * Sexually Interactive Autonomous Robots (Friedman and Kubat, M.I.T.) * Interview with David Levy, author of Robots Unlimited: Life in a Virtual Age * v * t * e Paraphilias List * Abasiophilia * Acrotomophilia * Agalmatophilia * Algolagnia * Apotemnophilia * Autassassinophilia * Biastophilia * Capnolagnia * Chremastistophilia * Chronophilia * Coprophagia * Coprophilia * Crurophilia * Crush fetish * Dacryphilia * Dendrophilia * Emetophilia * Eproctophilia * Erotic asphyxiation * Erotic hypnosis * Erotophonophilia * Exhibitionism * Formicophilia * Frotteurism * Gerontophilia * Homeovestism * Hybristophilia * Infantophilia * Kleptolagnia * Klismaphilia * Lactaphilia * Macrophilia * Masochism * Mechanophilia * Microphilia * Narratophilia * Nasophilia * Necrophilia * Object sexuality * Odaxelagnia * Olfactophilia * Omorashi * Paraphilic infantilism * Partialism * Pedophilia * Podophilia * Plushophilia * Pyrophilia * Sadism * Salirophilia * Scopophilia * Somnophilia * Sthenolagnia * Tamakeri * Telephone scatologia * Transvestic fetishism * Trichophilia * Troilism * Urolagnia * Urophagia * Vorarephilia * Voyeurism * Zoophilia * Zoosadism See also * Other specified paraphilic disorder * Erotic target location error * Courtship disorder * Polymorphous perversity * Sexual fetishism * Human sexual activity * Perversion * Sexology * Book * Category * v * t * e Sexual fetishism Actions, states * Aquaphilia * Autassassinophilia * Coprophilia * Cuckold / Cuckquean * Emetophilia * Erotic hypnosis * Erotic lactation * Erotic spanking * Exhibitionism * Forced seduction * Gaining and feeding * Medical fetishism * Omorashi * Paraphilic infantilism (adult baby) * Pregnancy * Smoking * Tickling * Total enclosure * Transvestic * Tightlacing * Tamakeri * Urolagnia * Vorarephilia * Wet and messy fetishism Body parts * Armpit * Breast * Belly * Buttocks * Eyeball * Fat * Feet * Hands * Height * Hair * Legs * Navels * Noses Clothing * Boots * Ballet boots * Boot worship * Thigh-high boots * Clothing * Corset * Diapers * Gloves * Pantyhose * Latex * Rubber and PVC * Shoes * Spandex * Underwear * Uniforms Objects * Balloons * Dolls * Latex and PVC * Robots * Spandex Controversial / illegal * Lust murder * Necrophilia * Rape fantasy * Zoophilia Culture / media * Artists * Fetish art * Fetish clubs * Fashion * Magazines * Models Race * Asian sexual fetishism * Ethnic pornography * Sexual racism Related topics * BDSM * FetLife * International Fetish Day * Kink * Leather subculture * Leather Pride flag * Sexual roleplay * Book * Category * v * t * e Androids Gynoids * Actroid * EveR * HRP-4C * Meinü robot * Repliee Q1Expo Male (androids) * Ibn Sina Robot * Geminoid Babies and children * iCub See also * Fictional robots and androids * Fictional gynoids * Android science * Humanoids * Cyborgs * Category * v * t * e Humanoid robots Legged Mini * ASRA C1 * Bioloid * Choromet * Coco * Evolta * FemiSapien * RoboSapien * Robosapien v2 * Ropid * RS Media * HOAP * JO-ZERO * KHR-1 * Kirobo & Mirata * KT-X * Manav * Nao * PALRO * PERSIA * PINO * PLEN * QRIO * Robovie-PC * RX * SIGMO Small / medium * Archie * ASIMO * Athlete Robot * AR-600 * E-nuvo * Flame * GuRoo * HUBO * iCub * J4 * Lara * Murata Boy and Murata Girl * REEM * Toyota Partner Robot * Xianxingzhe Human-sized * Ai-Da * Atlas * ATOM-7xp * Dr. Motor * E series * Eric * FEDOR * George * HRP-4 * IsaacRobot * Johnnie * Kiyomori * Kobian * Leonardo's robot * Manny * MAHRU / AHRA * Musa * P series * PETMAN * Robot Man of Szeged * SAM10 * Sophia * SURALP * Surena * TOPIO * Wabian * Wabot * WASUBOT * WHL-11 Big * Elektro * Land Walker Wheeled * GuRoo * EMIEW * Enon * Hadaly-2 * i-SOBOT * Justin * Nexi * Pepper * RI-MAN * ROBINA * Sanbot * Seropi * TOPIO Dio * TWENDY-ONE * Wakamaru * Mitra Robot With tracks * BEAR Upper torso * Domo * Gakutensoku * Geoff Peterson * Greenman * Junior * LUDWIG * Robonaut * Saika * Simon * Sota * Telenoid R1 See also Androids Cyborgs Robot fetishism * v * t * e Robotics Main articles * Outline * Glossary * Index * History * Geography * Hall of Fame * Ethics * Laws * Competitions * AI competitions Types * Anthropomorphic * Humanoid * Android * Cyborg * Claytronics * Companion * Animatronic * Audio-Animatronics * Industrial * Articulated * arm * Domestic * Educational * Entertainment * Juggling * Military * Medical * Service * Disability * Agricultural * Food service * Retail * BEAM robotics * Soft robotics Classifications * Biorobotics * Unmanned vehicle * aerial * ground * Mobile robot * Microbotics * Nanorobotics * Robotic spacecraft * Space probe * Swarm * Underwater * remotely-operated Locomotion * Tracks * Walking * Hexapod * Climbing * Electric unicycle * Robot navigation Research * Evolutionary * Kits * Simulator * Suite * Open-source * Software * Adaptable * Developmental * Paradigms * Ubiquitous Related * Technological unemployment * Terrainability * Fictional robots * Category * 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Robot fetishism	None	3,574	wikipedia	https://en.wikipedia.org/wiki/Robot_fetishism	2021-01-18T18:28:27	{"wikidata": ["Q623401"]}
PHIP-related disorder, also known as Chung-Jansen syndrome, is a rare condition caused by a change in the pleckstrin homology domain-interacting protein (PHIP) gene. The most common signs and symptoms, include mild to severe learning problems, behavior problems, and a tendency toward being overweight. PHIP-related disorder is an autosomal dominant condition. This means that a person with the disorder has a 1 in 2 or 50% chance of passing the condition to each child. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PHIP-Related disorder	c4693860	3,575	gard	https://rarediseases.info.nih.gov/diseases/13514/phip-related-disorder	2021-01-18T17:58:20	{"omim": ["617991"], "synonyms": ["Chung-Jansen syndrome", "CHUJANS", "Intellectual disability-overweight syndrome caused by PHIP haploinsufficiency", "Developmental delay, intellectual disability, obesity, and dysmorphism"]}
A number sign (#) is used with this entry because of evidence that mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (MEDNIK) is caused by homozygous mutation in the AP1S1 gene (603531) on chromosome 7q22. Description MEDNIK is a severe multisystem disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It shows phenotypic similarities to CEDNIK (609528) (summary by Montpetit et al., 2008). Clinical Features Erythrokeratodermia variabilis (EKV; 133200) is a congenital disorder of the skin that causes hyperkeratosis and red patches of variable sizes, shapes, and duration. In 5 children from 3 families originating from the Kamouraska region of the province of Quebec, Saba et al. (2005) described an atypical form of erythrokeratodermia variabilis, designated erythrokeratodermia variabilis-3 (Kamouraska type) and symbolized EKV3. This form was similar to a disorder previously described by Beare et al. (1972) and included sensorineural deafness, peripheral neuropathy, and psychomotor retardation; however, in addition to these symptoms, the Kamouraska patients had congenital diarrhea, an elevation of very long chain fatty acids (VLCFAs), and a recessive mode of inheritance. Two of the children died at an early age from severe congenital diarrhea. Montpetit et al. (2008) restudied the patients reported by Saba et al. (2005) and identified another family from Quebec with the disorder. Features included high forehead with upslanting palpebral fissures, congenital sensorineural deafness, psychomotor retardation and mental retardation, peripheral neuropathy, hypotonia, and ichthyosiform erythroderma. Gastrointestinal problems included severe diarrhea, resulting in death in infancy in 4 patients, hepatic fibrosis, cirrhosis, and cholestasis. Two patients had cataracts. Inheritance The transmission pattern of MEDNIK in the families reported by Saba et al. (2005) and Montpetit et al. (2008) was consistent with autosomal recessive inheritance. Mapping By homozygosity mapping, Saba et al. (2005) excluded GJB3 (603324) on chromosome 1 as a candidate gene for EKV3; the same approach identified a large region on chromosome 7 that was identical by descent in all affected individuals but not in an unaffected first-degree relative. The assignment was narrowed to a 6.8-Mb region of chromosome 7q22 containing approximately 100 genes, 1 of which was CX31.3 (GJC3; 611925). Sequencing of the 2 known coding exons of the GJC3 gene revealed no mutations. Montpetit et al. (2008) identified another family from Quebec with a phenotype similar to that described by Saba et al. (2005). Linkage analysis refined the critical region to 5.3 Mb between D7S2539 and D7S518. Molecular Genetics In affected members from 4 families with MEDNIK, Montpetit et al. (2008) identified the same homozygous splice site mutation in the AP1S1 gene (603531.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation was predicted to result in a truncated protein with loss of function, but a small amount of an AP1S1 protein with an in-frame deletion was also produced, which may have contributed some residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in skin and neurologic defects. The AP1S1 gene is involved in protein trafficking between organelles. Population Genetics All 3 families with MEDNIK reported by Saba et al. (2005) were likely to share common ancestors, as they lived in a relatively isolated population descended from founders of French origin who settled south of the St. Lawrence downstream of Quebec City in the 17th and 18th centuries. History See 606945.0025 for a deletion of the promoter and exon 1 of the LDLR gene causing a form of familial hypercholesterolemia called French Canadian-1, which has been identified in individuals living in the Kamouraska region of the province of Quebec. INHERITANCE \- Autosomal recessive GROWTH Other \- Growth retardation HEAD & NECK Head \- High forehead Ears \- Deafness, sensorineural, congenital Eyes \- Upslanting palpebral fissures \- Cataracts (uncommon) ABDOMEN Liver \- Hepatic fibrosis \- Cirrhosis \- Cholestasis Gastrointestinal \- Diarrhea \- Enteropathy SKIN, NAILS, & HAIR Skin \- Erythema \- Ichthyosis MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation \- Hypotonia Peripheral Nervous System \- Peripheral neuropathy LABORATORY ABNORMALITIES \- Increased very-long chain fatty acids MISCELLANEOUS \- Onset at birth \- May result in early death from severe diarrhea \- Prevalent in Quebec MOLECULAR BASIS \- Caused by mutation in the adaptor-related protein complex 1, sigma-1 subunit gene (AP1S1, 603531.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	MENTAL RETARDATION, ENTEROPATHY, DEAFNESS, PERIPHERAL NEUROPATHY, ICHTHYOSIS, AND KERATODERMA	c1836330	3,576	omim	https://www.omim.org/entry/609313	2019-09-22T16:06:16	{"doid": ["0060483"], "mesh": ["C563739"], "omim": ["609313"], "orphanet": ["171851"], "synonyms": ["Alternative titles", "ERYTHROKERATODERMIA VARIABILIS 3", "ERYTHROKERATODERMIA VARIABILIS, KAMOURASKA TYPE"]}
For a general phenotypic description and a discussion of genetic heterogeneity of hypophosphatemic rickets, see (193100). Clinical Features Brownstein et al. (2008) described a 23-year-old woman with hypophosphatemic rickets and hyperparathyroidism who presented at 13 months of age with a prominent forehead, large open anterior fontanel, knobby wrists, moderately bowed legs with refusal to stand, and 'rachitic rosary' of the anterior ribs. Radiographs of knees and wrists showed florid rachitic changes of the growth plates. After unsuccessful treatment with vitamin D2 for presumed nutritional rickets, further evaluation revealed hypophosphatemia and elevated serum parathyroid hormone (PTH) levels with inappropriate renal phosphate wasting, and treatment was changed to 1,25(OH)2-vitamin D with oral phosphate salt supplementation; her bone pain improved, and she began to walk shortly before her second birthday. At age 7 she developed hypercalcemia and upon examination was noted to have normal leg alignment with no bowing, macrocephaly, prominent frontal bossing, and dysplasia of the nasal bones with exaggerated midface protrusion. She had persistent hypophosphatemia with hypercalcemia and hyperparathyroidism, and underwent surgical removal of 3.5 hyperplastic parathyroid glands; histology showed benign multigland hyperplasia. At age 19 years she redeveloped hypercalcemia, and underwent 75% removal of the then-enlarged parathyroid remnant, with histopathology again showing benign hyperplasia. At age 23, she had intermittent headaches and was found to have Arnold-Chiari I malformation; she had an adult height of 151 cm with normal leg alignment, a mildly elevated PTH, and was functioning well at university studies. Cytogenetics Holm et al. (1997) reported a female with apparently sporadic hypophosphatemia and an apparently balanced de novo 9;13 translocation with breakpoints at 9q22 and 13q14, but no clinical details were provided. Brownstein et al. (2008) performed a cytogenetic analysis on a 23-year-old woman with hypophosphatemic rickets and hyperparathyroidism and identified a de novo balanced translocation t(9;13)(q21.13;q13.1). Normal karyotypes were present in both unaffected parents. The authors mapped the translocation breakpoints and found that the 5-prime end of the KLOTHO gene (604824) was -49 kb distal to the breakpoint on chromosome 13. Plasma alpha-klotho levels and beta-glucuronidase (611499) activity were markedly increased in the patient, as was circulating fibroblast growth factor-23 (605380). Brownstein et al. (2008) concluded that the patient's novel phenotype was caused by a positional effect of the translocation, causing increased levels of alpha-klotho. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Head \- Macrocephaly \- Frontal bossing Nose \- Dysplasia of nasal bones with midface protrusion CHEST Ribs Sternum Clavicles & Scapulae \- Rachitic rosary GENITOURINARY Kidneys \- Renal phosphate wasting SKELETAL \- Rickets \- Bone pain Limbs \- Bowing of lower extremities NEUROLOGIC Central Nervous System \- Arnold-Chiari I malformation ENDOCRINE FEATURES \- Parathyroid hyperplasia, benign LABORATORY ABNORMALITIES \- Hypophosphatemia \- Hypercalcemia \- Elevated serum parathyroid hormone (PTH) \- Translocation of chromosomes 9 and 13 MISCELLANEOUS \- 2 patients described ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	HYPOPHOSPHATEMIC RICKETS AND HYPERPARATHYROIDISM	c2677524	3,577	omim	https://www.omim.org/entry/612089	2019-09-22T16:02:21	{"mesh": ["C567423"], "omim": ["612089"]}
"Phone phobia" redirects here. For the fear of loud sounds, see Phonophobia. Telephone phobia (telephonophobia, telephobia, phone phobia) is reluctance or fear of making or taking phone calls, literally, "fear of telephones".[1] It is considered to be a type of social phobia or social anxiety.[1] It may be compared to glossophobia, in that both arise from having to engage with an audience, and the associated fear of being criticized, judged or made a fool of.[2] As is common with other fears and phobias, there is a wide spectrum of severity of the fear of phone conversations and corresponding difficulties.[1] In 1993, it was reported that about 2.5 million people in Great Britain had telephone phobia.[3] A 2019 survey of UK office workers found that 40% of baby boomers, and 70% of millennials, experience anxious thoughts when the phone rings.[4] The term "telephone apprehension" refers to a lower degree of telephone phobia, in which sufferers experience anxiety about the use of telephones, but to a less severe degree than that of an actual phobia.[5] Sufferers may have no problem communicating face to face, but have difficulty doing so over the telephone. ## Contents * 1 Causes * 2 Symptoms * 3 Effects * 4 Coping and avoidance strategies * 5 Treatment * 6 See also * 7 References ## Causes[edit] A fear of receiving calls may range from fear of the action or thought of answering the phone to fear of its actual ringing. The ringing can generate a string of anxieties, characterized by thoughts associated with having to speak, perform and converse.[2][6] Sufferers may perceive the other end as threatening or intimidating.[7] Anxiety may be triggered by concerns that the caller may bear bad or upsetting news, or be a prank caller. Fear of making calls may be associated with concerns about finding an appropriate time to call, in fear of being a nuisance.[6] A sufferer calling a household or office in which they know several people may be concerned at the prospect of failing to recognize the voice of the person who answers, with resultant embarrassment.[6] Some sufferers may be anxious about having to "perform" in front of a real or perceived audience at their end of the line: this is a particular problem for those required to use a phone in the workplace.[6] Fear of using the phone in any context (for either making or receiving calls) may be associated with anxiety about poor sound quality, and concerns that one or other party will not understand what has been said, resulting either in misunderstandings, or in the need for repetition, further explanation, or other potentially awkward forms of negotiation. These fears are often linked to the absence of body language over a phone line, and the individual fearing a loss of their sense of control.[6][7] Sufferers typically report fear that they might fail to respond appropriately in the conversation,[1] or find themselves with nothing to say, leading to embarrassing silence, stammering, or stuttering.[1][6] Past experiences, such as receiving traumatic news, or enduring an unpleasant and angry call, may also play a part in creating fear.[2] ## Symptoms[edit] A variety of symptoms can be seen in someone suffering from telephone phobia, many of which are shared with anxiety. These symptoms may include nervous stomach, sweaty palms,[2] rapid heartbeat, shortness of breath, nausea, dry mouth and trembling. The sufferer may experience feelings of panic, terror and dread.[8] Resulting panic attacks can include hyperventilation and stress. These negative and agitating symptoms can be produced by both the thought of making and receiving calls and the action of doing so. ## Effects[edit] Open-plan offices, in which phone conversations may be readily overheard by co-workers, pose particular challenges for sufferers from telephone phobia The telephone is important for both contacting others and accessing important and useful services. As a result, this phobia causes a great deal of stress and impacts people's personal lives, work lives and social lives.[2] Sufferers avoid many activities, such as scheduling events or clarifying information.[9] Strain is created in the workplace because use of phones may play a crucial role within a career.[7] ## Coping and avoidance strategies[edit] Coping strategies may consist of planning the conversation ahead of time and rehearsing, writing or noting down what needs to be said.[2][6] Anxiety may be lessened by having privacy in which to make a call, so that the sufferer need not be concerned about the conversation being overheard.[6] Associated avoidance behaviour may include asking others (e.g. relatives at home) to take phone calls and exclusively using answering machines.[1] The rise in the use of electronic text-based communication (the Internet, email and text messaging) has given many sufferers alternative means of communication that they may find considerably less stressful than the phone.[6] At the same time, members of a younger generation who have grown up with digital communication increasingly find both making or receiving phone calls "intrusive", preferring to use media that allow them to "participate in the conversation at the pace [they] choose".[10] In the 2019 survey, 61% of UK millennial office workers reported that they would "display physical, anxiety-induced behaviours when they're the only ones in the office and the phone rings".[4] Sufferers may find it helpful to explain the nature of the phobia to friends, so that a failure to respond to messages is not misinterpreted as rudeness or an unwillingness to communicate. ## Treatment[edit] Phobias of this sort can usually be treated by different types of therapies, including: cognitive behavioral therapy (CBT), psychotherapy, behavior therapy and exposure therapy.[8] Practice may play an important part in overcoming fear. It may be helpful to sufferers to increase phone usage at a slow pace, starting with simple calls and gradually working their way up. For example, they may find it easier to start with automated calls, move on to conversations with family and friends, and then further extend both the length of conversations and the range of people with whom conversations are held.[7] ## See also[edit] * List of phobias * Nomophobia * Stuttering ## References[edit] 1. ^ a b c d e f Marshall, John R. (1995). "Telephone Phobia". Social Phobia: From Shyness to Stage Fright. New York: BasicBooks. p. 30. ISBN 0-465-07896-6. "telephone phobia." 2. ^ a b c d e f Doctor, Ronald M. (2000). The Encyclopedia of Phobias, Fears, and Anxieties. New York: Facts On File. p. 493. ISBN 0-8160-3989-5. 3. ^ Keeble, Richard (2001). The Newspapers Handbook (3rd ed.). London: Routledge. p. 64. ISBN 0-415-24083-2. 4. ^ a b "Phone anxiety affects over half of UK office workers". Face for Business. Retrieved 2019-05-03. 5. ^ Fielding, Richard G. "Telephone apprehension: a study of individual differences in attitudes to, and usage of the telephone". Retrieved 3 April 2013. 6. ^ a b c d e f g h i Scott, Susie (2007). Shyness and Society: the illusion of competence. Basingstoke: Palgrave Macmillan. pp. 105–9. ISBN 9781403996039. 7. ^ a b c d Rowlands, Barbara (24 August 1993). "Health: Don't call me, please, and I won't call you: To most of us, the ringing of the phone is at least a potential pleasure. But to some it is a source of anguish". The Independent. Retrieved 3 April 2013. 8. ^ a b "Telephonophobia". Right Diagnosis. Retrieved 3 April 2013. 9. ^ "Break the bipolar cycle: a day-by-day guide to living with bipolar disorder", by Elizabeth Brondolo, Xavier Amador, p. 179 10. ^ Buchanan, Daisy (26 August 2016). "Wondering why that millennial won't take your phone call? Here's why". The Guardian. Retrieved 2019-05-03. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Telephone phobia	None	3,578	wikipedia	https://en.wikipedia.org/wiki/Telephone_phobia	2021-01-18T19:01:22	{"wikidata": ["Q612851"]}
