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Smoker's face describes the characteristic changes that happen to the faces of many people who smoke.[1][2] The general appearance is of accelerated ageing of the face, with a characteristic pattern of facial wrinkling and sallow coloration. A summary of a study published by the National Institutes of Health found that certain facial features appeared in about 46% of continuing smokers and 8% of former smokers who had smoked a full decade while those same features were absent in a control group of non-smokers.[3] ## References[edit] 1. ^ Smoker's Face: Beauty is only skin deep Archived 2012-05-03 at the Wayback Machine, UK Department of Health 2. ^ Personal Health: Smoker's Face, The New York Times, June 19, 1996 3. ^ Model D (1985). "Smoker's face: an underrated clinical sign?". Br Med J (Clin Res Ed). 291 (6511): 1760–1762. doi:10.1136/bmj.291.6511.1760. PMC 1419177. PMID 3936573. * v * t * e Smoking Country and region Africa * Egypt * Nigeria * South Africa Asia * Afghanistan * East Timor * Hong Kong * India * Indonesia * Iran * Iraq * Japan * Korea * North * South * Macau * Mainland China * Malaysia * New Zealand * Tokelau * Pakistan * Philippines * Saudi Arabia * Singapore * Syria * Taiwan * Turkey * Vietnam Europe * Albania * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Latvia * Norway * Sweden * United Kingdom South America * Argentina * Brazil * Colombia * Ecuador * Uruguay North America * Canada * United States Religion * Smoking in Jewish law * Tobacco fatwa * Ceremonial pipe * Chanunpa * Kinnikinnick * Pipe bag Health * Health effects of tobacco (Nicotine poisoning * Nicotine withdrawal) * Passive smoking * Third-hand smoke * Prevalence of tobacco use * Schizophrenia and smoking * Sidestream smoke * Smokeless tobacco keratosis * Smoker's face * Smoker's melanosis * Stomatitis nicotina * Smoking age * Smoking and male infertility * Smoking cessation * Tobacco-Free Pharmacies * Tobacco packaging warning messages * WHO Framework Convention on Tobacco Control * Protocol to Eliminate Illicit Trade in Tobacco Products * World No Tobacco Day * Youth smoking Women and smoking * Breastfeeding difficulties * Breast cancer * Cervical cancer * Menopause * Ptosis of the breast * Smoking and female infertility * Smoking and pregnancy Smoking ban * Inflight smoking * List of smoking bans * Smoking bans in private vehicles * Tobacco-Free College Campuses Country and region * Australia * England * France * United States Other * Chain smoking * Cigarette consumption per capita * History of smoking * Smokeasy * Smoking fetishism * Smoking pipe * tobacco pipe * Tobacco advertising * Tobacco bowdlerization * Tobacco industry * Tobacco smoking * Category 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 [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Smoker's face	None	5,000	wikipedia	https://en.wikipedia.org/wiki/Smoker%27s_face	2021-01-18T18:37:52	{"wikidata": ["Q7545938"]}
A number sign (#) is used with this entry because of evidence that Thauvin-Robinet-Faivre syndrome (TROFAS) is caused by homozygous mutation in the FIBP gene (608296) on chromosome 11q13. Description Thauvin-Robinet-Faivre syndrome is an autosomal recessive disorder characterized by generalized overgrowth, mainly of height, and mildly delayed psychomotor development with mild or severe learning difficulties. More variable features may include congenital heart defects, kidney abnormalities, and skeletal defects. Patients may have an increased risk for Wilms tumor (summary by Akawi et al., 2016). Clinical Features Thauvin-Robinet et al. (2016) reported a 23-year-old man, born of consanguineous North African parents, with an overgrowth syndrome and severe learning disabilities. He was born at term with macrosomia and macrocephaly, and the overgrowth persisted throughout childhood. He had developmental delay with language disabilities. Additional features included retinal coloboma, ventricular septal defect, mitral valve prolapse, renal malrotation with left bifid ureter, and transient neutropenia. At age 21, he had surgery for inguinal hernia and severe varicose veins. Dysmorphic facial features included long and downslanting palpebral fissures, large prominent ears, thick lips, and macroglossia. He had large hands and feet with large thumbs and halluces. Brain imaging and cardiac function were normal. Akawi et al. (2016) reported 3 sibs, born of consanguineous Arab parents, with an overgrowth syndrome associated with mildly delayed developmental milestones and intellectual disability. The sibs were 14, 10, and 3 years of age. Common features included tall stature and mild dysmorphic facial features, such as round face with widely spaced and deep-set eyes, epicanthal folds, flat midface, and full lips. Additional abnormalities were variable. The oldest sib had ventricular septal defect, double chamber right ventricle, sensorineural hearing loss, and astigmatism. She developed a Wilms tumor at age 4 years. The middle child had several skeletal abnormalities, including talipes equinovarus, internal rotation of the femurs and tibias, bowing of the legs, and spina bifida occulta. The youngest child had nephromegaly with cystic dysplastic kidneys and a nonfunctioning right kidney. The 2 older sibs had chronic benign neutropenia with normal bone marrow examination. There was a family history of 3 miscarriages and 3 stillbirths. Inheritance The transmission pattern of TROFAS in the family reported by Akawi et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In a 23-year-old man, born of consanguineous North African parents, with TROFAS, Thauvin-Robinet et al. (2016) identified a homozygous nonsense mutation in the FIBP gene (Q218X; 608296.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed excessive proliferation compared to controls. In 3 sibs, born of consanguineous Arab parents, with TROFAS, Akawi et al. (2016) identified a homozygous mutation in the FIBP gene (608296.0002). Patient fibroblasts showed increased cellular proliferation compared to controls. INHERITANCE \- Autosomal recessive GROWTH Height \- Tall stature Other \- Overgrowth \- Macrosomia HEAD & NECK Head \- Macrocephaly (in some patients) Face \- Round face \- Flat midface Ears \- Sensorineural hearing loss (1 patient) \- Large ears (patient A) Eyes \- Hypertelorism \- Epicanthal folds \- Deep-set eyes \- Strabismus \- Coloboma (patient A) \- Downslanting palpebral fissures (patient A) Mouth \- Thick lips \- Macroglossia (patient A) CARDIOVASCULAR Heart \- Ventricular septal defect (in some patients) \- Mitral valve prolapse (patient A) Vascular \- Varicose veins, severe (patient A) GENITOURINARY Kidneys \- Renal abnormalities (in some patients) \- Renal malrotation \- Cystic kidneys (1 patient) \- Dysplastic kidneys (1 patient) Ureters \- Bifid ureter (patient A) SKELETAL Limbs \- Bowing of the legs (1 patient) \- Internal rotation of the leg bones (1 patient) Hands \- Large hands (patient A) \- Large thumbs (patient A) Feet \- Large feet (patient A) \- Large halluces (patient A) \- Flat feet (1 patient) NEUROLOGIC Central Nervous System \- Delayed psychomotor development, mild \- Intellectual disability, mild \- Learning disabilities \- Language disabilities IMMUNOLOGY \- Neutropenia, benign (in some patients) NEOPLASIA \- Wilms tumor (1 patient) LABORATORY ABNORMALITIES \- Fibroblasts showed increased proliferation compared to controls MISCELLANEOUS \- Three sibs from a consanguineous family and 1 unrelated patient (patient A) have been reported (last curated September 2016) \- Variable features MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor, acidic, intracellular binding protein gene (FIBP, 608296.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	THAUVIN-ROBINET-FAIVRE SYNDROME	c4310715	5,001	omim	https://www.omim.org/entry/617107	2019-09-22T15:46:53	{"omim": ["617107"], "orphanet": ["500095"], "synonyms": ["Thauvin-Robinet-Faivre syndrome"]}
Ring chromosome 21 is a rare chromosome abnormality in which the ends of chromosome 21 join together to form a ring shape. Many people with ring chromosome 21 have normal development and are healthy, having been diagnosed after having chromosome testing due to infertility, multiple miscarriages, or a child with a chromosome abnormality. However, others with ring chromosome 21 have developmental and/or medical problems which can range from mild to severe. This is due to having extra or missing genetic material on the ring chromosome, which can happen when the ring chromosome forms. Signs and symptoms of ring chromosome 21 that may be present can include short stature, delayed puberty in males, small head size, seizures, learning disabilities, underdeveloped sex organs, susceptibility to infections, and/or a variety of birth defects. Some people have signs and symptoms similar to those that occur in people with Down syndrome. Ring chromosome 21 may be inherited from a parent (typically the mother), or it may occur sporadically (by chance) during the formation of egg or sperm cells or shortly after the egg and sperm join together. A chromosome test of the parents can help determine whether it was inherited and whether future children have an increased chance to have a chromosome abnormality. Treatment for ring chromosome 21 depends on the signs and symptoms present in each person. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Ring chromosome 21	c2931422	5,002	gard	https://rarediseases.info.nih.gov/diseases/6083/ring-chromosome-21	2021-01-18T17:57:53	{"mesh": ["C537109"], "umls": ["C2931422"], "orphanet": ["1445"], "synonyms": ["Chromosome 21 ring", "Ring 21", "R21"]}
Tooth disease Regional odontodysplasia Other namesOdontogenesis imperfecta SpecialtyOral and maxillofacial surgery Regional odontodysplasia is an uncommon developmental abnormality of teeth, usually localized to a certain area of the mouth. The condition is nonhereditary. There is no predilection for race, but females are more likely to get regional odontodysplasia. The enamel, dentin, and pulp of teeth are affected, to the extent that the affected teeth do not develop properly. These teeth are very brittle. On radiographs the teeth appear more radiolucent than normal, so they are often described as "ghost teeth".[1] Most cases are considered idiopathic, but some cases are associated with syndromes, growth abnormalities, neural disorders, and vascular malformations. Permanent teeth usually show effects of regional odontodysplasia if the deciduous tooth was affected. Many of these teeth do not erupt, and those that do have an increased risk of caries and periapical inflammation. ## Treatment and prognosis[edit] Treatment and prognosis are usually based upon keeping these teeth and preserving the alveolus. For erupted teeth, endodontics is an option if the tooth is devitalized and restorable. For unerupted teeth, function can be restored with a removable partial denture until all major growth has been completed and a final restoration can be placed.[2] ## References[edit] 1. ^ Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001. 2. ^ Neville, Brad et al. Oral and Maxillofacial Pathology, Third Edition, 2009. ## External links[edit] Classification D * ICD-10: K00.4 * ICD-9-CM: 520.4 * MeSH: D018126 * v * t * e Developmental tooth disease/tooth abnormality Quantity * Anodontia/Hypodontia * Hyperdontia Shape and size * Concrescence * Fusion * Gemination * Dens evaginatus/Talon cusp * Dens invaginatus * Enamel pearl * Macrodontia * Microdontia * Taurodontism * Supernumerary roots Formation * Dilaceration * Regional odontodysplasia * Turner's hypoplasia * Enamel hypoplasia * Ectopic enamel Other hereditary * Amelogenesis imperfecta * Dentinogenesis imperfecta * Dentin dysplasia * Regional odontodysplasia Other * Dental fluorosis * Tooth impaction This dentistry article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Regional odontodysplasia	c0206554	5,003	wikipedia	https://en.wikipedia.org/wiki/Regional_odontodysplasia	2021-01-18T18:54:31	{"mesh": ["D018126"], "icd-9": ["520.4"], "icd-10": ["K00.4"], "orphanet": ["83450"], "synonyms": ["Ghost teeth"], "wikidata": ["Q3349339"]}
Meyer dysplasia of the femoral head is a mild localized form of skeletal dysplasia characterized by delayed, irregular ossification of femoral capital epiphysis. ## Epidemiology Prevalence is unknown. ## Clinical description The condition is often discovered incidentally during early childhood (during the second or third year of life). It is often bilateral, although severity may be asymmetric. Clinical manifestations may include a waddling gait, genu valgum, hip pain and restricted movement, although these manifestations are usually transient and the majority of patients are asymptomatic. Resolution without treatment by six years of age has been reported in some cases, however, permanent deformity (flattening) of the femoral head has also been described and could represent a mild form of multiple epiphyseal dysplasia (see this term). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Dysplasia of head of femur, Meyer type	None	5,004	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=168621	2021-01-23T17:41:07	{"icd-10": ["Q78.8"], "synonyms": ["Dysplasia epiphysealis capitis femoris", "Meyer dysplasia"]}
Many types of sense loss occur due to a dysfunctional sensation process, whether it be ineffective receptors, nerve damage, or cerebral impairment. Unlike agnosia, these impairments are due to damages prior to the perception process. ## Contents * 1 Vision loss * 2 Hearing loss * 3 Anosmia * 4 Somatosensory loss * 5 Ageusia * 6 See also * 7 References * 8 External links ## Vision loss[edit] Main article: Vision loss Degrees of vision loss vary dramatically, although the ICD-9 released in 1979 categorized them into three tiers: normal vision, low vision, and blindness. Two significant causes of vision loss due to sensory failures include media opacity and optic nerve diseases, although hypoxia and retinal disease can also lead to blindness. Most causes of vision loss can cause varying degrees of damage, from total blindness to a negligible effect. Media opacity occurs in the presence of opacities in the eye tissues or fluid, distorting and/or blocking the image prior to contact with the photoreceptor cells. Vision loss often results despite correctly functioning retinal receptors. Optic nerve diseases such as optic neuritis or retrobulbar neuritis lead to dysfunction in the afferent nerve pathway once the signal has been correctly transmitted from retinal photoreceptors. Partial or total vision loss may affect every single area of a person's life. Though loss of eyesight may occur naturally as we age, trauma to the eye or exposure to hazardous conditions may also cause this serious condition. Workers in virtually any field may be at risk of sustaining eye injuries through trauma or exposure. A traumatic eye injury occurs when the eye itself sustains some form of trauma, whether a penetrating injury such as a laceration or a non-penetrating injury such as an impact. Because the eye is a delicate and complex organ, even a slight injury may have a temporary or permanent effect on eyesight. ## Hearing loss[edit] Main article: Hearing loss Similarly to vision loss, hearing loss can vary from full or partial inability to detect some or all frequencies of sound which can typically be heard by members of their species. For humans, this range is approximately 20 Hz to 20 kHz at ~6.5 dB, although a 10 dB correction is often allowed for the elderly.[1] Primary causes of hearing loss due to an impaired sensory system include long-term exposure to environmental noise, which can damage the mechanoreceptors responsible for receiving sound vibrations, as well as multiple diseases, such as CMV or meningitis, which damage the cochlea and auditory nerve, respectively.[2] Hearing loss may be gradual or sudden. Hearing loss may be very mild, resulting in minor difficulties with conversation, or as severe as complete deafness. The speed with which hearing loss occurs may give clues as to the cause. If hearing loss is sudden, it may be from trauma or a problem with blood circulation. A gradual onset is suggestive of other causes such as aging or a tumor. If you also have other associated neurological problems, such as tinnitus or vertigo, it may indicate a problem with the nerves in the ear or brain. Hearing loss may be unilateral or bilateral. Unilateral hearing loss is most often associated with conductive causes, trauma, and acoustic neuromas. Pain in the ear is associated with ear infections, trauma, and obstruction in the canal. ## Anosmia[edit] Main article: Anosmia Anosmia is the inability to perceive odor, or in other words a lack of functioning olfaction. Many patients may experience unilateral or bilateral anosmia. A temporary loss of smell can be caused by a blocked nose or infection. In contrast, a permanent loss of smell may be caused by death of olfactory receptor neurons in the nose or by brain injury in which there is damage to the olfactory nerve or damage to brain areas that process smell. The lack of the sense of smell at birth, usually due to genetic factors, is referred to as congenital anosmia. The diagnosis of anosmia as well as the degree of impairment can now be tested much more efficiently and effectively than ever before thanks to "smell testing kits" that have been made available as well as screening tests which use materials that most clinics would readily have.[3] Many cases of congenital anosmia remain unreported and undiagnosed. Since the disorder is present from birth the individual may have little or no understanding of the sense of smell, hence are unaware of the deficit.[4] ## Somatosensory loss[edit] The somatosensory system is a complex sensory system made up of a number of different receptors, including thermoreceptors, nociceptors, mechanoreceptors and chemoreceptors. It also comprises essential processing centres, or sensory modalities, such as proprioception, touch, temperature, and nociception. The sensory receptors cover the skin and epithelia, skeletal muscles, bones and joints, internal organs, and the cardiovascular system. While touch (also called tactile or tactual perception) is considered one of the five traditional senses, the impression of touch is formed from several modalities. In medicine, the colloquial term "touch" is usually replaced with "somatic senses" to better reflect the variety of mechanisms involved. Insensitivity to somatosensory stimuli, such as heat, cold, touch, and pain, are most commonly a result of a more general physical impairment associated with paralysis. Damage to the spinal cord or other major nerve fiber may lead to a termination of both afferent and efferent signals to varying areas of the body, causing both a loss of touch and a loss of motor coordination. Other types of somatosensory loss include hereditary sensory and autonomic neuropathy, which consists of ineffective afferent neurons with fully functioning efferent neurons; essentially, motor movement without somatosensation.[5] Sensory loss can occur due to a minor nick or lesion on the spinal cord which creates a problem within the neurosystem. This can lead to loss of smell, taste, touch, sight, and hearing. In most cases it often leads to issues with touch. Sometimes people cannot feel touch at all while other times a light finger tap feels like someone has punched them. There are medications and therapies[example needed] that can help control the symptoms of sensory loss and deprivation. ## Ageusia[edit] Main article: Ageusia Ageusia is the loss of taste, particularly the inability to detect sweetness, sourness, bitterness, saltiness, and umami (meaning "pleasant/savory taste"). It is sometimes confused with anosmia (a loss of the sense of smell). Because the tongue can only indicate texture and differentiate between sweet, sour, bitter, salty, and umami, most of what is perceived as the sense of taste is actually derived from smell. True ageusia is relatively rare compared to hypogeusia (a partial loss of taste) and dysgeusia (a distortion or alteration of taste). Tissue damage to the nerves that support the tongue can cause ageusia, especially damage to the lingual nerve and the glossopharyngeal nerve. The lingual nerve passes taste for the front two-thirds of the tongue and the glossopharyngeal nerve passes taste for the back third of the tongue. The lingual nerve can also be damaged during otologic surgery, causing a feeling of metal taste. Taste loss can vary from true ageusia, a complete loss of taste, to hypogeusia, a partial loss of taste, to dysgeusia, a distortion or alteration of taste. The primary cause of ageusia involves damage to the lingual nerve, which receives the stimuli from taste buds for the front two-thirds of the tongue, or the glossopharyngeal nerve, which acts similarly for the back third. Damage may be due to neurological disorders, such as Bell’s palsy or multiple sclerosis, as well as infectious diseases such as meningoencephalopathy. Other causes include a vitamin B deficiency, as well as taste bud death due to acidic/spicy foods, radiation, and/or tobacco use.[6] ## See also[edit] * Perception * Ideasthesia ## References[edit] 1. ^ Hawkins, S. (2010). "Phonological features, auditory objects, and illusions". Journal of Phonetics. 38 (1): 60–89. doi:10.1016/j.wocn.2009.02.001. 2. ^ Bizley, J. K.; Walker, K. M. M. (2010). "Sensitivity and Selectivity of Neurons in Auditory Cortex to the Pitch, Timbre, and Location of Sounds". Neuroscientist. 16 (4): 453–469. doi:10.1177/1073858410371009. PMID 20530254. S2CID 5931412. 3. ^ Craig JC (1999). "Grating orientation as a measure of tactile spatial acuity". Somatosensory & Motor Research. 16 (3): 197–206. doi:10.1080/08990229970456. PMID 10527368. 4. ^ Stevens, Joseph C.; Alvarez-Reeves, Marty; Dipietro, Loretta; Mack, Gary W.; Green, Barry G. (September 2003). "Decline of tactile acuity in aging: a study of body site, blood flow, and lifetime habits of smoking and physical activity". Somatosensory & Motor Research. 20 (3–4): 271–279. doi:10.1080/08990220310001622997. PMID 14675966. S2CID 19729552. 5. ^ Li, X. (1976). "Acute Central Cord Syndrome Injury Mechanisms and Stress Features". Spine. 35 (19): E955–E964. doi:10.1097/brs.0b013e3181c94cb8. PMID 20543769. S2CID 36635584. 6. ^ Macaluso, E. (2010). "Orienting of spatial attention and the interplay between the senses. [Review]". Cortex. 46 (3): 282–297. doi:10.1016/j.cortex.2009.05.010. PMID 19540475. S2CID 2762445. ## External links[edit] Look up sensation in Wiktionary, the free dictionary. * v * t * e Psychophysiology * Appetite * Arousal * Biofeedback * Blushing * Consciousness * Cerebral dominance * Habituation * Lie detection * Orientation * Reaction time * Reflex * Satiation * Self stimulation * Sensation * Sleep * Psychological stress [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Sensory loss	c0278134	5,005	wikipedia	https://en.wikipedia.org/wiki/Sensory_loss	2021-01-18T18:46:19	{"wikidata": ["Q2289481"]}
Mucopolysaccharidosis type 1 (MPS 1) is a rare lysosomal storage disease belonging to the group of mucopolysaccharidoses. There are three variants, differing widely in their severity, with Hurler syndrome being the most severe, Scheie syndrome the mildest and Hurler-Scheie syndrome giving an intermediate phenotype. ## Epidemiology Prevalence is estimated at 1/100,000, with Hurler syndrome accounting for 57% of cases, Hurler-Scheie syndrome accounting for 23% of cases and Scheie syndrome accounting for 20% of cases. ## Clinical description In the severe form (Hurler syndrome or MPS I-H; see this term) skeletal deformities and a delay in motor and intellectual development are the leading symptoms. Onset occurs 6-8 months after birth. Other manifestations include corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism and hirsutism. Radiological examination of the skeleton reveals the characteristic pattern of dysostosis multiplex. Hydrocephaly can occur after the age of two. Patients with the adult-onset form (Scheie syndrome or MPS I-S; see this term) are of almost normal height and do not show intellectual deficiency. Typical symptoms are stiff joints, corneal opacities, carpal tunnel syndrome and mild skeletal changes. Aortic valve disease can be present. Compression of the cervical spinal cord, caused by glycosaminoglycan infiltration of the dura, may lead to spastic paresis if not corrected by neurosurgical intervention. Patients with the intermediate form (Hurler-Scheie syndrome or MPS I-H/S; see this term) have normal or almost normal intelligence, but exhibit various degrees of physical impairment. ## Etiology The different phenotypes are caused by allelic mutations in the alpha-L-iduronidase (IDUA) gene (localized to 4p16.3). The mutations result in complete deficiency of the enzyme in Hurler syndrome or partial function in Scheie syndrome, leading to lysosomal accumulation of dermatan sulfate (DS) and heparan sulfate (HS). ## Diagnostic methods Early diagnosis is difficult as the first clinical signs are not specific (hernias, respiratory infections, etc.) but it is very important to allow early treatment. Biological diagnosis relies on detection of increased urinary excretion of DS and HS and the demonstration of the enzymatic deficiency (in plasma, leucocytes, fibroblasts, trophoblastic cells or amniocytes). ## Differential diagnosis Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; see this term) resembles mucopolysaccharidosis type I in many aspects, MPS VI patients, however, never have intellectual impairment. Mucopolysaccharidosis type II (see this term), an X-linked recessive disorder in which severe joint contractures are a characteristic symptom, also has many features in common with mucopolysaccharidosis type I. ## Antenatal diagnosis Antenatal diagnosis can be performed by enzyme assay or molecular genetics in families where the mutation has been identified. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling is recommended. ## Management and treatment The genotype should be established at diagnosis in all patients as this may aid in determining the therapeutic approach. Symptomatic treatment should be proposed by a multidisciplinary team. Hematopoietic stem cell transplantation has been shown to be useful in some patients. Treatment with the enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. All patients including those who have not received a transplant or whose graft has failed may benefit significantly from enzyme replacement therapy (ERT). Given as weekly infusions, it leads to improvement of lung function and joint mobility. ## Prognosis Early treatment slows progression of the disease. However, it is not effective against neurological lesions. Life expectancy is normal or only slightly affected in Scheie syndrome, but is reduced in Hurler syndrome, with death occurring before adolescence due to serious cardiovascular and respiratory complications. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Mucopolysaccharidosis type 1	c0023786	5,006	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=579	2021-01-23T17:51:29	{"gard": ["10335"], "mesh": ["D008059"], "omim": ["607014", "607015", "607016"], "umls": ["C0023786", "C2713321"], "icd-10": ["E76.0"], "synonyms": ["Alpha-L-iduronidase deficiency", "MPS1", "MPSI", "Mucopolysaccharidosis type I"]}
A number sign (#) is used with this entry because of evidence that pontocerebellar hypoplasia type 2B (PCH2B) is caused by homozygous or compound heterozygous mutation in the TSEN2 gene (608753) on chromosome 3p25. Additional forms of type 2 PCH, PCH2A (277470) and PCH2C (612390), are caused by mutations in the TSEN54 (608755) and TSEN34 (608754) genes, respectively. Description Pontocerebellar hypoplasia (PCH) represents a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. PCH type 2 is characterized by progressive microcephaly from birth combined with extrapyramidal dyskinesia and chorea, epilepsy, and normal spinal cord findings (Barth, 1993). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596). Clinical Features Namavar et al. (2011) reported 2 sibs with PCH2B. The patients presented in early infancy with jitteriness, clonus, and impaired swallowing. One patient had dystonia, dyskinesia, central visual impairment, and seizures. Both had progressive microcephaly, and brain imaging of 1 patient showed pontocerebellar hypoplasia and dilated ventricles. Both sibs were alive at ages 1 month and 4 years, but had no hand control and no postural antigravity control. Additional clinical details were not provided. Bierhals et al. (2013) reported a 4-year-old German boy with PCH2B. At birth, he showed microcephaly (-3.54 SD) and a receding forehead with overlapping cranial sutures. He had poor sucking and intermittent opisthotonus. At age 3.5 months, his microcephaly had progressed (-6.8 SD), and brain imaging showed simplified gyration with a thin corpus callosum, cerebral atrophy, enlarged ventricles, and hypoplasia of the brainstem, cerebellum, and cerebellar vermis, creating a 'dragonfly-like' pattern. At age 8 months, he developed an epileptic encephalopathy with refractory myoclonic and tonic seizures. He was unable to fix or follow visually and had axial hypotonia, limb hypertonia, and extensor plantar responses. At age 3 years, his head circumference was -11.4 SD and he showed severe spasticity with hyperkinetic involuntary movements. He died at age 4 years, 6 months. Inheritance The transmission pattern of PCH2B in the families reported by Namavar et al. (2011) and Bierhals et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In a Pakistani individual with PCH2 in whom no mutation in TSEN54 was found, Budde et al. (2008) found homozygosity for a missense mutation in the TSEN2 gene (608753.0001). This mutation was not found in 188 Pakistani, 92 Dutch, 54 Chinese, or 28 Palestinian controls. In 2 sibs with PCH2B, Namavar et al. (2011) identified compound heterozygous mutations in the TSEN2 gene (608753.0001 and 608753.0002). Functional studies of the variants were not performed. In a German male infant with PCH2B, Bierhals et al. (2013) identified compound heterozygous mutations in the TSEN2 gene (608753.0003 and 608753.0004). INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly, progressive (up to -11 SD) Face \- Sloping forehead Eyes \- Central visual impairment \- Lack of visual fixation ABDOMEN Gastrointestinal \- Feeding difficulties MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- No psychomotor development \- Dyskinesias \- Dystonia \- Clonus \- Spasticity \- Opisthotonus \- Hyperkinetic involuntary movements \- Chorea \- Axial hypotonia \- Limb hypertonia \- Extensor plantar responses \- Seizures (in some patients) \- Cerebellar atrophy, particularly of the hemispheres \- Brainstem hypoplasia \- Pontine atrophy \- 'Dragonfly' pattern on imaging \- Thin corpus callosum \- Cerebral atrophy (in some patients) \- Ventricular dilatation (in some patients) \- Simplified gyral pattern (in some patients) MISCELLANEOUS \- Onset at birth \- Most patients die in early childhood \- Four patients from 3 families have been reported (last curated February 2015) MOLECULAR BASIS \- Caused by mutation in the tRNA splicing endonuclease, subunit 2 gene (TSEN2, 608753.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	PONTOCEREBELLAR HYPOPLASIA, TYPE 2B	c2932714	5,007	omim	https://www.omim.org/entry/612389	2019-09-22T16:01:34	{"doid": ["0060268"], "mesh": ["C548070"], "omim": ["612389"], "orphanet": ["2524"]}
Myopathy with hexagonally cross-linked tubular arrays is a rare, congenital, non-dystrophic, mild, slowly progressive, proximal myopathy characterized by exercise intolerance and post-exercise myalgia without rhabdomyolysis, associated with highly organized hexagonally cross-linked tubular arrays in skeletal muscle biopsy. Additional features may include muscle atrophy (or diffuse hypotrophy), myalgia with or without musclar weakness, paresis of truncal and limb-girdle musculature, minimal ptosis, lumbar hyperlordosis, decreased deep tendon reflexes, contractures and pes equinovarus. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Myopathy with hexagonally cross-linked tubular arrays	c4707259	5,008	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171889	2021-01-23T16:59:04	{"icd-10": ["G71.2"]}
A number sign (#) is used with this entry because cerebral creatine deficiency syndrome-1 (CCDS1) is caused by mutation in the creatine transporter gene (SLC6A8; 300036) on chromosome Xq28. Description Cerebral creatine deficiency syndrome-1 is an X-linked disorder of creatine (Cr) transport characterized by mental retardation, severe speech delay, behavioral abnormalities, and seizures. It has a prevalence of 0.3 to 3.5% in males. Carrier females may show mild neuropsychologic impairment (summary by van de Kamp et al., 2011). ### Genetic Heterogeneity of Cerebral Creatine Deficiency Syndrome See also CCDS2 (612736), caused by mutation in the GAMT gene (601240) on chromosome 19p13, and CCDS3 (612718), caused by mutation in the AGAT gene (GATM; 602360) on chromosome 15q21. Clinical Features Salomons et al. (2001) reported a male patient with developmental delay and hypotonia. Proton magnetic resonance spectroscopic imaging (H-MRSI) of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate (see 612718) levels were normal. Fibroblasts from the index patient were defective in creatine uptake. Three female relatives had mild biochemical abnormalities and learning disabilities. Bizzi et al. (2002) reported a child with severe neurologic disturbances including seizures, behavioral problems, speech delay, and inability to engage in structured play, as well as creatine deficiency. H-MRSI showed absence of creatine in the whole brain, which was not corrected by creatine supplementation. Hahn et al. (2002) described a family in which 5 males in a sibship of 10 had mental retardation with seizures. Head circumference was normal in all. Adult height (162.5-167.5 cm) was less than the adult height of the unaffected brother (175.5 cm). Midface hypoplasia was also described. Gastrointestinal disturbances in the form of chronic constipation, megacolon, gastric and duodenal ulcer disease, and bowel perforation were also observed. Two sisters had mild cognitive impairment, and one of them had chronic behavioral disturbances. Biochemical analyses confirmed a defect in creatine metabolism in this family. In affected males patients, the level of urinary creatine was substantially increased, and creatine uptake in fibroblasts was decreased. Schiaffino et al. (2005) reported a patient with X-linked creatine deficiency confirmed by genetic analysis (300036.0006). The patient was first seen at age 21 months for failure to thrive, recurrent vomiting, and motor delay. His weight, length, and head circumference were all under the third percentile. Neurologic examination showed truncal hypotonia, impaired eye-hand coordination, and severe cognitive and language retardation. EEG showed slow, diffuse hypersynchronisms with abnormal multifocal spikes. Plasma creatine levels were consistently low, and biochemical studies on fibroblasts showed impaired creatine uptake. Schiaffino et al. (2005) noted that few patients with SLC6A8 deficiency had been described, precluding a definite clinical description. However, most affected males have mental retardation, seizures, and language impairment. Kleefstra et al. (2005) described 2 brothers with X-linked creatine deficiency, in whom Rosenberg et al. (2004) had identified a missense mutation in the SLC6A8 gene (300036.0007). The older brother, born with severe mental retardation, was examined at age 70 and found to have myopathic facies with ptosis, external ophthalmoplegia, and open, hanging mouth. The younger brother had milder mental retardation and learned to read and write, but underwent regression at age 51 after the death of their father. In his fifties, he had urethral stenosis, chronic constipation, and ileus, and spontaneous luxations of several digits occurred. Neurologic examination at age 67 showed apparent medication-related Parkinsonism, upward gaze paresis, expressionless face, and hanging mouth and shoulders; comparison of photographs at age 57 and 64 revealed the striking progression of clinical features in the latter patient. Their sister, a carrier of the mutation, had short stature, learning difficulties, and developed severe constipation requiring surgical intervention in her fifties. Clark et al. (2006) reported 6 unrelated males with X-linked mental retardation associated with mutations in the SLC6A8 gene. Clinical features included increased urinary creatine:creatinine (Cr:Crn) ratio, microcephaly, long, narrow face, and prominent chin. Two patients were tall and thin, and 3 had short stature. Battini et al. (2007) reported a 9.5-year-old Italian boy with moderate mental retardation and verbal dyspraxia associated with mutation in the SLC6A8 gene. He had delayed psychomotor development, hypotonia, seizures, and severe language deficit with oral-motor dyspraxia, irritability, and temper tantrums. Detailed language evaluation showed problems in picture naming and phonetics, whereas receptive vocabulary was less severely affected. Social interaction was good despite the severe expressive limitation. Battini et al. (2011) reported a 6.5-year-old boy with X-linked creatine deficiency syndrome confirmed by genetic analysis. In infancy, he showed poor feeding, hypotonia, and delayed psychomotor development with walking and speaking his first words at age 3 years. Examination at age 5 years showed mild intellectual disability and comparatively severe language delay with mild oromotor dyspraxia and clumsiness. Social interaction was good. Detailed neuropsychologic studies showed a discrepancy between nonverbal and verbal skills, with mild impairment of social personal performance and eye-hand coordination and moderate impairment of speech and practical reasoning. Spontaneous language performance was markedly reduced. Biochemical analysis showed increased urinary Cr, increased Cr/Crn ratio, and undetectable uptake of Cr in fibroblasts, and magnetic resonance spectroscopy showed a reduced Cr peak in the brain. The patient's mother, who also carried the mutation, had a normal biochemical profile, but borderline intellectual functioning with difficulties in reading comprehension. Comeaux et al. (2013) reported 22 patients with confirmed deleterious mutations in the SLC6A8 gene who had clinical information available. Clinical features included developmental delay (86%), seizures (27%), autistic features (18%), speech delay (27%), ataxia (14%), and choreoathetosis (9%). All 6 patients with MRS results had decreased or absent creatine peaks. Van de Kamp et al. (2013) performed a retrospective analysis of 101 male patients from 85 families with X-linked creatine transporter deficiency confirmed by genetic analysis. Many of the patients had previously been reported. All patients presented in infancy or early childhood, most often due to delayed psychomotor development. All had intellectual disability of varying degrees, and 85% had behavioral problems. Speech development was especially delayed, but almost a third of patients could speak in sentences. Other features included seizures (59%), hypotonia (40%), spasticity (26%), gastrointestinal symptoms (35%), and ophthalmologic abnormalities (10%). Various facial dysmorphic features were present in 45%. MRI showed mild structural abnormalities in 53 of 76 patients studied, and MRS showed reduced creatine in all 66 patients for whom results were available. Urinary creatine was increased in 81 patients for whom results were available. A few patients studied had unexpectedly high creatine levels in CSF, suggesting that the brain is able to synthesize creatine and that the creatine deficiency is caused by a defect in the reuptake of creatine within neurons. Most patients had missense mutations or deletions of 1 amino acid in the SLC6A8 gene. A third of patients had a de novo mutation in the SLC6A8 gene. However, van de Kamp et al. (2013) suggested that a mother with an affected son with a de novo mutation may have a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. ### Carrier Females Van de Kamp et al. (2011) studied 8 unrelated female carriers of SLC6A8 mutations identified though affected male relatives. One woman had mental retardation, 1 required special education, 3 failed a year during elementary school, and 3 had no learning difficulties. IQ scores ranged from 48 to 96; 2 had scores in the mental retardation range, and 4 had scores in the borderline range. MRI showed mild cerebellar symptoms in 2, and constipation was reported in 2. Only 3 of 8 women had a mildly elevated urine creatine/creatinine ratio. H-MRSI studies showed decreased total creatine concentrations in the brain overall, but individual females had levels overlapping that of controls. X-inactivation studies in cultured fibroblasts showed severely skewed patterns in 2 woman, 1 favoring the mutant allele and 1 favoring the wildtype allele, but this may have been an artifact. Van de Kamp et al. (2011) concluded that carrier females may have mild symptoms of the disorder, and suggested that the most accurate diagnostic strategy in females should be molecular diagnosis, as biochemical changes may be subtle or not present. Diagnosis The biochemical test for CCDS1 is the urine creatine:creatinine ratio, which should be above 1.5 for a diagnosis of the disorder in males. Among 69 patients referred for SLC6A8 mutation testing, Comeaux et al. (2013) found that 45 had normal primary or secondary urine screens and did not meet the criteria for gene testing. Twelve of the 45 were females, whose ratios may have been uninformative due to random X-chromosome inactivation. Seven males and 2 females with increased ratios in the first screen had normal ratios in a second sample; none of these patients carried SLC6A8 mutations. The negative predictive value of this test in this study was 100%; all 45 patients with urine creatine:creatinine ratios below 1.5, regardless of gender, had no SLC6A8 mutations. Comeaux et al. (2013) emphasized that the urine creatine:creatinine ratio may be misleading because of diet and the possibility of creatine supplementation. Clinical Management Van de Kamp et al. (2012) recorded the long-term follow-up and treatment of 9 boys between the ages of 8 months and 10 years with creatine transporter defect. The patients underwent repeated magnetic resonance spectroscopy (MRS) and neuropsychologic assessments during 4 to 6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, van de Kamp et al. (2012) noticed an age-related decline in IQ subscales in boys affected with creatine transporter defect. Valayannopoulos et al. (2012) reported a series of 6 patients with severe creatine transporter deficiency, 4 males and 2 females. Clinical presentations included mild to severe mental retardation in all 6 patients, associated with psychiatric symptoms (autistic behavior, chronic hallucinatory psychosis) in 5 of 6, seizures in 2 of 6, and muscular symptoms in 2 of the 4 males. Diagnosis was confirmed by molecular analysis in all patients. All patients were treated successively according to the same protocol with creatine alone and then by creatine combined to its precursors L-glycine and L-arginine for 42 months. Valayannopoulos et al. (2012) reported benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations. Treatment failed to modify brain creatine content in either male or female patients. Dunbar et al. (2014) performed a systematic literature review (2001-2013) comprising 7 publications that described 25 patients with creatine transporter deficiency, and 3 additional patients treated at the authors' institution. Two patients received creatine-monohydrate supplementation; 7 received L-arginine; 2 received creatine-monohydrate and L-arginine; and 17 received a combination of creatine-monohydrate, L-arginine, and glycine. Median treatment duration was 34.6 months (range 3 months to 5 years). A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine or improved clinical parameters. Seven of the 28 patients had quantified pre- and posttreatment creatine, and it was significantly increased posttreatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. Ninety percent of the patients who improved were initiated on treatment before 9 years of age. Dunbar et al. (2014) proposed systematic screening for creatine transporter deficiency in patients with intellectual disability, to allow early initiation of treatment with oral creatine, arginine, and/or glycine supplementation. Molecular Genetics In a male patient with developmental delay and defective creatine uptake, Salomons et al. (2001) identified a hemizygous nonsense mutation in the SLC6A8 gene (300036.0001). Three mildly affected female relatives were heterozygous for the mutation. In the child with severe neurologic deficits and creatine deficiency, Bizzi et al. (2002) identified a hemizygous 3-bp deletion in the SLC6A8 gene (300036.0003). The patient's mother was heterozygous for the mutation. In the family described by Hahn et al. (2002), linkage to Xq28 was indicated by a lod score of 2.40 at zero recombination with 7 markers. Mutation analysis of candidate genes in that region revealed a splice site mutation in the SLC6A8 gene (300036.0002). Two sisters of the 5 affected males were heterozygous for the SLC6A8 mutation and exhibited mild mental retardation with behavior and learning problems. Rosenberg et al. (2004) identified 2 different mutations in the SLC6A8 gene (300036.0004; 300036.0005) in affected members of 2 unrelated families with X-linked mental retardation. Clark et al. (2006) identified 4 pathogenic (see, e.g., 300036.0010) and 2 potentially pathogenic mutations in the SLC6A8 gene in 6 of 478 unrelated males with X-linked mental retardation, yielding a frequency of approximately 1%. The authors stated that a total of 18 pathogenic mutations in the SLC6A8 gene had been reported, and suggested that urinary screening for an increased creatine:creatinine ratio could lead to focused mutation testing among appropriate patients. Lion-Francois et al. (2006) identified 4 unrelated boys with severe mental retardation due to X-linked creatine deficiency. Four different mutations were identified in the SLC6A8 gene (see, e.g., 300036.0008; 300036.0009). Together with a fifth case of creatine deficiency due to mutation in the GAMT gene (612736), Lion-Francois et al. (2006) found that the prevalence of cerebral creatine deficiency syndromes was 2.7% in their study population of 188 mentally retarded children. The prevalence rose to 4.4% when only boys were considered. INHERITANCE \- X-linked recessive GROWTH Height \- Short stature \- Tall stature Weight \- Low weight Other \- Failure to thrive HEAD & NECK Head \- Decreased head circumference \- Microcephaly Face \- Broad forehead \- Midface hypoplasia \- Long, thin face \- Prominent chin \- Myopathic facies Ears \- Unfolded superior helices Eyes \- Exotropia \- Hypermetropia \- Ptosis ABDOMEN Gastrointestinal \- Constipation \- Megacolon \- Ileus \- Poor feeding \- Vomiting SKELETAL Limbs \- Hyperextensible joints Hands \- Stub thumb Feet \- Pes cavus (less common) NEUROLOGIC Central Nervous System \- Hypotonia, neonatal \- Developmental delay \- Motor delay \- Mental retardation \- Hypotonia \- Speech and language delay, severe \- Poor hand-eye coordination \- Spasticity \- Gait abnormalities \- Dystonia \- Seizures \- Decreased creatine signal seen on magnetic resonance spectroscopy \- Mild structural abnormalities seen MRI (in some patients) \- Delayed myelination \- Thin corpus callosum Behavioral Psychiatric Manifestations \- Behavioral changes consistent with an autistic disorder \- Stereotypical motor behaviors \- Impaired social interaction \- Aggressive behavior \- Attention deficit hyperactivity disorder LABORATORY ABNORMALITIES \- Impaired creatine uptake in fibroblasts \- Increased urinary creatine \- Increased plasma creatine \- Increased urinary creatine-to-creatinine ratio MISCELLANEOUS \- Onset in first months of life \- Carrier females may show neuropsychologic impairment MOLECULAR BASIS \- Caused by mutation in the creatine transporter gene (SLC6A8, 300036.