A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with poor language and loss of hand skills (NDPLHS) is caused by heterozygous mutation in the GABBR2 gene (607340) on chromosome 9q22. Description NDPLHS is an autosomal dominant disorder characterized by developmental stagnation or regression apparent in the first years of life and manifest as loss of purposeful hand movements, loss of language, and intellectual disability. Additional features may include stereotypic movements, dystonia, gait abnormalities, sleep disturbances, and small hands and feet. The phenotype is reminiscent of Rett syndrome (RTT; 312750) (summary by Yoo et al., 2017). Clinical Features Lopes et al. (2016) reported a 19-year-old Portuguese woman (patient 9), born of unrelated parents, with a neurodevelopmental disorder reminiscent of atypical Rett syndrome. She was noted to have stagnation of psychomotor development around 7 months of age, followed by regression and lack of interest in the environment. She walked at age 24 months, but never achieved purposeful hand grasp, language, or sphincter control. She had severe intellectual disability with autistic features, agitation, bruxism, sleep disturbances, crying spells, and hyperventilation. Additional features included stereotypic movements, dystonia of the lower limbs, swallowing difficulties, small and cold hands and feet, and enlarged ventricles on brain imaging. She did not have seizures. Yoo et al. (2017) reported 4 unrelated patients, ranging in age from 8 to 28 years, with NDPLHS. Two Korean patients were ascertained from a cohort of 34 patients with a Rett-like syndrome who did not carry mutations in the MECP2 gene (300005). Two additional European patients were found through the GeneMatcher database. All patients showed a period of neurodevelopmental regression in the first years of life, had partial or complete loss of acquired purposeful hand skills, and had stereotypic hand movements. Two patients had partial or complete loss of acquired language skills, and 3 had gait abnormalities, including inability to walk in 1 and dyspraxia in 2. Other more variable features included microcephaly, macrocephaly, sleep disturbances, abnormal breathing, bruxism, self-injurious behavior, autonomic dysfunction, and small and cold hands and feet. One patient developed generalized tonic-clonic seizures at age 9 years. Brain imaging, performed in 3 patients, was normal. Vuillaume et al. (2018) reported a 12-year-old girl with profound intellectual disability, hand stereotypies, and sleep and breathing abnormalities, but no seizures. The phenotype was reminiscent of Rett syndrome. Molecular Genetics In a 19-year-old Portuguese woman (patient 9) with NDPLHS, Lopes et al. (2016) identified a de novo heterozygous missense mutation in the GABBR2 gene (A567T; 607340.0007). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 19 Portuguese patients with a clinical phenotype similar to Rett syndrome who underwent exome sequencing. Yoo et al. (2017) identified a de novo heterozygous A567T mutation in 2 unrelated Korean patients (RTT01-1 and RTT02-1) with NDPLHS. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were found in a study of 34 Korean patients with a Rett-like phenotype who did not carry mutations in the MECP2 gene (300005). A GeneMatcher search enabled the identification of 2 additional patients of European ancestry (RTT83-1 and RTT84-1) who also carried this de novo variant and had a similar disorder. In vitro functional expression studies in HEK293 cells showed that the A567T mutation significantly lowered agonist-induced activity (about 30% of wildtype), suggesting that the mutation exerts a hypomorphic effect through a dominant-negative mechanism. In a 12-year-old girl with NDPLHS, Vuillaume et al. (2018) identified a de novo heterozygous missense mutation in transmembrane 6 of the GABBR2 gene (A707T; 607340.0007). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the A707T mutation resulted in increased basal activity but weakly (nonsignificant) decreased GABA agonist-induced signaling activity compared to wildtype. Similar results were obtained with studies of the A567T mutation. These findings suggested that the phenotype could result from constitutive activity of the mutant receptor. Animal Model Yoo et al. (2017) found that transfection of the A567T mutation into tadpoles resulted in abnormal swimming patterns and increased frequencies of seizure-like behavior compared to wildtype. The variant could not rescue the defect in tadpoles with morpholino knockdown of the Gabbr2 gene, consistent with a loss of function. The addition of baclofen to the water partially rescued the phenotype in animals, suggesting a potential therapeutic target in humans with GABBR2 mutations. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly \- Macrocephaly RESPIRATORY \- Breathing abnormalities \- Hyperventilation \- Apneic episodes SKELETAL Hands \- Small hands \- Cold hands Feet \- Small feet \- Cold feet NEUROLOGIC Central Nervous System \- Stagnation of psychomotor development \- Developmental regression \- Intellectual disability \- Loss of language \- Lack of purposeful hand movements \- Gait abnormalities \- Seizures (in some patients) \- Sleep disturbances \- Dystonia \- Autonomic dysfunction \- Enlarged ventricles Behavioral Psychiatric Manifestations \- Autistic features \- Agitation \- Bruxism \- Hyperventilation \- Stereotypic movements MISCELLANEOUS \- Onset in first years of life \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the gamma-aminobutyric acid B receptor 2 gene (GABBR2, 607340.0007 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	NEURODEVELOPMENTAL DISORDER WITH POOR LANGUAGE AND LOSS OF HAND SKILLS	c2748910	3,579	omim	https://www.omim.org/entry/617903	2019-09-22T15:44:28	{"mesh": ["C567576"], "omim": ["617903"], "orphanet": ["3095"]}
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by moderate intellectual disability, dysmorphic facial features (such as prominent glabella, synophrys, and prognathism), generalized hirsutism, bilateral single palmar creases, and seizures. Additional reported manifestations include slowly progressive neurological deterioration with muscular weakness and impaired gait and balance, as well as hypogammaglobulinemia with specific absence of plasma and/or secretory IgA, among others. Brain imaging may show mild cerebellar atrophy and thin corpus callosum. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome	None	3,580	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85317	2021-01-23T19:11:41	{"icd-10": ["Q87.8"]}
Kandori fleck retina is a rare, genetic retinal dystrophy disorder characterized by irregular, sharply defined, yellowish-white lesions of variable size that are distributed mainly in the nasal equatorial region of the retina, with a tendency to confluence, that are not associated with any vascular or optic nerve abnormalities. They frequently manifest as mild and stationary night 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Kandori fleck retina	c0271257	3,581	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99179	2021-01-23T18:38:26	{"mesh": ["C562701"], "omim": ["228990"], "umls": ["C0271257"], "icd-10": ["H35.5"]}
Miliary tuberculosis Other namesDisseminated tuberculosis, tuberculosis cutis acuta generalisata, tuberculosis cutis disseminata[1] Chest X ray showing miliary tuberculosis SpecialtyInfectious disease Miliary tuberculosis is a form of tuberculosis that is characterized by a wide dissemination into the human body and by the tiny size of the lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest radiograph of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds—thus the term "miliary" tuberculosis. Miliary TB may infect any number of organs, including the lungs, liver, and spleen.[2] Miliary tuberculosis is present in about 2% of all reported cases of tuberculosis and accounts for up to 20% of all extra-pulmonary tuberculosis cases.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 History * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Patients with miliary tuberculosis often experience non-specific signs, such as coughing and enlarged lymph nodes. Miliary tuberculosis can also present with enlarged liver (40% of cases), enlarged spleen (15%), inflammation of the pancreas (<5%), and multiple organ dysfunction with adrenal insufficiency (adrenal glands do not produce enough steroid hormones to regulate organ function).[2] Miliary tuberculosis may also present with unilateral or bilateral pneumothorax rarely.[4] Stool may also be diarrheal in nature and appearance. Other symptoms include fever, hypercalcemia, choroidal tubercles, and cutaneous lesions. Firstly, many patients can experience a fever lasting several weeks with daily spikes in morning temperatures.[5] Secondly, hypercalcemia prevails in 16 to 51% of tuberculosis cases.[6] It is thought that hypercalcemia occurs as a response to increased macrophage activity in the body. Such that, 1,25 dihydroxycholecalciferol (also referred to as calcitriol) improves the ability of macrophages to kill bacteria; however, higher levels of calcitriol lead to higher calcium levels, and thus hypercalcemia in some cases.[7] Thus, hypercalcemia proves to be an important symptom of miliary tuberculosis.[7] Thirdly, chorodial tubercules, pale lesions on the optic nerve, typically indicate miliary tuberculosis in children. These lesions may occur in one eye or both; the number of lesions varies between patients.[8] Chorodial tubercules may serve as important symptoms of miliary tuberculosis, since their presence can often confirm suspected diagnosis.[9] Lastly, between 10 and 30% of adults, and 20–40% of children with miliary tuberculosis have tuberculosis meningitis.[5] This relationship results from mycobacteria from miliary tuberculosis spreading to the brain and the subarachnoid space; as a result, leading to tuberculosis meningitis.[10] The risk factors for contracting miliary tuberculosis are being in direct contact with a person who has it, living in unsanitary conditions, and poor nutrition. In the U.S., risk factors for contracting the disease include homelessness and HIV/AIDS.[11] ## Cause[edit] Miliary tuberculosis is a form of tuberculosis that is the result of Mycobacterium tuberculosis travelling to extrapulmonary organs, such as the liver, spleen and kidneys.[12] Although it is well understood that the bacteria spread from the pulmonary system to the lymphatic system and eventually the blood stream, the mechanism by which this occurs is not well understood.[13] One proposed mechanism is that tuberculous infection in the lungs results in erosion of the epithelial layer of alveolar cells and the spread of infection into a pulmonary vein.[13][14] Once the bacteria reach the left side of the heart and enter the systemic circulation, they may multiply and infect extrapulmonary organs.[14] Once infected, the cell-mediated immune response is activated. The infected sites become surrounded by macrophages, which form granuloma, giving the typical appearance of miliary tuberculosis.[15] Alternatively, the bacteria may attack the cells lining the alveoli and enter the lymph node(s).[13] The bacteria then drain into a systemic vein and eventually reach the right side of the heart. From the right side of the heart, the bacteria may seed—or re-seed as the case may be—the lungs, causing the eponymous "miliary" appearance. ## Diagnosis[edit] Tuberculosis of the lungs Tuberculosis of the lungs Testing for miliary tuberculosis is conducted in a similar manner as for other forms of tuberculosis, although a number of tests must be conducted on a patient to confirm diagnosis.[5] Tests include chest x-ray, sputum culture, bronchoscopy, open lung biopsy, head CT/MRI, blood cultures, fundoscopy, and electrocardiography.[11] The tuberculosis (TB) blood test, also called an Interferon Gamma Release Assay or IGRA, is a way to diagnose latent TB. A variety of neurological complications have been noted in miliary tuberculosis patients—tuberculous meningitis and cerebral tuberculomas being the most frequent. However, a majority of patients improve following antituberculous treatment. Rarely lymphangitic spread of lung cancer could mimic miliary pattern of tuberculosis on regular chest X-ray. [16] The tuberculin skin test, commonly used for detection of other forms of tuberculosis, is not useful in the detection of miliary tuberculosis. The tuberculin skin test fails due to the high numbers of false negatives.[17] These false negatives may occur because of higher rates of tuberculin anergy compared to other forms of tuberculosis.[5] A case of miliary tuberculosis in an 82-year-old woman: * X-ray, 13 days after onset, showing bilateral interstitial infiltrates * CT, 16 days after onset, showing extensive pulmonary parenchymal involvement consisting of irregular septal thickenings with ground-glass areas and centrilobular nodules with a peri-lymphatic distribution. * X-ray, 22 days after onset, showing extensive bilateral reticulo-nodular infiltrates * Gross pathology of the lung, spleen and kidney, showing micronodules (1–4 mm in diameter) which resemble millet seeds. * Histopathology, showing epithelioid granulomas with multinucleated giant cells and acid-fast bacilli. ## Treatment[edit] Main article: Tuberculosis treatment The standard treatment recommended by the WHO is with isoniazid and rifampicin for six months, as well as ethambutol and pyrazinamide for the first two months. If there is evidence of meningitis, then treatment is extended to twelve months. The U.S. guidelines recommend nine months' treatment.[18] "Common medication side effects a patient may have such as inflammation of the liver if a patient is taking pyrazinamide, rifampin, and isoniazid. A patient may also have drug resistance to medication, relapse, respiratory failure, and acute respiratory distress syndrome."[11] ## Prognosis[edit] If left untreated, miliary tuberculosis is almost always fatal. Although most cases of miliary tuberculosis are treatable, the mortality rate among children with miliary tuberculosis remains 15 to 20% and for adults 25 to 30%.[12] One of the main causes for these high mortality rates includes late detection of disease caused by non-specific symptoms.[9] Non-specific symptoms include: coughing, weight loss, or organ dysfunction.[3] These symptoms may be implicated in numerous disorders, thus delaying diagnosis. Misdiagnosis with tuberculosis meningitis is also a common occurrence when patients are tested for tuberculosis, since the two forms of tuberculosis have high rates of co-occurrence.[12] ## History[edit] John Jacob Manget described a form of disseminated tuberculosis in 1700 and expressed its resemblance to numerous millet seeds in size and appearance and coined the term from Latin word miliarius, meaning related to millet seed.[19] ## See also[edit] * Lupus vulgaris * Metastatic tuberculous abscess or ulceration * Thomas Wolfe * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. Chapter 74. ISBN 1-4160-2999-0. 2. ^ a b Miliary Tuberculosis at eMedicine 3. ^ a b Ray, Sayantan; Talukdar, Arunansu; Kundu, Supratip; Khanra, Dibbendhu; Sonthalia, Nikhil (2013). "Diagnosis and management of miliary tuberculosis: current state and future perspectives". Therapeutics and Clinical Risk Management. 9: 9–26. doi:10.2147/TCRM.S29179. PMC 3544391. PMID 23326198. 4. ^ Dhamgaye, TM; Mishra Gyanshankar; Deokar Kunal (December 2012). "Miliary tuberculosis with bilateral pneumothorax – A case report" (PDF). Asian Pacific Journal of Tropical Disease. 2 (6): 492–494. doi:10.1016/S2222-1808(12)60109-1. Archived from the original (PDF) on 22 December 2012. Retrieved 14 February 2013. 5. ^ a b c d Sharma, S., Mohan, A., & Sharma, A. (2012). Challenges in the diagnosis & treatment of miliary tuberculosis. Indian J Med Res, 135, 703–730. 6. ^ Ko, Y., Lee, C., Cheng, Y., Hung, K., Kuo, C., Huang, C., et al. (2004). Hypercalcaemia And Haemophagocytic Syndrome: Rare Concurrent Presentations Of Disseminated Tuberculosis In A Dialysis Patient. International Journal of Clinical Practice, 58(7), 723–725. 7. ^ a b Soofi, A., Malik, A., Khan, J., & Muzzafer, S. (2004). Severe Hypercalcemia in Tuberculosis. J Pak Med Assoc, 54(4), 213–215. 8. ^ Rodin, F., & Dickey, L. (1928). Tubercle of the choroid in miliary tuberculosis. Case Reports, 28(6), 807–809. 9. ^ a b Sahn, S. A., & Neff, T. A. (1974). Miliary Tuberculosis. The American Journal of Medicine, 56(4), 495–505. 10. ^ Donald, P., Schaaf, H., & Schoeman, J. (2005). Tuberculous Meningitis And Miliary Tuberculosis: The Rich Focus Revisited. Journal of Infection, 50(3), 193–195. 11. ^ a b c MedlinePlus Encyclopedia: Disseminated tuberculosis 12. ^ a b c Sharma, S. K., Mohan, A., Sharma, A., & Mitra, D. K. (2005). Miliary Tuberculosis: New Insights Into An Old Disease. The Lancet Infectious Diseases, 5(7), 415–430. 13. ^ a b c Krishnan, N., Robertson, B. D., & Thwaites, G. (2010). The Mechanisms And Consequences Of The Extra-pulmonary Dissemination Of Mycobacterium Tuberculosis. Tuberculosis, 90(6), 361–366. 14. ^ a b Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 516–522 ISBN 978-1-4160-2973-1 15. ^ Jumaah, S. (2012). Tuberculosis. Textbook of Clinical Pediatrics, 1, 1053–1059. 16. ^ Furqan, M; Butler, J (2010). "Miliary pattern on chest radiography: TB or not TB?". Mayo Clinic Proceedings. 85 (2): 108. doi:10.4065/mcp.2009.0523. PMC 2813816. PMID 20118384. 17. ^ Lee, Y., Park, K., Kim, S., Park, S., Lee, S., Choi, S., et al. (2013). Risk factors for false-negative results of T-SPOT.TB and tuberculin skin test in extrapulmonary tuberculosis. Infection, 41, 1089–1095 18. ^ American Thoracic Society, CDC, and Infectious Diseases Society of America (June 20, 2003). "Treatment of Tuberculosis".CS1 maint: multiple names: authors list (link) 19. ^ Manget, JJ (1700). Sepulcretum size anatomia practica. Vol. 1 (Observatio XLVII (3 vols) ed.). London: Cramer and Perrachon. ## Further reading[edit] * Sharma, SK; Mohan, A; Sharma, A (2012). "Challenges in the diagnosis & treatment of miliary tuberculosis" (PDF). The Indian Journal of Medical Research. 135 (5): 703–30. PMC 3401706. PMID 22771605. * Reichman, Lee B., M.D., M.P.H. & Tanne, Janice H. (2002). "Timebomb: The Global Epidemic of Multi-Drug-Resistant Tuberculosis. Mcgraw-Hill. ISBN 0-07-135924-9 * Albino, Juan A.; Reichman, Lee B. (1 January 1998). "The Treatment of Tuberculosis". Respiration. 65 (4): 237–255. doi:10.1159/000029271. * Rieder, Hans L (November–December 1998). "How to Combat Tuberculosis in the Year 2000?". Respiration. 65 (6). doi:10.1159/000029309. ## External links[edit] * Media related to Miliary tuberculosis at Wikimedia Commons Classification D * ICD-10: A19 * ICD-9-CM: 018 * MeSH: D014391 External resources * MedlinePlus: 000624 * eMedicine: med/1476 * v * t * e Gram-positive bacterial infection: Actinobacteria Actinomycineae Actinomycetaceae * Actinomyces israelii * Actinomycosis * Cutaneous actinomycosis * Tropheryma whipplei * Whipple's disease * Arcanobacterium haemolyticum * Arcanobacterium haemolyticum infection * Actinomyces gerencseriae Propionibacteriaceae * Propionibacterium acnes Corynebacterineae Mycobacteriaceae M. tuberculosis/ M. bovis * Tuberculosis: Ghon focus/Ghon's complex * Pott disease * brain * Meningitis * Rich focus * Tuberculous lymphadenitis * Tuberculous cervical lymphadenitis * cutaneous * Scrofuloderma * Erythema induratum * Lupus vulgaris * Prosector's wart * Tuberculosis cutis orificialis * Tuberculous cellulitis * Tuberculous gumma * Lichen scrofulosorum * Tuberculid * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Miliary * Tuberculous pericarditis * Urogenital tuberculosis * Multi-drug-resistant tuberculosis * Extensively drug-resistant tuberculosis M. leprae * Leprosy: Tuberculoid leprosy * Borderline tuberculoid leprosy * Borderline leprosy * Borderline lepromatous leprosy * Lepromatous leprosy * Histoid leprosy Nontuberculous R1: * M. kansasii * M. marinum * Aquarium granuloma R2: * M. gordonae R3: * M. avium complex/Mycobacterium avium/Mycobacterium intracellulare/MAP * MAI infection * M. ulcerans * Buruli ulcer * M. haemophilum R4/RG: * M. fortuitum * M. chelonae * M. abscessus Nocardiaceae * Nocardia asteroides/Nocardia brasiliensis/Nocardia farcinica * Nocardiosis * Rhodococcus equi Corynebacteriaceae * Corynebacterium diphtheriae * Diphtheria * Corynebacterium minutissimum * Erythrasma * Corynebacterium jeikeium * Group JK corynebacterium sepsis Bifidobacteriaceae * Gardnerella vaginalis Authority control * GND: 4250309-7 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Miliary tuberculosis	c0041321	3,582	wikipedia	https://en.wikipedia.org/wiki/Miliary_tuberculosis	2021-01-18T18:56:41	{"mesh": ["D014391"], "umls": ["C0041321"], "wikidata": ["Q17583"]}
Late-life depression refers to a major depressive episode occurring for the first time in an older person (usually over 50 or 60 years of age). The term can also include depression that develops in an older person who suffered from the illness earlier in life.[1] Concurrent medical problems and lower functional expectations of elderly patients often obscure the degree of impairment. Typically, elderly patients with depression do not report depressed mood, but instead present with less specific symptoms such as insomnia, anorexia, and fatigue. Elderly persons sometimes dismiss less severe depression as an acceptable response to life stress or a normal part of aging.[2][3][4][5][6][7] Primary care is most often where diagnosis and treatment of late-life depression occurs, though is often missed or not treated even following a diagnosis.[8] Diagnosis is made in the same way as other age groups, using DSM-5 criteria for major depressive disorder;however, diagnosis can be more difficult due to the unique challenges the elderly face.[9][8] Common reasons for this difficulty include: medical illnesses and medication side effects that present similarly to depression, difficulty communicating with providers, lack of time in an appointment, and beliefs about mental illness and treatment from the patient, friends, family members, and society.[8][10] Treatments for late-life depression include medicine and psychotherapy, along with lifestyle changes such as exercise, bright light therapy, and family support[8] In patients who do not respond to initial treatments, neurostimulation techniques such as electroconvulsive therapy (ECT) can be used.[9] ECT has demonstrated effectiveness in treating the elderly.[11] ## Contents * 1 Symptoms and diagnosis * 2 Causes * 3 Treatments * 3.1 Psychotherapy * 3.2 Pharmacotherapy * 3.3 Neurostimulation * 4 Epidemiology * 5 Research * 6 See also * 7 References ## Symptoms and diagnosis[edit] Diagnosis of depression in late life is made using the same criteria for Major Depressive Disorder found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) To meet criteria for a major depressive episode, a patient must have five of the nine symptoms listed below nearly every day for at least two weeks and must have at least either a depressed mood or anhedonia.[12][13] The symptoms they are facing must also harm their ability to function in daily life and must not be better explained by a medical illness or a substance.[13] To further meet criteria for Major Depressive Disorder, the depressive episode must not be attributable to another psychiatric disorder such as psychosis or a bipolar disorder.[13] 1. Depressed or sad mood 2. Anhedonia (loss of interest in pleasurable activities) 3. Sleep disturbance (increased or decreased sleep) 4. Appetite disturbance (increased or decreased appetite) typically with weight change 5. Energy disturbance (increased or decreased energy/activity level), usually fatigue 6. Poor memory or concentration 7. Feelings of guilt or worthlessness 8. Psychomotor retardation or agitation (a change in mental and physical speed perceived by other people) 9. Thoughts of wishing they were dead; suicidal ideation or suicide attempts ## Causes[edit] The exact changes in brain chemistry and function that cause either late life or earlier onset depression are unknown. It is known, however, that brain changes can be triggered by the stresses of certain life events such as illness, childbirth, death of a loved one, life transitions (such as retirement), interpersonal conflicts, or social isolation. Risk factors for depression in elderly persons include a history of depression, chronic medical illness, female sex, being single or divorced, brain disease, alcohol abuse, use of certain medications, and stressful life events. ## Treatments[edit] Treatment is effective in about 80% of identified cases, when treatment is provided. Effective management requires a biopsychosocial approach, combining pharmacotherapy and psychotherapy. Therapy generally results in improved quality of life, enhanced functional capacity, possible improvement in medical health status, increased longevity, and lower health care costs. Improvement should be evident as early as two weeks after the start of therapy, but full therapeutic effects may require several months of treatment. Therapy for older patients should be continued for longer periods than are typically used in younger patients.[14][15] ### Psychotherapy[edit] Psychologic therapies are recommended for elderly patients with depression because of this group’s vulnerability to adverse effects and high rates of medical problems and medication use. Psychotherapeutic approaches include cognitive behavioral therapy, supportive psychotherapy, problem-solving therapy, and interpersonal therapy.[16] Life review therapy is another type of therapy with evidence supporting its usefulness in older adults.[17] The potential benefit of psychotherapy is not diminished by increasing age. Older adults often have better treatment compliance, lower dropout rates, and more positive responses to psychotherapy than younger patients.[16] While therapy can be beneficial, it is not always provided due to factors such as lack of trained therapists or lack of coverage by health insurance.[18] ### Pharmacotherapy[edit] Pharmacotherapy for acute episodes of depression usually is effective and free of complications. Antidepressant medications are often the first treatment choice for adults with moderate or severe depression, sometimes along with psychotherapy. The most promising therapeutic effect is achieved when the treatment continues for at least six weeks.[19] Underuse or misuse of antidepressants and prescribing inadequate dosages are the most common mistakes physicians make when treating elderly patients for depression. Only 10% to 40% of depressed elderly patients are given medication. Selective serotonin reuptake inhibitors, commonly referred to as SSRIs, are considered first line pharmacotherapy for depression in late life as they are more tolerable and safer than other antidepressants.[20] Serotonin-norepinephrine reuptake inhibitors (SNRIs) are considered second-line but also can be useful for patients suffering from chronic pain.[21][22] Atypical antidepressants such as bupropion and mirtazapine have not been studied extensively in older adults but appear to offer some benefit.[23][24] Monoamine oxidase inhibitors (MAOIs) similarly have been shown to offer some benefit, but have not been studied extensively[25] MAOIs must be used with caution to prevent side effects such as serotonin syndrome and adrenergic crisis.[26] Tricyclic antidepressants are no longer the first line therapy for depression, but can still benefit patients who do not respond to initial therapies.[22] TCAs have also demonstrated a unique ability to prevent re-occurrence of depression following electroconvulsive therapy.[27][28][29] TCAs are typically not used initially due to their side effects and risk from overdose compared to SSRIs.[30][31] A TCA overdose can be fatal at a much lower dose than SSRIs.[31] Antidepressants, in general, may also work by playing a neuroprotective role in how they relieve anxiety and depression. It's thought that antidepressants may increase the effects of brain receptors that help nerve cells keep sensitivity to glutamate which is an organic compound of a nonessential amino acid. This increased support of nerve cells lowers glutamate sensitivity, providing protection against the glutamate overwhelming and exciting key brain areas related to depression. Although antidepressants may not cure depression, they can lead to remission, which is the disappearance or nearly complete reduction of depression symptoms.[32][33][34] ### Neurostimulation[edit] Neurostimulation, specifically electroconvulsive therapy (ECT) is an effective treatment for depression in the elderly. It is particularly useful in treating severe major depression that does not respond well to the above treatments.[35] In the geriatric population specifically, including patients over the age of 85, ECT provides a safe and effective treatment option.[36][37] Compared to treatment with younger patients, ECT appears to work more effectively in the older patients.[38] A typical course of ECT treatment ranges from 6 to 12 treatments, with some requiring more or less.[39] A normal treatment schedule in the United States might include three treatments a week on Monday, Wednesday, and Friday. Two treatments a week compares favorably with three and can also be used.[40] Maintenance ECT, which is ECT given longitudinally after the initial set of acute treatments, also helps depression in late life and helps prevent reoccurring depression.[41] If an older person requires hospitalization for their depression, ECT has been shown in multiple studies to work faster than medicine and reduce mortality associated with depression.[42][43] Even in cases such as depression following a stroke, ECT can be efficacious; however, the evidence is not as strong on its ability to treat vascular depression caused by long-term disease, versus an acute event like a stroke.[44][45] Transcranial magnetic stimulation (TMS) is another example of neurostimulation used to treat depression, but ECT is considered to be the more effective modality.[46][47][48] ## Epidemiology[edit] Major depression is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Nearly five million of the 31 million Americans who are 65 years or older are clinically depressed, and one million have major depression. Approximately 3% of healthy elderly persons living in the community have major depression. Recurrence may be as high as 40%. Suicide rates are nearly twice as high in depressed patients as in the general population. Major depression is more common in medically ill patients who are older than 70 years and hospitalized or institutionalized. Severe or chronic diseases associated with high rates of depression include stroke (30–60%), coronary heart disease (8–44%), cancer (1–40%), Parkinson's disease (40%), Alzheimer's disease (20–40%), and dementia (17–31%).[49] Minor depression is a clinically significant depressive disorder that does not fulfill the duration criterion or the number of symptoms necessary for the diagnosis of major depression. Minor depression, which is more common than major depression in elderly patients, may follow a major depressive episode. It also can be a reaction to routine stressors in older populations. 15–50% of patients with minor depression develop major depression within two years.[50] ## Research[edit] Brain imaging (functional/structural MRI) may help direct the search for microscopic abnormalities in brain structure and function responsible for late life depression. Ultimately, imaging technologies may serve as tools for early diagnosis and subtyping of depression.[51] ## See also[edit] * Major depressive disorder * Depression * Clinical geropsychology * Electroconvulsive therapy * Deep brain stimulation * Tricyclic antidepressant * Monoamine oxidase inhibitor ## References[edit] 1. ^ Taylor, Warren D. (25 September 2014). "Clinical practice. Depression in the elderly". The New England Journal of Medicine. 371 (13): 1228–1236. doi:10.1056/NEJMcp1402180. ISSN 1533-4406. PMID 25251617. 2. ^ Alexopoulos GS, Kelly RE (October 2009). "Research advances in geriatric depression". World Psychiatry. 8 (3): 140–9. doi:10.1002/j.2051-5545.2009.tb00234.x. PMC 2755271. PMID 19812743. 3. ^ Steffens DC, Potter GG (February 2008). "Geriatric depression and cognitive impairment". Psychol Med. 38 (2): 163–75. doi:10.1017/S003329170700102X. PMID 17588275. 4. ^ Mitchell AJ, Subramaniam H (September 2005). "Prognosis of depression in old age compared to middle age: a systematic review of comparative studies". Am J Psychiatry. 162 (9): 1588–601. doi:10.1176/appi.ajp.162.9.1588. PMID 16135616. 5. ^ Yohannes AM, Baldwin RC (2008). "Medical Comorbidities in Late-Life Depression". Psychiatric Times. 25 (14). 6. ^ Krishnan KR (January 2007). "Concept of disease in geriatric psychiatry". Am J Geriatr Psychiatry. 15 (1): 1–11. doi:10.1097/01.JGP.0000224600.37387.4b. PMID 17095750. 7. ^ Alexopoulos GS (2005). "Depression in the elderly". Lancet. 365 (9475): 1961–70. doi:10.1016/S0140-6736(05)66665-2. PMID 15936426. 8. ^ a b c d "UpToDate". www.uptodate.com. Retrieved 20 November 2019. 9. ^ a b "UpToDate". www.uptodate.com. Retrieved 20 November 2019. 10. ^ Sirey, J. A.; Bruce, M. L.; Alexopoulos, G. S.; Perlick, D. A.; Raue, P.; Friedman, S. J.; Meyers, B. S. (March 2001). "Perceived stigma as a predictor of treatment discontinuation in young and older outpatients with depression". The American Journal of Psychiatry. 158 (3): 479–481. doi:10.1176/appi.ajp.158.3.479. ISSN 0002-953X. PMID 11229992. 11. ^ van der Wurff, F. B.; Stek, M. L.; Hoogendijk, W. J. G.; Beekman, A. T. F. (October 2003). "The efficacy and safety of ECT in depressed older adults: a literature review". International Journal of Geriatric Psychiatry. 18 (10): 894–904. doi:10.1002/gps.944. ISSN 0885-6230. PMID 14533122. 12. ^ Birrer RB, Vemuri SP (May 2004). "Depression in later life: a diagnostic and therapeutic challenge". Am Fam Physician. 69 (10): 2375–82. PMID 15168957. 13. ^ a b c American Psychiatric Association (22 May 2013). Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.). American Psychiatric Association. CiteSeerX 10.1.1.988.5627. doi:10.1176/appi.books.9780890425596. ISBN 978-0-89042-555-8. 14. ^ Frazer CJ, Christensen H, Griffiths KM (June 2005). "Effectiveness of treatments for depression in older people". Med. J. Aust. 182 (12): 627–32. doi:10.5694/j.1326-5377.2005.tb06849.x. PMID 15963019. 15. ^ Smith GS, Alexopoulos GS (August 2009). "Neuroimaging in geriatric psychiatry". Int J Geriatr Psychiatry. 24 (8): 783–7. doi:10.1002/gps.2335. PMC 5675131. PMID 19593778. 16. ^ a b Alexopoulos GS, Raue PJ, Kanellopoulos D, Mackin S, Arean PA (August 2008). "Problem solving therapy for the depression-executive dysfunction syndrome of late life". Int J Geriatr Psychiatry. 23 (8): 782–8. doi:10.1002/gps.1988. PMID 18213605. 17. ^ Korte, J.; Bohlmeijer, E. T.; Cappeliez, P.; Smit, F.; Westerhof, G. J. (June 2012). "Life review therapy for older adults with moderate depressive symptomatology: a pragmatic randomized controlled trial". Psychological Medicine. 42 (6): 1163–1173. doi:10.1017/S0033291711002042. ISSN 1469-8978. PMID 21995889. 18. ^ "UpToDate". www.uptodate.com. Retrieved 4 December 2019. 19. ^ Wilson K, Mottram P, Sivanranthan A, Nightingale A (2001). "Antidepressant versus placebo for depressed elderly". Cochrane Database Syst Rev (2): CD000561. doi:10.1002/14651858.CD000561. PMC 7066642. PMID 11405969. 20. ^ Solai, L. K.; Mulsant, B. H.; Pollock, B. G. (2001). "Selective serotonin reuptake inhibitors for late-life depression: a comparative review". Drugs & Aging. 18 (5): 355–368. doi:10.2165/00002512-200118050-00006. ISSN 1170-229X. PMID 11392444. 21. ^ Nelson, J. Craig; Wohlreich, Madelaine M.; Mallinckrodt, Craig H.; Detke, Michael J.; Watkin, John G.; Kennedy, John S. (March 2005). "Duloxetine for the treatment of major depressive disorder in older patients". The American Journal of Geriatric Psychiatry. 13 (3): 227–235. doi:10.1176/appi.ajgp.13.3.227. ISSN 1064-7481. PMID 15728754. 22. ^ a b "UpToDate". www.uptodate.com. Retrieved 4 December 2019. 23. ^ Steffens, D. C.; Doraiswamy, P. M.; McQuoid, D. R. (September 2001). "Bupropion SR in the naturalistic treatment of elderly patients with major depression". International Journal of Geriatric Psychiatry. 16 (9): 862–865. doi:10.1002/gps.424. ISSN 0885-6230. PMID 11571765. 24. ^ Anttila, S. A.; Leinonen, E. V. (2001). "A review of the pharmacological and clinical profile of mirtazapine". CNS Drug Reviews. 7 (3): 249–264. doi:10.1111/j.1527-3458.2001.tb00198.x. ISSN 1080-563X. PMC 6494141. PMID 11607047. 25. ^ Georgotas, A.; McCue, R. E.; Hapworth, W.; Friedman, E.; Kim, O. M.; Welkowitz, J.; Chang, I.; Cooper, T. B. (October 1986). "Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly". Biological Psychiatry. 21 (12): 1155–1166. doi:10.1016/0006-3223(86)90222-2. ISSN 0006-3223. PMID 3756264. 26. ^ "UpToDate". www.uptodate.com. Retrieved 4 December 2019. 27. ^ Flint, A. J.; Rifat, S. L. (January 1998). "The treatment of psychotic depression in later life: a comparison of pharmacotherapy and ECT". International Journal of Geriatric Psychiatry. 13 (1): 23–28. doi:10.1002/(SICI)1099-1166(199801)13:1<23::AID-GPS725>3.0.CO;2-J. ISSN 0885-6230. PMID 9489577. 28. ^ Sackeim, H. A.; Haskett, R. F.; Mulsant, B. H.; Thase, M. E.; Mann, J. J.; Pettinati, H. M.; Greenberg, R. M.; Crowe, R. R.; Cooper, T. B.; Prudic, J. (14 March 2001). "Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial". JAMA. 285 (10): 1299–1307. doi:10.1001/jama.285.10.1299. ISSN 0098-7484. PMID 11255384. 29. ^ Mittmann, N.; Herrmann, N.; Shulman, K. I.; Silver, I. L.; Busto, U. E.; Borden, E. K.; Naranjo, C. A.; Shear, N. H. (October 1999). "The effectiveness of antidepressants in elderly depressed outpatients: a prospective case series study". The Journal of Clinical Psychiatry. 60 (10): 690–697. doi:10.4088/jcp.v60n1008. ISSN 0160-6689. PMID 10549686. 30. ^ Anderson, I. M.; Ferrier, I. N.; Baldwin, R. C.; Cowen, P. J.; Howard, L.; Lewis, G.; Matthews, K.; McAllister-Williams, R. H.; Peveler, R. C.; Scott, J.; Tylee, A. (June 2008). "Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines". Journal of Psychopharmacology (Oxford, England). 22 (4): 343–396. doi:10.1177/0269881107088441. ISSN 0269-8811. PMID 18413657. 31. ^ a b Nelson, J. (May 2017), "Tricyclic and Tetracyclic Drugs", The American Psychiatric Association Publishing Textbook of Psychopharmacology, American Psychiatric Association Publishing, doi:10.1176/appi.books.9781615371624.as09, ISBN 978-1-58562-523-9 32. ^ Taylor WD, Kuchibhatla M, Payne ME, Macfall JR, Sheline YI, Krishnan KR, Doraiswamy PM (September 2008). "Frontal white matter anisotropy and antidepressant remission in late-life depression". PLOS ONE. 3 (9): e3267. Bibcode:2008PLoSO...3.3267T. doi:10.1371/journal.pone.0003267. PMC 2533397. PMID 18813343. 33. ^ Murphy GM, Kremer C, Rodrigues HE, Schatzberg AF (October 2003). "Pharmacogenetics of antidepressant medication intolerance". Am J Psychiatry. 160 (10): 1830–5. doi:10.1176/appi.ajp.160.10.1830. PMID 14514498. 34. ^ Serafeim A, Holder MJ, Grafton G, Chamba A, Drayson MT, Luong QT, Bunce CM, Gregory CD, Barnes NM, Gordon J (April 2003). "Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells". Blood. 101 (8): 3212–9. doi:10.1182/blood-2002-07-2044. PMID 12515726. 35. ^ Pagnin, Daniel; de Queiroz, Valéria; Pini, Stefano; Cassano, Giovanni Battista (March 2004). "Efficacy of ECT in depression: a meta-analytic review". The Journal of ECT. 20 (1): 13–20. doi:10.1097/00124509-200403000-00004. ISSN 1095-0680. PMID 15087991. 36. ^ Kerner, Nancy; Prudic, Joan (February 2014). "Current electroconvulsive therapy practice and research in the geriatric population". Neuropsychiatry. 4 (1): 33–54. doi:10.2217/npy.14.3. ISSN 1758-2008. PMC 4000084. PMID 24778709. 37. ^ Geduldig, Emma T.; Kellner, Charles H. (April 2016). "Electroconvulsive Therapy in the Elderly: New Findings in Geriatric Depression". Current Psychiatry Reports. 18 (4): 40. doi:10.1007/s11920-016-0674-5. ISSN 1535-1645. PMID 26909702. 38. ^ Rhebergen, Didi; Huisman, Anne; Bouckaert, Filip; Kho, King; Kok, Rob; Sienaert, Pascal; Spaans, Harm-Pieter; Stek, Max (March 2015). "Older age is associated with rapid remission of depression after electroconvulsive therapy: a latent class growth analysis". The American Journal of Geriatric Psychiatry. 23 (3): 274–282. doi:10.1016/j.jagp.2014.05.002. ISSN 1545-7214. PMID 24951182. 39. ^ "UpToDate". www.uptodate.com. Retrieved 27 November 2019. 40. ^ Kellner, Charles H. (2012). Brain Stimulation in Psychiatry. Cambridge: Cambridge University Press. doi:10.1017/cbo9780511736216. ISBN 978-0-511-73621-6. 41. ^ van Schaik, Audrey M.; Comijs, Hannie C.; Sonnenberg, Caroline M.; Beekman, Aartjan T.; Sienaert, Pascal; Stek, Max L. (January 2012). "Efficacy and safety of continuation and maintenance electroconvulsive therapy in depressed elderly patients: a systematic review". The American Journal of Geriatric Psychiatry. 20 (1): 5–17. doi:10.1097/JGP.0b013e31820dcbf9. ISSN 1545-7214. PMID 22183009. 42. ^ Philibert, R. A.; Richards, L.; Lynch, C. F.; Winokur, G. (September 1995). "Effect of ECT on mortality and clinical outcome in geriatric unipolar depression". The Journal of Clinical Psychiatry. 56 (9): 390–394. ISSN 0160-6689. PMID 7665536. 43. ^ pubmeddev. "Speed of remission in elderly patients with depression: electroconvulsive therapy v. medication. - PubMed - NCBI". www.ncbi.nlm.nih.gov. Retrieved 27 November 2019. 44. ^ Kales, Helen C.; Maixner, Daniel F.; Mellow, Alan M. (February 2005). "Cerebrovascular disease and late-life depression". The American Journal of Geriatric Psychiatry. 13 (2): 88–98. doi:10.1176/appi.ajgp.13.2.88. ISSN 1064-7481. PMID 15703317. 45. ^ Currier, M. B.; Murray, G. B.; Welch, C. C. (1992). "Electroconvulsive therapy for post-stroke depressed geriatric patients". The Journal of Neuropsychiatry and Clinical Neurosciences. 4 (2): 140–144. doi:10.1176/jnp.4.2.140. ISSN 0895-0172. PMID 1627974. 46. ^ Berlim, Marcelo T.; Van den Eynde, Frederique; Daskalakis, Zafiris J. (July 2013). "Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive therapy (ECT) for major depression: a systematic review and meta-analysis of randomized trials". Depression and Anxiety. 30 (7): 614–623. doi:10.1002/da.22060. ISSN 1520-6394. PMID 23349112. 47. ^ Slotema, Christina W.; Blom, Jan Dirk; Hoek, Hans W.; Sommer, Iris E. C. (July 2010). "Should we expand the toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders". The Journal of Clinical Psychiatry. 71 (7): 873–884. doi:10.4088/JCP.08m04872gre. ISSN 1555-2101. PMID 20361902. 48. ^ Health Quality Ontario (2016). "Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Ontario Health Technology Assessment Series. 16 (5): 1–66. ISSN 1915-7398. PMC 4808719. PMID 27099642. 49. ^ American Psychiatric Association 2000a, p. 354 50. ^ Rapaport MH, Judd LL, Schettler PJ, Yonkers KA, Thase ME, Kupfer DJ, Frank E, Plewes JM, Tollefson GD, Rush AJ (2002). "A descriptive analysis of minor depression". Am J Psychiatry. 159 (4): 637–43. doi:10.1176/appi.ajp.159.4.637. PMID 11925303. 51. ^ Soares JC, Mann JJ (1997). "The anatomy of mood disorders--review of structural neuroimaging studies". Biol Psychiatry. 41 (1): 86–106. doi:10.1016/S0006-3223(96)00006-6. PMID 8988799. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Late life depression	None	3,583	wikipedia	https://en.wikipedia.org/wiki/Late_life_depression	2021-01-18T18:41:32	{"wikidata": ["Q438896"]}
A number sign (#) is used with this entry because the P1PK blood group system is determined by the A4GALT gene (607922) on chromosome 22q13. A distinct, but related antigen, P, which belongs to the globoside (GLOB) system (615021), is defined by activity of the B3GALT3 gene (603094) on chromosome 3q25. B3GALT3 synthesizes the P antigen from the P(k) antigen. Clinical Features Different combinations or absences of 2 antigens, P1 and P(k), (see BIOCHEMICAL FEATURES) define 5 different P blood group system phenotypes: P(1), P(2), P(1)(k), P(2)(k), and p. The P(1) red cell phenotype is defined as P1+ and P+ antigens and is the most common phenotype with a prevalence of approximately 75%. The P(2) red cell phenotype is defined as P1- and P+, and has a prevalence of about 25%. Both P(1) and P(2) red cells also express the frequent P antigen (see GLOB, 615021). The rare P(1)(k) red cell phenotype is defined as P1+ and P(k+) and the rare P(2)(k) red cell phenotype is defined as P1- and P(k+). The P(k+) phenotypes result from inactivating mutations in the B3GALT3 gene, and thus do not express the P antigen. The rare p phenotype does not express any of these antigens and is known as 'null' (Marcus et al., 1976; Koda et al., 2002). Marcus et al. (1976) noted that the P(k) phenotype lacks the P antigen and that the p phenotype lacks both P and P(k) antigens. P(k) red cells contained only traces of globoside and a marked excess of trihexosyl ceramide, whereas p cells lacked both globoside and trihexosyl ceramide and contained an excess of lactosyl ceramide and other complex glycolipids. Individuals with the P(2), P(k), and p phenotypes have clinically significant antibodies against whichever antigen is lacking. Anti-P1 antibodies can be associated with hemolytic transfusion reactions, and P and P(k)-related antibodies are implicated in hemolytic transfusion reactions, hemolytic disease of the newborn, and spontaneous abortion. Anti-P antibodies are associated with paroxysmal cold hemoglobinuria (Cantin and Lyonnais, 1983; Soderstrom et al., 1985; Spitalnik and Spitalnik, 1995). ### NOR Polyagglutination Syndrome Polyagglutination is the occurrence of red cell agglutination by virtually all human sera, but not by autologous serum or sera from newborns. Harris et al. (1982) reported a 2-generation American family in which the red blood cells from 5 healthy individuals showed polyagglutination in vitro when exposed to almost all ABO compatible normal sera, but not to cord sera. The trait was transmitted in an autosomal dominant pattern of inheritance. This polyagglutination syndrome was designated 'NOR,' since the family was from Norton, Virginia. There was some degree of variability in the agglutination among family members. Agglutination with control human serum samples could be enhanced when the NOR red blood cells were treated with proteolytic enzymes. The anti-NOR antibody was determined to be IgM. NOR-positive red cells did not agglutinate in response to the lectin from D. biflorus. The agglutination was inhibited by hydatid cyst fluid and avian P1 blood group substance, suggesting that NOR may be related to the P1PK blood group system, although the reactivity was not due to human anti-P1. This report delineated an inherited form of polyagglutination syndrome. Kusnierz-Alejska et al. (1999) reported a Polish family in which 4 individuals showed polyagglutination syndrome consistent with NOR. The trait was ascertained during blood typing, and the trait was transmitted in an autosomal dominant pattern. Treatment of the NOR+ cells with alpha-galactosidase impaired the polyagglutination, whereas papain or neuraminidase enhanced the polyagglutination. Further characterization indicated that the NOR+ red blood cells contained neutral glycolipids with an abnormal oligosaccharide structure, most likely terminated with alpha-linked galactose residues. Duk et al. (2006) determined that the unique NOR-related glycolipids from both the American and Polish families were identical. Monoclonal anti-NOR and the lectin GSL-IB4 (Griffonia simplicifolia lectin IB4) strongly stained NOR glycolipids that migrated identically in NOR samples from both families. Using mass spectrometry and immunochemical methods to analyze blood from the Polish proband reported by Kusnierz-Alejska et al. (1999), Duk et al. (2001) determined that NOR1, a component of the NOR antigen, was a unique glycosphingolipid. It was a pentaglycosylceramide; an alpha-galactosylated globoside terminated with a novel Gal(alpha)1-4GalNAc sequence. The NOR glycolipids were recognized by human antibodies that were distinct from known anti-Gal(alpha)1-3Gal xenoantibodies. Duk et al. (2007) determined that the NOR2 component was a disaccharide extension of NOR1, with a terminally linked additional Gal(alpha)1-4GalNAc(beta)1-3 unit. They also identified an intermediate glycolipid (NOR-int) that migrated between NOR1 and NOR2 when NOR2 was treated with alpha-galactosidase. NOR-int did not react with anti-NOR antibodies, but did react with GalNAc-specific soybean agglutinin. NOR-int was found to be a relatively abundant component of a neutral glycolipid fraction from NOR erythrocytes, suggesting it was a precursor to NOR2. The results indicated that polyagglutination in NOR individuals is due to unique erythrocyte glycolipids that are synthesized by sequential addition of Gal(alpha)1-4 and GalNAc(beta)1-3 to globoside (Gb4Cer). Biochemical Features The human P1PK blood group system consists of 2 main antigens: P1 and P(k). P (see 615021) is a related antigen and is synthesized from P(k). These antigens are synthesized by the sequential addition of monosaccharide residues to ceramide by different glycosyltransferases. The first step in the biosynthesis of all 3 antigens is the glucosylation of ceramide, followed by the addition of beta-galactose to form lactosylceramide (LacCer), a common precursor. After this, the biosynthetic pathways diverge. P(k) results from the addition of alpha-Gal by alpha-1,4-galactosyltransferase (A4GALT). P(k) is the substrate for beta-3-galactosyltransferase-3 (B3GALT3), which adds N-acetylglucosamine to form the P antigen. Thus, P(k) and P are closely related. The biosynthesis of P1 is different, but the final step requires the activity of an alpha-1,4-galactosyltransferase (Hellberg et al., 2002). Iwamura et al. (2003) and Thuresson et al. (2011) determined that the P1 synthase is A4GALT. Mapping The possible assignment of P1 to chromosome 22 was first suggested by McAlpine et al. (1978) who found linkage to the NADH-diaphorase locus (DIA1; 613213). Julier et al. (1985) presented family linkage data in support of this assignment: maximum lod of 1.66 at theta 0.03 with the SIS oncogene (190040). Julier et al. (1988) found evidence for linkage of P1 with markers on chromosome 22 and suggested the following order on 22q: IGL--0.10--D22S1--0.20--MB--0.24--(SIS, P1)--ter. ### Exclusion Studies Phillips and Rodey (1975) reported a large family that gave strongly negative lod scores for linkage of HLA and P, which had previously been suggested by cell hybrid studies (Fellous et al., 1971). Molecular Genetics In 4 blood samples from patients with the P(k) phenotype, Hellberg et al. (2002) identified 4 homozygous mutations (603094.0001-603094.0004) in the B3GALT3 gene that are predicted to render the enzyme nonfunctional. The absence of enzyme activity results in the P(k) phenotype. In Japanese and Swedish individuals with the p phenotype, Steffensen et al. (2000), Furukawa et al. (2000), and Koda et al. (2002) identified homozygous mutations in the A4GALT gene (see, e.g., 607922.0001). Absence or decrease in the enzyme activity results in the p phenotype. In red blood cells with the P(2) phenotype (P1-) of the P1PK blood group system, Thuresson et al. (2011) identified a homozygous 42C-T transition in exon 2a of the A4GALT gene (607922.0007). There was full concordance between genotype and phenotype among 207 samples. All the P(1) phenotypes were homozygous for C or were C/T heterozygotes. There was 1 possible discrepancy, a P(1) phenotype with a T/T genotype, but this could not be followed up. Thuresson et al. (2011) postulated that the variant may exhibit regulatory function. ### NOR Polyagglutination Syndrome In NOR+ individuals from the American and Polish families with NOR polyagglutination syndrome (Harris et al., 1982 and Kusnierz-Alejska et al., 1999) Suchanowska et al. (2012) identified a heterozygous mutation in the A4GALT gene (Q211E; 607922.0008). Transfection of the mutation in teratocarcinoma cells resulted in binding of both the anti-P1 antibody, which recognizes Gal(alpha)1-4Gal, and the anti-NOR antibodies, which recognize Gal(alpha)1-4GalNAc. Expression of the NOR antigen correlated with expression of the P1 antigen. All NOR+ individuals had at least one P1 allele (42C; 607922.0007) The Q211E mutation broadened the acceptor specificity of the enzyme, causing the transferase to acquire the ability