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CEREBRAL CREATINE DEFICIENCY SYNDROME 1	c1845862	5,009	omim	https://www.omim.org/entry/300352	2019-09-22T16:20:26	{"doid": ["0050800"], "mesh": ["C535598"], "omim": ["300352"], "orphanet": ["52503"], "synonyms": ["Alternative titles", "CREATINE DEFICIENCY SYNDROME, X-LINKED", "CREATINE TRANSPORTER DEFECT", "MENTAL RETARDATION, X-LINKED, WITH SEIZURES, SHORT STATURE, AND MIDFACE HYPOPLASIA", "MENTAL RETARDATION, X-LINKED, WITH CREATINE TRANSPORT DEFICIENCY"], "genereviews": ["NBK3794"]}
Rare genetic condition Rubinstein–Taybi syndrome Other namesBroad thumb-hallux syndrome or Rubinstein syndrome[1] Child with Rubinstein–Taybi syndrome SpecialtyMedical genetics Rubinstein–Taybi syndrome (RTS), is a condition characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes.[2] Other features of the disorder vary among affected individuals. These characteristics are caused by a mutation or deletion in the CREBBP and/or EP300 gene located on chromosome 16. People with this condition have an increased risk of developing noncancerous and cancerous tumors, leukemia, and lymphoma. This condition is sometimes inherited as an autosomal dominant pattern and is uncommon. Many times it occurs as a de novo (not inherited) occurrence. It occurs in an estimated 1 in 125,000-300,000 births. ## Contents * 1 Presentation * 2 Genetics * 3 Treatment * 4 History * 5 See also * 6 References * 7 External links ## Presentation[edit] Facial features (A), left hand and feet showing broad thumb and big toes (B, C) and X-ray of both hands showing short broad thumbs (D). (Limb Malformations & Skeletal Dysplasia) Rubinstein-Taybi Syndrome presents itself from birth, and is usually hallmarked by delayed physical and cognitive growth.[citation needed] Typical features of the disorder include: * Broad thumbs and broad first toes and clinodactyly of the 5th finger[3] * Mental disability * Small height, low bone growth, small head * Cryptorchidism in males * Unusual facies involving the eyes, nose, and palate * Anesthesia may be dangerous in these patients: "According to the medical literature, in some cases, individuals with Rubinstein–Taybi syndrome may have complications (e.g., respiratory distress and/or irregular heart beats [cardiac arrythmias]) associated with a certain muscle relaxant (succinylcholine) and certain anesthesia. Any situations requiring the administration of anesthesia or succinylcholine (e.g., surgical procedures) should be closely monitored by skilled professionals (Anesthesiologists)."[4] Primary literature suggests the children may have a higher rate of cardiac physical and conduction abnormalities which may cause unexpected results with cardioactive medications.[5] A further editorial reply in the British Journal of Anaesthesia discusses changes in the face and airway structure making it more difficult to secure the airway under anaesthesia, however, complications appeared in a minority of cases, and routine methods of airway control in the operating room appears to be successful. They recommended close individual evaluation of Rubinstein–Taybi patients for anaesthetic plans.[6] A 2009 study found that children with RTS were more likely to be overweight and to have a short attention span, motor stereotypies, and poor coordination. The study hypothesized that the identified CREBBP gene impaired motor skills learning.[7] Other research has shown a link with long-term memory (LTM) deficit.[8][9] See also: Epigenetics in learning and memory. It is diagnosed when a heterozygous pathogenic variant of the CREBBP gene is identified in the individual. It exhibits an autosomal dominant inheritance pattern, but some documented cases show heterozygous individuals exhibiting germline mosaicism. This condition affects men and women equally, and is often misdiagnosed with other diseases or disabilities that result in delayed mental development. ## Genetics[edit] Rubinstein–Taybi syndrome is inherited in an autosomal dominant fashion. Rubinstein–Taybi syndrome is a microdeletion syndrome involving chromosomal segment 16p13.3 and is characterized by mutations in the CREBBP gene.[10][11] Varying amounts of material is deleted from this section of the chromosome and accounts for the spectrum of physiological symptoms.[12] The CREBBP gene makes a protein that helps control the activity of many other genes. The protein, called CREB-binding protein, plays an important role in regulating cell growth and division and is essential for normal fetal development. If one copy of the CREBBP gene is deleted or mutated, cells make only half of the normal amount of CREB binding protein. A reduction in the amount of this protein disrupts normal development before and after birth, leading to the signs and symptoms of Rubinstein–Taybi syndrome.[13] Mutations in the EP300 gene are responsible for a small percentage of cases of Rubinstein–Taybi syndrome. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein–Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development. A mouse model has been identified in order to perform experimental research procedures. The model has exhibited the same clinical symptoms seen in humans and has become a foundation for future research.[14] Unfortunately, in nearly 40% of cases, neither gene, CREBBP or EP300, can be implicated in the cause of the disease. In these cases, there is no mutation on the 16th chromosome leaving many more questions yet to be answered. ## Treatment[edit] There is no existing treatment that reverses or cures RTS. There are, however, ways to manage and reduce symptoms for patients. Patients with RTS suffer from a diverse breadth of symptoms. These include cognitive-developmental impairment, heart abnormalities, delayed bone growth, and skeletal abnormalities, auditory impairment, urinary tract abnormalities, including kidney problems, and dental and speech problems. Not every patient will suffer from all or multiple symptoms, and not every patient will experience the same symptoms, meaning they differ from patient to patient. Due to there being a wide range of symptoms, RTS patients are referred to specialists that focus on each specific symptom. There is not a specialist for RTS. For example, patients will go to an orthopedic surgeon and physical therapy for skeletal and growth abnormalities, like scoliosis but will go to a cardiologist if they suffer from heart abnormalities or a dentist if they suffer from dental abnormalities. Individuals suffering from cognitive developments usually are part of special education programs and speech therapy. The specialists the individuals go to match the symptoms the individuals have. Regular check-ups and monitoring are needed for cardiac, dental, auditory, and renal abnormalities. Genetic counseling is also recommended for affected individuals and their families.[15] ## History[edit] Rubinstein Taybi Syndrome was first unofficially mentioned in a French orthopedic medical journal in 1957 by Greek physicians’ doctors: Michail, Matsoukas, and Theodorou. The medical journal reported a case concerning a 7-year old boy with radically deviated/arched thumbs, long nose, muscular hypotonia, along with physical and mental underdevelopment. At this point in time the case study mentioned by the Greek physicians was considered to be an anomaly due to the fact that there hadn’t been any other reported cases of children with these specific physical and mental characteristics. The doctors accredited with discovering the syndrome and therefore bear its name-sake were unaware of this journal at the time of their discovery. However, it is acknowledged that the 1957 case reported in the French journal of orthopedic medicine is most likely the first reported case of RTS. Dr. Jack Herbert Rubinstein, an American pediatrician reported assessing a 3-year old girl with unusual facial and digital findings in 1958. Similarly, that same year Dr. Rubinstein had evaluated another child with similar characteristics, this time a 7-year old boy. Having sensed a striking similarity between these two unrelated cases Dr. Rubinstein tried distributing photos and information concerning these two cases to other clinics in the U.S. from 1959 to 1960. Dr. Jack Herbert Rubinstein graduated from Harvard Medical School and worked as the director of the Hamilton County Diagnostic Clinic for the Mentally Retarded. He has worked in behavioral and developmental pediatrics for many years prior to the discovery of this new syndrome. In 1961 Dr. Hooshang Taybi an Iranian-American pediatric radiologist reported having assessed a 3-year old boy that appeared to have the same syndrome as described by Dr. Rubinstein. During the summer of 1963 Dr. Taybi reported having evaluated seven children with characteristics such as broad thumbs and great toes, “unusual” facial features, and intellectual disabilities – these findings went on to appear in the American Journal of Diseases of Children documenting these characteristics as a syndrome. Dr. Hooshang Taybi graduated from Tehran University School of Medicine and worked for the Ministry of Health. Later in his career he taught and practiced pediatric radiology in Oklahoma and Indiana. He had identified three new syndromes with his colleagues, among them is Rubinstein–Taybi syndrome. In 1992 the first genetic abnormalities that act as markers for Rubinstein-Taybi syndrome were identified. These abnormalities are said to affect either chromosome 16 or chromosome 22. The specific chromosome impacted by a mutation determines the type of Rubinstein-Taybi syndrome that may occur. A mutation of the CREBP gene on chromosome 16 gives rise to the first form of RTS (most common). While a mutation of the EP300 gene on chromosome 22 is characteristic of the second form of RTS. ## See also[edit] * Nasodigitoacoustic syndrome * List of cutaneous conditions ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): Rubinstein–Taybi syndrome - 180849 2. ^ Petrij, F; Dauwerse, HG; Blough, RI; Giles, RH; van der Smagt, JJ; Wallerstein, R; Maaswinkel-Mooy, PD; van Karnebeek, CD; van Ommen, GJ; van Haeringen, A; Rubinstein, JH; Saal, HM; Hennekam, RC; Peters, DJ; Breuning, MH (March 2000). "Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations". Journal of Medical Genetics. 37 (3): 168–76. doi:10.1136/jmg.37.3.168. PMC 1734540. PMID 10699051. 3. ^ Hennekam RC (Sep 2006). "Rubinstein-Taybi syndrome". Eur J Hum Genet. 14 (9): 981–985. doi:10.1038/sj.ejhg.5201594. PMID 16868563. 4. ^ "Anesthesia". Archived from the original on 2011-10-18. Retrieved 2012-04-11.[full citation needed] 5. ^ Stirt JA (July 1981). "Anesthetic problems in Rubinstein-Taybi syndrome". Anesthesia and Analgesia. 60 (7): 534–6. doi:10.1213/00000539-198107000-00016. PMID 7195672. S2CID 37522638. 6. ^ Dearlove OR, Perkins R (March 2003). "Anaesthesia in an adult with Rubinstein-Taybi syndrome". British Journal of Anaesthesia. 90 (3): 399–400, author reply 399–400. doi:10.1093/bja/aeg537. PMID 12594162. 7. ^ Galéra C, Taupiac E, Fraisse S, et al. (2009). "Socio-behavioral sharacteristics of children with Rubinstein–Taybi syndrome". J Autism Dev Disord. 39 (9): 1252–1260. doi:10.1007/s10803-009-0733-4. PMID 19350377. S2CID 5456561. 8. ^ Bourtchouladze R, Lidge R, Catapano R, et al. (September 2003). "A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4". Proceedings of the National Academy of Sciences of the United States of America. 100 (18): 10518–22. Bibcode:2003PNAS..10010518B. doi:10.1073/pnas.1834280100. JSTOR 3147748. PMC 193593. PMID 12930888. 9. ^ Alarcón JM, Malleret G, Touzani K, et al. (June 2004). "Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration". Neuron. 42 (6): 947–59. doi:10.1016/j.neuron.2004.05.021. PMID 15207239. S2CID 15669747. 10. ^ Wójcik, C; Volz, K; Ranola, M; Kitch, K; Karim, T; O'Neil, J; Smith, J; Torres-Martinez, W (February 2010). "Rubinstein-Taybi syndrome associated with Chiari type I malformation caused by a large 16p13.3 microdeletion: a contiguous gene syndrome?". American Journal of Medical Genetics Part A. 152A (2): 479–83. doi:10.1002/ajmg.a.33303. PMID 20101707. 11. ^ Petrij F, Giles RH, Dauwerse HG, et al. (July 1995). "Rubinstein–Taybi syndrome caused by mutations in the transcriptional co-activator CBP". Nature. 376 (6538): 348–51. Bibcode:1995Natur.376..348P. doi:10.1038/376348a0. PMID 7630403. S2CID 4254507. 12. ^ Reference, Genetics Home. "Rubinstein-Taybi syndrome". Genetics Home Reference. Retrieved 2020-05-06. 13. ^ Milani, Donatella; Manzoni, Francesca Maria Paola; Pezzani, Lidia; Ajmone, Paola; Gervasini, Cristina; Menni, Francesca; Esposito, Susanna (2015-01-20). "Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management". Italian Journal of Pediatrics. 41 (1): 4. doi:10.1186/s13052-015-0110-1. ISSN 1824-7288. PMC 4308897. PMID 25599811. 14. ^ Oike, Y.; Hata, A.; Mamiya, T.; Kaname, T.; Noda, Y.; Suzuki, M.; Yasue, H.; Nabeshima, T.; Araki, K.; Yamamura, K. (March 1999). "Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism". Human Molecular Genetics. 8 (3): 387–396. doi:10.1093/hmg/8.3.387. ISSN 0964-6906. PMID 9949198. 15. ^ "Rubinstein Taybi Syndrome". NORD (National Organization for Rare Disorders). Retrieved 2020-05-06. ## External links[edit] Wikimedia Commons has media related to Rubinstein-Taybi syndrome. * GeneReview/UW/NIH entry on Rubinstein-Taybi syndrome * Rubinstein-Taybi syndrome due to 16p13.3 microdeletion on ORPHAnet Classification D * ICD-10: Q87.2 * ICD-9-CM: 759.89 * OMIM: 180849 * MeSH: D012415 * DiseasesDB: 29344 * SNOMED CT: 45582004 External resources * MedlinePlus: 001249 * eMedicine: derm/711 ped/2026 * GeneReviews: Rubinstein–Taybi syndrome * Orphanet: 783 * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome * v * t * e Genetic disorders relating to deficiencies of transcription factor or coregulators (1) Basic domains 1.2 * Feingold syndrome * Saethre–Chotzen syndrome 1.3 * Tietz syndrome (2) Zinc finger DNA-binding domains 2.1 * (Intracellular receptor): Thyroid hormone resistance * Androgen insensitivity syndrome * PAIS * MAIS * CAIS * Kennedy's disease * PHA1AD pseudohypoaldosteronism * Estrogen insensitivity syndrome * X-linked adrenal hypoplasia congenita * MODY 1 * Familial partial lipodystrophy 3 * SF1 XY gonadal dysgenesis 2.2 * Barakat syndrome * Tricho–rhino–phalangeal syndrome 2.3 * Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome * Denys–Drash syndrome * Duane-radial ray syndrome * MODY 7 * MRX 89 * Townes–Brocks syndrome * Acrocallosal syndrome * Myotonic dystrophy 2 2.5 * Autoimmune polyendocrine syndrome type 1 (3) Helix-turn-helix domains 3.1 * ARX * Ohtahara syndrome * Lissencephaly X2 * MNX1 * Currarino syndrome * HOXD13 * SPD1 synpolydactyly * PDX1 * MODY 4 * LMX1B * Nail–patella syndrome * MSX1 * Tooth and nail syndrome * OFC5 * PITX2 * Axenfeld syndrome 1 * POU4F3 * DFNA15 * POU3F4 * DFNX2 * ZEB1 * Posterior polymorphous corneal dystrophy * Fuchs' dystrophy 3 * ZEB2 * Mowat–Wilson syndrome 3.2 * PAX2 * Papillorenal syndrome * PAX3 * Waardenburg syndrome 1&3 * PAX4 * MODY 9 * PAX6 * Gillespie syndrome * Coloboma of optic nerve * PAX8 * Congenital hypothyroidism 2 * PAX9 * STHAG3 3.3 * FOXC1 * Axenfeld syndrome 3 * Iridogoniodysgenesis, dominant type * FOXC2 * Lymphedema–distichiasis syndrome * FOXE1 * Bamforth–Lazarus syndrome * FOXE3 * Anterior segment mesenchymal dysgenesis * FOXF1 * ACD/MPV * FOXI1 * Enlarged vestibular aqueduct * FOXL2 * Premature ovarian failure 3 * FOXP3 * IPEX 3.5 * IRF6 * Van der Woude syndrome * Popliteal pterygium syndrome (4) β-Scaffold factors with minor groove contacts 4.2 * Hyperimmunoglobulin E syndrome 4.3 * Holt–Oram syndrome * Li–Fraumeni syndrome * Ulnar–mammary syndrome 4.7 * Campomelic dysplasia * MODY 3 * MODY 5 * SF1 * SRY XY gonadal dysgenesis * Premature ovarian failure 7 * SOX10 * Waardenburg syndrome 4c * Yemenite deaf-blind hypopigmentation syndrome 4.11 * Cleidocranial dysostosis (0) Other transcription factors 0.6 * Kabuki syndrome Ungrouped * TCF4 * Pitt–Hopkins syndrome * ZFP57 * TNDM1 * TP63 * Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8 Transcription coregulators Coactivator: * CREBBP * Rubinstein–Taybi syndrome Corepressor: * HR (Atrichia with papular 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 [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Rubinstein–Taybi syndrome	c0035934	5,010	wikipedia	https://en.wikipedia.org/wiki/Rubinstein%E2%80%93Taybi_syndrome	2021-01-18T19:09:50	{"gard": ["7593"], "mesh": ["D012415"], "umls": ["C0035934"], "orphanet": ["783"], "wikidata": ["Q666980"]}
Milroy disease is a condition that affects the normal function of the lymphatic system. The lymphatic system produces and transports fluids and immune cells throughout the body. Impaired transport with accumulation of lymph fluid can cause swelling (lymphedema). Individuals with Milroy disease typically have lymphedema in their lower legs and feet at birth or develop it in infancy. The lymphedema typically occurs on both sides of the body and may worsen over time. Milroy disease is associated with other features in addition to lymphedema. Males with Milroy disease are sometimes born with an accumulation of fluid in the scrotum (hydrocele). Males and females may have upslanting toenails, deep creases in the toes, wart-like growths (papillomas), and prominent leg veins. Some individuals develop non-contagious skin infections called cellulitis that can damage the thin tubes that carry lymph fluid (lymphatic vessels). Episodes of cellulitis can cause further swelling in the lower limbs. ## Frequency Milroy disease is a rare disorder; its incidence is unknown. ## Causes Mutations in the FLT4 gene cause some cases of Milroy disease. The FLT4 gene provides instructions for producing a protein called vascular endothelial growth factor receptor 3 (VEGFR-3), which regulates the development and maintenance of the lymphatic system. Mutations in the FLT4 gene interfere with the growth, movement, and survival of cells that line the lymphatic vessels (lymphatic endothelial cells). These mutations lead to the development of small or absent lymphatic vessels. If lymph fluid is not properly transported, it builds up in the body's tissues and causes lymphedema. It is not known how mutations in the FLT4 gene lead to the other features of this disorder. Many individuals with Milroy disease do not have a mutation in the FLT4 gene. In these individuals, the cause of the disorder is unknown. ### Learn more about the gene associated with Milroy disease * FLT4 ## Inheritance Pattern Milroy disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In many cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the FLT4 gene. These cases occur in people with no history of the disorder in their family. About 10 percent to 15 percent of people with a mutation in the FLT4 gene do not develop the features of Milroy disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Milroy disease	c1704423	5,011	medlineplus	https://medlineplus.gov/genetics/condition/milroy-disease/	2021-01-27T08:25:01	{"gard": ["7220"], "mesh": ["D008209"], "omim": ["153100"], "synonyms": []}
A number sign (#) is used with this entry because congenital fiber-type disproportion (CFTD) can be caused by mutation in the ACTA1 (102610), SEPN1 (606210), or TPM3 (191030) genes. Mutations in the SEPN1 gene also cause rigid spine muscular dystrophy (RSMD1; 602771), which shows clinical overlap with CFTD. See also CFTDX (300580), which has been mapped to chromosome Xq13.1-q22.1. Description Congenital fiber-type disproportion (CFTD) myopathy is a genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. Clarke and North (2003) stated that the diagnosis of 'congenital fiber-type disproportion' as a disease entity is one of exclusion. They also suggested that the nonspecific histologic findings should be termed 'fiber size disproportion,' thus reserving the term CFTD for those cases in which no secondary cause can be found. Clinical Features Brooke (1973) reported 12 cases and coined the term 'congenital fiber-type disproportion.' All patients had hypotrophy of type 1 muscle fibers, which were at least 12% smaller than either type 2A or type 2B fibers. Clinical features included congenital hypotonia, generalized weakness, and failure to thrive. Other features included long, thin face, scoliosis, high-arched palate, and multiple joint contractures. One patient had an affected parent. Cavanagh et al. (1979) described 9 children with congenital fiber-type disproportion. Hypotonia, joint laxity, and congenital dislocation of the hip were the usual features. Muscle biopsies showed type 1 fibers that were smaller than the largest type 2 fibers by at least 13.5%. The natural history of the disorder was variable, with some children having fatal respiratory events. The parents in 1 case were second cousins. One mother was said to have weak legs in childhood, and another patient was said to have 2 affected paternal cousins. Somer (1981) reported a 22-year-old man with muscle weakness and marfanoid features, including scoliosis. He had been a floppy infant. He worked as a television technician but could not lift TVs. Muscle biopsy showed type 1 fibers to be smaller than type 2 fibers. Type 2A fibers showed compensatory hypertrophy, and type 2B fibers were lacking. Jaffe et al. (1988) described this disorder in a 12-year-old male and his infant sister. The parents were healthy and unrelated. Vestergaard et al. (1995) reported a family in which of 2 of 3 sons had CFTD and insulin-resistant diabetes mellitus. The brothers, aged 15 and 8 at the time of the study, were born of nonconsanguineous healthy parents. Both had delayed milestones and muscle weakness. The diagnosis of CFTD was made in both probands at the age of 6 years. Muscle biopsy showed 74% small type 1 fibers of 16 micro m diameter and 26% type 2 fibers of 22 micro m diameter. No nemaline bodies were seen. Physical examination showed universal muscle hypotrophy and hirsutism. Glucosuria and postprandial hyperglycemia were discovered by chance at the age of 13 years in proband 1 and 6 years in proband 2; neither had been symptomatic. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity. Clarke and North (2003) clarified the definition of CFTD through a comprehensive literature review and analysis. Of 218 reported cases of fiber size disproportion on muscle biopsy, they classified 67 cases as having CFTD, using inclusion criteria of (1) clinical muscle weakness and/or hypotonia, and (2) mean type 1 fiber diameter at least 12% smaller than mean type 2 fiber diameter. Exclusion criteria consisted of insufficient clinical information; a coexisting disorder of muscle or the nervous system; 2 or more syndromal features present; histologic features of a muscular dystrophy; and a coefficient of variation greater than 250 for type 2 fibers. In most cases, limb weakness was greatest in the limb girdle and proximal muscle groups, although many children had generalized muscle weakness. There was variable facial weakness (42% of patients), ophthalmoplegia (19%), and severe respiratory involvement (18%). Long face and high-arched palate were commonly reported. Reflexes were usually decreased or absent. Many patients had contractures, either at birth or developing later, of the ankles (10 cases), fingers (4 cases), hips (3 cases), elbows (3 cases), and knees (2 cases). Fifteen patients had scoliosis. Only 2 patients had cardiac involvement: dilated cardiomyopathy and atrial fibrillation, respectively (Banwell et al., 1999). Two patients had intellectual disability and 3 males had cryptorchidism. Fifty patients had type 1 fiber diameters that were 25% smaller than type 2, and these patients tended to have a more severe clinical phenotype. Family history was present in 43% of families, suggesting that genetics may play a role in a subset of patients. Laing et al. (2004) identified 3 unrelated patients with severe CFTD from a muscle repository. The fiber size disproportion in these patients ranged from 45 to 54%, far exceeding the minimum level of 12%. Clinical records showed that all 3 had neonatal hypotonia with weak breathing, eventually requiring mechanical ventilation. There was also marked generalized proximal muscle and facial weakness. Two patients had a high-arched palate and a long, thin face, and 1 patient had scoliosis. None of the patients had ophthalmoplegia or cardiac involvement. Two patients died at ages 1.1 and 3.5 years, respectively, and the third was bedridden at age 3 years. Each patient carried a different heterozygous mutation in the ACTA1 gene (102610.0011-102610.0013). Sobrido et al. (2005) reported a large Spanish family with CFTD inherited in an autosomal dominant pattern. Seven of 25 examined family members were affected. Onset of slowly progressive muscle weakness was in early childhood, manifest by clumsiness and difficulty running, climbing stairs, and getting up from the floor. As adults, all retained independent ambulation but demonstrated waddling gait, proximal upper and lower extremity weakness and atrophy, and hypo- or areflexia. Notably, none of the affected individuals had neonatal respiratory or sucking difficulties. MRI studies showed loss of volume and fatty infiltration of proximal muscles; EMG showed myopathic changes. Skeletal muscle biopsies of 2 affected individuals showed characteristic findings of CFTD without dystrophic changes. No mutations were identified in the coding sequence of the ACTA1 gene. Clarke et al. (2006) reported 2 sisters, ages 32 and 30, respectively, with a diagnosis of congenital fiber-type disproportion. Skeletal muscle biopsies showed that type 1 fibers were at least 12% smaller than type 2 fibers, and there was no evidence of multiminicore disease or other findings typical of RSMD1. Clinically, the women had a severe congenital myopathy with truncal hypotonia in infancy, progressive scoliosis, progressive respiratory impairment, and osteopenia. One woman was wheelchair-bound and had had bilateral hip fractures in her twenties. Both patients had abnormal glucose tolerance tests and showed biochemical abnormalities suggesting insulin resistance. Inheritance Fardeau et al. (1975) reported a family with CFTD in which the father and 2 sisters were affected. Curless and Nelson (1977) described this form of myopathy in identical twins. Although this occurrence in sibs and the parental consanguinity suggested autosomal recessive inheritance, parental involvement pointing to an autosomal dominant mode was reported by Kula et al. (1980) and Sulaiman et al. (1983). Cytogenetics Gerdes et al. (1994) reported a child with congenital fiber-type disproportion who was born with arthrogryposis multiplex congenita, dislocation of the hips, and mild scoliosis. By age 5 years, she had developed marked muscle weakness. Cytogenetic analysis identified a balanced chromosomal translocation, t(10;17)(p11.2;q25), transmitted by the clinically healthy mother. Maternal uniparental disomy for loci on either chromosome 10 or chromosome 17 was excluded. Although the mother had normal muscle strength and mass, muscle biopsy showed type 1 fiber predominance and EMG showed myopathic changes. Gerdes et al. (1994) suggested that congenital fiber-type disproportion in this family was dominantly inherited with variable expressivity, and that the translocation breakpoints may represent candidate gene regions. The chromosome 1p36 deletion syndrome (607872) is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism (Shapira et al., 1997; Slavotinek et al., 1999). Muscle hypotonia and delayed motor development are almost constant features of the syndrome. Colmenares et al. (2002) suggested that the SKI protooncogene (164780) may contribute to phenotypes common in 1p36 deletion syndrome, particularly to facial clefting; Ski -/- mice showed features reminiscent of the syndrome. Okamoto et al. (2002) described a patient with the 1p36 deletion syndrome in whom FISH demonstrated that the SKI gene was deleted. The patient was a 4-year-old Japanese girl in whom dysmorphic features were evident at birth and right congenital hip dislocation necessitated surgical treatment. Dilated cardiomyopathy was recognized at the age of 7 months. A diagnosis of congenital fiber-type disproportion myopathy was made on muscle biopsy. Molecular Genetics In 3 unrelated patients with severe CFTD myopathy, Laing et al. (2004) identified 3 different mutations in the ACTA1 gene (D292V, 102610.0011; L221P, 102610.0012; P332S, 102610.0013). The authors reported that ACTA1 mutations accounted for approximately 6% of cases in their cohort, indicating genetic heterogeneity. In 2 women with CFTD, Clarke et al. (2006) identified a homozygous mutation in the SEPN1 gene (G315S; 606210.0008). This mutation had previously been reported in patients with RSMD1. Clarke et al. (2008) identified 5 different heterozygous TPM3 mutations (see, e.g., 191030.0005; 191030.0007; 191030.0008), in affected members of 6 unrelated families with congenital myopathy with fiber-type disproportion on skeletal muscle biopsy. The mutations were identified among 23 unrelated probands, making TPM3 the most common cause of CFTD to date. ### Associations Pending Confirmation For discussion of a possible association between CFTD and variation in the PTPLA gene, see 610467.0001. Pathogenesis Using mass spectrometry and gel electrophoresis to examine patient skeletal muscle, Clarke et al. (2007) determined that D292V- and P332S-actin accounted for 50% and 25 to 30% of total sarcomeric actin, respectively. In vitro assays showed that D292V-actin resulted in decreased motility due to abnormal interactions between actin and tropomyosin, with tropomyosin stabilized in the 'off' position. However, similar findings were not observed with P332S-actin, suggesting that tropomyosin dysfunction may not be a common mechanism in CFTD. Cellular transfection studies demonstrated that the mutant proteins incorporated into actin filaments and did not result in increased actin aggregation or disruption of the sarcomere. Clarke et al. (2007) concluded that ACTA1 mutations resulting in CFTD cause weakness by interfering with sarcomeric function rather than structure. INHERITANCE \- Autosomal dominant \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Face \- Long face \- Thin face \- Facial muscle weakness Eyes \- Ophthalmoplegia (in 20%) \- Ptosis Mouth \- High-arched palate CARDIOVASCULAR Heart \- Dilated cardiomyopathy has been reported in 1 patient RESPIRATORY \- Respiratory distress due to muscle weakness \- Decreased forced vital capacity \- Mechanical ventilation required in severe cases \- Weak cry ABDOMEN Gastrointestinal \- Poor feeding \- Poor swallowing SKELETAL \- Contractures Spine \- Scoliosis (in 25%) \- Lumbar lordosis Pelvis \- Congenital dislocation of the hips (in 13%) Limbs \- Limb contractures (in 25%) MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Proximal muscle weakness \- Generalized muscle weakness \- Bulbar weakness \- Muscle biopsy shows hypotrophy of type 1 muscle fibers \- Type 1 fibers are at least 12% smaller than type 2 fibers \- Increased numbers of type 1 fibers \- Decreased numbers of type 2B fibers \- Centralized nuclei may be seen PRENATAL MANIFESTATIONS Movement \- Decreased fetal movement MISCELLANEOUS \- Onset usually at birth \- Variable severity \- Approximately 25% have a severe course and die of respiratory failure \- Usually follows a static course or is slowly progressive \- Allelic disorder to rigid spine muscular dystrophy (RSMD1, 602771 ) \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the skeletal muscle alpha-1 actin gene (ACTA1, 102610.0011 ) \- Caused by mutation in the selenoprotein N, 1 gene (SEPN1, 606210.0008 ) \- Caused by mutation in the tropomyosin 3 gene (TPM3, 191030.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	MYOPATHY, CONGENITAL, WITH FIBER-TYPE DISPROPORTION	c0546264	5,012	omim	https://www.omim.org/entry/255310	2019-09-22T16:24:39	{"doid": ["0080102"], "mesh": ["D020914"], "omim": ["255310"], "icd-10": ["G71.2"], "orphanet": ["2020"], "synonyms": ["Alternative titles", "FIBER-TYPE DISPROPORTION MYOPATHY, CONGENITAL"]}
Hypertrophic neuropathy of Dejerine-Sottas (Dejerine-Sottas syndrome) is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease (sometimes called type 3) that is characterized by sensory loss with ataxia in the limbs furthest from the body and pes cavus with progression towards the limbs closest to the body. Depending on the specific gene that is altered, this severe, early onset form of the disorder may also be classified as type 1 or type 4. Dejerine-Sottas syndrome has been associated with mutations in the MPZ, PMP22, EGR2, and PRX genes. Autosomal dominant and autosomal recessive inheritance 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 [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hypertrophic neuropathy of Dejerine-Sottas	c0011195	5,013	gard	https://rarediseases.info.nih.gov/diseases/9204/hypertrophic-neuropathy-of-dejerine-sottas	2021-01-18T17:59:54	{"mesh": ["D015417"], "omim": ["145900"], "orphanet": ["64748"], "synonyms": ["Dejerine-Sottas syndrome", "DSS", "Charcot-Marie-Tooth Disease, type 3", "CMT3", "Hereditary motor and sensory neuropathy 3", "HMSN3", "Dejerine-Sottas neuropathy", "DSN", "Charcot-Marie-Tooth disease type 3", "Hereditary motor and sensory neuropathy type 3", "HMSN 3", "Hypertrophic neuropathy of infancy", "Hereditary motor and sensory neuropathy type III", "HMSN III"]}
Symmetrical thalamic calcifications are clinically distinguished by a low Apgar score, spasticity or marked hypotonia, weak or absent cry, poor feeding, and facial diplegia or weakness. ## Epidemiology It is an extremely rare condition, with about 30 cases described in the literature. ## Diagnostic methods The calcifications are revealed by computed tomography scanning. ## Prognosis The prognosis is very poor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Symmetrical thalamic calcifications	None	5,014	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1314	2021-01-23T18:53:28	{"gard": ["5070"], "icd-10": ["G93.8"], "synonyms": ["Bilateral symmetrical thalamic gliosis"]}
A number sign (#) is used with this entry because of evidence that Noonan syndrome-like disorder with loose anagen hair-1 (NSLH1) is caused by heterozygous mutation in the SHOC2 gene (602775) on chromosome 10q25. Description Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017). ### Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23. Clinical Features Tosti et al. (1991, 1997) reported 2 unrelated children with loose anagen hair in association with Noonan syndrome (see 163950). Mazzanti et al. (2003) restudied these children and described a third unrelated child. All 3 children had short stature, the same facial phenotype, macrocephaly, enlarged cerebrospinal fluid spaces, short neck with redundant skin, severe growth hormone deficiency, mild psychomotor delay with attention deficit/hyperactivity disorder, mild dilatation of the pulmonary root in 2 of them, and a unique combination of ectodermal abnormalities. The skin was generally darkly pigmented and hairless. The hair of the head had the characteristics of loose anagen hair syndrome (600628). The hair was easily pluckable, sparse, thin, slow growing, and generally silver-blond. Mazzanti et al. (2003) suggested that the disorder in these children is distinct from Noonan syndrome. Cordeddu et al. (2009) studied 25 patients with Noonan syndrome-like disorder with loose anagen hair and observed facial features that were typical of Noonan syndrome, including macrocephaly, high forehead, hypertelorism, palpebral ptosis, and low-set and posteriorly rotated ears, in addition to short and webbed neck and pectus anomalies. These features were associated with reduced growth that was frequently associated with proven growth hormone (GH; 139250) deficiency, cognitive deficits, distinctive hyperactive behavior that improved with age in most subjects, and hair anomalies including easily pluckable, sparse, thin, slow-growing hair. In 12 individuals, a diagnosis of loose anagen hair was confirmed by microscopic examination. Most of the patients also had darkly pigmented skin with eczema or ichthyosis. Cardiac anomalies were observed in the majority of the subjects, with mitral valve and septal defects overrepresented compared to the general population of Noonan syndrome patients. The affected individuals' voices were characteristically hypernasal. Gripp et al. (2013) reported 5 unrelated children with molecularly confirmed Noonan syndrome-like disorder and loose anagen hair. All had skin hyperpigmentation, sparse light-colored hair that was slow-growing and unruly in texture, increased fine wrinkles, ligamentous laxity, and developmental delay; 4 also had documented structural cardiac anomalies. Hypotonia and macrocephaly were present in 4, and 3 had polyhydramnios, high birth weight, and/or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3 of 5 patients). Molecular Genetics Based on a systems biology approach that identified SHOC2 (602775) as a candidate gene, Cordeddu et al. (2009) sequenced SHOC2 coding exons in a Noonan syndrome cohort that included 96 individuals who were negative for mutations in known disease genes and identified a heterozygous mutation (S2G; 602775.0001) in 4 unrelated individuals. They then analyzed the SHOC2 gene in a cohort of 410 mutation-negative patients with Noonan syndrome or a related phenotype and identified 21 individuals with the same S2G mutation. All 25 patients with the S2G mutation had a relatively consistent Noonan syndrome-like phenotype with loose anagen hair. Functional studies of S2G-mutant SHOC2 demonstrated introduction of an N-myristoylation site, resulting in aberrant localization and signaling. Hoban et al. (2012) reported a male infant with typical dysmorphic facial features and other signs of Noonan syndrome, including thickened nuchal folds, generalized perinatal edema, hepatosplenomegaly, coagulopathy, hypertrophic cardiomyopathy (CMH), leukocytosis, thrombocytopenia, bleeding dyscrasia, hearing loss, and cryptorchidism, who was found to have the recurrent S2G mutation in the SHOC2 gene. The infant had rapidly progressive CMH and died of congestive heart failure at 4 months of age. Hoban et al. (2012) stated that the 'loose anagen hair' phenotype 'was not clinically noted' in the patient, who also had not developed any of the previously reported skin features in patients with the S2G mutation. They noted that the cardiac anomaly expanded the clinical phenotype associated with the SHOC2 mutation. In 5 unrelated children with Noonan syndrome-like disorder and loose anagen hair, Gripp et al. (2013) identified heterozygosity for the S2G mutation in the SHOC2 gene. One of the patients was a 2-year-old boy who developed myelofibrosis (254450), which the authors noted is exceedingly rare in children and young adults; he was negative for the V617F JAK2 mutation (147796.0001) seen in the majority of myelofibrosis patients, suggesting that germline or somatic SHOC2 mutations might be involved in myelofibrosis. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Weight \- Increased birth weight (in some patients) HEAD & NECK Head \- Macrocephaly Face \- Prominent forehead Ears \- Low-set ears \- Posteriorly rotated ears Eyes \- Hypertelorism \- Strabismus \- Long eyelashes (in some patients) Neck \- Short neck \- Webbed neck CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect \- Mitral/tricuspid valve dysplasia \- Pulmonic stenosis \- Hypertrophic cardiomyopathy CHEST Ribs Sternum Clavicles & Scapulae \- Pectus anomalies ABDOMEN Gastrointestinal \- Feeding difficulties (in some patients) SKELETAL \- Ligamentous laxity (in some patients) SKIN, NAILS, & HAIR Skin \- Darkly pigmented skin \- Eczema (in some patients) \- Keratosis pilaris (in some patients) \- Ichthyosis (in some patients) \- Increased fine wrinkles (in some patients) \- Deep palmar creases (in some patients) Hair \- Sparse scalp hair \- Absent scalp hair \- Loose anagen hair NEUROLOGIC Central Nervous System \- Mental retardation \- Hypotonia (in some patients) \- Thin corpus callosum (in some patients) \- Decreased white matter volume (in some patients) \- Vertical tentorium (in some patients) \- Cerebellar tonsilar ectopia (in some patients) Behavioral Psychiatric Manifestations \- Hyperactivity VOICE \- Hypernasal voice (in some patients) ENDOCRINE FEATURES \- Low or absent growth hormone (in some patients) PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios MOLECULAR BASIS \- Caused by mutation in homolog of the C. elegans suppressor of clear gene (SHOC2, 602775.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1	c3501846	5,015	omim	https://www.omim.org/entry/607721	2019-09-22T16:08:46	{"mesh": ["C564342"], "omim": ["607721"], "orphanet": ["2701"], "synonyms": ["Alternative titles", "NSLH", "TOSTI SYNDROME"]}