to catalyze the synthesis of Gal(alpha)1-4GalNAc present in NOR-related glycolipids, without losing its ability to transfer the Gal residue to the C4 of Gal (Gal(alpha)1-4). In NOR+ erythrocytes, the mutant enzyme transfers alpha-Gal to the GalNAc of Cb4Cer, transforming a small portion of Gb4Cer into the NOR1 glycolipid. This becomes a new substrate for highly active B3GALNT1, resulting in the synthesis of NOR-int. A small portion of NOR-int is then further elongated by mutant A4GALT, giving rise to NOR2. Genotype/Phenotype Correlations The ability of bacteria to adhere to epithelial cells of the host is a prerequisite for many bacterial infections. In human urinary tract infections (UTI), there is a high correlation between the ability of bacteria to adhere to the urinary epithelium and their virulence (Svanborg Eden et al. (1976, 1978)). The adhesive capacity is likely to endow the bacteria with higher resistance to mechanical elimination by the flow of urine and thus aid in their ascent to the upper urinary tract and kidney. In uroepithelial cells and red cells, P blood group system antigens are receptor for pyelonephritogenic E. coli (see Korhonen et al., 1982). Svanborg Eden et al. (1983) found that individuals with the P1 phenotype had a higher density of receptor glycolipids in their red cell membrane than did those with the P2 phenotype, and that the P1 phenotype was overrepresented among patients with recurrent pyelonephritis without reflux: 97% as compared to 75% in healthy children. This patient group also showed a higher frequency of 'attaching bacteria.' In cases of recurrent pyelonephritis with reflux, no significant increase in prevalence of P1 or of attaching bacteria was seen. Lomberg et al. (1983) presented evidence that the P1 blood group phenotype and bacteria that attach to glycolipid epithelial cell receptors are especially common in girls with recurrent pyelonephritis if they do not have vesicoureteral reflux. The P1 blood group phenotype is not more common in patients with reflux and recurrent pyelonephritis than in the healthy population. In the nonreflux group, bacteria causing the pyelonephritis were often of the type with adhesions, whereas these were rare in patients with reflux. The presence of reflux appears to compensate for the defect in the capacity of the bacteria to attach. Sheinfeld et al. (1989) reviewed work on the relationship between P blood group phenotype and recurrent urinary tract infections. In their own studies they could find no peculiarity in the distribution of P phenotypes in a group of 49 white women with histories of recurrent urinary tract infections. Lichodziejewska-Niemierko et al. (1995) examined the distribution of P antigen, Lewis blood group phenotypes (111100), and secretor (182100) status in 65 patients with E. coli UTI (20 asymptomatic bacteriuria, 20 cystitis with normal radiology, and 25 reflux nephropathy) and 45 healthy controls who had never experienced a UTI episode. The distribution of Lewis blood group antigens was similar in all UTI groups and in the controls. The incidence of nonsecretors in the reflux nephropathy group was similar to that in controls. P1 phenotype was present in 100% of patients with asymptomatic bacteriuria, 80% with cystitis and in controls, and only 44% with reflux nephropathy. Combined P1/nonsecretor phenotype was observed in 45% of patients with asymptomatic bacteriuria, 30% with cystitis, 12% with reflux nephropathy, and 22% of control individuals. P2/secretor phenotype was demonstrated in 44% of patients with reflux nephropathy and in only 11% of controls. The data suggested to the authors that having the P2 blood group protects against asymptomatic colonization of urinary tract, but is associated with the type of infection responsible for scarring in reflux nephropathy. It also appears that being a nonsecretor does not predispose to renal scarring and that the combined P2/secretor phenotype may be linked with susceptibility to reflux nephropathy. Population Genetics The phenotype p, originally called Tj(a-), is rare (Race and Sanger, 1975). There is a relatively high frequency of the p phenotype in Vasterbotten County, Sweden (Cedergren, 1973), and the same rare blood type has been found in the Old Order Amish of Holmes County, Ohio, where the Tj(a-) gene was traced through several generations of a Schwartzentruber Amish kindred (Lehmann, 1991). Patients with the p phenotype have anti-P, anti-P1, and anti-P(k) antibodies (collectively called anti-Tj(a)), like anti-A and anti-B in the ABO system. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). History By immunochemical studies, Naiki and Marcus (1975) identified the P(k) and P blood group antigens as ceramide trihexoside (CTH) and globoside, respectively, and proposed a structure for the P1 antigen. Although the P1 and P(k) determinants had identical terminal disaccharides, CTH did not inhibit anti-P1, and P1 antigens did not react with anti-P(k) serum. Further studies showed no cross-reactions between P, P1, or P(k) antigens. These authors suggested that the P1 and P2 antigens (P and P1 in the newer nomenclature) are not allelic, i.e., that there are at least 2 loci determining the P system blood phenotype. In a large kindred studied in connection with acrokeratoelastoidosis (101850), Greiner et al. (1983) found a suggestion of linkage of HLA and P (maximum lod of 1.48 at theta 0.27). Similar data were reported by Keats et al. (1979). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	BLOOD GROUP, P1PK SYSTEM	c1292199	3,584	omim	https://www.omim.org/entry/111400	2019-09-22T16:44:13	{"omim": ["111400"]}
Visual effect whose source is within the eye itself For the archaeological term, see Entoptic phenomena (archaeology). Entoptic phenomena (from Ancient Greek ἐντός "within" and ὀπτικός "visual") are visual effects whose source is within the eye itself. (Occasionally, these are called entopic phenomena, which is probably a typographical mistake.) In Helmholtz's words: "Under suitable conditions light falling on the eye may render visible certain objects within the eye itself. These perceptions are called entoptical." ## Contents * 1 Overview * 2 Examples * 3 See also * 4 References * 5 Sources * 6 External links ## Overview[edit] Entoptic images have a physical basis in the image cast upon the retina. Hence, they are different from optical illusions, which are caused by the visual system and characterized by a visual percept that (loosely said) appears to differ from reality. Because entoptic images are caused by phenomena within the observer's own eye, they share one feature with optical illusions and hallucinations: the observer cannot share a direct and specific view of the phenomenon with others. Helmholtz[1] commented on entoptic phenomena which could be seen easily by some observers, but could not be seen at all by others. This variance is not surprising because the specific aspects of the eye that produce these images are unique to each individual. Because of the variation between individuals, and the inability for two observers to share a nearly identical stimulus, these phenomena are unlike most visual sensations. They are also unlike most optical illusions which are produced by viewing a common stimulus. Yet, there is enough commonality between the main entoptic phenomena that their physical origin is now well understood. ## Examples[edit] Some examples of entoptical effects include: Floaters depiction Purkinje tree depiction * Floaters or muscae volitantes are slowly drifting blobs of varying size, shape, and transparency, which are particularly noticeable when viewing a bright, featureless background (such as the sky) or a point source of diffuse light very close to the eye. They are shadow images of objects floating in liquid between the retina and the jelly inside the eye (the vitreous) or in the vitreous humor itself. They are visible because they move; if they were pinned to retina by the vitreous or fixed within the vitreous they would be as invisible as ordinary viewing of any stationary object, such as the retinal blood vessels (see Purkinje tree below). Some may be individual red blood cells swollen due to osmotic pressure. Others may be chains of red blood cells stuck together; diffraction patterns can be seen around these.[2] Others may be "coagula of the proteins of the vitreous gel, to embryonic remnants, or the condensation round the walls of Cloquet's canal" that exist in pockets of liquid within the vitreous.[3] The first two sort of floaters may collect over the fovea (the center of vision), and therefore be more visible, when a person is lying on his or her back looking upwards. * Blue field entoptic phenomenon has the appearance of tiny bright dots moving rapidly along squiggly lines in the visual field. It is much more noticeable when viewed against a field of pure blue light and is caused by white blood cells moving in the capillaries in front of the retina. White cells are larger than red blood cells and can be larger than the diameter of a capillary, so must deform to fit. As a large, deformed white blood cell goes through a capillary, a space opens up in front of it and red blood cells pile up behind. This makes the dots of light appear slightly elongated with dark tails.[4][5] * Haidinger's brush is a very subtle bowtie or hourglass shaped pattern that is seen when viewing a field with a component of blue light that is plane or circularly polarized. It's easier to see if the polarisation is rotating with respect to the observer's eye, although some observers can see it in the natural polarisation of sky light.[1] If the light is all blue, it will appear as a dark shadow; if the light is full spectrum, it will appear yellow. It is due to the preferential absorption of blue polarized light by pigment molecules in the fovea.[6][7] * Purkinje images are the reflections from the anterior and posterior surfaces of the cornea and the anterior and posterior surfaces of the lens. Although these first four reflections are not entoptic—they are seen by others who are looking at someone’s eye— Becker[8] described how light can reflect from the posterior surface of the lens and then again from the anterior surface of the cornea to focus a second image on the retina, this one much fainter and inverted. Tscherning[9] referred to this as the sixth image (the fifth image is formed by reflections from the anterior surfaces of the lens and cornea to form an image too far in front of the retina to be visible) and noted it was much fainter and best seen with a relaxed emmetropic eye. To see it, one must be in a dark room, with one eye closed; one must look straight ahead while moving a light back and forth in the field of the open eye. Then one should see the sixth Purkinje as a dimmer image moving in the opposite direction. * The Purkinje tree is an image of the retinal blood vessels in one's own eye, first described by Purkyně in 1823.[10] It can be seen by shining the beam of a small bright light through the pupil from the periphery of a subject's vision. This results in an image of the light being focused on the periphery of the retina. Light from this spot then casts shadows of the blood vessels (which lie on top of the retina) onto unadapted portions of the retina. Normally the image of the retinal blood vessels is invisible because of adaptation. Unless the light moves, the image disappears within a second or so. If the light is moved at about 1 Hz, adaptation is defeated, and a clear image can be seen indefinitely. The vascular figure is often seen by patients during an ophthalmic examination when the examiner is using an ophthalmoscope. Another way in which the shadows of blood vessels may be seen is by holding a bright light against the eyelid at the corner of the eye. The light penetrates the eye and casts a shadow on the blood vessels as described previously. The light must be jiggled to defeat adaptation. Viewing in both cases is improved in a dark room while looking at a featureless background. This topic is discussed in more detail by Helmholtz. * Purkinje's blue arcs are associated with the activity of the nerves sending signals from where a spot of light is focussed on the retina near the fovea to the optic disk. To see it, one needs to look at the right edge of a small red light in a dark room with the right eye (left eye closed) after dark-adapting for about 30 seconds; one should see two faint blue arcs starting at the light and heading towards the blind spot. When one looks at the left edge, one will see a faint blue spike going from the light to the right.[11] * A phosphene is the perception of light without light actually entering the eye, for instance caused by pressure applied to the closed eyes. A phenomenon that could be entoptical if the eyelashes are considered to be part of the eye is seeing light diffracted through the eyelashes. The phenomenon appears as one or more light disks crossed by dark blurry lines (the shadows of the lashes), each having fringes of spectral colour. The disk shape is given by the circular aperture of the pupil. ## See also[edit] * Endaural phenomena * Form constant – Geometric pattern recurringly observed during hypnagogia, hallucinations and altered states of consciousness. * Hypnagogia – State of consciousness in transition from wakefulness to sleep * Isolation tank – Pitch-black, light-proof, soundproof environment heated to the same temperature as the skin * Prisoner's cinema * Scintillating scotoma – A visual aura associated with migraine * Visual snow – Visual impairment ## References[edit] 1. ^ Minnaert, M. G. J. (1940). Light and colour in the open air (H. M. Kremer-Priest, Trans.). London: G. Bell and Sons. ## Sources[edit] * Jan E. Purkyně, 1823: Beiträge zur Kenntniss des Sehens in subjectiver Hinsicht in Beobachtungen und Versuche zur Physiologie der Sinne, In Commission der J.G. Calve'schen Buchhandlung, Prag. * H. von Helmholtz, Handbuch der Physiologischen Optik, published as "Helmholtz's Treatise on Physiological Optics, Translated from the Third German Edition," ed. James P. C. Southall; 1925; The Optical Society of America. * Leonard Zusne, 1990: Anomalistic Psychology: A Study of Magical Thinking; Lea; ISBN 0-8058-0508-7 [12] * Becker, O., 1860, “Über Wahrnehmung eines Reflexbildes im eigenen Auge [About perception of a reflected image in your own eye],” Wiener Medizinische Wochenschrift, pp. 670 672 & 684 688. * M. Tscherning, 1920, Physiologic Optics; Third Edition, (English translation by C. Weiland). Philadelphia: Keystone Publishing Co. pp. 55–56. * White, Harvey E., and Levatin, Paul, 1962, "'Floaters' in the eye," Scientific American, Vol. 206, No. 6, June, 1962, pp. 199 127. * Duke Elder, W. S. (ed.), 1962, System of Ophthalmology, Volume 7, The Foundations of Ophthalmology: heredity pathology diagnosis and therapeutics, St. Louis, The C.V. Mosby Company. p450. * Snodderly, D.M., Weinhaus, R.S., & Choi, J.C. (1992). Neural-vascular relationships in central retina of Macaque monkeys (Macaca fascicularis). Journal of Neuroscience, 12(4), 1169-1193. Available online at: http://www.jneurosci.org/cgi/reprint/12/4/1169.pdf. * Sinclair, S.H., Azar-Cavanagh, M., Soper, K.A., Tuma, R.F., & Mayrovitz, H.N. (1989). Investigation of the source of the blue field entoptic phenomenon. Investigative Ophthalmology & Visual Science, 30(4), 668-673. Available online at: http://www.iovs.org/. * Giles Skey Brindley, Physiology of the Retina and Visual Pathway, 2nd ed. (Edward Arnold Ltd., London, 1970), pp. 140–141. * Bill Reid, “Haidinger's brush,” Physics Teacher, Vol. 28, p. 598 (Dec. 1990). * Walker, J., 1984, “How to stop a spinning object by humming and perceive curious blue arcs around the light,” Scientific American, February, Vol. 250, No. 2, pp. 136 138, 140, 141, 143, 144, 148. ## External links[edit] * Entoptic+Vision at the US National Library of Medicine Medical Subject Headings (MeSH) * Picture of the entoptic phenomenon: Vitreous Floaters (PDF file, requires an Acrobat Reader or plugin) * Diagram of entoptic subjective visual phenomena * Video describing history and science of first entoptic viewing technique * Video describing history and science of second entoptic viewing technique * The Relation Between Migraine, Typical Migraine Aura and “Visual Snow” * v * t * e Phenomena of the visual system Entoptic phenomena * Blind spot * Phosphene * Floater * Afterimage * Haidinger's brush * Prisoner's cinema * Blue field entoptic phenomenon * Purkinje images Other phenomena * Aura * Form constant * Scintillating scotoma * Palinopsia * Visual snow * Afterimage on empty shape * Cosmic ray visual phenomena * Scotopic sensitivity syndrome * Closed-eye hallucination [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Entoptic phenomenon	c0042795	3,585	wikipedia	https://en.wikipedia.org/wiki/Entoptic_phenomenon	2021-01-18T18:42:20	{"mesh": ["D014788"], "wikidata": ["Q2337182"]}
Primary hypertrophic osteoarthropathy (PHO) is a genetically and clinically heterogeneous inherited disorder characterized by digital clubbing and osteoarthropathy, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease. There are two types of PHO: pachydermoperiostosis and cranio-osteoarthropathy (see these terms). ## Epidemiology Prevalence is unknown. Cranio-osteoarthropathy is the rarest form, with about 30 cases reported to date. ## Clinical description Patients typically present in infancy with clubbing, hyperhidrosis, bone and joint pain and skin thickening. The clinical constellation of PHO includes skin thickening and excessive sweating (pachydermoperiostosis), delayed closure of the cranial sutures (cranio-osteoarthropathy) and congenital heart disease, especially patent arterial duct (see this term). ## Etiology Mutations in the HPGD gene (4q33-q34) encoding 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the main enzyme of prostaglandin degradation, have been identified. ## Diagnostic methods Diagnosis is based on clinical signs and X-ray exam, magnetic resonance imaging (MRI) or radionucleotide bone imaging showing typical bone abnormalities, such as diaphyseal periostosis and acro-osteolysis. ## Differential diagnosis Differential diagnoses include secondary hypertrophic osteoarthropathy, chronic recurrent non-bacterial osteomyelitis, SAPHO and Camurati-Engelman syndromes (see these terms) and chronic bacterial osteomyelitis. ## Genetic counseling PHO is inherited as an autosomal recessive trait; however, heterozygous carriers can have a mild phenotype. Since mutations in the HPGD gene have recently been reported, genetic counseling and prenatal diagnosis might be considered. ## Management and treatment Rheumatological symptoms can be improved by nonsteroidal anti-inflammatory drugs, which have been shown to directly influence the pathogenesis. In addition, corticosteroids or colchicine have been tried. Clinical improvement of the dermatological symptoms is achieved by retinoids. Plastic surgery may be helpful for facial involvement. Finger clubbing surgical reduction has been tried with success. ## Prognosis PHO progresses constantly, leaving patients with chronic debilitating complications, such as clubbing and arthritis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Primary hypertrophic osteoarthropathy	c0029411	3,586	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=248095	2021-01-23T18:20:17	{"mesh": ["D010004"], "umls": ["C0029411"], "icd-10": ["M89.4"], "synonyms": ["Idiopathic hypertrophic osteoarthropathy", "PHO"]}
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. (July 2019) Mendelian susceptibility to mycobacterial disease Other namesMendelian susceptibility to atypical mycobacteria[1] SpecialtyImmunology Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disease. It is a primary immunodeficiency featured by molecular defects in IL12/IFNγ dependent signalling pathway, leading to increased susceptibility to local or disseminated infections by environmental mycobacteria, Mycobacterium bovis Bacille Calmette-Guerin strain, nontyphoidal and typhoidal Salmonella serotypes.[2][3][4] ## Contents * 1 Symptoms and signs * 2 Pathophysiology * 3 Diagnosis * 4 References * 5 External links ## Symptoms and signs[edit] Normally patients who suffer from this disease are young children under 3 years which have also lack of response to IFN-γ cytokine replacement therapy. This disease is very rare and have high index of mortality.[5][6] Following symptoms and signs are: * recurrent wheezing * dyspnea * asthma-like symptoms * recurring fever * productive cough * endobronchial mycobacterial infection[5] * low hemoglobin Patients with IFNγR1 deficiency can also suffer of disorders of the lung, parenchymal lung diseases caused by mycobacterial infections, hylar lymphadenopathy, or endobronchial disease. If these patients have nontubercular mycobacterial infection[7] there should be suspicion for immunodeficiency.[8] Transplantation of hematopoietic stem cell is the only one curative therapy for these patients. Children with partial MSMD usually have milder clinical phenotype, later onset, less severe infections, better response for IFNγ and antibiotic therapy, better survival rates and normally they don't need hematopoietic stem cell transplant.[6][5] ## Pathophysiology[edit] Phagocytes are important components of the innate immune system for the body defence against infections by mycobacteria and other intracellular pathogens. The professional phagocytes include neutrophils, dendritic cells, macrophages and monocytes.[9] These cells engulf the pathogens by phagocytosis and activate the adaptive immune system to facilitate the elimination of the infection. Cytokine signalling is the key for the interplay between the innate and adaptive limbs of the immune system, the most important of which is the IL12-dependent, IFNγ-mediated pathway.[10] The phagocytes recognize mycobacteria and other pathogens by their pattern recognition receptors (PRR), which include Toll-like receptors (TLR) and NOD2.[9] Once the pathogen is phagocytosed, the macrophages secrete IL12, which is a heterodimer formed by IL12p40 and IL12p35. IL12 receptors, composed of IL12Rβ1 and IL12Rβ2 subunits, are expressed on T lymphocytes and NK cells. It is associated with the signalling cascade formed by TYK and JAK2 kinases, eventually leading to STAT4 phosphorylation and nuclear translocation. The final response to IL12 stimulation is IFNγ production and secretion.[10] The IFNγ receptor is expressed on the macrophages and other cells and consists of IFNγR1 and IFNγR2 subunits. It is associated with the signalling pathway of JAK1 and JAK2, leading to the homodimerization of STAT1 molecule. It is the common pathway for enhancing expression of a variety of IFNγ-inducible genes, accounting for the confinement and killing of intracellular pathogens.[2][10][11] Genetic defects impairing the IL12/IFNγ pathway increase the susceptibility to mycobacterial infections by impeding either the production or the response to IFNγ.[12] Since the discovery of MSMD in 1996, multiple autosomal and two X-linked genes are identified in MSMD phenotypes, classified under the category of defects in intrinsic and innate immunity in the 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies.[9][13][14][15] IFNγR1 deficiency was the first identified genetic disorder described as MSMD. Mutation in genes encoding IFNγR1 can be dominant or recessive and it can lead to partial or complete deficiency of this receptor.[16] IFNγR1 gene is located in to chromosome 6q23.3 and it is formed of 22 868 base pairs which are composed in 7 exons.[5][17][18][19] ## Diagnosis[edit] Mendelian susceptibility to mycobacterial disease may be suspected in people with disseminated infections caused by environmental mycobacteria or BCG. Children with a complete deficiency in the interferon-gamma receptor have significant elevations in plasma concentrations of interferon-gamma, which can be measured by ELISA.[20] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Mendelian susceptibility to mycobacterial diseases". www.orpha.net. Retrieved 28 July 2019. 2. ^ a b Esser, Monika; Suchard, Melinda; Buldeo, Suvarna (2017). Rezaei, Nima; Aghamohammadi, Asghar; Notarangelo, Luigi D. (eds.). Primary Immunodeficiency Diseases. doi:10.1007/978-3-662-52909-6. hdl:10019.1/83317. ISBN 978-3-662-52907-2. 3. ^ Cottle LE (January 2011). "Mendelian susceptibility to mycobacterial disease". Clinical Genetics. 79 (1): 17–22. doi:10.1111/j.1399-0004.2010.01510.x. PMID 20718793. 4. ^ "IMMUNODEFICIENCY 27A; IMD27A". OMIM. Johns Hopkins University. 8 September 2014. 5. ^ a b c d Gutierrez, Maria J.; Kalra, Neelu; Horwitz, Alexandra; Nino, Gustavo (November 2016). "Novel Mutation of Interferon-γ Receptor 1 Gene Presenting as Early Life Mycobacterial Bronchial Disease". Journal of Investigative Medicine High Impact Case Reports. 4 (4): 232470961667546. doi:10.1177/2324709616675463. ISSN 2324-7096. PMC 5103323. PMID 27868075. 6. ^ a b Holland, Steven M.; Casanova, Jean-Laurent; Kumararatne, Dinakantha; Roesler, Joachim; Levin, Michael; Newport, Melanie; Rosenzweig, Sergio D.; Baretto, Richard; Dissel, Jaap T. van (2004-12-11). "Clinical features of dominant and recessive interferon γ receptor 1 deficiencies". The Lancet. 364 (9451): 2113–2121. doi:10.1016/S0140-6736(04)17552-1. ISSN 0140-6736. PMID 15589309. S2CID 54388577. 7. ^ Wu, U. I.; Holland, S. M. (2015). "Host susceptibility to non-tuberculous mycobacterial infections". The Lancet. Infectious Diseases. 15 (8): 968–80. doi:10.1016/S1473-3099(15)00089-4. PMID 26049967. 8. ^ Jouanguy, E.; Dupuis, S.; Pallier, A.; Döffinger, R.; Fondanèche, M. C.; Fieschi, C.; Lamhamedi-Cherradi, S.; Altare, F.; Emile, J. F.; Lutz, P.; Bordigoni, P.; Cokugras, H.; Akcakaya, N.; Landman-Parker, J.; Donnadieu, J.; Camcioglu, Y.; Casanova, J. L. (2000). "In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ". The Journal of Clinical Investigation. 105 (10): 1429–1436. doi:10.1172/JCI9166. PMC 315467. PMID 10811850. 9. ^ a b c Reed B, Dolen WK (June 2018). "The Child with Recurrent Mycobacterial Disease". Current Allergy and Asthma Reports. 18 (8): 44. doi:10.1007/s11882-018-0797-3. PMID 29936646. S2CID 207324525. 10. ^ a b c Ramirez-Alejo N, Santos-Argumedo L (May 2014). "Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella". Journal of Interferon & Cytokine Research. 34 (5): 307–17. doi:10.1089/jir.2013.0050. PMC 4015507. PMID 24359575. 11. ^ Rosenzweig, Sergio D.; Holland, Steven M. (2005). "Defects in the interferon-γ and interleukin-12 pathways". Immunological Reviews. 203 (1): 38–47. doi:10.1111/j.0105-2896.2005.00227.x. ISSN 1600-065X. PMID 15661020. 12. ^ Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL (December 2014). "Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity". Seminars in Immunology. 26 (6): 454–70. doi:10.1016/j.smim.2014.09.008. PMC 4357480. PMID 25453225. 13. ^ Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, Levin M, Blanche S, Seboun E, Fischer A, Casanova JL (December 1996). "Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection". The New England Journal of Medicine. 335 (26): 1956–61. doi:10.1056/nejm199612263352604. PMID 8960475. 14. ^ Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M (December 1996). "A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection". The New England Journal of Medicine. 335 (26): 1941–9. doi:10.1056/nejm199612263352602. PMID 8960473. 15. ^ Bousfiha A, Jeddane L, Picard C, Ailal F, Bobby Gaspar H, Al-Herz W, et al. (January 2018). "The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies". Journal of Clinical Immunology. 38 (1): 129–143. doi:10.1007/s10875-017-0465-8. PMC 5742599. PMID 29226301. 16. ^ Seelow, Dominik; Markus Schuelke; Cooper, David N.; Schwarz, Jana Marie (April 2014). "MutationTaster2: mutation prediction for the deep-sequencing age". Nature Methods. 11 (4): 361–362. doi:10.1038/nmeth.2890. ISSN 1548-7105. PMID 24681721. S2CID 19382079. 17. ^ Filipe-Santos, Orchidée; Bustamante, Jacinta; Chapgier, Ariane; Vogt, Guillaume; de Beaucoudrey, Ludovic; Feinberg, Jacqueline; Jouanguy, Emmanuelle; Boisson-Dupuis, Stéphanie; Fieschi, Claire (2006-12-01). "Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features". Seminars in Immunology. Human Genetics of Infectious Diseases: Immunological Implications. 18 (6): 347–361. doi:10.1016/j.smim.2006.07.010. ISSN 1044-5323. PMID 16997570. 18. ^ "IFNGR1 interferon gamma receptor 1 [ Homo sapiens (human) ]". 19. ^ Bryant, Stephen H.; Kans, Jonathan A.; Chappey, Colombe; Geer, Lewis Y.; Wang, Yanli; Bryant, Stephen H.; Kans, Jonathan A.; Chappey, Colombe; Geer, Lewis Y. (2000-06-01). "Cn3D: sequence and structure views for Entrez". Trends in Biochemical Sciences. 25 (6): 300–302. doi:10.1016/S0968-0004(00)01561-9. ISSN 0968-0004. PMID 10838572. 20. ^ Fieschi, Claire; Dupuis, Stéphanie; Picard, Capucine; Smith, C. I. Edvard; Holland, Steven M.; Casanova, Jean-Laurent (1 April 2001). "High Levels of Interferon Gamma in the Plasma of Children With Complete Interferon Gamma Receptor Deficiency". Pediatrics. 107 (4): e48–e48. doi:10.1542/peds.107.4.e48. ## External links[edit] Classification D * ICD-10: D84.8 External resources * Orphanet: 748 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Mendelian susceptibility to mycobacterial disease	c3266863	3,587	wikipedia	https://en.wikipedia.org/wiki/Mendelian_susceptibility_to_mycobacterial_disease	2021-01-18T18:55:51	{"gard": ["12977"], "mesh": ["D009165"], "umls": ["C3266863"], "orphanet": ["748"], "wikidata": ["Q25324130"]}
A number sign (#) is used with this entry because variation in several different genes influences susceptibility and resistance to HIV-1 infection and the rate of progression to AIDS after infection (see PATHOGENESIS and MOLECULAR GENETICS). Description The pathogenesis of HIV infection and the progression from infection to AIDS vary significantly between exposed individuals. Infection occurs after the virus, which has macrophage (M)- and T lymphocyte (T)-tropic strains and more than 12 subtypes, survives an array of nonspecific, nongenetic environmental and host factors. Pathogenesis ### Viral Entry Entry of HIV-1 into host cells requires expression of the host cell receptor CD4 (186940) and fusion coreceptors. CCR5 (601373) and CCR2 (601267) act as fusion coreceptors for M-tropic HIV-1 strains, and CXCR4 (162643) and CX3CR1 (601470) act as fusion coreceptors for T-tropic HIV-1 strains. The HIV-1 viral envelope protein gp120 also uses DCSIGN (CD209; 604672) and syndecans (e.g., SDC2; 142460) as intermediary receptors on dendritic cells and endothelial cells, respectively. Polymorphisms in any of these receptors may confer either increased susceptibility or resistance to HIV-1 infection. In addition, ligands for the coreceptors (CCL5 (187011), CCL3 (182283), CCL3L1 (601395), and CCL4 (182284) for CCR5, and CXCL12 (600835) for CXCR4) can prevent HIV-1 entry into cells. Polymorphisms in these ligands may alter susceptibility to infection and disease progression. For further information, see MOLECULAR GENETICS and reviews by Trkola (2004), O'Brien and Nelson (2004), and Kaslow et al. (2005). Granelli-Piperno et al. (2006) used a monoclonal antibody recognizing BDCA1 (CD1C; 188340) to directly isolate myeloid dendritic cells (DCs) from human blood. These cells expressed the HIV-1 entry receptors CD4, CCR5, and CXCR4, but not CD209. HIV-1 infected a small fraction of the blood DCs that failed to mature in culture and exhibited weak immunostimulatory functions. Granelli-Piperno et al. (2006) proposed that HIV-1 exploits myeloid DCs in blood not only for replication and transmission, but also for immune evasion. Zhou et al. (2007) constructed stabilized gp120 molecules constrained to stay in the CD4-bound conformation, even in the absence of CD4, and determined the crystal structure of gp120 in complex with the neutralizing IgG1 antibody b12 at 2.3-angstrom resolution. Their analyses revealed the functionally conserved surface that allows for initial CD4 attachment and delineated the b12 epitope at the atomic level. Zhou et al. (2007) proposed that the b12 epitope serves as a key target for humoral neutralization of HIV-1 in long-term nonprogressors. Hladik et al. (2007) developed an ex vivo model of intraepithelial HIV-1 infection in human vagina and found that HIV-1 rapidly penetrated both intraepithelial Langerhans cells and CD4-positive T cells. HIV-1 entered CD4-positive T cells almost exclusively through CD4 and CCR5 receptor-mediated direct fusion, without passage from Langerhans cells, and productive infection ensued. In contrast, HIV-1 entered CD1A (188370)-positive Langerhans cells through endocytosis by means of multiple receptors, and virions persisted intact within the cytoplasm for several days. Hladik et al. (2007) concluded that HIV-1 simultaneously enters CD4-positive T cells and Langerhans cells in human vaginal epithelium and that antiviral microbicides need to target both CCR5 and viral entry into Langerhans cells. As part of a clinical trial to evaluate participants for treatment with a CCR5 inhibitor, Wilkin et al. (2007) determined coreceptor use for 391 HIV-1-infected and antiretroviral-treated patients. Half of the patients had virus that used the CCR5 coreceptor, 46% had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4, and only 4% had virus that used CXCR4. Patients with dual-tropic or mixed HIV-1 populations had a significantly lower CD4-positive T-cell count than did those whose virus used CCR5 only. Using a large-scale small interfering RNA screen to identify host factors required by HIV-1, Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. The HDFs RAB6A (179513) and VPS53 (615850), retrograde Golgi transport proteins, were involved in viral entry. Brass et al. (2008) proposed that targeting HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation. Using yeast 2-hybrid analysis and protein pull-down assays, Jimenez-Baranda et al. (2007) showed that CD4 and the HIV-1 coreceptors CCR5 and CXCR4 interacted with filamin A (FLNA; 300017), which regulated clustering of the HIV-1 receptors on the cell surface. Binding of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1; 601442) phosphorylation inactivation through a RHOA (165390)-ROCK (see 601702)-dependent mechanism. Blockade of FLNA interaction with CD4 and/or the coreceptors inhibited gp120-induced RHOA activation and cofilin inactivation. Jimenez-Baranda et al. (2007) concluded that FLNA is an adaptor protein that links HIV-1 receptors to the actin skeleton remodeling machinery, possibly facilitating virus infection. By incubating DARC (613665)-positive and DARC-negative red blood cells (RBCs) with HIV-1 and using flow cytometry, He et al. (2008) showed that DARC bound the virus to RBCs and, after cell washing, could mediate transfer of the virus, particularly strains using the CXCR4 coreceptor, to susceptible target cells. HIV-1 binding to DARC could be inhibited by the DARC ligands CCL5 and CXCL8 (IL8; 146930), but not by the nonligand CCL3. KLF2 (602016) is a transcription factor that promotes T-cell quiescence and regulates T-cell migration. Richardson et al. (2012) found that CD4-positive T cells stimulated with phytohemagglutinin plus IL2 (147680) had increased expression of KLF2 and CCR5 and increased susceptibility to infection with HIV-1 compared with T cells stimulated with immobilized anti-CD3 (see 186740) and anti-CD28 (186760). Enhanced expression of KLF2 did not regulate expression of chemokine receptor ligands (e.g., CCL3) that downregulate CCR5 expression. Knockdown of KLF2 in CD4-positive T cells via small interfering RNA resulted in reduced CCR5 expression. Chromatin immunoprecipitation analysis showed that KLF2 bound to the CCR5 promoter in resting, but not CD3/CD28-activated, CD4-positive T cells. Transduction of KLF2 induced CCR5 in some, but not all, transformed T-cell lines. CCR5 upregulation after KLF2 transduction restored susceptibility to CCR5-tropic HIV-1 in the Jurkat T-cell line, which expresses little to no KLF2. Richardson et al. (2012) concluded that KLF2 is a host factor that modulates CCR5 expression in CD4-positive T cells and influences susceptibility to CCR5-tropic viruses. ### Viral Replication Transcription of HIV-1, which resides predominantly in introns of active host genes in resting CD4-positive T cells, requires CD4-positive T-cell activation, the presence of sufficient concentrations of transcription factors, such as NFKB (164011) and NFAT (600490), the HIV transcriptional activator (Tat), and Tat-associated activation-dependent host factors. Viral replication, and thereby disease progression, may be modified by intracellular factors, such as APOBEC3G (607113) and MURR1 (607238). These intracellular factors may be countered by viral factors, such as the Vif regulatory protein. For further information, see reviews by Lassen et al. (2004) and Trkola (2004). Triboulet et al. (2007) provided evidence for a physiologic role of the miRNA silencing machinery in controlling HIV-1 replication. Type III RNAses Dicer (606241) and Drosha (608828), responsible for miRNA processing, inhibited virus replication both in peripheral blood mononuclear cells from HIV-1-infected donors and in latently infected cells. In turn, HIV-1 actively suppressed the expression of polycistronic miRNA cluster miR17-92 (see 609416). This suppression was found to be required for efficient viral replication and was dependent on the histone acetyltransferase Tat cofactor PCAF (602303). Triboulet et al. (2007) concluded that their results highlighted the involvement of the miRNA silencing pathway in HIV-1 replication and latency. Latency of HIV-1 in resting primary CD4-positive T cells is the major barrier for eradication of the virus in patients on suppressive highly active antiretroviral treatment (HAART). Huang et al. (2007) showed that a cluster of cellular miRNAs, including miRNA28, miRNA125B (see MIRN125B1; 610104), miRNA150 (MIRN150; 611114), miRNA223, and miRNA382, were enriched in resting compared to activated CD4-positive T cells and that these miRNAs targeted the 3-prime ends of HIV-1 mRNAs. Specific inhibitors of these miRNAs, particularly when used in combination, counteracted their inhibition of HIV-1 expression, as assessed by HIV-1 protein translation in transfected CD4-positive T cells or by HIV-1 production from resting CD4-positive T cells from HIV-1-infected individuals on suppressive HAART. Huang et al. (2007) concluded that miRNAs have a pivotal role in HIV-1 latency and proposed that manipulation of miRNAs may enable purging of the latent HIV-1 reservoir. Using a large-scale small interfering RNA screen to identify host factors required by HIV-1, Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. Depletion of the HDF TNPO3 (610032), a karyopherin, resulted in HIV inhibition after reverse transcription, but before integration. Several components of the Mediator complex were identified as HDFs, and knockdown of MED28 (610311) inhibited viral transcription. Brass et al. (2008) proposed that targeting HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation. Manganaro et al. (2010) noted that resting peripheral blood T lymphocytes do not support efficient HIV infection and reverse transcription. They found that JNK (see 601158), which Western blot analysis showed was not expressed in resting lymphocytes, regulated permissiveness to HIV-1 infection. In activated T cells, JNK phosphorylated HIV-1 viral integrase on a highly conserved serine in its core domain. Phosphorylated integrase was a substrate for PIN1, which catalyzed a conformational modification of integrase, increasing its stability. This pathway of protein modification was required for efficient HIV-1 integration and infection and was present in activated, but not nonactivated, primary resting CD4-positive T lymphocytes. HIV-1, produces Vif, which counteracts host antiviral defense by highjacking a ubiquitin ligase complex consisting of CUL5 (601741), ELOC (600788), ELOB (600787), and RBX1 (603814) that targets the restriction factor APOBEC3G for degradation. Using affinity tag/purification mass spectrometry, Jager et al. (2011) showed that Vif also recruited CBFB (121360) to this ubiquitin ligase complex. CBFB allowed the reconstitution of a recombinant 6-protein assembly that elicited specific polyubiquitination activity with APOBEC3G, but not with APOBEC3A (607109). RNA knockdown and genetic complementation studies demonstrated that CBFB was required for Vif-mediated degradation of APOBEC3G and the preservation of HIV-1 infectivity. Vif from the simian immunodeficiency virus also bound to and required Cbfb to degrade rhesus Apobec3g, indicating functional conservation across primate species. Jager et al. (2011) proposed that disruption of the CBFB-Vif interaction might restrict HIV-1 and be a supplemental antiviral therapy. Independently, Zhang et al. (2012) identified the role of CBFB in Vif-mediated degradation of APOBEC3G. The N-terminal region of Vif was required for interaction with CBFB, and Vif interacted with regions of CBFB distinct from those used by CBFB to interact with RUNX. Zhang et al. (2012) suggested that the CBFB-Vif interaction is a potential target for intervention against HIV-1. ### Host Immune Response Recognition of HIV-1 by protective immune mechanisms, such as cytotoxic lymphocytes, depends largely on antigen recognition molecules encoded within the major histocompatibility complex (MHC) on chromosome 6. This region of the genome is characterized by intense polymorphism, and the inheritance of specific HLA alleles has profound effects on the outcome of infection. For example, certain allele groups (e.g., HLA-B35 and HLA-B53; see 142830) may be associated with less favorable prognosis or higher viral loads, while others (e.g., HLA-B57 and HLA-B27) may be associated with protection. HLA heterozygosity or lack of sharing of HLA antigens between the infectious donor and the recipient may also confer some protection. In addition, the adaptive immune response uses auxiliary systems of antigen recognition that are also highly polymorphic, such as the KIR gene cluster on chromosome 19 (e.g., KIR3DS1; 604946). Cytokines, such as IL10 (124092) and IFNG (147570), also inhibit HIV-1 replication. Chemokines that do not bind the primary HIV-1 coreceptors, such as CCL2 (158105), CCL7 (158106), and CCL11 (601156), may influence HIV-1 transmission by activating the immune response. For further information, see MOLECULAR GENETICS and reviews by Nolan et al. (2004), Kaslow et al. (2005) and O'Brien and Nelson (2004). High-level immune activation and T-cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic simian immunodeficiency virus (SIV) infections in natural primate hosts. Schindler et al. (2006) found that all primate lentiviral Nef proteins downmodulated CD4, CD28 (186760), and MHC class I, but the ability to modulate surface expression of the T-cell receptor (TCR; see 186880) complex differed depending on the particular lentiviral lineage analyzed. Nef proteins from nearly all primate lentiviruses efficiently downmodulated TCR-CD3 (see 186740), thereby suppressing the responsiveness of infected T cells to activation and activation-induced cell death. In contrast, the Nef proteins of HIV-1 and its closest simian relatives failed to downmodulate TCR-CD3 and to prevent activation-induced cell death. Schindler et al. (2006) concluded that Nef exerts an important protective function that was lost during lentiviral evolution in a lineage that gave rise to HIV-1. They proposed that this Nef activity is needed to prevent chronic generalized T-cell activation typical of HIV infection and thus contributes to the nonpathogenic phenotype of natural SIV infections. SIV does not cause progression to AIDS, loss of Cd4-positive T cells, and aberrant immune activation in its natural reservoir hosts, such as sooty mangabeys. In contrast, SIV in rhesus macaques, a non-natural reservoir host, and HIV in humans leads to CD4-positive T-cell depletion, progression to AIDS, and relentless immune system activation. Mandl et al. (2008) found that sooty mangabeys exhibited reduced innate immune system activation during acute and chronic SIV infection. Sooty mangabey plasmacytoid DCs produced markedly less Ifna (147660) in response to SIV and other Tlr7 (300365) and Tlr9 (605474) ligands compared with plasmacytoid DCs from rhesus macaques. Comparative sequence analysis of genes encoding proteins in the human, rhesus macaque, and sooty mangabey TLR7 and TLR9 signaling pathways identified 5 amino acid changes in the transactivation domain of sooty mangabey Irf7 (605047). Four of the 5 residues changed in sooty mangabey Irf7 are conserved in rhesus macaque and human IRF7, whereas 1 is different in all 3 species. The findings suggested that Irf7 is the most probable candidate responsible for the reduction in sooty mangabey Ifna production after Tlr7 and Tlr9 signaling. Mandl et al. (2008) proposed that chronic stimulation of plasmacytoid dendritic cells by SIV and HIV in non-natural hosts may drive the aberrant immune activation and dysfunction underlying AIDS progression and immunopathology. Yan et al. (2010) observed enhanced Ifnb (147640) and Il6 (147620) expression in Trex1 (606609) -/- mouse embryonic fibroblasts (MEFs) infected with pseudotyped HIV-1 compared with uninfected Trex1 -/- MEFs or infected wildtype MEFs. Ifnb induction was mediated by reverse transcribed HIV in an Irf3 (603734)-dependent manner. HIV reverse transcripts accumulated in Trex -/- MEFs. HIV-stimulated Ifnb from Trex1 -/- MEFs inhibited HIV. Yan et al. (2010) observed an increase in cytosolic HIV DNA and reduced viral spreading, accompanied by increased IFNA (147660) and IFNB expression, in human monocyte-derived macrophages treated with small interfering RNA (siRNA) against TREX1 and subsequently infected with HIV-1. Treatment of Trex1 -/- MEFs with siRNA against genes related to innate immunity showed that HIV DNA was detected by a pathway that signaled through Sting (TMEM173; 612374), Tbk1 (604834), and Irf3 but not nucleic acid sensors. Yan et al. (2010) proposed that HIV-1 uses TREX1 to avoid triggering antiviral innate immunity. Harman et al. (2015) had previously shown that DCs and macrophages failed to produce type I IFN in response to HIV-1, but that the failure was not mediated through HIV-1 targeting IRF3, as occurs in T cells. Harman et al. (2015) found that cells exposed to HIV-1, but not herpes simplex-2 or Sendai virus, failed to induce expression of either type I or type III IFNs, in spite of sensing the virus and inducing pathogen recognition receptor signaling. Phosphorylation of TBK1 was completely inhibited through binding of HIV-1 Vpr and Vif proteins to TBK1. HIV-1 lacking either protein induced IFNB expression. Harman et al. (2015) concluded that inhibition of TBK1 autophosphorylation due to binding of Vpr and Vif proteins is the principal mechanism by which HIV-1 blocks type I and type III IFN induction in myeloid cells. Using a targeted RNA interference screen on primary human monocyte-derived dendritic cells (MDDCs), Yoh et al. (2015) identified PQBP1 (300463) as an immune regulator that directly interfaced with HIV-1 to initiate an innate immune response. PQBP1 bound to reverse-transcribed HIV-1 DNA and interacted with cGAS (MB21D1; 613973) to initiate an IRF3-dependent innate immune response. MDDCs from Renpenning syndrome (309500) patients, who harbor PQBP1 mutations, possessed a severely attenuated innate immune response to HIV-1 challenge, supporting the role of PQBP1 as a proximal innate sensor of HIV-1 infection. Yoh et al. (2015) concluded that PQBP1 is an essential component of the cGAS/IRF3-dependent innate response to HIV through its association with cGAS and regulation of cGAS activity. By screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5 (614551), and to a lesser extent SERINC3 (607165), inhibited infectivity of HIV-1 and murine leukemia retrovirus (MLV). The HIV-1 Nef protein and the structurally unrelated glycosylated Gag (glycoGag) from MLV counteracted SERINC5 inhibition of infectivity. The ability of Nef to counteract SERINC5 depended on myristoylation of Nef. SERINC5 localized to plasma membrane, where it was incorporated into budding HIV-1 virions and impaired subsequent virion penetration of susceptible target cells. Nef redirected SERINC5 to a RAB7 (602298)-positive endosomal compartment and excluded it from HIV-1 particles. Ectopic expression of SERINC5 potently inhibited HIV-1, even in the presence of Nef. Rosa et al. (2015) proposed that SERINC5 might be exploited for antiretroviral therapy. The HIV-1 Nef protein and the unrelated MLV glycoGag protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Sperandio et al. (2015) found that TOE1 (613931) could inhibit HIV-1 replication. TOE1 was secreted by activated human CD8-positive T lymphocytes and could be cleaved by granzyme B (GZMB; 123910). When administered extracellularly, both full-length and cleaved TOE1 could spontaneously cross the plasma membrane, and they retained HIV-1 inhibitory activity. The antiviral and cell-penetrating functions of TOE1 were mapped to a 35-amino acid region containing the nuclear localization sequence. This region interacted directly with the HIV-1 transactivator response (TAR) element. Sperandio et al. (2015) proposed that TOE1 is a cellular mediator of HIV-1 inhibition. Molecular Genetics ### Variation in Genes Involved in Viral Entry Both Liu et al. (1996) and Samson et al. (1996) identified a molecular basis for HIV-1 resistance. In an HIV-1-infected patient with slow disease progression, Samson et al. (1996) identified a heterozygous 32-bp deletion in the CCR5 gene (601373.0001) that resulted in a frameshift and premature termination of translation of the transcript. Liu et al. (1996) identified the same homozygous 32-bp deletion with CCR5 in 2 individuals who, though multiply exposed to HIV-1 