Pretibial myxedema Hands showing related condition thyroid acropachy and shins of someone with pretibial myxedema SpecialtyEndocrinology Pretibial myxedema (myxoedema (UK), also known as Graves' dermopathy, thyroid dermopathy,[1] Jadassohn-Dösseker disease or Myxoedema tuberosum) is an infiltrative dermopathy, resulting as a rare complication of Graves' disease,[2] with an incidence rate of about 1-5%. ## Contents * 1 Signs and symptoms * 2 Risk factors * 3 Diagnosis * 4 Management * 5 References * 6 External links ## Signs and symptoms[edit] Pretibial myxedema is almost always preceded by the ocular signs found in Graves' disease.[3] It usually presents itself as a waxy, discolored induration of the skin—classically described as having a so-called peau d'orange (orange peel) appearance—on the anterior aspect of the lower legs, spreading to the dorsum of the feet, or as a non-localised, non-pitting edema of the skin in the same areas.[4] In advanced cases, this may extend to the upper trunk (torso), upper extremities, face, neck, back, chest and ears. The lesions are known to resolve very slowly. Application of petroleum jelly on the affected area could relieve the burning sensation and the itching. It occasionally occurs in non-thyrotoxic Graves' disease, Hashimoto's thyroiditis, and stasis dermatitis. The serum contains circulating factors which stimulate fibroblasts to increase synthesis of glycosaminoglycans. ## Risk factors[edit] There are suggestions in the medical literature that treatment with radioactive iodine for Graves' hyperthyroidism may be a trigger for pretibial myxedema[5] which would be consistent with radioiodine ablation causing or aggravating ophthalmopathy, a condition which commonly occurs with pretibial myxedema and is believed to have common underlying features.[6] Other known triggers for ophthalmopathy include thyroid hormone imbalance, and tobacco smoking, but there has been little research attempting to confirm these are also risk factors for pretibial myxedema. ## Diagnosis[edit] A biopsy of the affected skin reveals mucin in the mid- to lower- dermis. There is no increase in fibroblasts. Over time, secondary hyperkeratosis may occur, which may become verruciform. Many of these patients may also have co-existing stasis dermatitis. Elastic stains will reveal a reduction in elastic tissue. ## Management[edit] Treating the symptoms and correction of dysthyroid state to euthyroid state. This section needs expansion. You can help by adding to it. (April 2020) ## References[edit] 1. ^ Schwartz, K. M.; Vahab Fatourechi; Debra D. F. Ahmed; Gregory R. Pond (1 February 2002). "Dermopathy of Graves' Disease (Pretibial Myxedema): Long-Term Outcome". Journal of Clinical Endocrinology & Metabolism. 87 (2): 438–446. doi:10.1210/jc.87.2.438. 2. ^ Prajapati VH, Mydlarski PR (March 2008). "Dermacase. Pretibial myxedema". Can Fam Physician. 54 (3): 357, 369. PMC 2278349. PMID 18337527. 3. ^ Dennis, Mark; Bowen, William Talbot; Cho, Lucy (2012). "Pre-tibial myxoedema (thyroid dermopathy)". Mechanisms of Clinical Signs. Elsevier. p. 550. ISBN 978-0729540759; pbk 4. ^ Rongioletti F, Rebora A (2007). "Mucinoses". In Bolognia JL (ed.). Dermatology. St. Louis: Mosby. pp. 616–7. ISBN 1-4160-2999-0. 5. ^ Harvey, R. D.; Metcalfe, R. A.; Morteo, C.; Furmaniak, W.; Weetman, A. P.; Bevan, J. S. (1 June 1995). "Acute pre-tibial myxoedema following radioiodine therapy for thyrotoxic Graves' disease". Clinical Endocrinology. 42 (6): 657–660. doi:10.1111/j.1365-2265.1995.tb02695.x. 6. ^ PEACEY, S.R.; FLEMMING, L.; MESSENGER, A.; WEETMAN, A.P. (1 February 1996). "Is Graves' Dermopathy a Generalized Disorder?". Thyroid. 6 (1): 41–45. doi:10.1089/thy.1996.6.41. ## External links[edit] Classification D * ICD-9-CM: 242.9 * DiseasesDB: 25147 External resources * eMedicine: derm/347 * v * t * e Thyroid disease Hypothyroidism * Iodine deficiency * Cretinism * Congenital hypothyroidism * Myxedema * Myxedema coma * Euthyroid sick syndrome * Signs and symptoms * Queen Anne's sign * Woltman sign * Thyroid dyshormonogenesis * Pickardt syndrome Hyperthyroidism * Hyperthyroxinemia * Thyroid hormone resistance * Familial dysalbuminemic hyperthyroxinemia * Hashitoxicosis * Thyrotoxicosis factitia * Thyroid storm Graves' disease * Signs and symptoms * Abadie's sign of exophthalmic goiter * Boston's sign * Dalrymple's sign * Stellwag's sign * lid lag * Griffith's sign * Möbius sign * Pretibial myxedema * Graves' ophthalmopathy Thyroiditis * Acute infectious * Subacute * De Quervain's * Subacute lymphocytic * Palpation * Autoimmune/chronic * Hashimoto's * Postpartum * Riedel's Enlargement * Goitre * Endemic goitre * Toxic nodular goitre * Toxic multinodular goiter * Thyroid nodule * Colloid nodule [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Pretibial myxedema	c0033103	5,016	wikipedia	https://en.wikipedia.org/wiki/Pretibial_myxedema	2021-01-18T18:58:41	{"umls": ["C0033103"], "icd-9": ["242.9"], "wikidata": ["Q3130277"]}
A number sign (#) is used with this entry because remitting megalencephalic leukoencephalopathy with subcortical cysts-2B (MLC2B) is caused by heterozygous mutation in the HEPACAM gene (611642) on chromosome 11q24. Description Autosomal dominant remitting MLC2B is characterized by infantile-onset of macrocephaly and mildly delayed motor development associated with white matter abnormalities on brain MRI that improve with age. As children, some patients have mild residual hypotonia or clumsiness, but otherwise have no residual motor abnormalities. About 40% of patients have mental retardation (summary by van der Knaap et al., 2010 and Lopez-Hernandez et al., 2011). Homozygous or compound heterozygous mutations in the HEPACAM gene can cause a more severe and progressive disorder associated with ataxia, spasticity, and mental retardation (MLC2A; 613925). For a discussion of genetic heterogeneity of megalencephalic leukoencephalopathy with subcortical cysts, see MLC1 (604004). Clinical Features Lopez-Hernandez et al. (2011) reported 18 patients from 16 families with the remitting MLC2B phenotype. All developed macrocephaly within the first year of life; 2 showed subsequent normalization of head circumference. Most patients had delayed early motor and language development, which subsequently normalized in most, although some patients had mild hypotonia or clumsiness later in childhood. Intelligence was more variable: 11 had normal intelligence and 7 had mental retardation, associated with autism (209850) in 3. MRI initially showed diffuse swelling of the cerebral white matter and subcortical cysts in the anterior temporal lobe. There was involvement of the posterior limb of the internal capsule and the external capsule. Other changes included cavum septi pellucidi and cavum vergae, as well as cerebellar and brainstem involvement in some. These initial changes were similar to those seen in MLC2A. On follow-up, however, all patients showed major improvement in the MRI changes, with loss of white matter swelling, disappearance of cysts in some cases, and lack of involvement of other brain regions (van der Knaap et al., 2010). Inheritance The transmission pattern of MLC2B in the families reported by Lopez-Hernandez et al. (2011) was consistent with autosomal dominant inheritance with incomplete penetrance. Molecular Genetics In 18 patients from 16 families with remitting MLC2B, Lopez-Hernandez et al. (2011) identified a heterozygous mutation in the HEPACAM gene (see, e.g., 611642.0006-611642.0008). All the mutations were located in a putative extracellular interface of the first immunoglobulin domain. Eight of 11 parents with a mutant allele had macrocephaly, 1 had transient macrocephaly as a child, and 2 reportedly never had macrocephaly. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Macrocephaly NEUROLOGIC Central Nervous System \- Megalencephaly \- Delayed motor development \- Mental retardation (about 40%) \- Hypotonia (mild) \- Clumsiness (mild) \- Diffuse white matter abnormalities seen on brain MRI \- Diffuse swelling of cerebral white matter \- Cavum septi pellucidi \- Cavum Vergae \- Subcortical cysts temporal lobe MISCELLANEOUS \- Onset of macrocephaly in the first year of life \- Brain MRI abnormalities show improvement with time \- Brainstem, cerebellum, anterior inner rim of the corpus callosum, posterior limb of the internal capsule and the external capsule, and anterior inner rim of the corpus callosum may show disease involvement on MRI MOLECULAR BASIS \- Caused by mutation in the hepatocyte cell adhesion molecule gene (HEPACAM, 611642.0006 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH OR WITHOUT MENTAL RETARDATION	c1858854	5,017	omim	https://www.omim.org/entry/613926	2019-09-22T15:57:02	{"doid": ["0080317"], "mesh": ["C536141"], "omim": ["613926"], "orphanet": ["2478", "210548"], "genereviews": ["NBK1535"]}
Alström syndrome is a rare condition that affects many body systems. Many of the signs and symptoms of this condition begin in infancy or early childhood, although some appear later in life. Alström syndrome is characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), obesity, type 2 diabetes (the most common form of diabetes), and short stature. This disorder can also cause serious or life-threatening medical problems involving the liver, kidneys, bladder, and lungs. Some individuals with Alström syndrome have a skin condition called acanthosis nigricans, which causes the skin in body folds and creases to become thick, dark, and velvety. The signs and symptoms of Alström syndrome vary in severity, and not all affected individuals have all of the characteristic features of the disorder. ## Frequency More than 900 people with Alström syndrome have been reported worldwide. ## Causes Mutations in the ALMS1 gene cause Alström syndrome. The ALMS1 gene provides instructions for making a protein whose function is unknown. Mutations in this gene probably lead to the production of an abnormally short, nonfunctional version of the ALMS1 protein. This protein is normally present at low levels in most tissues, so a loss of the protein's normal function may help explain why the signs and symptoms of Alström syndrome affect many parts of the body. ### Learn more about the gene associated with Alström syndrome * ALMS1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Alström syndrome	c0268425	5,018	medlineplus	https://medlineplus.gov/genetics/condition/alstrom-syndrome/	2021-01-27T08:24:37	{"gard": ["5787"], "mesh": ["D056769"], "omim": ["203800"], "synonyms": []}
Wiedemann–Steiner syndrome Other namesHypertrichosis-short stature-facial dysmorphism-developmental delay syndrome[1] Wiedemann–Steiner syndrome is a rare genetic disorder that causes developmental delay, unusual facial features, short stature, and reduction in muscle tone (hypotonia). All cases reported so far are sporadic.[2] The syndrome was originally described in 1989[3] by Hans-Rudolf Wiedemann. The genetic basis for the syndrome was identified by Dr. Wendy D. Jones in 2012.[4] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 References * 7 External links ## Signs and symptoms[edit] Features described in Wiedemann–Steiner syndrome include:[5] * Short stature * Developmental delay * Low muscle tone (hypotonia) especially in infancy * Characteristic facial features * Hairy elbows (hypertrichosis cubiti) Wiedemann–Steiner syndrome may be related to global developmental delays, sleeping difficulties, feeding and digestion complexities, unusual facial features, short/petite stature, hypotonia, dental issues, hairy elbows, long eyelashes, etc.[6] ## Cause[edit] Wiedemann–Steiner syndrome results from mutations in the MLL (also known as KMT2A) gene on the long arm of chromosome 11.[4] The gene encodes a histone-modification enzyme — that is, it helps modify the expression of other genes.[7] The condition is autosomal dominant, meaning that only one abnormal copy of the gene is needed for a person to have the syndrome. In a majority of cases to date, the mutation occurred de novo — that is, neither parent was affected and the mutation is sporadic. Offspring of those with WSS have a 50% chance of having WSS.[6] The mechanism by which mutations in the MLL gene cause the phenotype of Wiedemann–Steiner syndrome is not yet known.[citation needed] ## Diagnosis[edit] If Wiedemann–Steiner syndrome is suspected, analysis of the MLL gene can be carried out. Otherwise, it may be diagnosed by whole-exome sequencing or whole genome sequencing. There is limited diagnostic testing in this area. The standard screening tests that take place during pregnancy that can diagnose syndromes such as Down Syndrome do not diagnose WSS. In addition, baseline genetics diagnostic tests conducted after birth do not include testing for WSS. Whole exome sequencing has been used to identify most people with WSS. Often, medical professionals do not offer the option for whole exome testing or the costs associated are not covered by insurance or require a large copay limiting individuals from having the testing done. Frequently, patients are given other incorrect medical explanations or a less specific and broader diagnosis, like autism and Rubinstein–Taybi syndrome. Additionally, once a person reaches a certain age or phase in their lifetime having been mis-diagnosed or gone undiagnosed, he/she may stop looking for answers to their medical trials and tribulations meaning they may never come across a formal WSS diagnosis.[6] There have also been patients with Wiedemann–Steiner syndrome who were initially mis-diagnosed with Kabuki syndrome.[8] ## Treatment[edit] There is no specific cure or treatment for Wiedemann–Steiner syndrome. Children with this condition may benefit from a range of supportive treatments such as physiotherapy, speech therapy, supplementary nutrition for poor feeding, and special educational support.[citation needed] Those affected with Wiedemann–Steiner syndrome often receive physical, occupational, speech, feeding, and/or behavioral therapies. Hippotherapy and music therapy have also been helpful to those affected by WSS. School-aged children affected with WSS may benefit from one-on-one aides, modified instruction, and/or special day class environments.[6] ## Epidemiology[edit] A few hundred people have been documented with the condition worldwide. Once thought to have an incidence of 1 in 1,000,000, some research has suggested the incidence may be as high as 1 in 40,000[citation needed] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Wiedemann Steiner syndrome". www.orpha.net. Retrieved 14 March 2019. 2. ^ "Error 403". 3. ^ Wiedemann H-R, Kunze J, Dibbern H. 1989. Atlas der klinischen Syndrome für Klinik und Praxis 3rd edition. Stuttgart: Schattauer. pp 198–199. ISBN 9783794516827 4. ^ a b Jones, WD; Dafou, D; McEntagart, M; Woollard, WJ; Elmslie, FV; Holder-Espinasse, M; Irving, M; Saggar, AK; Smithson, S; Trembath, RC; Deshpande, C; Simpson, MA (10 August 2012). "De novo mutations in MLL cause Wiedemann–Steiner syndrome". American Journal of Human Genetics. 91 (2): 358–64. doi:10.1016/j.ajhg.2012.06.008. PMC 3415539. PMID 22795537. 5. ^ Steiner, CE; Marques, AP (April 2000). "Growth deficiency, mental retardation and unusual facies". Clinical Dysmorphology. 9 (2): 155–6. doi:10.1097/00019605-200009020-00021. PMID 10826636. 6. ^ a b c d "What is Wiedemann–Steiner Syndrome? – WSS Foundation". WSS Foundation. Retrieved 2017-10-28. 7. ^ "Error 403". 8. ^ Miyake, N., Tsurusaki, Y., Koshimizu, E., Okamoto, N., Kosho, T., Brown, N.J., Tan, T.Y., Yap, P.J.J., Suzumura, H., Tanaka, T., Nagai, T., Nakashima, M., Saitsu, H., Niikawa, N. and Matsumoto, N. (January 2016). "Delineation of clinical features in Wiedemann–Steiner syndrome caused by KMT2A mutations". Clinical Genetics. 89 (1): 115–119. doi:10.1111/cge.12586. PMID 25810209.CS1 maint: multiple names: authors list (link) ## External links[edit] * WIEDEMANN–STEINER SYNDROME; WDSTS * Wiedemann–Steiner syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Wiedemann–Steiner syndrome	c1854630	5,019	wikipedia	https://en.wikipedia.org/wiki/Wiedemann%E2%80%93Steiner_syndrome	2021-01-18T18:48:51	{"gard": ["5565"], "mesh": ["C565358"], "umls": ["C1854630", "C2931294"], "orphanet": ["319182"], "wikidata": ["Q24975353"]}
Primary mediastinal (thymic) large B cell lymphoma Other namesMediastinal large B cell lymphoma, primary mediastinal large B-cell lymphoma (PMLBCL), mediastinal large B-cell lymphoma SpecialtyHematology, oncology Primary mediastinal (thymic) large B-cell lymphoma is a distinct type of diffuse large B-cell lymphoma involving the mediastinum, recognized in the WHO 2008 classification.[1][2]:370–374 ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Treatment * 4 Epidemiology * 5 Grey zone lymphoma * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Superior vena cava syndrome occurs in 30–50%, and pleural or pericardial effusions occur in about one-third.[3] ## Pathophysiology[edit] PMLBCL arises from a putative thymic peripheral B cell.[3][4] It has several distinctive biological features.[3] Molecular analysis shows that PMLBCL is distinct from other types of diffuse large B-cell lymphomas (DLBCL).[4] MAL gene expression is seen in 70%, unlike other diffuse large B-cell lymphomas.[2]:370 Gene expression profiling shows considerable variance from other DLBCLs and similarity to Hodgkin disease.[5]:290–293 PMLBCL is CD20 positive, expresses pan-B markers including CD79a, and has clonal immunoglobulin gene rearrangements and mRNA but paradoxically does not express cytoplasmic or cell surface immunoglobulin.[2]:370 Clinically, PMLBCL is unusual in several respects. Despite 80% PMLBCL being stage I or II, the presenting anterior mediastinal mass is often over 10 cm and is locally invasive of lung, chest wall, pleura, and pericardium.[3] At initial presentation, PMLBCL is usually confined to mediastinum, but its bulk, rather than additional adenopathy, can sometimes be palpated at the low neck.[3] Increased LDH is seen in approximately 75%,[2]:370[3] but unlike other large cell lymphomas, no increase in beta-2 microglobulin is seen even when bulky[2]:370 which may relate to defective major histocompatibility complex expression.[2]:370 ## Treatment[edit] Multiagent chemotherapy is recommended, but the preferred regimen is controversial, as is consolidative radiotherapy.[3][6][7][8] ## Epidemiology[edit] It affects primarily young adults; the median age is 37 years.[2]:370 It is more common in females.[3] ## Grey zone lymphoma[edit] This section needs expansion. You can help by adding to it. (March 2015) "In-between CHD and NHL"[3][6][9][10] ## See also[edit] * Lymphoma * Diffuse large B cell lymphoma ## References[edit] 1. ^ Swerdlow, Steven H.; International Agency for Research on Cancer; World Health Organization (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours. 2 (4th ed.). International Agency for Research on Cancer. ISBN 9789283224310. 2. ^ a b c d e f g Jaffe, ES; Harris NL; Vardiman JW; Campo E; Arber DA (2011). Hematopathology (1st ed.). Elsevier Saunders. ISBN 9780721600406. 3. ^ a b c d e f g h i Armitage, JO; Mauch PM; Harris NL; et al. (2010). "Chapter 21". Non-Hodgkin Lymphomas (2nd ed.). Lippincott Williams & Wilkins. ISBN 9780781791168. 4. ^ a b Martelli M, Di Rocco A, Russo E, et al. (2015). "Primary mediastinal lymphoma: diagnosis and treatment options". Expert Rev Hematol. 8 (2): 173–86. doi:10.1586/17474086.2015.994604. hdl:11573/780924. PMID 25537750. 5. ^ Sweetenham, J. Lymphomas (Emerging Cancer Therapeutics V3 I2). Demos. November 2, 2012. ISBN 9781936287789 6. ^ a b http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf 7. ^ Faris JE, LaCasce AS (2009). "Primary mediastinal large B-cell lymphoma". Clin Adv Hematol Oncol. 7 (2): 125–33. PMID 19367254. 8. ^ Dabrowska-Iwanicka A, Walewski JA (2014). "Primary mediastinal large B-cell lymphoma". Curr Hematol Malig Rep. 9 (3): 273–83. doi:10.1007/s11899-014-0219-0. PMC 4180024. PMID 24952250. 9. ^ Hutchinson CB, Wang E (2011). "Primary mediastinal (thymic) large B-cell lymphoma: a short review with brief discussion of mediastinal gray zone lymphoma". Arch. Pathol. Lab. Med. 135 (3): 394–8. doi:10.1043/2009-0463-RSR.1. PMID 21366467. 10. ^ Grant C, Dunleavy K, Eberle FC, et al. (2011). "Primary mediastinal large B-cell lymphoma, classic Hodgkin lymphoma presenting in the mediastinum, and mediastinal gray zone lymphoma: what is the oncologist to do?". Curr Hematol Malig Rep. 6 (3): 157–63. doi:10.1007/s11899-011-0090-1. PMC 6324553. PMID 21590365. ## External links[edit] Classification D * ICD-O: 9679/3 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Primary mediastinal (thymic) large B cell lymphoma	c1292754	5,020	wikipedia	https://en.wikipedia.org/wiki/Primary_mediastinal_(thymic)_large_B_cell_lymphoma	2021-01-18T18:59:48	{"umls": ["C1292754"], "wikidata": ["Q6806161"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (April 2015) HIV associated cardiomyopathy SpecialtyCardiology Heart problems are more common in people with HIV/AIDS. Those with left ventricular dysfunction have a median survival of 101 days as compared to 472 days in people with AIDS with healthy hearts.[1] HIV is a major cause of cardiomyopathy (problems with the heart muscle that reduce the efficiency with which the heart pumps blood). The most common type of HIV induced cardiomyopathy is dilated cardiomyopathy also known as eccentric ventricular hypertrophy which leads to impaired contraction of the ventricles due to volume overload. The annual incidence of HIV associated dilated cardiomyopathy was 15.9/1000 before the introduction of highly active antiretroviral therapy (HAART).[2] However, in 2014, a study found that 17.6% of HIV patients have dilated cardiomyopathy (176/1000) meaning the incidence has greatly increased.[3] ## Contents * 1 Presentation * 2 Cause * 2.1 Myocarditis * 2.2 Myocardial cytokine expression * 2.3 Autoimmune cardiomyopathy * 2.4 Encephalopathy * 2.5 Drug cardiotoxicity * 3 Treatment * 4 References ## Presentation[edit] Signs and symptoms such as malabsorption and diarrhea respectively, may occur with HIV infection causing many HIV patients to have nutritional deficiencies and altered levels of vitamin B12, carnitine, and growth and thyroid hormones - all have been associated with left ventricular dysfunction.[4] A lowered BMI in HIV patients is also associated with cardiomyopathy.[5] ## Cause[edit] Dilated cardiomyopathy can be due to pericardial effusion or infective endocarditis, especially in intravenous drug users which are common in the HIV population.[6][7] However, the most researched cause of cardiomyopathy is myocarditis (myocardial inflammation and infection) caused by HIV-1, which the main subtype of HIV (the other being HIV-2), with greater likelihood of transmission and shorter period between infection and illness. HIV-1 virions infect cardiomyocytes in patches but there is no direct correlation between viral infection and dysfunction of cardiomyocytes. HIV-related cardiomyopathy is often not associated with any specific opportunistic infection, and approximately 40% of patients have not experienced any opportunistic infection before the onset of cardiac symptoms.[8][9] ### Myocarditis[edit] Myocarditis has been documented at autopsy in 40–52% of patients who died of AIDS before the introduction of HAART.