infection, remained uninfected. They showed that the severely truncated protein could not be detected at the surface of cells that normally express the protein. Through in vitro fusion assays, both Liu et al. (1996) and Samson et al. (1996) determined that the truncated receptor did not allow fusion of CD4+ cells with cells expressing env protein from either macrophage-tropic or dual-tropic viruses. Samson et al. (1996) found that coexpression of the deletion mutant with wildtype CCR5 reduced the fusion efficiency of 2 different viral envelope proteins in 3 independent experiments. Dean et al. (1996) reported results of their CCR5 studies in 1,955 individuals included in 6 well-characterized AIDS cohort studies. They identified 17 individuals who were homozygous for the CCR5 32-bp deletion allele. Deletion homozygotes occurred exclusively among the 612 members of the HIV-1-exposed, antibody-negative group and not at all in 1,343 HIV-1 infected individuals. The frequency of the CCR5 deletion heterozygotes was significantly elevated in groups of individuals who had survived HIV-1 infection for more than 10 years. In some risk groups the frequency of CCR5 deletion heterozygotes was twice as frequent as in groups with rapid progressors to AIDS. Survival analysis clearly showed that the disease progression was slower in CCR5 deletion heterozygotes than in individuals homozygous for the normal CCR5 allele. Dean et al. (1996) postulated that the CCR5 32-bp deletion may act as 'a recessive restriction gene against HIV-1 infection' and may exert a dominant phenotype of delayed progression to AIDS among infected individuals. Dean et al. (1996) reported that in addition to the CCR5 32-bp deletion allele, they found unique single-strand conformation polymorphisms (SSCPs) in other patients, some of whom were long-term nonprogressors. They speculated that at least some of these alleles disrupt CCR5 function and inhibit the spread of HIV-1 or the progression to AIDS. Martin et al. (1998) showed by genetic association analysis of 5 cohorts of people with AIDS that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. An estimated 10 to 17% of patients who developed AIDS within 3.5 years of HIV-1 infection did so because they were homozygous for CCR5P1/P1, and 7 to 13% of all people carry this susceptible genotype. Smith et al. (1997) identified a val64-to-ile polymorphism (64I; 601267.0001) in the first transmembrane region of CCR2, at an allele frequency of 10 to 15% among Caucasians and African Americans. Studies of 2 cohorts of AIDS patients showed that the CCR2-64I allele exerted no influence on the incidence of HIV-1 infection, but that HIV-1 infected persons carrying the 64I allele progressed to AIDS 2 to 4 years later than persons homozygous for the more common allele. Smith et al. (1997) analyzed 2-locus genotypes and found that the 32-bp deletion at the CCR5 locus (CCR5-del32) and the 64I allele at the CCR2 locus are in strong, perhaps complete, linkage disequilibrium with each other. This means that CCR5-del32 invariably occurs on a chromosome with allele CCR2-64V, whereas CCR2-64I occurs on a chromosome that has the wildtype (undeleted) allele at the CCR5 locus. Thus, they could estimate the independent effects of the CCR2 and CCR5 polymorphisms. Rapid progression of less than 3 years from HIV-1 exposure to onset of AIDS symptoms in an estimated 38 to 45% of AIDS patients could be attributed to their wildtype status at one or the other of these loci, whereas the survival of 28 to 29% of long-term survivors, who avoided AIDS for 16 years or more, could be explained by a mutant genotype for CCR2 or CCR5. RANTES (CCL5) is one of the natural ligands for CCR5 and potently suppresses in vitro replication of R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showing that peripheral blood mononuclear cells or CD4+ lymphocytes obtained from different individuals have wide variations in their ability to secrete RANTES prompted Liu et al. (1999) to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. They found 2 polymorphic positions, 1 of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This -28G mutation of the RANTES gene (187011.0001) occurred at an allele frequency of approximately 17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the -28G mutation increases transcription of the RANTES gene. Taken together, these data suggested that the -28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease. An et al. (2002) tested the influence of 4 RANTES SNPs and their haplotypes on HIV-1 infection and AIDS progression in 5 AIDS cohorts. Three SNPs in the RANTES gene region on chromosome 17 (403A in the promoter, In1.1C in the first intron, and 3-prime 222C in the 3-prime UTR) were associated with increased frequency of HIV-1 infection. The In1.1C SNP allele is nested within an intronic regulatory sequence element (168923T/C; 187011.0002) that exhibits differential allele binding to nuclear proteins and a downregulation of gene transcription. The In1.1C allele, or haplotypes that include In1.1C, display a strong dominant association with rapid progression to AIDS among HIV-1-infected individuals in African American, European American, and combined cohorts. The principal RANTES SNP genetic influence on AIDS progression derives from the downregulating RANTES In1.1C allele, although linkage disequilibrium with adjoining RANTES SNPs, including a weaker upregulating RANTES promoter allele (-28G), can modify the observed epidemiologic patterns. The In1.1C-bearing genotypes accounted for 37% of the attributable risk for rapid progression among African Americans and may also be an important influence on AIDS progression in Africa. The diminished transcription of RANTES afforded by the In1.1C regulatory allele is consistent with increased HIV-1 spread in vivo, leading to accelerated progression to AIDS. SDF1 (CXCL12) is the principal ligand for CXCR4, a coreceptor with CD4 for T-lymphocyte cell line-tropic HIV-1. Winkler et al. (1998) identified a common polymorphism, designated SDF1-3-prime-A (600835.0001), in an evolutionarily conserved segment of the 3-prime untranslated region of the SDF1 structural gene transcript. In homozygous state, SDF1-3-prime-A delayed the onset of AIDS, according to a genetic association analysis of 2,857 patients enrolled in 5 AIDS cohort studies. The recessive protective effect of the polymorphism was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants, and was complementary with these mutations in delaying the onset of AIDS. Gonzalez et al. (2005) examined the effect of CCL3L1 copy number, which varies due to segmental duplication on chromosome 17q, on susceptibility to HIV-1. Mean CCL3L1 copy number varied in different population groups, being generally highest in Africans, followed by East Asians, Amerindians, Central/South Asians, Middle Easterners, and Europeans. Cloning and characterization of the chimpanzee CCL3L1 gene led to the observation that this species has a substantially higher copy number than any human population. Individual susceptibility to HIV-1, however, was related not to the absolute copy number but to having a CCL3L1 copy number lower than the population-specific average. Susceptibility was even greater in individuals having disease-accelerating CCR5 genotypes, and Gonzalez et al. (2005) showed that CCR5 protein expression is, in part, influenced by CCL3L1. Gonzalez et al. (2005) concluded that CCL3L1 dose plays a central role in HIV/AIDS pathogenesis and suggested that the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases. CX3CR1 is an HIV coreceptor as well as a leukocyte chemotactic/adhesion receptor for fractalkine. Faure et al. (2000) identified 2 single nucleotide polymorphisms in the CX3CR1 gene in Caucasians and demonstrated that HIV-infected patients homozygous for I249/M280 (601470.0001) progressed to AIDS more rapidly than those with other haplotypes (relative risk = 2.13, P = 0.039). Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, Faure et al. (2000) concluded that CX3CR1-I249/M280 is a recessive genetic risk factor for HIV/AIDS. Martin et al. (2004) found that European Americans at risk for parenteral HIV infection were more likely to carry the -336C SNP than the -336T SNP in the promoter of DCSIGN (604672.0001). This association was not observed in those at risk for mucosally acquired infection. Although the -336C SNP was common in African Americans, no significant association with risk of infection was observed in this group. Colobran et al. (2005) identified a polymorphism in the CCL4L gene (603782), a G-to-A change at position +590 in the acceptor splice site of intron 2. They designated this allele L2 and the original allele L1. The frequency of the L2 allele was significantly higher in 175 Spanish HIV-positive patients (28.6%) compared with 220 healthy controls (16.6%). By analysis of IL4R (147781) allele and genotype frequencies in individuals with different risk factors for HIV acquisition and different rates of progression to AIDS, Soriano et al. (2005) determined that the V50 allele of the ile50-to-val polymorphism (I50V; 147781.0002) predominated in HIV-positive long-term nonprogressors (LTNPs), whereas the I50 allele predominated in healthy controls, typical progressors, and those at risk for infection due to sexual exposure or treatment of hemophilia. Homozygosity for V50 was increased in LTNPs compared with other groups. Soriano et al. (2005) concluded that V50 homozygosity appears to be associated with slow progression to AIDS after HIV infection. Vasilescu et al. (2007) identified a CXCR1 (IL8RA; 146929) haplotype (CXCR1-Ha; 146929.0001) carrying 2 SNPs that resulted in nonsynonymous amino acid changes: 92T-G (rs16858811), which caused a met31-to-arg change (M31R) in the N-terminal extracellular domain, and 1003C-T (rs1658808), which caused an arg335-to-cys change (R335C) in the C-terminal intracellular domain. Flow cytometric, RT-PCR, and Western blot analysis showed that expression of CXCR1-Ha in different cell lines led to reduced expression of CD4 and CXCR4 compared with cell lines transfected with the alternative haplotype. HIV-1 isolates preferentially using the CXCR4 receptor were less efficient in infecting cells expressing CXCR1-Ha than those expressing the alternative haplotype. Patients infected with HIV-1 who progressed rapidly to AIDS were significantly less likely to have CXCR1-Ha compared with patients who progressed slowly to AIDS. Vasilescu et al. (2007) concluded that the CXCR1-Ha allele protects against rapid progression to AIDS by modulating CD4 and CXCR4 expression. Burt et al. (2008) examined a large cohort of HIV-positive European and African American subjects and found that those homozygous for the APOE4 allele (107741.0016) of APOE (107741) had an accelerated disease course and progression to death compared with those homozygous for the APOE3 allele (107741.0015). The increased risk was independent of CD4-positive T-cell count, delayed-type hypersensitivity reactivity, and CCL3L1-CCR5 type. APOE4 alleles showed a weak association with higher viral load. No association was observed with APOE4 homozygosity and HIV-associated dementia or with an increased risk of acquiring HIV infection. Expression of recombinant APOE4 or APOE3 in HeLa cells also expressing CD4 and CCR5 revealed that the presence of APOE4 enhanced HIV fusion/cell entry of both R5 (macrophage-tropic) and X4 (T lymphocyte-tropic) HIV strains in vitro. Burt et al. (2008) concluded that APOE4 is a determinant of AIDS pathogenesis. He et al. (2008) showed that HIV-1 attached to RBCs via DARC and effected trans-infection of target cells. The -46T-C promoter SNP in DARC (110700.0002) is widely prevalent in populations of African descent, and -46CC genotype results in selective loss of DARC expression on RBCs. In the admixed African-American population, the DARC -46C allele was in Hardy-Weinberg equilibrium in HIV-negative subjects, but it was in disequilibrium in HIV-positive patients. Genotype analysis indicated that the prevalence of -46CC was greater in HIV-positive patients, and -46CC individuals had a 50% higher risk of acquiring HIV. Calculation of the population attributable fraction for excess HIV burden was estimated to be 11% for DARC -46CC in African settings. In contrast, DARC -46CC was associated with slower disease progression in terms of death or development of dementia. He et al. (2008) proposed that the interplay between DARC and chemokines may influence the amount of free versus DARC-bound virus available for eventual transfer from RBCs to target cells. Kulkarni et al. (2009) found that ethnic leukopenia present in healthy African Americans was also present in the setting of HIV infection. The disease course among HIV+ African Americans with low WBC was slower than that of HIV+ European Americans with low WBC. DARC -46CC was present nearly exclusively in African Americans (69.1%) compared to European Americans (0.2%), and there was a trend toward a survival advantage for HIV+ African Americans with -46CC compared to HIV+ European Americans or to African Americans with DARC -46CT or -46TT. However, the survival advantage associated with -46CC was highly dependent on WBC counts, as this association was greatly magnified in subjects with low WBC and muted in those with high WBC. Overall, the observations indicated that ethnic leukopenia in HIV-infected African Americans may be associated with a more benign phenotype, despite HIV-induced immunodeficiency. ### Variation in Genes Involved in Host Immune Response Carrington et al. (1999) reported that the extended survival of 28 to 40% of HIV-1-infected Caucasian patients who avoided AIDS for 10 or more years could be attributed to their being fully heterozygous at HLA class I loci, to lacking the AIDS-associated alleles B35 and Cw04, or to both. Gao et al. (2001) examined subtypes of HLA-B35 in 5 cohorts and analyzed the relation of structural differences between subtypes to the risk of progression to AIDS. Two subtypes were identified according to peptide-binding specificity: the HLA-B35-PY group, which consists primarily of HLA-B3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B35-Px group, which also binds epitopes with proline in position 2 but combines several different amino acids (not including tyrosine) in position 9. The influence of HLA-B35 in accelerating progression to AIDS was completely attributable to HLA-B35-Px alleles, some of which differ from HLA-B35-Py alleles by only 1 amino acid residue. Gao et al. (2001) concluded that the previously observed association of HLA-Cw04 with progression to AIDS was due to its linkage disequilibrium with HLA-B35-Px alleles. The fact that the association with B35-Px was observed in both blacks and whites supported the hypothesis that these HLA-B alleles exert an effect on the immune response to HIV-1 infection. Gao et al. (2005) found that HLA-B alleles acted during distinct intervals after HIV infection. HLA-B35-Px and HLA-B57 were associated with rate of progression to 4 outcomes: (1) progression to CD4+ T cells less than 200 (CD4 less than 200), (2) CD4 less than 200 and/or an AIDS-defining illness, (3) an AIDS-defining illness, and (4) death. HLA-B27, on the other hand, was only associated with the last 3 outcomes. Protection mediated by HLA-B57 occurred early after infection, whereas HLA-B27-mediated protection instead delayed progression to an AIDS-defining illness after the decline in CD4 counts. HLA-B35-Px showed an early susceptibility effect associated with rapid progression from seroconversion to CD4 less than 200. Gao et al. (2005) proposed that the presence of the various HLA-B alleles may lead to different scenarios for viral escape from CTL pressure and virus subtypes with different fitnesses. Martin et al. (2002) reported that the activating KIR allele KIR3DS1, in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with HIV-1 (604946.0001). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations strongly suggested a model involving an epistatic interaction between the 2 loci. The strongest synergistic effect of these loci was on progression to depletion of CD4+ T cells, which suggested that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection. Jennes et al. (2006) genotyped HLA and KIR alleles in HIV-exposed seronegative female sex workers (FSWs), HIV-seropositive FSWs, and HIV-seronegative female blood donors from Abidjan, Cote d'Ivoire. HIV-exposed seronegative FSWs had an increased frequency of inhibitory KIR genes in the absence of their cognate HLA genes: KIR2DL2 (604937)/KIR2DL3 (604938) heterozygosity in the absence of HLA-C1 (142840), and KIR3DL1 (604936) homozygosity in the absence of HLA-Bw4. In contrast, HIV-seropositive FSWs were characterized by corresponding KIR/HLA pairings: KIR2DL3 homozygosity with HLA-C1 and a trend toward KIR3DL1/HLA-Bw4 homozygosity. Jennes et al. (2006) proposed that a lack of inhibitory KIRs may lower the threshold for NK-cell activation and that NK cells and KIR/HLA interactions may be important in antiviral immunity. Using short tandem repeat polymorphism (i.e., microsatellite) analysis, Shin et al. (2000) identified significant genotype associations for HIV-1 infection and progression to AIDS with markers adjacent to and tracking common single nucleotide polymorphic variants in the promoter region of IL10, a powerful inhibitor of HIV-1 replication. Individuals carrying the 5-prime -592A promoter allele (124092.0001) were at increased risk for HIV-1 infection, and once infected they progressed to AIDS more rapidly than homozygotes for the alternative -592C/C genotype. Approximately 25 to 30% of long-term nonprogressors (i.e., those who avoid clinical AIDS for 10 or more years after HIV-1 infection) carried the -592C/C promoter genotype. Additional protection or susceptibility was associated with the relevant CCR5 and CCR2 alleles. EMSA analysis indicated that the -592A allele, but not the 592C/C allele, retains a binding site for ETS (see 164720) family DNA-binding proteins, whereas both alleles interact with SP1 (189906). Shin et al. (2000) noted studies (e.g., Rosenwasser and Borish (1997)) that showed that the -592A allele is associated with diminished IL10 production. They suggested that progression to AIDS might be retarded by immunotherapeutic strategies mimicking or enhancing the natural inhibitory role of IL10. An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173G-T (147570.0003), and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF (191160). An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans, and proposed that the increased IFNG production may cause CD4 depletion by apoptosis. Modi et al. (2003) genotyped 9 SNPs spanning the CCL2-CCL7-CCL11 gene cluster on chromosome 17q in more than 3,000 DNA samples from 5 AIDS cohorts. Extensive linkage disequilibrium was observed, particularly for 3 SNPs, -2136T in the CCL2 promoter (158105.0001), 767G in intron 1 of the CCL2 gene (158105.0002), and -1385A in the CCL11 promoter (601156.0001), that formed a 31-kb haplotype (H7) containing the 3 genes. The frequencies of these 3 SNPs and the H7 haplotype were significantly elevated in uninfected individuals repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 or CXCR4, Modi et al. (2003) proposed that the influence of the H7 haplotype on HIV-1 transmission may result from activation of the immune system rather than receptor blockage. Using a whole-genome association strategy, Fellay et al. (2007) identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these lies within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B5701 (142830.0003), whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated 2 genes, 1 of which encodes an RNA polymerase I subunit, ZNRD1 (607525). Fellay et al. (2007) noted that ZNRD1 expression significantly associated with the identified SNPs; 2 of them (rs3869068 and rs9261174) are located in a putative regulatory 5-prime region, 25 and 32 kb away from the gene, respectively. Using genotyping for an HLA-C promoter variant, -35C-T (142840.0002), and flow cytometric analysis in 1,698 HIV-infected patients of European ancestry, Thomas et al. (2009) found that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high surface expression better control viremia and progress more slowly to AIDS. Thomas et al. (2009) concluded that high HLA-C expression results in more effective control of HIV-1, possibly through better antigen presentation to cytotoxic T lymphocytes. Kosmrlj et al. (2010) noted that although most people infected with HIV ultimately progress to AIDS, rare individuals (elite controllers) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. The HLA-B57 class I allele is enriched in elite controllers (Migueles et al., 2000). In silico analysis showed that HLA-B57 binds to fewer self peptides than does HLA-B7, an allele associated with HIV disease progression. Binding to fewer self peptides in the thymus means that HLA-B57-restricted CD8+ T cells should be more cross-reactive to point mutants of targeted viral peptides. Analysis of 2 large HLA-typed cohorts indicated that elite controllers are more likely to be HLA-B27 or, particularly, HLA-B57 positive, whereas progressors are more likely to be HLA-B7 or HLA-B35 positive. Kosmrlj et al. (2010) noted that HLA-B57 is also protective against HCV (609532), another chronic highly mutable viral pathogen, whereas HLA-B8, which binds to a greater diversity of self peptides, is associated with faster HCV and HIV disease progression. Kosmrlj et al. (2010) concluded that HLA self-peptide analysis provides a conceptual framework, unifying diverse empirical observations, and has implications for vaccination strategies. Human ERAP1 (606832) and ERAP2 (609497) encode 2 endoplasmic reticulum aminopeptidases. These enzymes trim peptides prior to loading onto major histocompatibility complex class I molecules and shape the antigenic repertoire presented to CD8+ T cells. Cagliani et al. (2010) resequenced 2 genic regions in ERAP1 and ERAP2 in 3 HapMap populations. They observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and reduced population genetic differentiation. The genealogy of ERAP1 and ERAP2 haplotypes was split into 2 major branches with deep coalescence times. Analysis of the lys528-to-arg (rs30187 in ERAP1) and asn392-to-lys (rs2549782 in ERAP2) variants in an Italian population of HIV-1-exposed seronegative (ESN) individuals and a larger number of Italian controls indicated that rs2549782 significantly deviated from Hardy-Weinberg equilibrium in ESN individuals but not in controls. The genotype distribution of rs2549782 was significantly different in the 2 cohorts (p = 0.004), mainly as the result of an overrepresentation of lys/lys genotypes in the ESN sample (p value for a recessive model: 0.00097). The authors concluded that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 may confer resistance to HIV-1 infection via the presentation of a distinctive peptide repertoire to CD8+ T cells. Sironi et al. (2012) genotyped a TLR3 (603029) SNP, rs3775291, that confers a leu412-to-phe (L412F; 603029.0002) change in 102 Spanish HIV-1-exposed seronegative intravenous drug users and 131 age- and sex-matched healthy controls. They found that the frequency of individuals carrying at least 1 F412 allele was significantly higher in HIV-1-exposed seronegative individuals than in controls (odds ratio for a dominant model = 1.87; p = 0.023). They replicated this finding in 83 seronegative Italians who had been sexually exposed to HIV-1 and 238 healthy matched controls (odds ratio = 1.79; p = 0.029). The combined results for the Spanish and Italian samples suggested that the F412 allele protects from HIV-1 with a dominant effect (p = 0.003). In vitro analysis in peripheral blood mononuclear cells (PBMCs) showed significantly reduced HIV-1 replication in PBMCs carrying F412 compared with those homozygous for L412 (p = 0.025), and this reduced replication was associated with higher expression of immune activation markers, such as IL6 (147620), CCL3 (182283), and CD69 (107273). Stimulation of PBMCs with a TLR3 agonist showed that the presence of F412 resulted in significantly increased expression of CD69 and higher production of proinflammatory cytokines. Sironi et al. (2012) concluded that the F412 TLR3 allele confers immunologically mediated protection from HIV-1. Ramsuran et al. (2018) analyzed 9,763 HIV-infected individuals from 21 cohorts and found that higher HLA-A (142800) levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E (143010), the ligand for the inhibitory NKG2A (see 161555) natural killer cell receptor. HLA-B (142830) haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. Clinical Management Gulick et al. (2007) evaluated the use of a CCR5 inhibitor, vicriviroc, in 118 HIV-1-infected patients whose virus used the CCR5 coreceptor exclusively and who were experiencing virologic failure while receiving a ritonavir-containing treatment regimen. They found significant reductions in viral load after adding vicriviroc to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. At 24 weeks, the reduction in viral load persisted, and a significant increase in CD4-positive cell counts was observed in those who received higher doses of vicriviroc. Gulick et al. (2007) concluded that vicriviroc is generally well tolerated and effective, although they noted an uncertain relationship between vicriviroc and malignancy. Cressey and Lallemant (2007) reviewed the known pharmacogenetics of antiretrovirals used in AIDS treatment, including efavirenz, nevirapine, nelfinavir, indinavir, and atazanavir. See 614546 for information on poor metabolism of efavirenz and susceptibility to efavirenz central nervous system toxicity, which are associated with variation in the CYP2B6 gene (123930). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease	HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO	c1836230	3,588	omim	https://www.omim.org/entry/609423	2019-09-22T16:06:04	{"omim": ["609423"], "synonyms": ["Alternative titles", "HIV-1, SUSCEPTIBILITY TO"]}