[10] Toxoplasma gondii is the most common opportunistic infectious agent associated with myocarditis in AIDS occurring in 12% of deaths from AIDS 1987-1991 in one autopsy series.[11] Myocardial toxoplasmosis causes an increase in the myocardial fraction of creatine kinase (CK-MB). In situ hybridization or polymerase chain reaction studies illustrate a high frequency of cytomegalovirus and HIV-1 in AIDS patients with lymphocytic myocarditis and severe left ventricular dysfunction.[12][13] Thus, it supports the hypothesis that HIV-1 has a pathogenetic action and influences dilated cardiomyopathy. Coinfection with viruses (usually, coxsackievirus B3 and cytomegalovirus) seems to have an important effect as the GISCA autopsy records show that 83% of patients with myocarditis and 50% with dilated cardiomyopathy were coinfected with viruses.[14] ### Myocardial cytokine expression[edit] HIV-1 invades the myocardium through endothelial cells by micropinocytosis infecting perivascular macrophages which produce additional virus and cytokines such as tumour necrosis factor-α (TNF-α). This induces cardiomyocyte apoptosis either by signalling through CCR3, CCR5 or CXCR4, by entry into cardiomyocytes (after binding to ganglioside GM1), or through TNF-α.[15][16] In addition, HIV-1-associated protein gp 120 may induce apoptosis through a mitochondrion-controlled pathway after activating inflammatory cytokines.[17] TNF-α is produced by infected macrophages and the interaction between dendritic cells presenting the antigen to CD8 (T Killer cells).[18][19] It causes a negative inotropic effect by interfering with the intracellular calcium ion concentrations perhaps by inducing the synthesis of nitric oxide (NO), also decreasing contractility.[20][21] The intensity of the stains for TNF-α and inducible nitric oxide synthase (iNOS) of the myocardium was greater in patients with HIV associated cardiomyopathy (as opposed to idiopathic cardiomyopathy), myocardial viral infection and was inversely correlated with CD4 count with antiretroviral therapy having no effect.[citation needed] ### Autoimmune cardiomyopathy[edit] Cardiac autoimmunity affects the pathogenesis of HIV-related heart disease as HIV-infected patients with dilated cardiomyopathy are more likely to have cardiac-specific autoantibodies (anti-α-myosin autoantibodies) than HIV-infected patients with healthy hearts and HIV-negative controls.[22] In addition, patients with echocardiographic evidence of left ventricular dysfunction had a higher chance of having cardiac autoantibodies. Furthermore, impaired myocardial growth and left ventricular dysfunction may be immunologically mediated as monthly intravenous immunoglobulins (IVIG) in HIV-infected children reduces left ventricular dysfunction, increases left ventricular wall thickness, and reduces peak left ventricular wall stress. Perhaps this is because immunoglobulins inhibit the cardiac autoantibodies by competing for Fc receptors. Alternatively, the immunoglobulins can reduce the effects or secretions of cytokines and cellular growth factors.[23] ### Encephalopathy[edit] HIV-infected patients with encephalopathy are more likely to die of congestive heart failure than are those without encephalopathy; the hazard ratio is 3.4.[24][25] Cardiomyopathy and encephalopathy are hypothesised to be linked by the HIV reservoir cells which are in the myocardium and cerebral cortex and keep HIV-1 on their surfaces for long periods of time even after receiving HAART. They also secrete TNF-α, interleukin-6 (IL-6) and endothelin-1 which are cytotoxic cytokines causing tissue damage.[citation needed] ### Drug cardiotoxicity[edit] Zidovudine is an example of a nucleoside analogue and has been shown to cause: myocarditis and dilated cardiomyopathy as well as an increase in total cholesterol, triglycerides, LDL, HDL and insulin resistance.[26][27] Protease inhibitors are another group of drugs (e.g. ritonavir) and some of them can cause a range of problems such as: lipodystrophy, atherosclerosis, increase total cholesterol, triglyceride, HDL, LDL, and insulin resistance. Amphotericin B can cause dilated cardiomyopathy, hypertension and bradycardia whereas, Ganciclovir can cause ventricular tachycardia. Interferon-alpha can cause arrhythmia and myocardial infarction/ischemia.[28][29] ## Treatment[edit] Mortality in HIV-infected patients with cardiomyopathy is increased independently of CD4 count, age, sex, and HIV risk group.[30][31] The therapy is similar to therapy for non-ischemic cardiomyopathy: after medical therapy is begun, serial echocardiographic studies should be performed at 4-months intervals. If function continues to worsen or the clinical course deteriorates, a biopsy should be considered.[32][33] HAART has reduced the incidence of myocarditis thus reducing the prevalence of HIV-associated cardiomyopathy by about 30% in developed countries.[34][35] However, the prevalence in developing countries is 32% and increasing as HAART is scarce – not to mention the effects of other risk factors such as high cholesterol and lipid diet.[36] IVIGs can also help patients with HIV-associated myocarditis as mentioned earlier.[citation needed] ## References[edit] 1. ^ Barbarini G, Barbaro G. Incidence of the involvement of the cardiovascular system in HIV infection. AIDS 2003;17:Suppl 1:S46–50. 2. ^ Barbarini G, Barbaro G. Incidence of the involvement of the cardiovascular system in HIV infection. AIDS 2003;17:Suppl 1:S46–50. 3. ^ Jain N, Reddy DH, Verma SP, Khanna R, Vaish AK, Usman K, Tripathi AK, Singh A, Mehrotra S, Gupta A. Cardiac Abnormalities in HIV-Positive Patients: Results from an Observational Study in India. J Int Assoc Provid AIDS Care. 2014 Jan-Feb;13(1):40-6. 4. ^ Miller TL, Orav EJ, Colan SD, et al. Nutritional status and cardiac mass and function in children infected with the human immunodeficiency virus. Am J Clin Nutr 1997;66:660–4. 5. ^ Lemmer CE, Badri M, Visser M, Mayosi BM. A lower body mass index is associated with cardiomyopathy in people with HIV infection: evidence from a case comparison study. S Afr Med J. 2011 Feb;101(2):119-21. 6. ^ Barbaro G, Di Lorenzo G, Grisorio B, et al., and the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. Cardiac involvement in the acquired immunodeficiency syndrome: a multicentre clinical-pathological study. AIDS Res Hum Retroviruses 1998;14:1071–7. 7. ^ Klatt EC. Cardiovascular pathology in AIDS. Adv Cardiol 2003;40:23–48. 8. ^ Barbaro et.al., Incidence of Dilated Cardiomyopathy and Detection of HIV in Myocardial Cells of HIV-positive patients, NEJM 2002;347(2):140. 9. ^ Braunwald’s, Heart Disease A Textbook of Cardiovascular Medicine, Volume II, 1793-1805. 10. ^ Klatt EC, Nichols L, Noguchi TT. Emerging patterns of heart disease in human immunodeficiency virus infection. Hum Pathol 1994;118:884–90. 11. ^ Klatt EC, Nichols L, Noguchi TT. Emerging patterns of heart disease in human immunodeficiency virus infection. Hum Pathol 1994;118:884–90. 12. ^ Barbaro G, Di Lorenzo G, Grisorio B, et al., and the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. Cardiac involvement in the acquired immunodeficiency syndrome: a multicentre clinical-pathological study. AIDS Res Hum Retroviruses 1998;14:1071–7. 13. ^ Herskowitz A, Tzyy-Choou W, Willoughby SB, et al. Myocarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus. J Am Coll Cardiol 1994;24:1025–32. 14. ^ Barbaro G, Di Lorenzo G, Grisorio B, et al., and the Gruppo Italiano per lo Studio Cardiologico dei pazienti affetti da AIDS Investigators. Cardiac involvement in the acquired immunodeficiency syndrome: a multicentre clinical-pathological study. AIDS Res Hum Retroviruses 1998;14:1071–7. 15. ^ Fiala M, Popik W, Qiao J-H, et al. HIV-1 induces cardiomyopathy by cardiomyocyte invasion and gp120,Tat, and cytokine apoptotic signaling. Cardiovasc Toxicol 2004;4:97–107. 16. ^ Twu C, Liu QN, Popik W, et al. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion and death receptor- controlled pathways. Proc Natl Acad Sci USA 2002;99:14386–91. 17. ^ Twu C, Liu QN, Popik W, et al. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion and death receptor- controlled pathways. Proc Natl Acad Sci USA 2002;99:14386–91. 18. ^ Liu QN, Reddy S, Sayre JW, et al. Essential role of HIV-1 infected and cyclooxygenase 2 activated macrophages and T cells in HIV type 1 myocarditis. AIDS Res Hum Retroviruses 2001;17:1423–33. 19. ^ Matsumori A. Cytokines in myocarditis and cardiomyopathy. Curr Opin Cardiol 1996;11:302–9. 20. ^ Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387–9. 21. ^ Yokohama T, Vaca L, Rossen RD, et al. Cellular basis for the negative inotropic effect of tumor necrosis factor alpha in the adult mammalian heart. J Clin Invest 1993;92:2303–12. 22. ^ Currie PF, Goldman JH, Caforio AL, et al. Cardiac autoimmunity in HIV related heart muscle disease. Heart 1998;79:599–604. 23. ^ Lipshultz SE, Easley KA, Orav EJ, et al. Cardiac dysfunction and mortality in HIV-infected children. The Prospective P2C2 HIV Multicenter Study. Circulation 2000;102:1542–8. 24. ^ Cooper ER, Hanson C, Diaz C, et al. Encephalopathy and progression of human immunodeficiency virus disease in a cohort of children with perinatally acquired human immunodeficiency virus infection. J Pediatr 1998;132:808–12. 25. ^ Lipshultz SE, Easley KA, Orav EJ, et al. Left ventricular structure and function in children infected with human immunodeficiency virus. The prospective P2C2 HIV multicenter study. Circulation 1998;97:1246–56. 26. ^ Lewis W, Grupp IL, Grupp G, et al. Cardiac dysfunction in the HIV-1 transgenic mouse treated with zidovudine. Lab Invest 2000;80:187–97. 27. ^ Lewis W, Simpson JF, Meyer RR. Cardiac mitochondrial DNA polymerase gamma is inhibited competitively and noncompetitively by phosphorylated zidovudine. Circ Res 1994;74:344–8. 28. ^ Barbaro et.al., Incidence of Dilated Cardiomyopathy and Detection of HIV in Myocardial Cells of HIV-positive patients, NEJM 2002;347(2):140 29. ^ Braunwald’s, Heart Disease A Textbook of Cardiovascular Medicine, Volume II, 1793-1805 30. ^ Barbaro et.al., Incidence of Dilated Cardiomyopathy and Detection of HIV in Myocardial Cells of HIV-positive patients, NEJM 2002;347(2):140. 31. ^ Braunwald’s, Heart Disease A Textbook of Cardiovascular Medicine, Volume II, 1793-1805. 32. ^ Barbaro et.al., Incidence of Dilated Cardiomyopathy and Detection of HIV in Myocardial Cells of HIV-positive patients, NEJM 2002;347(2):140. 33. ^ Braunwald’s, Heart Disease A Textbook of Cardiovascular Medicine, Volume II, 1793-1805. 34. ^ Bijl M, Dieleman JP, Simoons M, et al. Low prevalence of cardiac abnormalities in an HIV-seropositive population on antiretroviral combination therapy. J Acquir Immune Defic Syndr 2001;27:318–20. 35. ^ Pugliese A, Isnardi D, Saini A, et al. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect 2000;40:282–4. 36. ^ Nzuobontane D, Blackett KN, Kuaban C. Cardiac involvement in HIV-infected people in Yaounde, Cameroon. Postgrad Med J 2002;78:678–81. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	HIV associated cardiomyopathy	c2721728	5,021	wikipedia	https://en.wikipedia.org/wiki/HIV_associated_cardiomyopathy	2021-01-18T19:07:14	{"umls": ["C2721728"], "wikidata": ["Q18210950"]}
Omenn syndrome is an inherited disorder of the immune system (immunodeficiency). Omenn syndrome is one of several forms of severe combined immunodeficiency (SCID), a group of disorders that cause individuals to have virtually no immune protection from bacteria, viruses, and fungi. Individuals with SCID are prone to repeated and persistent infections that can be very serious or life-threatening. Infants with Omenn syndrome typically experience pneumonia and chronic diarrhea. Often the organisms that cause infection in people with this disorder are described as opportunistic because they ordinarily do not cause illness in healthy people. In addition to immunodeficiency, children with Omenn syndrome develop autoimmunity, in which the immune system attacks the body's own tissues and organs. This abnormal immune reaction can cause very red skin (erythroderma), hair loss (alopecia), and an enlarged liver and spleen (hepatosplenomegaly). In addition, affected individuals have enlargement of tissues that produce infection-fighting white blood cells called lymphocytes. These include the thymus, which is a gland located behind the breastbone, and lymph nodes, which are found throughout the body. If not treated in a way that restores immune function, children with Omenn syndrome usually survive only until age 1 or 2. ## Frequency Overall, the various forms of SCID are estimated to affect 1 in 75,000 to 100,000 newborns. The exact prevalence of Omenn syndrome is unknown. ## Causes Mutations in several genes involved in immune system function can cause Omenn syndrome. The two most frequent causes are mutations in the RAG1 and RAG2 genes. These genes provide instructions for making proteins that are active in two types of lymphocytes called B cells and T cells. To help fight infections, B cells and T cells have special proteins on their surface that help them recognize foreign invaders; these proteins must be somewhat different from each other to be able to recognize a wide variety of substances. The RAG1 and RAG2 proteins help increase the diversity of proteins that are on the surface of these cells. RAG1 and RAG2 gene mutations that cause Omenn syndrome drastically reduce the respective protein's function. As a result, the diversity of proteins on the surface of B cells and T cells is severely limited, impairing the cells' ability to recognize foreign invaders and fight infections. The abnormal B cells and T cells result in the frequent, life-threatening infections of Omenn syndrome. The decrease in lymphocyte function leads to a reduction in the numbers of B cells. The number of T cells is typically normal, although they are highly similar because they are derived from just a few functional precursor cells. The abnormal T cells attack the body's own cells and tissues, accounting for the autoimmune features of Omenn syndrome. ### Learn more about the genes associated with Omenn syndrome * CARD11 * IL7R * RAG1 * RAG2 Additional Information from NCBI Gene: * DCLRE1C * LIG4 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Omenn syndrome	c2700553	5,022	medlineplus	https://medlineplus.gov/genetics/condition/omenn-syndrome/	2021-01-27T08:24:58	{"gard": ["8198"], "mesh": ["D016511"], "omim": ["603554"], "synonyms": []}
A number sign (#) is used with this entry because spastic paraplegia-26 (SPG26) is caused by homozygous or compound heterozygous mutation in the B4GALNT1 gene (601873) on chromosome 12q13. Description SPG26 is an autosomal recessive form of complicated spastic paraplegia characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive (summary by Boukhris et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800). Clinical Features Farag et al. (1994) reported a consanguineous Kuwaiti family in which 5 sibs had complicated spastic paraplegia. At age 8 years, the proband developed progressive dysarthria and walking difficulties with high step and frequent falls. Clinical examination at age 13 years showed spastic paraparesis, scissor gait, toe walking, brisk reflexes, extensor plantar responses and pes cavus, and wasting of the small muscles of the hands and feet. Cerebellar function, EEG, and nerve conduction velocities were all normal. The clinical phenotype was similar in all affected sibs. Wilkinson et al. (2005) reported that mild intellectual impairment was present in some affected individuals. Boukhris et al. (2013) reported 5 families in which several family members had autosomal recessive spastic paraplegia. The families were from various countries of origin, including Spain, Tunisia, Brazil, Portugal, and Germany. Several of the families were consanguineous. Patients had onset in the first or second decades (range, 2 to 19 years) of gait abnormalities due to lower limb spasticity, hyperreflexia, extensor plantar responses, muscle weakness and atrophy, and mild to moderate intellectual disability. About a third of patients also had mild upper limb involvement. Other features were more variable, including decreased vibration sense at the ankles, pseudobulbar dysarthria, pes cavus, scoliosis, urinary symptoms, dyskinesia, dystonia, cataracts, and cerebellar signs. Four males had decreased testosterone, and 1 female had early menopause. EMG in many patients showed an axonal sensorimotor neuropathy, and brain MRI showed cortical atrophy and white matter hyperintensities. Two additional patients were later identified from a cohort of 65 index cases. The severity was variable; 4 patients became wheelchair-bound or bedridden after many years. Hyporeflexia became apparent later in the disease course. Inheritance The transmission pattern of SPG26 in the families reported by Boukhris et al. (2013) was consistent with autosomal recessive inheritance. Mapping In a follow-up study of the family reported by Farag et al. (1994), Wilkinson et al. (2005) identified a putative 22.8-cM disease locus on chromosome 12p11.1-q14 between markers D12S59 and D12S1676 (multipoint lod score of 5.1). No mutations were identified in the KIF5A gene (602821), which lies within this region. Molecular Genetics By exome sequencing of 5 families with autosomal recessive SPG, Boukhris et al. (2013) identified 5 different homozygous mutations in the B4GALNT1 gene. The mutations segregated with the disorder in the family and were not found in large control databases. Subsequent analysis of this gene identified mutations in 2 of 65 additional probands with a similar disorder. All mutations were truncating, except for 2 missense mutations that occurred at highly conserved residues (see, e.g., 601873.0001-601873.0005). No functional studies were performed. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Cataracts (in some patients) \- Nystagmus (in some patients) \- Saccadic pursuit (in some patients) GENITOURINARY Bladder \- Urinary urgency (in some patients) SKELETAL Spine \- Scoliosis Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Distal amyotrophy, especially of the hands and feet NEUROLOGIC Central Nervous System \- Lower limb spasticity \- Difficulty walking \- Toe-walking \- Spastic gait \- Frequent falls \- Upper limb involvement (in some patients) \- Hyperreflexia \- Extensor plantar responses \- Dysarthria \- Mental retardation, mild to moderate \- Cerebellar signs (in some patients) \- Ataxia \- Dysmetria \- Dystonia \- Dyskinesias \- Cortical atrophy \- White matter hyperintensities Peripheral Nervous System \- Sensorimotor axonal neuropathy (in some patients) \- Hyporeflexia (later in disease course) Behavioral Psychiatric Manifestations \- Emotional lability ENDOCRINE FEATURES \- Decreased testosterone (in some patients) MISCELLANEOUS \- Onset in first or second decades of life \- Slowly progressive disorder MOLECULAR BASIS \- Caused by mutation in the beta-1,4-N-acetylgalactosaminyltransferase 1 gene (B4GALNT1, 601873.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SPASTIC PARAPLEGIA 26, AUTOSOMAL RECESSIVE	c1836632	5,023	omim	https://www.omim.org/entry/609195	2019-09-22T16:06:33	{"doid": ["0110777"], "mesh": ["C536862"], "omim": ["609195"], "orphanet": ["101006"]}
RAPADILINO syndrome is a rare condition that involves many parts of the body. Bone development is especially affected, causing many of the characteristic features of the condition. Most affected individuals have underdevelopment or absence of the bones in the forearms and the thumbs, which are known as radial ray malformations. The kneecaps (patellae) can also be underdeveloped or absent. Other features include an opening in the roof of the mouth (cleft palate) or a high arched palate; a long, slender nose; and dislocated joints. Many infants with RAPADILINO syndrome have difficulty feeding and experience diarrhea and vomiting. The combination of impaired bone development and feeding problems leads to slow growth and short stature in affected individuals. Some individuals with RAPADILINO syndrome have harmless light brown patches of skin that resemble a skin finding known as café-au-lait spots. In addition, people with RAPADILINO syndrome have a slightly increased risk of developing a type of bone cancer known as osteosarcoma or a blood-related cancer called lymphoma. In individuals with RAPADILINO syndrome, osteosarcoma most often develops during childhood or adolescence, and lymphoma typically develops in young adulthood. The condition name is an acronym for the characteristic features of the disorder: RA for radial ray malformations, PA for patella and palate abnormalities, DI for diarrhea and dislocated joints, LI for limb abnormalities and little size, and NO for slender nose and normal intelligence. The varied signs and symptoms of RAPADILINO syndrome overlap with features of other disorders, namely Baller-Gerold syndrome and Rothmund-Thomson syndrome. These syndromes are also characterized by radial ray defects, skeletal abnormalities, and slow growth. All of these conditions can be caused by mutations in the same gene. Based on these similarities, researchers are investigating whether Baller-Gerold syndrome, Rothmund-Thomson syndrome, and RAPADILINO syndrome are separate disorders or part of a single syndrome with overlapping signs and symptoms. ## Frequency RAPADILINO syndrome is a rare condition, although its worldwide prevalence is unknown. The condition was first identified in Finland, where it affects an estimated 1 in 75,000 individuals, although it has since been found in other regions. ## Causes Mutations in the RECQL4 gene cause RAPADILINO syndrome. This gene provides instructions for making one member of a protein family called RecQ helicases. Helicases are enzymes that bind to DNA and temporarily unwind the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for copying (replicating) DNA in preparation for cell division and for repairing damaged DNA. The RECQL4 protein helps stabilize genetic information in the body's cells and plays a role in replicating and repairing DNA. The most common RECQL4 gene mutation involved in RAPADILINO syndrome causes the RECQL4 protein to be pieced together incorrectly. This genetic change results in the production of a protein that is missing a region called exon 7 and is unable to act as a helicase. The loss of helicase function may prevent normal DNA replication and repair, causing widespread damage to a person's genetic information over time. These changes may result in the accumulation of DNA errors and cell death, although it is unclear exactly how RECQL4 gene mutations lead to the specific features of RAPADILINO syndrome. ### Learn more about the gene associated with RAPADILINO syndrome * RECQL4 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	RAPADILINO syndrome	c1849453	5,024	medlineplus	https://medlineplus.gov/genetics/condition/rapadilino-syndrome/	2021-01-27T08:24:47	{"gard": ["4637"], "mesh": ["C535288"], "omim": ["266280"], "synonyms": []}