This article is about cysts in the body. For the ICAO airport code CYST, see St. Theresa Point Airport. For hard-shelled resting stages of some small organisms, see Microbial cyst. Closed sac growth on the body Cyst H&E stained micrograph of a mediastinal bronchogenic cyst SpecialtyPathology, general surgery A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that has grouped together to form a sac (like the manner in which water molecules group together to form a bubble); however, the distinguishing aspect of a cyst is that the cells forming the "shell" of such a sac are distinctly abnormal (in both appearance and behaviour) when compared with all surrounding cells for that given location. A cyst may contain air, fluids, or semi-solid material. A collection of pus is called an abscess, not a cyst. Once formed, a cyst may resolve on its own. When a cyst fails to resolve, it may need to be removed surgically, but that would depend upon its type and location. Cancer-related cysts are formed as a defense mechanism for the body following the development of mutations that lead to an uncontrolled cellular division. Once that mutation has occurred, the affected cells divide incessantly and become cancerous, forming a tumour. The body encapsulates those cells to try to prevent them from continuing their division and contain the tumour, which becomes known as a cyst. That said, the cancerous cells still may mutate further and gain the ability to form their own blood vessels, from which they receive nourishment before being contained. Once that happens, the capsule becomes useless, and the tumour may advance from benign to cancerous. Some cysts are neoplastic, and thus are called cystic tumors. Many types of cysts are not neoplastic; some are dysplastic or metaplastic. Pseudocysts are similar to cysts in that they have a sac filled with fluid, but lack an epithelial lining. ## Contents * 1 Terminology * 2 Cysts by location * 2.1 Female reproductive system * 2.2 Scrotum * 2.3 Cutaneous and subcutaneous * 2.4 Head and neck * 2.5 Chest * 2.6 Abdomen * 2.7 Central nervous system * 2.8 Musculoskeletal system * 2.9 Seen in various locations * 3 Infectious cysts * 4 Neoplastic cysts * 5 Treatment * 6 Related structures * 7 Cystic fibrosis * 8 See also * 9 References * 10 External links ## Terminology[edit] * microcyst – a small cyst that requires magnification to be seen * macrocyst – a cyst that is larger than usual or compared to others ## Cysts by location[edit] ### Female reproductive system[edit] Relative incidences of different types of ovarian cysts[1] * Vaginal cyst (vagina) * Gartner's duct cyst (lateral wall of vagina) * Bartholin's cyst (labia minora) * Nabothian cyst (on the surface of the cervix) * Skene's duct cyst (lateral to urinary meatus) * Ovarian cyst (ovary) * Paratubal cyst (fallopian tube) ### Scrotum[edit] * Epididymal cyst (in the vessels attached to the testes): containing serous liquid * Hydrocele testis (testicle): clear fluid within the cavum vaginale * Spermatocele (testicle): clear or milky white fluid that may contain sperm ### Cutaneous and subcutaneous[edit] * Acne cyst – Pseudocysts associated with cystic acne \- an inflammatory nodule with or without an associated epidermoid inclusion cyst * Arachnoid cyst (between the surface of the brain and the cranial base or on the arachnoid membrane) * Epidermoid cyst * Myxoid cyst (cutaneous condition often characterized by nail plate depression and grooves) * Pilar cyst (cyst of the scalp) * Pilonidal cyst (skin infection near tailbone) * Sebaceous cyst – sac below skin * Trichilemmal cyst – same as a pilar cyst, a familial cyst of the scalp ### Head and neck[edit] Relative incidence of odontogenic cysts[2] * Odontogenic cyst * Ceruminous cyst (ear) * Chalazion cyst (eyelid) * Mucous cyst of the oral mucosa * Nasolabial cyst * Thyroglossal cyst * Vocal fold cyst ### Chest[edit] * Fibrous cyst (breast cyst) * Pulmonary cyst (air pocket in the lung) * Pericardial cyst (abnormal dilatation of pericardium) ### Abdomen[edit] * Adrenal cyst: Types of adrenal cysts include parasitic cysts, epithelial cysts, endothelial cysts, and pseudocysts. 56% of all adrenal cyst-like changes are pseudocysts, and only 7% of those pseudocysts are malignant or potentially malignant.[3] * Parapelvic cyst (kidney)[4] * Renal cyst (kidneys) * Polycystic liver disease * Pancreatic cyst * Peritoneal cyst (lining of the abdominal cavity) ### Central nervous system[edit] * Choroid plexus cyst * Colloid cyst * Pineal gland cyst (in the pineal gland in the brain) * Glial cyst * Tarlov cyst (spinal canal) ### Musculoskeletal system[edit] * Aneurysmal bone cyst, a benign bone tumor with a radiographic cystic appearance.[5] * Baker's cyst or popliteal cyst (behind the knee joint) * Mucoid cyst (ganglion cysts of the digits) * Stafne static bone cyst (an anatomic variant with radiographic cystic appearance in the posterior mandible) ### Seen in various locations[edit] * Dermoid cyst (seen in ovaries, testes, and many other locations, from head to tailbone) * Ganglion cyst (hand and foot joints and tendons) * Mucoid cyst (ganglion cysts of the digits) ## Infectious cysts[edit] * Cysticercal cyst – an infection due to the larval stage of Taenia sp. (Crain's backs) * Hydatid cyst – an infection in the liver or other parts of the body due to the larval stage of Echinococcus granulosus (tapeworm) ## Neoplastic cysts[edit] * Dermoid cyst * Keratocystic odontogenic tumor * Calcifying odontogenic cyst ## Treatment[edit] Treatment ranges from simple enucleation of the cyst to curettage to resection. There are cysts—e.g., buccal bifurcation cyst—that resolve on their own, in which just close observation may be employed, unless it is infected and symptomatic.[6] ## Related structures[edit] A pseudocyst is very similar to a cyst, but is a collection of cells without a distinct membrane (epithelial or endothelial cells). A syrinx in the spinal cord or brainstem is sometimes inaccurately referred to as a "cyst". ## Cystic fibrosis[edit] Despite being described in 1938 as "the microscopic appearance of cysts in the pancreas",[7] cystic fibrosis is an example of a genetic disorder whose name is related to fibrosis of the cystic duct (which serves the gallbladder) and does not involve cysts.[8] This is just one example of how the Greek root cyst-, which simply means a fluid-filled sac, also is found in medical terms that relate to the urinary bladder and the gallbladder, neither of which involve cysts. ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Abduljabbar, Hassan; Bukhari, Yasir; Al Hachim, Estabrq; Alshour, Ghazal; Amer, Afnan; Shaikhoon, Mohammed; Khojah, Mohammed (2015). "Review of 244 cases of ovarian cysts". Saudi Medical Journal. 36 (7): 834–838. doi:10.15537/smj.2015.7.11690. ISSN 0379-5284. 2. ^ Leandro Bezerra Borges; Francisco Vagnaldo Fechine; Mário Rogério Lima Mota; Fabrício Bitu Sousa; Ana Paula Negreiros Nunes Alves (2012). "Odontogenic lesions of the jaw: a clinical-pathological study of 461 cases". Revista Gaúcha de Odontologia. 60 (1). 3. ^ Kar, Mitryan; Pucci, Ed; Brody, Fred (2006). "Laparoscopic Resection of an Adrenal Pseudocyst". Journal of Laparoendoscopic & Advanced Surgical Techniques. 16 (5): 478–81. doi:10.1089/lap.2006.16.478. PMID 17004872. 4. ^ "Parapelvic Cyst \| Health And Nutrition Tips". www.healthandnutritiontips.net. Retrieved 8 December 2020. 5. ^ Zadik, Yehuda; Aktaş Alper; Drucker Scott; Nitzan W Dorrit (2012). "Aneurysmal bone cyst of mandibular condyle: A case report and review of the literature". J Craniomaxillofac Surg. 40 (8): e243–8. doi:10.1016/j.jcms.2011.10.026. PMID 22118925. 6. ^ Zadik Y, Yitschaky O, Neuman T, Nitzan DW (May 2011). "On the Self-Resolution Nature of the Buccal Bifurcation Cyst". J Oral Maxillofac Surg. 69 (7): e282. doi:10.1016/j.joms.2011.02.124. PMID 21571416. 7. ^ Andersen, D.H. (1938). "Cystic fibrosis of the pancreas and its relation to celiac disease". Am J Dis Child. 56: 344–399. doi:10.1001/archpedi.1938.01980140114013. 8. ^ Greenholz SK, Krishnadasan B, Marr C, Cannon R (1997). "Biliary obstruction in infants with cystic fibrosis requiring Kasai portoenterostomy". J. Pediatr. Surg. 32 (2): 175–79, discussion 179–80. doi:10.1016/S0022-3468(97)90174-3. PMID 9044117. ## External links[edit] Classification D * MeSH: D003560 External resources * MedlinePlus: 003240 * "Cyst Symptoms and Causes" by Melissa Conrad Stöppler, MD and William C. Shiel Jr., MD, FACP, FACR. * v * t * e Overview of tumors, cancer and oncology Conditions Benign tumors * Hyperplasia * Cyst * Pseudocyst * Hamartoma Malignant progression * Dysplasia * Carcinoma in situ * Cancer * Metastasis * Primary tumor * Sentinel lymph node Topography * Head and neck (oral, nasopharyngeal) * Digestive system * Respiratory system * Bone * Skin * Blood * Urogenital * Nervous system * Endocrine system Histology * Carcinoma * Sarcoma * Blastoma * Papilloma * Adenoma Other * Precancerous condition * Paraneoplastic syndrome Staging/grading * TNM * Ann Arbor * Prostate cancer staging * Gleason grading system * Dukes classification Carcinogenesis * Cancer cell * Carcinogen * Tumor suppressor genes/oncogenes * Clonally transmissible cancer * Oncovirus * Carcinogenic bacteria Misc. * Research * Index of oncology articles * History * Cancer pain * Cancer and nausea * v * t * e Cystic diseases Respiratory system * Langerhans cell histiocytosis * Lymphangioleiomyomatosis * Cystic bronchiectasis Skin * stratified squamous: follicular infundibulum * Epidermoid cyst and Proliferating epidermoid cyst * Milia * Eruptive vellus hair cyst * outer root sheath * Trichilemmal cyst and Pilar cyst and Proliferating trichilemmal cyst and Malignant trichilemmal cyst * sebaceous duct * Steatocystoma multiplex and Steatocystoma simplex * Keratocyst * nonstratified squamous: Cutaneous ciliated cyst * Hidrocystoma * no epithelium: Pseudocyst of the auricle * Mucocele * other and ungrouped: Cutaneous columnar cyst * Keratin implantation cyst * Verrucous cyst * Adenoid cystic carcinoma * Breast cyst Human musculoskeletal system * Cystic hygroma Human digestive system * oral cavity: Cysts of the jaws * Odontogenic cyst * Periapical cyst * Dentigerous cyst * Odontogenic keratocyst * Nasopalatine duct cyst * liver: Polycystic liver disease * Congenital hepatic fibrosis * Peliosis hepatis * bile duct: Biliary hamartomas * Caroli disease * Choledochal cysts * Bile duct hamartoma Nervous system * Cystic leukoencephalopathy Genitourinary system * Polycystic kidney disease * Autosomal dominant polycystic kidney * Autosomal recessive polycystic kidney * Medullary cystic kidney disease * Nephronophthisis * Congenital cystic dysplasia Other conditions * Hydatid cyst * Von Hippel–Lindau disease * Tuberous sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cyst	c0010709	3,589	wikipedia	https://en.wikipedia.org/wiki/Cyst	2021-01-18T18:50:16	{"mesh": ["D003560"], "wikidata": ["Q193211"]}
A localized disease is an infectious or neoplastic process that originates in and is confined to one organ system or general area in the body,[1] such as a sprained ankle, a boil on the hand, an abscess of finger. A localized cancer that has not extended beyond the margins of the organ involved can also be described as localized disease, while cancers that extend into other tissues are described as invasive. Tumors that are non-hematologic in origin but extend into the bloodstream or lymphatic system are known as metastatic. Localized diseases are contrasted with disseminated diseases and systemic diseases. Some diseases are capable of changing from local to disseminated diseases. Pneumonia, for example, is generally confined to one or both lungs but can become disseminated through sepsis, in which the microbe responsible for the pneumonia "seeds" the bloodstream or lymphatic system and is transported to distant sites in the body. When that occurs, the process is no longer described as a localized disease, but rather as a disseminated disease. ## See also[edit] * Disease * Nosology ## References[edit] 1. ^ Dorland's Illustrated Medical Dictionary,28th edition. W.B.Saunders, Harcourt Brace & Company [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Localized disease	c0277565	3,590	wikipedia	https://en.wikipedia.org/wiki/Localized_disease	2021-01-18T18:45:42	{"umls": ["C0277565"], "wikidata": ["Q6664621"]}
A number sign (#) is used with this entry because of evidence that spondylocostal dysostosis-6 (SCDO6) is caused by compound heterozygous mutation in the RIPPLY2 gene (609891) on chromosome 6q14. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of spondylocostal dysostosis, see SCDO1 (277300). Clinical Features McInerney-Leo et al. (2015) studied 2 brothers with segmentation defects of the vertebrae. The proband had failure of formation of the posterior elements of C1 to C4 with descent of the occipital bone, causing spinal canal stenosis and spinal cord compression. He also displayed hemivertebrae and butterfly vertebrae between T2 and T7, resulting in mild thoracic scoliosis. His brother had deficiency of the posterior elements of C1 to C3, left hemivertebrae at C4 and T9, and a right hemivertebra at T4, causing marked cervical kyphosis at the C2/C3 level with associated cord compression. Their nonconsanguineous parents, sister, and maternal grandfather and grandmother had normal spines by radiologic assessment. Molecular Genetics In 2 brothers with segmentation defects of the vertebrae, who had previously been tested negative for mutation in 4 genes known to be associated with autosomal recessive spondylocostal dysostosis, McInerney-Leo et al. (2015) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (R80X; 609891.0001) and a splice site mutation (c.240-4T-G; 609891.0002) in the RIPPLY2 gene that segregated with disease in the family. Analysis of the exome data for variation in 8 genes previously reported to be associated with SCDO or Klippel-Feil syndrome (see 118100) revealed no coding or splice site mutations, and no copy number variation affecting RIPPLY2 was detected. In vitro functional analysis demonstrated significantly reduced transcriptional repression activity with the R80X mutant compared to wildtype RIPPLY2. The authors stated that functional analysis of the splice site mutation could not be accomplished because of the location of the mutation and the likely restriction expression of RIPPLY2 to embryogenesis. INHERITANCE \- Autosomal recessive SKELETAL Skull \- Descent of occipital bone \- Spinal canal stenosis Spine \- Absence of posterior elements of upper cervical vertebrae \- Hemivertebrae in cervical and thoracic spine \- Butterfly vertebrae in thoracic spine \- Cervical kyphosis \- Mild thoracic scoliosis NEUROLOGIC Central Nervous System \- Compression of spinal cord MISCELLANEOUS \- Based on report of 2 affected brothers in 1 family (last curated October 2015) MOLECULAR BASIS \- Caused by mutation in the ripply transcriptional repressor-2 gene (RIPPLY2, 609891.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	SPONDYLOCOSTAL DYSOSTOSIS 6, AUTOSOMAL RECESSIVE	c0265343	3,591	omim	https://www.omim.org/entry/616566	2019-09-22T15:48:29	{"mesh": ["C537565"], "omim": ["616566"], "orphanet": ["2311"], "genereviews": ["NBK8828"]}
Refsum disease is an inherited condition that causes vision loss, absence of the sense of smell (anosmia), and a variety of other signs and symptoms. The vision loss associated with Refsum disease is caused by an eye disorder called retinitis pigmentosa. This disorder affects the retina, the light-sensitive layer at the back of the eye. Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. The first sign of retinitis pigmentosa is usually a loss of night vision, which often becomes apparent in childhood. Over a period of years, the disease disrupts side (peripheral) vision and may eventually lead to blindness. Vision loss and anosmia are seen in almost everyone with Refsum disease, but other signs and symptoms vary. About one-third of affected individuals are born with bone abnormalities of the hands and feet. Features that appear later in life can include progressive muscle weakness and wasting; poor balance and coordination (ataxia); hearing loss; and dry, scaly skin (ichthyosis). Additionally, some people with Refsum disease develop an abnormal heart rhythm (arrhythmia) and related heart problems that can be life-threatening. ## Frequency The prevalence of Refsum disease is unknown, although the condition is thought to be uncommon. ## Causes More than 90 percent of all cases of Refsum disease result from mutations in the PHYH gene. The remaining cases are caused by mutations in a gene called PEX7. The signs and symptoms of Refsum disease result from the abnormal buildup of a type of fatty acid called phytanic acid. This substance is obtained from the diet, particularly from beef and dairy products. It is normally broken down through a process called alpha-oxidation, which occurs in cell structures called peroxisomes. These sac-like compartments contain enzymes that process many different substances, such as fatty acids and certain toxic compounds. Mutations in either the PHYH or PEX7 gene disrupt the usual functions of peroxisomes, including the breakdown of phytanic acid. As a result, this substance builds up in the body's tissues. The accumulation of phytanic acid is toxic to cells, although it is unclear how an excess of this substance affects vision and smell and causes the other specific features of Refsum disease. ### Learn more about the genes associated with Refsum disease * PEX7 * PHYH ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Refsum disease	c0034960	3,592	medlineplus	https://medlineplus.gov/genetics/condition/refsum-disease/	2021-01-27T08:25:01	{"gard": ["5694"], "mesh": ["D012035"], "omim": ["266500"], "synonyms": []}
According to the WHO classification, three lesional patterns can be observed * Inflammatory myofibroblastic tumour, that can be associated with an ALK gene rearrangement * Plasmocytic pattern ("plasma cell granuloma"), that can be linked to IgG4-related disease * Fibrous and hyalinizing pattern: Pulmonary hyalinizing granuloma ## References[edit] This medical sign article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Inflammatory pseudotumor	c0334121	3,593	wikipedia	https://en.wikipedia.org/wiki/Inflammatory_pseudotumor	2021-01-18T19:08:13	{"mesh": ["D006104"], "umls": ["C0334121"], "wikidata": ["Q16882760"]}
Splenic marginal zone lymphoma SpecialtyHematology, oncology Splenic marginal zone lymphoma (SMZL) is a type of cancer (specifically a lymphoma) made up of B-cells that replace the normal architecture of the white pulp of the spleen. The neoplastic cells are both small lymphocytes and larger, transformed lymphoblasts, and they invade the mantle zone of splenic follicles and erode the marginal zone, ultimately invading the red pulp of the spleen. Frequently, the bone marrow and splenic hilar lymph nodes are involved along with the peripheral blood. The neoplastic cells circulating in the peripheral blood are termed villous lymphocytes due to their characteristic appearance.[1] ## Contents * 1 Cause * 2 Diagnosis * 3 Prognosis * 4 Molecular findings * 4.1 Immunophenotype * 4.2 Genetics * 5 Epidemiology * 6 Synonyms * 7 See also * 8 References * 9 External links ## Cause[edit] The cell of origin is postulated to be a post-germinal center B-cell with an unknown degree of differentiation.[1] SMZL is a form of cancer known to be associated with Hepatitis C virus infection.[citation needed] ## Diagnosis[edit] Enlargement of the spleen is a requirement for the diagnosis of SMZL and is seen in nearly all people affected by SMZL (often without lymphadenopathy).[1] Aside from the uniform involvement of the spleen, the bone marrow is frequently positive in patients with SMZL. Nodal and extranodal involvement are rare.[1] Circulating lymphoma cells are sometimes present in peripheral blood, and they occasionally show short villi at the poles of cells and plasmacytoid differentiation.[2] Autoimmune thrombocytopenia and anemia sometimes seen in patients with SMZL. Circulating villous lymphocytes are sometimes observed in peripheral blood samples.[1] A monoclonal paraprotein is detected in a third of patients without hypergammaglobulinemia or hyperviscosity.[3][4] Reactive germinal centers in splenic white pulp are replaced by small neoplastic lymphocytes that efface the mantle zone and ultimately blend in with the marginal zone with occasional larger neoplastic cells that resemble blasts.[4][5] The red pulp is always involved, with both nodules of larger neoplastic cells and sheets of the small neoplastic lymphocytes. Other features that may be seen include sinus invasion, epithelial histocytes, and plasmacytic differentiation of neoplastic cells. Involved hilar lymph nodes adjacent to the spleen show an effaced architecture without preservation of the marginal zone seen in the spleen.[1] SMZL in bone marrow displays a nodular pattern with morphology similar to what is observed in the splenic hilar lymph nodes.[6] ## Prognosis[edit] Three-quarters of patients survive five or more years; more than half of patients with SMZL survive more than a decade after diagnosis.[7] Patients who have a hemoglobin level of less than 12 g/dL, a lactate dehydrogenase level higher than normal, and/or a blood serum albumin levels of less than 3.5 g/dL are likely to have more an aggressive disease course and a shorter survival.[7] However, even high-risk patients have even odds of living for five years after diagnosis.[7] Some genetic mutations, such as mutations in NOTCH2, are also correlated with shorter survival. ## Molecular findings[edit] ### Immunophenotype[edit] Antigen Status CD20 Positive CD79a Positive CD5 Negative CD10 Negative CD23 Negative CD43 Negative cyclin D1 Negative The relevant markers that define the immunophenotype for SMZL are shown in the adjacent table.[8] [9] The lack of CD5 expression is helpful in the discrimination between SMZL and chronic lymphocytic leukemia/small lymphocytic lymphoma, and the lack of CD10 expression argues against follicular lymphoma. Mantle cell lymphoma is excluded due to the lack of CD5 and cyclin-D1 expression.[10] ### Genetics[edit] Clonal rearrangements of the immunoglobulin genes (heavy and light chains) are frequently seen.[11] The deletion 7q21-32 is seen in 40% of SMZL patients, and translocations of the CDK6 gene located at 7q21 have also been reported.[12] ## Epidemiology[edit] Less than 1% of all lymphomas are splenic marginal zone lymphomas[13] and it is postulated that SMZL may represent a large fraction of unclassifiable CD5- chronic lymphocytic leukemias.[1] The typical patient is over the age of 50, and gender preference has been described.[3] ## Synonyms[edit] Under older classification systems, the following names were used:[1] Classification system Name Rappaport well-differentiated lymphocytic lymphoma Lukes-Collins small lymphocytic lymphoma Working Formulation small lymphocytic lymphoma FAB splenic lymphoma with circulating villous lymphocytes ## See also[edit] * List of hematologic conditions ## References[edit] 1. ^ a b c d e f g h Elaine Sarkin Jaffe, Nancy Lee Harris, World Health Organization, International Agency for Research on Cancer, Harald Stein, J.W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 978-92-832-2411-2.CS1 maint: multiple names: authors list (link) 2. ^ Melo JV, Hegde U, Parreira A, Thompson I, Lampert IA, Catovsky D (June 1987). "Splenic B cell lymphoma with circulating villous lymphocytes: differential diagnosis of B cell leukaemias with large spleens". J. Clin. Pathol. 40 (6): 642–51. doi:10.1136/jcp.40.6.642. PMC 1141055. PMID 3497180. 3. ^ a b Berger F, Felman P, Thieblemont C, et al. (March 2000). "Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients". Blood. 95 (6): 1950–6. doi:10.1182/blood.V95.6.1950. PMID 10706860. 4. ^ a b Mollejo M, Menárguez J, Lloret E, et al. (October 1995). "Splenic marginal zone lymphoma: a distinctive type of low-grade B-cell lymphoma. A clinicopathological study of 13 cases". Am. J. Surg. Pathol. 19 (10): 1146–57. doi:10.1097/00000478-199510000-00005. PMID 7573673. 5. ^ Jaffe ES, Costa J, Fauci AS, Cossman J, Tsokos M (November 1983). "Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis". Am. J. Med. 75 (5): 741–9. doi:10.1016/0002-9343(83)90402-3. PMID 6638043. 6. ^ Franco V, Florena AM, Campesi G (December 1996). "Intrasinusoidal bone marrow infiltration: a possible hallmark of splenic lymphoma". Histopathology. 29 (6): 571–5. doi:10.1046/j.1365-2559.1996.d01-536.x. PMID 8971565. 7. ^ a b c Arcaini, L. (2006). "Splenic marginal zone lymphoma: a prognostic model for clinical use" (PDF). Blood. 107 (12): 4643–4649. doi:10.1182/blood-2005-11-4659. hdl:11380/584206. ISSN 0006-4971. PMID 16493005. 8. ^ Isaacson PG, Matutes E, Burke M, Catovsky D (1 December 1994). "The histopathology of splenic lymphoma with villous lymphocytes". Blood. 84 (11): 3828–34. doi:10.1182/blood.V84.11.3828.bloodjournal84113828. PMID 7949139. 9. ^ Matutes E, Morilla R, Owusu-Ankomah K, Houlihan A, Catovsky D (15 March 1994). "The immunophenotype of splenic lymphoma with villous lymphocytes and its relevance to the differential diagnosis with other B-cell disorders". Blood. 83 (6): 1558–62. doi:10.1182/blood.V83.6.1558.1558. PMID 8123845. 10. ^ Savilo E, Campo E, Mollejo M, et al. (July 1998). "Absence of cyclin D1 protein expression in splenic marginal zone lymphoma". Mod. Pathol. 11 (7): 601–6. PMID 9688179. 11. ^ Dunn-Walters DK, Boursier L, Spencer J, Isaacson PG (June 1998). "Analysis of immunoglobulin genes in splenic marginal zone lymphoma suggests ongoing mutation". Hum. Pathol. 29 (6): 585–93. doi:10.1016/S0046-8177(98)80007-5. PMID 9635678. 12. ^ Corcoran MM, Mould SJ, Orchard JA, et al. (November 1999). "Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations". Oncogene. 18 (46): 6271–7. doi:10.1038/sj.onc.1203033. PMID 10597225. 13. ^ Armitage JO, Weisenburger DD (August 1998). "New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project". J. Clin. Oncol. 16 (8): 2780–95. doi:10.1200/JCO.1998.16.8.2780. PMID 9704731. Archived from the original on 2013-04-15. ## External links[edit] Classification D * ICD-9-CM: 200.3 * ICD-O: M9689/3 * v * t * e Leukaemias, lymphomas and related disease B cell (lymphoma, leukemia) (most CD19 * CD20) By development/ marker TdT+ * ALL (Precursor B acute lymphoblastic leukemia/lymphoma) CD5+ * naive B cell (CLL/SLL) * mantle zone (Mantle cell) CD22+ * Prolymphocytic * CD11c+ (Hairy cell leukemia) CD79a+ * germinal center/follicular B cell (Follicular * Burkitt's * GCB DLBCL * Primary cutaneous follicle center lymphoma) * marginal zone/marginal zone B-cell (Splenic marginal zone * MALT * Nodal marginal zone * Primary cutaneous marginal zone lymphoma) RS (CD15+, CD30+) * Classic Hodgkin lymphoma (Nodular sclerosis) * CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma) PCDs/PP (CD38+/CD138+) * see immunoproliferative immunoglobulin disorders By infection * KSHV (Primary effusion) * EBV * Lymphomatoid granulomatosis * Post-transplant lymphoproliferative disorder * Classic Hodgkin lymphoma * Burkitt's lymphoma * HCV * Splenic marginal zone lymphoma * HIV (AIDS-related lymphoma) * Helicobacter pylori (MALT lymphoma) Cutaneous * Diffuse large B-cell lymphoma * Intravascular large B-cell lymphoma * Primary cutaneous marginal zone lymphoma * Primary cutaneous immunocytoma * Plasmacytoma * Plasmacytosis * Primary cutaneous follicle center lymphoma T/NK T cell (lymphoma, leukemia) (most CD3 * CD4 * CD8) By development/ marker * TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma) * prolymphocyte (Prolymphocytic) * CD30+ (Anaplastic large-cell lymphoma * Lymphomatoid papulosis type A) Cutaneous MF+variants * indolent: Mycosis fungoides * Pagetoid reticulosis * Granulomatous slack skin aggressive: Sézary disease * Adult T-cell leukemia/lymphoma Non-MF * CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma * Pleomorphic T-cell lymphoma * Lymphomatoid papulosis type B * CD30+: CD30+ cutaneous T-cell lymphoma * Secondary cutaneous CD30+ large-cell lymphoma * Lymphomatoid papulosis type A Other peripheral * Hepatosplenic * Angioimmunoblastic * Enteropathy-associated T-cell lymphoma * Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma) * Subcutaneous T-cell lymphoma By infection * HTLV-1 (Adult T-cell leukemia/lymphoma) NK cell/ (most CD56) * Aggressive NK-cell leukemia * Blastic NK cell lymphoma T or NK * EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma) * Large granular lymphocytic leukemia Lymphoid+ myeloid * Acute biphenotypic leukaemia Lymphocytosis * Lymphoproliferative disorders (X-linked lymphoproliferative disease * Autoimmune lymphoproliferative syndrome) * Leukemoid reaction * Diffuse infiltrative lymphocytosis syndrome Cutaneous lymphoid hyperplasia * Cutaneous lymphoid hyperplasia * with bandlike and perivascular patterns * with nodular pattern * Jessner lymphocytic infiltrate of the skin General * Hematological malignancy * leukemia * Lymphoproliferative disorders * Lymphoid leukemias [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Splenic marginal zone lymphoma	c0349632	3,594	wikipedia	https://en.wikipedia.org/wiki/Splenic_marginal_zone_lymphoma	2021-01-18T18:57:09	{"umls": ["C0349632"], "icd-9": ["200.3"], "icd-10": ["C83.0"], "orphanet": ["86854"], "wikidata": ["Q3832900"]}
Severe neonatal pyruvate carboxylase (PC) deficiency (Type B) is a rare, extremely severe form of PC deficiency characterized by severe, early-onset metabolic acidosis, and a generally fatal outcome in early infancy. ## Epidemiology The exact prevalence of Type B pyruvate carboxylase deficiency is not known. The disorder has been reported to be more common in populations of Arab descent (Algerian, Egyptian, and Saudi Arabian). Higher incidence is also reported in France, Germany and the United Kingdom. ## Clinical description Patients develop clinical manifestations during the first 72 hours of life with severe truncal hypotonia and tachypnea. Subsequent clinical signs include anorexia, failure to thrive, hepatomegaly, myoclonic or generalized tonic-clonic seizures, stupor, pyramidal dysfunction, abnormal movements (high-amplitude tremor and dyskinesia), abnormal limb and ocular movements and severe impairment of mental and motor development. Renal tubular acidosis has been reported. ## Etiology PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5). ## Diagnostic methods The biochemical hallmarks of Type B pyruvate carboxylase deficiency include elevated lactate/pyruvate (L/P) ratio, ketoacidosis with low hydroxybutyrate/acetoacetate (H/A) ratio in plasma, hypoglycemia, increased citrulline, proline, lysine and alanine levels, low glutamine, hyperammonemia and hypernatremia. Blood lactic acid levels are usually above 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing. ## Genetic counseling Pyruvate carboxylase deficiency is inherited in an autosomal recessive manner. ## Prognosis The prognosis is very poor with almost all affected infants dying within the first three months of life. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Pyruvate carboxylase deficiency, severe neonatal type	c0034341	3,595	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353314	2021-01-23T16:52:43	{"mesh": ["D015324"], "omim": ["266150"], "icd-10": ["E74.4"], "synonyms": ["Pyruvate carboxylase deficiency type B"]}
For a phenotypic description of primary pulmonary hypertension (PPH), see PPH1 (178600). Inheritance Several reports have suggested autosomal inheritance of primary pulmonary hypertension. Coleman et al. (1959) observed primary pulmonary hypertension in 2 sisters and a brother and confirmed the diagnosis by postmortem examination. Tsagaris and Tikoff (1968) reported a family in which 3 sibs were affected: 2 males and 1 female. Hood et al. (1968) reported the condition in 3 sisters. Their review of the literature led them to conclude that single-generation cases tend to be predominantly in women and to have later onset than multiple-generation cases, which tend to show more equal sex distribution. Cardiac \- Accentuated pulmonary valve closure \- Gallop rhythm \- Angina pectoris \- Right ventricular failure Pulmonary \- Exertional dyspnea \- Substernal oppression Radiology \- Enlarged pulmonary arteries \- Right ventricular hypertrophy Misc \- Fatigue \- Weakness \- Syncope Inheritance \- ? Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	PULMONARY HYPERTENSION, PRIMARY, AUTOSOMAL RECESSIVE	c1849552	3,596	omim	https://www.omim.org/entry/265400	2019-09-22T16:22:59	{"doid": ["14557"], "mesh": ["C564862"], "omim": ["265400", "178600"], "icd-10": ["I27.0"], "orphanet": ["422"], "synonyms": []}
Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. ## Epidemiology The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. ## Clinical description The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities (prolonged QT interval). In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. ## Etiology Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired beta-adrenergic receptor signal transduction and increased activity of negative-inotropic pathways mediated by cGMP. ## Diagnostic methods Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol consumption, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. ## Management and treatment Current management recommendations include empirical, nonspecific and mainly supportive measures. ## Prognosis The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Cirrhotic cardiomyopathy	c4511053	3,597	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=57777	2021-01-23T17:43:45	{"icd-10": ["I42.8"]}
Aniseikonia SpecialtyOphthalmology Symptomsobjects different sizes in each eye CausesCataract surgery, refractive surgery Aniseikonia is an ocular condition where there is a significant difference in the perceived size of images. It can occur as an overall difference between the two eyes, or as a difference in a particular meridian.[1] If the ocular image size in both eyes are equal, the condition is known as iseikonia.[2] ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Etymology * 6 See also * 7 References * 8 Further reading * 9 External links ## Symptoms[edit] Up to 7% difference in image size is well tolerated.[3] If magnification difference becomes excessive the effect can cause diplopia, suppression, disorientation, eyestrain, headache, and dizziness and balance disorders.[3] Asthenopic symptoms alone may occur even if image size difference is less than 7%.[4] ## Causes[edit] Retinal image size is determined by many factors. The size and position of the object being viewed affects the characteristics of the light entering the system. Corrective lenses affect these characteristics and are used commonly to correct refractive error. The optics of the eye including its refractive power and axial length also play a major role in retinal image size. Aniseikonia can occur naturally or be induced by the correction of a refractive error, usually anisometropia (having significantly different refractive errors between each eye) or antimetropia (being myopic (nearsighted) in one eye and hyperopic (farsighted) in the other.) Meridional aniseikonia occurs when these refractive differences only occur in one meridian (see astigmatism). One cause of significant anisometropia and subsequent aniseikonia has been aphakia. Aphakic patients do not have a crystalline lens. The crystalline lens is often removed because of opacities called cataracts. The absence of this lens left the patient highly hyperopic (farsighted) in that eye. For some patients the removal was only performed on one eye, resulting in the anisometropia / aniseikonia. Today, this is rarely a problem because when the lens is removed in cataract surgery, an intraocular lens, or IOL is left in its place.[citation needed] Retinal aniseikonia occur due to forward displacement, stretching or edema of retina.[4] ## Diagnosis[edit] A way to demonstrate aniseikonia is to hold a near target (ex. pen or finger) approximately 6 inches directly in front of one eye. The person then closes one eye, and then the other. The person should notice that the target appears larger to the eye that it is directly in front of. When this object is viewed with both eyes, it is seen with a small amount of aniseikonia. The principles behind this demonstration are relative distance magnification (closer objects appear larger) and asymmetrical convergence (the target is not an equal distance from each eye).[citation needed] ## Treatment[edit] Optical aniseikonia due to anisometropia can be corrected by spectacles, contact lenses or refractive corneal surgeries.[5] Spectacle correction is done by changing the optical magnification properties of the auxiliary optics (corrective lenses). The optical magnification properties of spectacle lenses can be adjusted by changing parameters like the base curve, vertex distance, and center thickness. Magnification size matched lenses that are used to correct aniseikonia are known as iseikonic lenses.[3] Contact lenses may also provide less difference in retinal image size.[4] Wider and better field of vision is another benefit of contact lens use. The difference in magnification can also be eliminated by a combination of contact lenses and glasses (creating a weak telescope system). The optimum design solution will depend on different parameters like cost, cosmetic implications, and if the patient can tolerate wearing a contact lens.[citation needed] For reducing aniseikonia, similar to contact lens correction, optical image size difference will be reduced in refractive surgeries also.[5][6] Aniseikonia due to uniocular aphakia is best corrected surgically by intraocular lens implantation.[4] Similarly retinal aniseikonia is corrected by treating causative retinal disease.[4] Note however that before the optics can be designed, first the aniseikonia should be measured. When the image disparity is astigmatic (cylindrical) and not uniform, images can appear wider, taller, or diagonally different. When the disparity appears to vary across the visual field (field-dependent aniseikonia), as may be the case with an epiretinal membrane or retinal detachment, the aniseikonia cannot fully be corrected with traditional optical techniques like standard corrective lenses. However, partial correction often improves the patient's vision comfort significantly. ## Etymology[edit] Gr. "an" = "not", + "is(o)" = "equal," + "eikōn" = "image"[citation needed] ## See also[edit] * Adelbert Ames, Jr. (Dartmouth Eye Institute, research in the 1930s and 1940s on aniseikonia) * macropsia, micropsia ## References[edit] 1. ^ Berens, Conrad; Loutfallah, Michael (1938), "Aniseikonia: A Study of 836 Patients Examined with the Ophthalmo-Eikonometer", Trans Am Ophthalmol Soc., 36, pp. 234–67, PMC 1315746, PMID 16693153 2. ^ "Fusion and binocularity". Borish's clinical refraction (2nd ed.). Butterworth Heinemann/Elsevier. ISBN 978-0-7506-7524-6. 3. ^ a b c "Aniseikonia - EyeWiki". eyewiki.aao.org. 4. ^ a b c d e Khurana, AK. "Errors of refraction and binocular optical defects". Theory and practice of optics and refraction (2nd ed.). Elsevier. ISBN 978-81-312-1132-8. 5. ^ a b "Patients with anisometropia and aniseikonia". Borish's clinical refraction (2nd ed.). Butterworth Heinemann/Elsevier. ISBN 978-0-7506-7524-6. 6. ^ Mravicic, Ivana; Bohac, Maja; Lukacevic, Selma; Jagaric, Kruno; Maja, Merlak; Patel, Sudi. "The relationship between clinical measures of aniseikonia and stereoacuity before and after LASIK". Journal of Optometry. 13 (1): 59–68. doi:10.1016/j.optom.2019.06.004. ISSN 1888-4296. ## Further reading[edit] * Bannon, Robert E.; Neumueller, Julius; Boeder, Paul; Burian, Hermann M. (June 1970), "Aniseikonia and space perception: After 50 years", American Journal of Optometry & Archives of American Academy of Optometry, 47 (6): 423–441, doi:10.1097/00006324-197006000-00001 * Bisno, David C. (1994), Eyes in the Storm—President Hopkins' Dilemma: The Dartmouth Eye Institute, Norwich, Vermont: Norwich Book Press, p. 288 ## External links[edit] Classification D * ICD-10: H52.3 * ICD-9-CM: 367.32 * MeSH: D000839 * DiseasesDB: 29646 * 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 [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	Aniseikonia	c0003078	3,598	wikipedia	https://en.wikipedia.org/wiki/Aniseikonia	2021-01-18T18:53:23	{"mesh": ["D000839"], "icd-9": ["367.32"], "icd-10": ["H52.3"], "wikidata": ["Q548913"]}
A number sign (#) is used with this entry because of evidence that generalized arterial calcification of infancy-2 (GACI2) can be caused by homozygous or compound heterozygous mutation in the ABCC6 gene (603234) on chromosome 16p13.11. Description Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (summary by Rutsch et al., 2003 and Cheng et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of GACI, see GACI1 (208000). Pseudoxanthoma elasticum (PXE; 264800) is an allelic disorder caused by mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (Nitschke et al., 2012). Clinical Features Glatz et al. (2006) described 2 patients with idiopathic infantile arterial calcification (IIAC). The first was an infant girl who presented at 33 days of life with tachypnea, tachycardia, cool extremities, and poor peripheral pulses. Echocardiography demonstrated cardiac dysfunction and an electrocardiogram and cardiac enzyme levels were suggestive of myocardial infarction (MI). Despite intensive care, her condition deteriorated over the next 2 weeks and the patient died after withdrawal of support at 6.5 weeks of age. Autopsy revealed a markedly enlarged heart, with multiple areas of focal hemorrhage, necrosis, and calcification consistent with MI. Microscopic examination of the vasculature revealed calcification of all major coronary arteries, as well as involvement of the aorta, main and branch pulmonary arteries, celiac, hepatic, suprarenal, pancreaticoduodenal, splenic, mesenteric, renal, and lumbar arteries. Involved arteries showed calcification primarily of the internal elastic lamina, with varying degrees of calcification of the external elastic lamina in areas of heavy calcification, which was circumferential in many sections. Inflammation was not a prominent feature. Intraparenchymal arterial calcifications were found in the spleen, pancreas, diaphragm, thymus, thyroid, trachea, larynx, and salivary glands. Extensive intratubular calcifications were found in the kidneys. Gross examination of the brain showed mild convolutional abnormalities, and microscopy showed rare focal parenchymal calcifications and a single vessel in the corpus striatum with early calcific changes. The second patient with IIAC was an infant girl who presented at age 2 months in cardiogenic shock, and after initial recovery was readmitted in the third month of life with severe heart failure, at which time cardiac MRI showed a large anterolateral and apical aneurysm of the left ventricle, with thinning of the myocardium and moderate to severe mitral regurgitation. The patient had progressively intractable heart failure and died at 4.5 months of age. Autopsy revealed a severely enlarged heart, with severe ischemic changes in the myocardium of the left ventricle and calcification within the subendocardial area. Upon microscopic examination of the arterial system, elastic arteries showed calcification primarily of the outer elastic layers, whereas muscular arteries had preferential calcification of the media with intimal proliferation, accompanied by a foreign body giant cell reaction. These findings were present in the coronary, pulmonary, and renal arteries, as well as the aorta and its branches in the neck. The coronary arteries showed luminal obstruction with near-occlusive changes in segments. Examined veins were normal. ### Intrafamilial Phenotypic Variability Le Boulanger et al. (2010) studied a nonconsanguineous French family in which a younger brother died of a condition 'strikingly reminiscent' of generalized arterial calcification of infancy (GACI) at 15 months of age, whereas his older brother developed uncomplicated pseudoxanthoma elasticum (PXE; 264800) in adolescence. The younger brother had a myocardial infarction complicated by heart failure at 6 months of age; skin biopsy at 1 year of age for evaluation of a possible connective tissue disorder showed elastic fiber dystrophy, with clumped and fragmented fibers in the mid dermis, as well as calcifications on the elastic fibers and sporadically in vessel walls of the subcutis. There were no periarticular calcifications on x-ray, and serum phosphate and calcium levels were normal. At 15 months of age, he had a second, fatal MI. Autopsy showed fibrosis of the coronary arteries with calcifications involving the intima, internal elastic lamina, and media, and medium-sized arteries in the adrenal glands, pancreas, thyroid, and testes also showed extensive arterial calcification. At 28 years of age, the older brother presented for evaluation of yellowish papules on his neck; he had no cardiovascular symptoms and cardiac examination and echocardiography were normal. Skin samples from the brother with PXE showed heavy staining of mineralized mid-dermal elastic fibers, with active MGP (154870) and fetuin-A (AHSG; 138680) antibodies, and fetuin-A also showed striking staining of the subepidermal area. All arteries in autopsy samples from the brother with GACI showed the same immunohistochemical profile, as well as calcifications. Molecular Genetics In an infant girl with generalized arterial calcification who died at 6.5 weeks of age, Glatz et al. (2006) analyzed the gene associated with GACI1 (208000), ENPP1 (173335), but no pathogenic mutations were found. Nitschke et al. (2012) restudied this patient and identified compound heterozygosity for splice site mutations in the ABCC6 gene (603234.0015 and 603234.0029). In a 28-year-old French man with pseudoxanthoma elasticum (PXE; 264800), who had a younger brother who died of GACI at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the known causative gene for PXE, ABCC6 (603234.0025 and 603234.0026), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in ENPP1. Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE. Nitschke et al. (2012) analyzed the ABCC6 gene in 28 GACI patients from 25 unrelated families who were negative for mutation in the ENNP1 gene, as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had been detected. They identified homozygosity or compound heterozygosity for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g., 603234.0001 and 603234.0006, and 603234.0027-603234.0029), including 1 of the infant girls originally described by Glatz et al. (2006) (see 603234.0029). In 6 patients from 5 unrelated families, only 1 mutation was detected in ABCC6; the authors noted that there was no phenotypic difference between these patients and those with biallelic mutations in ABCC6, and stated that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their approach. No mutation in the ABCC6 gene was found in 16 patients from 14 unrelated families, including the 2 patients who were known to carry monoallelic mutations in ENNP1. Overall, 13 different ABCC6 mutations were identified in GACI patients, all but 2 of which had previously been identified in typical PXE patients who had a much milder phenotype than the GACI patients. Based on the considerable overlap of phenotype and genotype of GACI and pseudoxanthoma elasticum, Nitschke et al. (2012) suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than 2 distinct disorders. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Coronary artery calcification \- Cardiac dysfunction \- Myocardial infarction (in some patients) \- Heart failure Vascular \- Generalized calcification of arteries, including aorta and intraparenchymal arteries \- Hypertension (in some patients) GENITOURINARY Kidneys \- Calcification of renal arteries \- Nephrocalcinosis (in some patients) \- Tubular calcification (in some patients) SKELETAL Limbs \- Hypophosphatemic rickets (in some patients) METABOLIC FEATURES \- Hypophosphatemic rickets (in some patients) MISCELLANEOUS \- Most patients die in infancy Features of pseudoxanthoma elasticum, an allelic disorder, have not yet been reported in GACI2 patients (the 4 surviving patients reported as of January 2012 are all age 5 years or less) MOLECULAR BASIS \- Caused by mutation in the ATP-binding cassette, subfamily C, member 6 gene (ABCC6, 603234.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis *[DDD]: degenerative disc disease	ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 2	c0264955	3,599	omim	https://www.omim.org/entry/614473	2019-09-22T15:55:08	{"doid": ["0050644"], "omim": ["614473"], "orphanet": ["51608"], "genereviews": ["NBK253403"]}

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