A number sign (#) is used with this entry because nephrotic syndrome type 1 (NPHS1), also known as Finnish congenital nephrosis, is caused by homozygous or compound heterozygous mutation in the gene encoding nephrin (NPHS1; 602716) on chromosome 19q13. Description The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996). Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (Kestila et al., 1998). Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature. ### Genetic Heterogeneity of Nephrotic Syndrome and Focal Segmental Glomerulosclerosis Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also NPHS2 (600995), caused by mutation in the podocin gene (604766); NPHS3 (610725), caused by mutation in the PLCE1 gene (608414); NPHS4 (256370), caused by mutation in the WT1 gene (607102); NPHS5 (614199), caused by mutation in the LAMB2 gene (150325); NPHS6 (614196), caused by mutation in the PTPRO gene (600579); NPHS7 (615008), caused by mutation in the DGKE gene (601440); NPHS8 (615244), caused by mutation in the ARHGDIA gene (601925); NPHS9 (615573), caused by mutation in the COQ8B gene (615567); NPHS10 (615861), caused by mutation in the EMP2 gene (602334); NPHS11 (616730), caused by mutation in the NUP107 gene (607617); NPHS12 (616892), caused by mutation in the NUP93 gene (614351); NPHS13 (616893), caused by mutation in the NUP205 gene (614352); NPHS14 (617575), caused by mutation in the SGPL1 gene (603729); NPHS15 (617609), caused by mutation in the MAGI2 gene (606382); NPHS16 (617783), caused by mutation in the KANK2 gene (614610), NPHS17 (618176), caused by mutation in the NUP85 gene (170285); NPHS18 (618177), caused by mutation in the NUP133 gene (607613); NPHS19 (618178), caused by mutation in the NUP160 gene (607614); and NPHS20 (301028), caused by mutation in the TBC1D8B gene (301027). FSGS1 (603278) is caused by mutation in the ACTN4 gene (604638) and FSGS2 (603965) by mutation in the TRPC6 gene (603652). FSGS3 (607832) is associated with variation in the CD2AP gene (604241). FSGS4 (612551) has been mapped to chromosome 22q12, and FSGS5 (613237) is caused by mutation in the INF2 gene (610982). Clinical Features Ongre (1961) described sibs with nephrosis starting in the neonatal period associated with cystic-like dilation of renal tubules. In a review of Finnish congenital nephrosis, Tryggvason et al. (2006) noted that affected persons have massive proteinuria in utero and the nephrotic syndrome develops soon after birth. Affected children are usually born prematurely, and the weight of the placenta is almost invariably more than 25% of the weight of the child at birth. Hypoalbuminemia, hyperlipidemia, abdominal distention, and edema appear soon after birth. Electron microscopic studies of the kidney show effacement of the podocytes, a narrow slit, and absence of the slit diaphragm. The disorder is lethal; immunosuppressive therapy does not induce a remission. Successful kidney transplant is curative, although there is a risk of recurrence of nephrotic syndrome after transplantation. At least half the patients with recurrence have circulating antinephrin antibodies, which probably have a pathogenic role in the recurrence. ### Clinical Variability Kitamura et al. (2007) reported a Japanese brother and sister, aged 11 years and 4 years, respectively, who had nephrotic syndrome in infancy and achieved partial remission without immunosuppressive therapy, with only mild relapsing proteinuria associated with upper respiratory infections thereafter. The sibs had normal growth, and renal function was preserved in both. Renal biopsies from the brother at ages 2 months and 5 years showed minimal-change histology; electron microscopy revealed diffuse podocyte foot process effacement with no other significant ultrastructural abnormalities. Immunohistochemical staining of the biopsy specimen showed nephrin and podocin in a continuous linear pattern along the glomerular capillary loops with an intensity comparable to control tissue, suggesting that foot process integrity was fairly well preserved. Genetic analysis identified compound heterozygosity for missense mutations in the nephrin gene (602716.0008 and 602716.0009). Other Features Twelve percent of 41 infants with congenital nephrotic syndrome described by Mahan et al. (1984) presented with pyloric stenosis. Grahame-Smith et al. (1988) described twins with Finnish congenital nephrosis. One twin was stillborn; the second presented with a diagnosis of pyloric stenosis. Inheritance Nephrotic syndrome type 1 is an autosomal recessive disorder (Kestila et al., 1998). Diagnosis ### Prenatal Diagnosis Seppala et al. (1976) demonstrated that this disorder can be diagnosed antenatally by elevated levels of alpha-fetoprotein (AFP; 104150) in amniotic fluid. Morris et al. (1995) described congenital Finnish nephrosis in 2 of 3 successive pregnancies of a nonconsanguineous couple with no known Finnish ancestry. They confirmed the usefulness of amniotic fluid alpha-fetoprotein determination in the prenatal diagnosis, since the fetus loses large amounts of AFP in the urine due to kidney damage. Clinical Management NPHS1 is a form of steroid-resistant nephrotic syndrome. Mahan et al. (1984) found that steroids or cytotoxic drugs, alone or in combination, were without benefit in 41 patients with congenital nephrotic syndrome. Intensive medical therapy to control bacterial infections, combined with renal transplantation, was judged to offer a good opportunity for survival with an acceptable quality of life for infants with congenital nephrotic syndrome. Pathogenesis Using radioimmunoassay methods, Risteli et al. (1982) found an accumulation of type IV collagen in the renal cortex in renal biopsies from patients with congenital nephrotic syndrome. The accumulation of the collagen was out of proportion to another basement membrane protein, laminin. They interpreted this to mean that metabolism of type IV collagen is disturbed in this disorder. The normal barrier to penetration of the renal glomerular basement membrane by anionic plasma proteins depends in part on the existence of negatively charged sites within the membrane (Cotran and Rennke, 1983). Vernier et al. (1983) found that normal subjects had anionic sites distributed at regular intervals in the lamina rara externa, with a frequency of 23.8 sites per 1,000 nm length of membrane, whereas 5 patients with congenital nephrosis had 8.9 sites. An in vitro histochemical technique was used in these studies. Vernier et al. (1983) concluded that the basic defect in congenital nephrosis is failure of heparan sulfate-rich anionic sites to develop in the lamina rara externa of the glomerular basement membrane. Tryggvason et al. (2006) stated that Finnish congenital nephrosis is caused by the absence of functional nephrin, which leads to the absence or malfunction of the slit diaphragm and loss of the size-selective slit filter. Mapping Kestila et al. (1994) assigned the locus for congenital nephrotic syndrome of the Finnish type (symbolized CNF by them) to 19q12-q13.1 on the basis of linkage analyses in 17 Finnish families. Although Dressler and Douglass (1992) had shown in transgenic mice that deregulation of the Pax2 gene (167409) resulted in severe kidney abnormalities resembling those found in patients with Finnish nephrosis, Kestila et al. (1994) showed that the disorder in these patients is not linked to the PAX2 gene locus on chromosome 10. Olsen et al. (1996) assembled a 1-Mb cosmid contig and restriction map spanning the candidate region for NPHS1 on chromosome 19q13.1. Mannikko et al. (1996) applied haplotype analysis to several non-Finnish CNF families to determine whether the same genetic locus is involved in these families as in Finnish families. The results indicated linkage to the 19q13.1 region. It was also observed that, in most cases, alleles typically found on CNF chromosomes of Finnish families were also found on CNF chromosomes of non-Finnish families from North America and Europe. Population Genetics Nephrotic syndrome type 1 has a relatively high frequency in Finland (Norio et al., 1964), where the incidence is about 1 in 8,000 (Norio, 1980). A large series of cases was collected by Hallman and Hjelt (1959) in Finland and by Vernier et al. (1957) and Worthen et al. (1959) in Minnesota, where many persons of Finnish extraction live. Worthen et al. (1959) were impressed with the high frequency of maternal toxemia in these cases. Nine of 41 patients (22%) with congenital nephrotic syndrome studied by Mahan et al. (1984) in Minneapolis, Minnesota, were shown to have Finnish ancestry. Bolk et al. (1999) observed a high incidence of NPHS1 in the Old Order Mennonites in Lancaster County, Pennsylvania. They identified 26 cases, dating from the 1950s. All but 1 of the cases occurred in a subgroup known as the Groffdale Conference Mennonites, formed as a result of a schism in the Weaverland Conference Mennonites in 1927. Bolk et al. (1999) estimated the frequency to be about 1 per 500 live births, giving an incidence 20 times greater than that observed in Finland and predicting that approximately 8% of Groffdale Mennonites are carriers of the NPHS1-causing allele. There was no known Finnish ancestry. Molecular Genetics By use of positional cloning strategies, Kestila et al. (1998) isolated the gene responsible for NPHS1 and identified pathogenic mutations in Finnish patients with congenital nephrosis. The most common Finnish mutation was a deletion of 2 nucleotides in exon 2 (602716.0001), resulting in a frameshift and a truncated protein. The predicted nephrin protein belongs to the immunoglobulin family of cell adhesion molecules and is specifically expressed in renal glomeruli. Bolk et al. (1999) confirmed the role of nephrin in NPHS1, showed that a major mutation (602716.0005) was shared by families with nephrosis that are in the Groffdale Conference, and showed that this mutation was most likely of recent origin, uncovered by inbreeding and amplified by genetic drift. The data suggested that the major Mennonite mutation probably predated the split from the Weaverland Conference, since 1 proband in the previous group was a double heterozygote with 1 copy of the major nephrin mutation and a second novel mutation (602716.0006), possibly contributed through a non-Mennonite lineage. Puffenberger (2003) published data on the surname distribution in the Weaverland and Groffdale Mennonite groups indicating appreciable differences. Frishberg et al. (2007) identified homozygosity or compound heterozygosity for 3 novel mutations in the NPHS1 gene in 12 children with congenital nephrotic syndrome living in a village near Jerusalem. All were descendants of 1 Muslim family with high inbreeding. ### Associations Pending Confirmation For discussion of a possible association between nephrotic syndrome and variation in the XPO5 gene, see 607845.0001. For discussion of a possible association between nephrotic syndrome and variation in the FAT1 gene, see 600976.0001. For discussion of a possible association between nephrotic syndrome and variation in the KANK1 gene, see 607704.0002. For discussion of a possible association between nephrotic syndrome and variation in the KANK4 gene, see 614612.0001. Nomenclature In the literature, use of the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) to refer to the same disease entity has generated confusion in the naming and classification of similar disorders. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. It is important to recognize that FSGS is a histologic pattern of renal injury: some patients with FSGS on biopsy have nephrotic syndrome, whereas others have only mild proteinuria. NPHS and FSGS represent a spectrum of hereditary renal diseases of the podocyte (see reviews by Pollak, 2002; Meyrier, 2005; Caridi et al., 2010; Hildebrandt, 2010). History Finnish congenital nephrosis is only one of many disorders, numbering more than 30, that are absent or infrequent elsewhere and exist in the Finnish population, sometimes at high carrier frequencies. Conversely, recessive autosomal diseases common in other European populations, such as cystic fibrosis (219700), phenylketonuria (261600), or galactosemia (230400), are rare or absent in Finland. Sajantila et al. (1996) noted that single mutations embedded in chromosomal regions exhibiting linkage disequilibrium have been demonstrated in the case of several of these 'Finnish' genetic disorders. In contrast, outside Finland, the rare cases of these disorders are usually due to several different mutations. Furthermore, many of the disorders occur in locally restricted areas in Finland. Sajantila et al. (1996) found that Y-chromosomal haplotypes in several European populations revealed an almost monomorphic pattern in the Finns, whereas Y-chromosomal diversity was significantly higher in other populations. Furthermore, analyses of nucleotide positions in the mitochondrial control region that evolves slowly showed a decrease in genetic diversity in Finns. Thus, relatively few men and women contributed to the genetic lineages that today survive in the Finnish population. This is likely to have caused the 'Finnish disease heritage,' i.e., the occurrence of several genetic diseases in the Finnish population that are rare elsewhere. A preliminary analysis of the mitochondrial mutations that had accumulated subsequent to the bottleneck suggested that it occurred about 4,000 years ago, presumably when populations using agriculture and animal husbandry arrived in Finland. The results suggested that genetic founder effects have played a role also in the biologic history of Estonians and the Basques. Fournier et al. (1963) observed a family in which 4 of 5 children had clinical and/or autopsy evidence of pulmonary stenosis and congenital nephrotic syndrome (see 265600). Zunin and Soave (1964) observed nephrosis in association with nephroblastoma in 2 sibs. In one of them, removal of the tumor was accompanied by amelioration of the nephrotic syndrome. INHERITANCE \- Autosomal recessive GROWTH Other \- Growth retardation GENITOURINARY Kidneys \- Nephrotic syndrome \- Proteinuria, severe \- Biopsy shows dilated proximal tubules \- Tubular atrophy \- Interstitial fibrosis \- Mesangial cell proliferation \- Diffuse mesangial sclerosis \- Glomerulosclerosis and fibrosis \- Loss of podocyte foot processes MUSCLE, SOFT TISSUES \- Edema PRENATAL MANIFESTATIONS Amniotic Fluid \- Proteinuria \- Increased alpha-fetoprotein Placenta & Umbilical Cord \- Enlarged placenta Delivery \- Prematurity LABORATORY ABNORMALITIES \- Hyperlipidemia \- Hypoalbuminemia MISCELLANEOUS \- Onset in utero \- Rapidly progressive \- End-stage renal failure in first decade \- Early death without kidney transplant \- Not responsive to steroid treatment \- Some patients may have a milder phenotype \- Incidence of 12.2 per 100,000 in Finland MOLECULAR BASIS \- Caused by mutation in the nephrin gene (NPHS1, 602716.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	NEPHROTIC SYNDROME, TYPE 1	c0403399	5,025	omim	https://www.omim.org/entry/256300	2019-09-22T16:24:25	{"doid": ["0080390"], "mesh": ["C535761"], "omim": ["256300"], "orphanet": ["839"], "synonyms": ["Alternative titles", "FINNISH CONGENITAL NEPHROSIS", "NEPHROTIC SYNDROME, CONGENITAL"]}
Further information: Malnutrition This article is about the medical syndrome. For similar terms with different meanings, see Waste (disambiguation). In medicine, wasting, also known as wasting syndrome, refers to the process by which a debilitating disease causes muscle and fat tissue to "waste" away. Wasting is sometimes referred to as "acute malnutrition" because it is believed that episodes of wasting have a short duration, in contrast to stunting, which is regarded as chronic malnutrition. According to the latest UN estimates, an estimated 52 million children under 5 years of age, or 8%, were wasted in 2011. The vast majority, about 70%, of the world's wasted children live in Asia, most in South-Central Asia.[1] ## Contents * 1 Causes * 2 Classification * 3 Treatment and prevention * 4 See also * 5 References * 6 External links ## Causes[edit] Wasting can be caused by an extremely low energy intake (e.g., caused by famine), nutrient losses due to infection, or a combination of low intake and high loss. Infections and conditions associated with wasting include tuberculosis, chronic diarrhea, AIDS, and superior mesenteric artery syndrome. The mechanism may involve cachectin – also called tumor necrosis factor, a macrophage-secreted cytokine. Caretakers and health providers can sometimes contribute to wasting if the patient is placed on an improper diet. Voluntary weight loss and eating disorders are excluded as causes of wasting. ## Classification[edit] * Children: Weight-for-height (WFH). In infants under 24 months, recumbent (supine) length is used. WFH as % of median reference value is calculated this way: W F H = weight of a given child median weight for a given child of that height × 100 {\displaystyle \mathrm {WFH} ={\frac {\mbox{weight of a given child}}{\mbox{median weight for a given child of that height}}}\times 100} Cutoff points may vary, but <80% (close to −2 Z-score) is often used. * Adults: * Body Mass Index (BMI) is the quotient between weight and height squared (kg/m2). An individual with a BMI < 18.5 is regarded as a case of wasting. * Percent of body weight lost (At Tufts, an unintentional loss of 6% or more in 6 months is regarded as wasting) ## Treatment and prevention[edit] Antiretrovirals and anabolic steroids have been used to treat HIV wasting syndrome.[2] Additionally, an increase in protein-rich foods such as peanut butter, eggs, and cheese can assist in controlling the loss of muscle mass.[3] ## See also[edit] * Anorexia * Atrophy * Cachexia * Superior mesenteric artery syndrome * Weight loss ## References[edit] 1. ^ United Nations Children’s Fund, World Health Organization, The World Bank. UNICEFWHO- World Bank Joint Child Malnutrition Estimates. (UNICEF, New York; WHO, Geneva; The World Bank, Washington, DC; 2012) 2. ^ Michael Powers, "Performance-Enhancing Drugs" in Joel Houglum, in Gary L. Harrelson, Deidre Leaver-Dunn, "Principles of Pharmacology for Athletic Trainers", SLACK Incorporated, 2005, ISBN 1-55642-594-5, p. 330 3. ^ "HIV wasting syndrome - HIV/AIDS". www.hiv.va.gov. Retrieved 20 August 2018. ## External links[edit] Look up wasting in Wiktionary, the free dictionary. * Chronic Wasting Disease and Potential Transmission to Humans, Center for Disease Control and Prevention * Unintentional Weight Loss/Wasting, Tufts University Nutrition/Infection Unit [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Wasting	c0043046	5,026	wikipedia	https://en.wikipedia.org/wiki/Wasting	2021-01-18T18:59:26	{"mesh": ["D019282"], "wikidata": ["Q7972881"]}
Pediculosis Pediculus humanus capitis (♀) SpecialtyInfectious disease Pediculosis is an infestation of lice (blood-feeding ectoparasitic insects of the order Phthiraptera).[1][2] The condition can occur in almost any species of warm-blooded animal (i.e. mammals and birds), including humans.[1][2] Although pediculosis in humans may properly refer to lice infestation of any part of the body, the term is sometimes used loosely to refer to pediculosis capitis, the infestation of the human head with the specific head louse. ## Contents * 1 Classification * 2 Head lice * 2.1 Presentation * 2.2 Diagnosis * 2.3 Treatment * 2.4 Epidemiology * 3 Body lice * 4 Pubic lice * 5 Other animals * 5.1 Treatment * 6 History * 7 See also * 8 References * 9 External links ## Classification[edit] Pediculosis may be divided into the following types:[3]:446–8 * Pediculosis capitis (Head lice infestation) * Pediculosis corporis (Pediculosis vestimenti, Vagabond's disease) * Pediculosis pubis (Crabs) ## Head lice[edit] Main article: Pediculosis capitis ### Presentation[edit] Play media Head louse crawling on a hairbrush Pediculosis in the head of a 6-year-old boy caused by the head louse, as confirmed by optical (c) and electron microscopy (d).[4] Head-lice infestation is most frequent on children aged 3–10 and their families. Approximately 3% of school children in the United States contract head lice.[5][failed verification] Females aged 3–12 years are most commonly infested.[6] Those of African descent rarely suffer infestation due to differences in hair texture.[6] Head lice are spread through direct head-to-head contact with an infested person. From each egg or "nit" may hatch one nymph that will grow and develop to the adult louse. Lice feed on blood once or more often each day by piercing the skin with their tiny needle-like mouthparts. While feeding they excrete saliva, which irritates the skin and causes itching.[5] Lice cannot burrow into the skin. ### Diagnosis[edit] To diagnose infestation, the entire scalp should be combed thoroughly with a louse comb and the teeth of the comb should be examined for the presence of living lice after each time the comb passes through the hair. The use of a louse comb is the most effective way to detect living lice.[7] The most characteristic symptom of infestation is pruritus (itching) on the head which normally intensifies 3 to 4 weeks after the initial infestation. The bite reaction is very mild and it can be rarely seen between the hairs. Excessive scratching of the infested areas can cause sores, which may become infected. ### Treatment[edit] The number of diagnosed cases of human louse infestations (or pediculosis) has increased worldwide since the mid-1960s, reaching hundreds of millions annually.[8] There is no product or method which assures 100% destruction of the eggs and hatched lice after a single treatment. However, there are a number of treatment methods that can be employed with varying degrees of success. These methods include chemical treatments, natural products, combs, shaving, hot air, silicone-based lotions, and ethanol (ethyl alcohol).[9] Pediculosis is commonly treated with permethrin lotion.[10][11] ### Epidemiology[edit] About 14 million people, mainly children, are treated annually for head lice in the United States alone. Only a small proportion of those treated, however, may have objective evidence of an extant infestation.[12] High levels of louse infestations have also been reported from all over the world including Denmark, Sweden, U.K., France and Australia.[13][14] Normally head lice infest a new host only by close contact between individuals, making social contacts among children and parent child interactions more likely routes of infestation than shared combs, brushes, towels, clothing, beds or closets. Head-to-head contact is by far the most common route of lice transmission. The United Kingdom's National Health Service, and many American health agencies,[15][16] report that lice "prefer" clean hair, because it's easier to attach eggs and to cling to the strands. Head lice (Pediculus humanus capitis) are not known to be vectors of diseases, unlike body lice (Pediculus humanus humanus), which are known vectors of epidemic or louse-borne typhus (Rickettsia prowazekii), trench fever (Rochalimaea quintana) and louse-borne relapsing fever (Borrelia recurrentis). ## Body lice[edit] Main article: Pediculosis corporis This condition is caused by body louse (Pediculus humanus humanus, sometimes called Pediculus humanus corporis),[17] a louse which infests humans and is adapted to lay eggs in clothing, rather than at the base of hairs, and is thus of recent evolutionary origin. Pediculosis is a more serious threat due to possible contagion of diseases such as typhus. Epidemiology and treatment of human body lice is described in the article on body lice. ## Pubic lice[edit] Main article: Pediculosis pubis The pubic or crab louse (Pthirus pubis) is a parasitic insect which spends its entire life on human hair and feeds exclusively on blood. Humans are the only known host of this parasite, although it is more closely related to the louse parasites in other primate species, than are human head or body lice which probably evolved from it as the "original" louse infestation of humans. Epidemiology and treatment of pubic lice is discussed in the article on pubic lice. ## Other animals[edit] Pediculosis is more common in cattle than any other type of domesticated animal.[18] This is a significant problem, as it can cause weight loss of 55 to 75 pounds per animal.[18] Some species of lice infesting cattle include the cattle biting louse (Bovicola bovis), the shortnosed cattle louse (Haematopinus eurysternus), the longnosed cattle louse (Linognathus vituli), and the little blue cattle louse (Solenopotes capillatus).[1] ### Treatment[edit] Cattle infested with bovine pediculosis are generally treated chemically, by drugs like ivermectin and cypermethrin. ## History[edit] In the 15th century, topical mercury treatment was used to treat pediculosis.[19] ## See also[edit] * Nitpicking ## References[edit] 1. ^ a b c "Lice (Pediculosis)". The Merck Veterinary Manual. Whitehouse Station, NJ USA: Merck & Co. 2008. Retrieved 2008-10-08. 2. ^ a b Maunder JW (1983). "The appreciation of lice". Proceedings of the Royal Institution of Great Britain. London: Royal Institution of Great Britain. 55: 1–31. 3. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 4. ^ Ran Yuping (2016). "Observation of Fungi, Bacteria, and Parasites in Clinical Skin Samples Using Scanning Electron Microscopy". In Janecek, Milos; Kral, Robert (eds.). Modern Electron Microscopy in Physical and Life Sciences. InTech. doi:10.5772/61850. ISBN 978-953-51-2252-4. 5. ^ a b Leung AK, Robson LM (May 1, 2008). "Pruritus in Children: What's Itching?". Consultant for Pediatricians. 6. ^ a b Ko, Christine; Elson, Dirk M. (2016). "Chapter 30. Pediculosis". In Tyring, Steven K.; Lupi, Omar; Hengge, Ulrich R. (eds.). Tropical Dermatology (2nd ed.). Elsevier Inc. p. 387. ISBN 978-0-323-296342. 7. ^ Mumcuoglu KY, Friger M, Ioffe-Uspensky I, Ben-Ishai F, Miller J (2001). "Louse comb versus direct visual examination for the diagnosis of head louse infestations". Pediatric Dermatology. 18 (1): 9–12. doi:10.1046/j.1525-1470.2001.018001009.x. PMID 11207962. S2CID 27464495. 8. ^ Gratz, N. (1998). "Human lice, their prevalence and resistance to insecticides". Geneva: World Health Organization (WHO). Cite journal requires `\|journal=` (help) 9. ^ Ethanol (ethyl alcohol, common alcohol) is toxic to arthropods including lice. It can be mixed with the everyday hair conditioner for a treatment. Marriott, JF (2010). Pharmaceutical Compounding and Dispensing. p. 77. ISBN 9780853699125. "ALCOHOL. After water, this is probably the next most important solvent used pharmaceutically. Although ethanol (ethyl alcohol) is rarely used as a lone solvent for preparations for internal use, it is used in the manufacture of some of the galenicals used in pharmacy (e.g. tinctures, see Chapter 2). In extemporaneous dispensing it is normally used for the production of lotions for external application to unbroken skin. It is particularly useful if rapid evaporation is required (e.g. for insecticidal lotions applied to hair for the treatment of lice)." Ethanol as an arthropod killing solution. Szinwelski N, Fialho VS, Yotoko KS, Seleme LR, Sperber CF (2012). "Ethanol fuel improves arthropod capture in pitfall traps and preserves DNA". ZooKeys (196): 11–22. doi:10.3897/zookeys.196.3130. PMC 3361084. PMID 22679388. "It has been shown that at concentrations higher than 95%, commercial alcohol preserves DNA (Nagy 2010), but the use of highly concentrated commercial alcohol as a killing solution may be prohibitively expensive when needed in large quantities, such as in large-scale biodiversity sampling. In Brazil, for example, it is illegal to carry large amounts of commercial alcohol on long journeys, which could hinder its use in extensive field expeditions. Here we propose the use of ethanol fuel as a cheaper and logistically feasible alternative" 10. ^ Gunning K, Pippitt K, Kiraly B, Sayler M (September 2012). "Pediculosis and scabies: treatment update" (PDF). American Family Physician. 86 (6): 535–41. PMID 23062045. 11. ^ Verma P, Namdeo C (2015). "Treatment of Pediculosis Capitis". Indian Journal of Dermatology. 60 (3): 238–47. doi:10.4103/0019-5154.156339. PMC 4458933. PMID 26120148. 12. ^ Pollack RJ, Kiszewski AE, Spielman A (August 2000). "Overdiagnosis and consequent mismanagement of head louse infestations in North America". The Pediatric Infectious Disease Journal. 19 (8): 689–93, discussion 694. doi:10.1097/00006454-200008000-00003. PMID 10959734. S2CID 2557006. 13. ^ Burgess IF (January 2004). "Human lice and their control". Annual Review of Entomology. Annual Reviews. 49: 457–81. doi:10.1146/annurev.ento.49.061802.123253. PMID 14651472. S2CID 21144817. 14. ^ Mumcuoglu KY, Barker SC, Burgess IE, Combescot-Lang C, Dalgleish RC, Larsen KS, Miller J, Roberts RJ, Taylan-Ozkan A (April 2007). "International guidelines for effective control of head louse infestations". Journal of Drugs in Dermatology. 6 (4): 409–14. PMID 17668538. 15. ^ "Lice (Pediculosis) - What are lice?". Archived from the original on 2007-07-08. Retrieved 2007-07-08. 16. ^ Head lice and nits - NHS Choices. Nhs.uk (2016-05-17). Retrieved on 2016-10-14. 17. ^ Buxton, Patrick A. (1947). "The Anatomy of Pediculus humanus". The Louse; an account of the lice which infest man, their medical importance and control (2nd ed.). London: Edward Arnold. pp. 5–23. 18. ^ a b Hussain MA, Khan MN, Iqbal Z, Sajid MS, Arshad M (2006). "Bovine pediculosis: prevalence and chemotherapeutic control in Pakistan". Livestock Research for Rural Development. 18 (145). Archived from the original (– Scholar search) on December 3, 2008. Retrieved 2008-10-08. 19. ^ Fornaciari G, Giuffra V, Marinozzi S, Picchi MS, Masetti M (July 2009). "'Royal' pediculosis in Renaissance Italy: lice in the mummy of the King of Naples Ferdinand II of Aragon (1467-1496)". Memórias do Instituto Oswaldo Cruz. 104 (4): 671–2. doi:10.1590/s0074-02762009000400026. PMID 19722098. ## External links[edit] Classification D * ICD-10: B85 * ICD-9-CM: 132.0 * MeSH: D010373 * DiseasesDB: 9725 External resources * MedlinePlus: 000840 * eMedicine: med/1769 * Head lice: Biology and Management at IdentifyUS LLC * National Pediculosis Association * Frankowski BL, Weiner LB (September 2002). "Head lice". Pediatrics. 110 (3): 638–43. PMID 12205271. Archived from the original on 2008-10-13. Retrieved 2004-07-12. * Morewitz H (2005). "A Brief History of Head Lice". * Speare R (2007). "Head Lice Information Sheet". James Cook University, N. Queensland, Australia. Archived from the original on 2014-05-29. * Pediculus humanus Head Lice Infestation: Symptoms, Causes & Diagnosis * v * t * e Human lice and pediculosis Species * Head louse * Crab louse * Body louse Infestation * Pediculosis * Pediculosis corporis * Phthiriasis Treatment * Nitpicking * Pediculicide * Lindane * Permethrin * Phenothrin * Delphinium Other terms of interest * Cooties * Sucking louse * Louse * v * t * e Arthropods and ectoparasite-borne diseases and infestations Insecta Louse * Body louse (pediculosis corporis) / Head louse (head lice infestation) * Crab louse (phthiriasis) Hemiptera * Bed bug (cimicosis) Fly * Dermatobia hominis / Cordylobia anthropophaga / Cochliomyia hominivorax (myiasis) * Mosquito (mosquito-borne disease) Flea * Tunga penetrans (tungiasis) Crustacea Pentastomida * Linguatula serrata (linguatulosis) * Porocephalus crotali / Armillifer armillatus (porocephaliasis) * For ticks and mites, see Template:Tick and mite-borne diseases and infestations [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Pediculosis	c0030756	5,027	wikipedia	https://en.wikipedia.org/wiki/Pediculosis	2021-01-18T18:51:44	{"mesh": ["D010373"], "umls": ["C0030756"], "wikidata": ["Q1343674"]}
McKittrick-Wheelock syndrome SpecialtyGastroenterology McKittrick-Wheelock syndrome is an uncommon syndrome caused by large, villous adenomas that secrete high quantities of electrolyte-rich mucin. This may lead to pre-renal acute kidney injury, secretory diarrhea, and dehydration. It is estimated that 2-3% of large villous adenomas, typically greater than 4 cm in diameter, will present with this hypersecretory pattern.[1] ## Contents * 1 Symptoms and Signs * 2 Diagnosis * 3 Treatment * 4 History * 5 See also * 6 References ## Symptoms and Signs[edit] Patients typically present with a history of chronic, watery diarrhea. Before the cause is established, they may have multiple hospitalizations for dehydration and kidney failure. Patients may present with hyponatremia, hypokalemia, and elevated creatinine.[2] ## Diagnosis[edit] This section is empty. You can help by adding to it. (March 2018) ## Treatment[edit] The treatment is supportive until the villous adenoma can be resected surgically.[citation needed] ## History[edit] The syndrome was first described by Leland S. McKittrick and Frank C. Wheelock. In 1954 they reported a case of an 84-year-old woman with a large villous papilloma of the rectum, who presented with weakness, syncope and oliguria.[3] ## See also[edit] * Colorectal cancer * Sessile serrated adenoma * Tubulovillous adenoma ## References[edit] 1. ^ Popescu, A; Orban-Schiopu, A; Becheanu, G; et al. (2005). "McKittrick-Wheelock syndrome: a rare cause of acute renal failure". Rom J Gastroenterology. 14: 63–66. PMID 15800695. 2. ^ Raphael, M; McDonald, C; Detsky, A (2015). "McKittrick-Wheelock syndrome". CMAJ. 187 (9): 676–678. doi:10.1503/cmaj.141195. PMC 4467932. PMID 25754711. 3. ^ McKittrick, LS; Wheelock, FC (1954). Carcinoma of the Colon. Charles C Thomas. pp. 61–63. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	McKittrick-Wheelock syndrome	c0268028	5,028	wikipedia	https://en.wikipedia.org/wiki/McKittrick-Wheelock_syndrome	2021-01-18T18:44:05	{"umls": ["C0268028"], "wikidata": ["Q42417222"]}
Maturity-onset diabetes of the young (MODY) is a group of several conditions characterized by abnormally high blood sugar levels. These forms of diabetes typically begin before age 30, although they can occur later in life. In MODY, elevated blood sugar arises from reduced production of insulin, which is a hormone produced in the pancreas that helps regulate blood sugar levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. The different types of MODY are distinguished by their genetic causes. The most common types are HNF1A-MODY (also known as MODY3), accounting for 50 to 70 percent of cases, and GCK-MODY (MODY2), accounting for 30 to 50 percent of cases. Less frequent types include HNF4A-MODY (MODY1) and renal cysts and diabetes (RCAD) syndrome (also known as HNF1B-MODY or MODY5), which each account for 5 to 10 percent of cases. At least ten other types have been identified, and these are very rare. HNF1A-MODY and HNF4A-MODY have similar signs and symptoms that develop slowly over time. Early signs and symptoms in these types are caused by high blood sugar and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, weight loss, and recurrent skin infections. Over time uncontrolled high blood sugar can damage small blood vessels in the eyes and kidneys. Damage to the light-sensitive tissue at the back of the eye (the retina) causes a condition known as diabetic retinopathy that can lead to vision loss and eventual blindness. Kidney damage (diabetic nephropathy) can lead to kidney failure and end-stage renal disease (ESRD). While these two types of MODY are very similar, certain features are particular to each type. For example, babies with HNF4A-MODY tend to weigh more than average or have abnormally low blood sugar at birth, even though other signs of the condition do not occur until childhood or young adulthood. People with HNF1A-MODY have a higher-than-average risk of developing noncancerous (benign) liver tumors known as hepatocellular adenomas. GCK-MODY is a very mild type of the condition. People with this type have slightly elevated blood sugar levels, particularly in the morning before eating (fasting blood sugar). However, affected individuals often have no symptoms related to the disorder, and diabetes-related complications are extremely rare. RCAD is associated with a combination of diabetes and kidney or urinary tract abnormalities (unrelated to the elevated blood sugar), most commonly fluid-filled sacs (cysts) in the kidneys. However, the signs and symptoms are variable, even within families, and not everyone with RCAD has both features. Affected individuals may have other features unrelated to diabetes, such as abnormalities of the pancreas or liver or a form of arthritis called gout. ## Frequency MODY is estimated to account for 1 to 3 percent of all cases of diabetes. ## Causes MODY can be caused by a mutation in one of several genes. HNF1A-MODY, GCK-MODY, HNF4A-MODY, and RCAD, are caused by mutations in the HNF1A, GCK, HNF4A, and HNF1B gene, respectively. All of these genes provide instructions for making proteins involved in the production of insulin to control blood sugar levels in the body. In particular, the proteins are important in specialized cells in the pancreas called beta cells, which secrete insulin. The proteins produced from the HNF1A, HNF4A, and HNF1B genes all act as transcription factors, which means they control the activity of other genes. In particular, these proteins regulate genes that direct the development and function of beta cells. HNF1A, HNF4A, or HNF1B gene mutations result in production of an altered transcription factor that is unable to function normally. These changes alter gene activity in cells, impairing normal beta cell development and function. As a result, beta cells are less able than normal to produce insulin in response to sugar in the blood, which means the body cannot control blood sugar. Elevated blood sugar results in the signs and symptoms of MODY. Some of these MODY-related genes play roles in the development of other body systems, in addition to beta cells. Disrupted development of these systems underlies additional signs and symptoms in particular forms of MODY. For example, the HNF1B gene is involved in kidney development, which helps explain the kidney abnormalities in people with RCAD. The protein produced from the GCK gene acts as a sensor that recognizes when the amount of glucose in the blood rises. In response, the protein helps stimulate the release of insulin from beta cells so sugar can be taken up and used by cells for energy. This protein also helps determine when excess sugar should be taken into liver cells and stored. Mutations in the GCK gene limit the protein's ability to sense a rise in blood sugar, so levels remain elevated. Other genes involved in controlling blood sugar cause rare types of MODY. It is likely that additional genes that have not been identified are also involved in the condition. ### Learn more about the genes associated with Maturity-onset diabetes of the young * ABCC8 * GCK * HNF1A * HNF1B * HNF4A * INS * KCNJ11 Additional Information from NCBI Gene: * APPL1 * BLK * CEL * KLF11 * NEUROD1 * PAX4 * PDX1 ## Inheritance Pattern MODY is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Maturity-onset diabetes of the young	c0342276	5,029	medlineplus	https://medlineplus.gov/genetics/condition/maturity-onset-diabetes-of-the-young/	2021-01-27T08:24:56	{"gard": ["3697"], "mesh": ["C562772"], "omim": ["606391", "125850", "125851", "600496", "137920"], "synonyms": []}
Group B Streptococcal infection Other namesGroup B streptococcal disease Streptococcus agalactiae\- Gram stain SpecialtyPediatrics Group B streptococcal infection, also known as Group B streptococcal disease or just Group B strep,[1] is the infection caused by the bacterium Streptococcus agalactiae (S. agalactiae) (also known as group B streptococcus or GBS). GBS infection can cause serious illness and sometimes death, especially in newborns, the elderly, and people with compromised immune systems. As other virulent bacteria, GBS harbours an important number of virulence factors,[2] the most important are the capsular polysaccharide (rich in sialic acid), and a pore-forming toxin, β-haemolysin.[3][4] The GBS capsule is probably the key virulence factor because it helps GBS escape from the host defence mechanisms interfering with phagocytic killing of GBS by human phagocytes.[5][3] The GBS β-haemolysin is considered almost identical to the GBS pigment (granadaene).[6][7][8][9] GBS was recognized as a pathogen in cattle by Edmond Nocard and Mollereau in the late 1880s. It can cause bovine mastitis (inflammation of the udder) in dairy cows. The species name "agalactiae" meaning "no milk", alludes to this.[10] Its significance as a human pathogen was first described in 1938, when Fry reported three fatal cases of puerperal infections caused by GBS.[11] In the early 1960s, GBS was recognized as a main cause of infections in newborns.[12] In general, GBS is a harmless commensal bacterium being part of the human microbiota colonizing the gastrointestinal and genitourinary tracts of up to 30% of healthy human adults (asymptomatic carriers).[13][14][5] ## Contents * 1 Laboratory identification * 1.1 Colonization versus infection * 2 Pregnancy * 2.1 Newborns * 2.2 Prevention of neonatal infection * 2.3 Identifying candidates to receive IAP * 2.4 Home births and water birth * 2.5 Screening for colonization * 2.5.1 Culture methods * 2.5.2 Point-of-care testing * 2.6 Missed opportunities of prevention * 2.7 Epidemiology * 2.8 Guidelines * 2.8.1 United Kingdom * 2.8.1.1 Royal College of Obstetricians and Gynaecologists (RCOG) * 2.8.1.2 NICE guidelines * 2.8.1.3 National Screening Committee * 2.8.2 United States * 2.8.3 Other guidelines * 3 Adults * 4 Society and culture * 5 Vaccine * 6 Nonhuman infections * 6.1 Cattle * 6.2 Fish * 7 References * 8 External links ## Laboratory identification[edit] β-haemolytic colonies of Streptococcus agalactiae, blood agar 18h at 36 °C Positive CAMP test indicated by the formation of an arrowhead where S. agalactiae meets Staphylococcus aureus (white middle streak) Red colonies of S. agalactiae in granada agar, vagino-rectal culture 18h incubation 36 °C anaerobiosis As mentioned, S. agalactiae is a Gram-positive coccus with a tendency to form chains, beta-haemolytic, catalase-negative, and facultative anaerobe. GBS grows readily on blood agar plates as microbial colonies surrounded by a narrow zone of β-haemolysis. GBS is characterized by the presence in the cell wall of the group B antigen of the Lancefield classification (Lancefield grouping) that can be detected directly in intact bacteria using latex agglutination tests.[15][16] The CAMP test is also another important test for the identification of GBS. The CAMP factor acts synergistically with the staphylococcal β-haemolysin inducing enhanced haemolysis of sheep or bovine erythrocytes.[15] GBS is also able to hydrolyse hippurate, and this test can also be used to identify GBS. Haemolytic GBS strains produce an orange-brick-red nonisoprenoid polyene pigment (ornythinrhamnododecaene) (granadaene) when cultivated on granada medium that allows its straightforward identification.[17] Identification of GBS could also be carried out easily using modern methods as matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry.[18][19] Additionally GBS colonies can be tentatively identified after their appearance in chromogenic agar media.[16][20][21] Nevertheless, GBS-like colonies that develop in chromogenic media should be confirmed as GBS using additional reliable tests (e.g.latex agglutination or the CAMP test) to avoid potential mis-identification.[16] A summary of the laboratory techniques for GBS identification is depicted in Ref 18.[16] ### Colonization versus infection[edit] GBS is found in the gastrointestinal and genitourinary tract of humans and is normal component of the intestinal and vaginal microbiota in some women.[22] In different studies, GBS vaginal colonization rate ranges from 4 to 36%, with most studies reporting rates over 20%. Vaginal or rectal colonization may be intermittent, transitory, or persistent.[22] These variations in the reported prevalence of asymptomatic (presenting no symptoms of disease) colonization could be related to the different detection methods used, and differences in populations studied.[23][24][20] Though GBS is an asymptomatic and harmless colonizer of the gastrointestinal human tract in up to 30% of otherwise healthy adults, including pregnant women,[5][23] this opportunistic harmless bacterium can, in some circumstances, cause severe invasive infections.[14] ## Pregnancy[edit] Though GBS colonization is asymptomatic and, in general, does not cause problems, it can sometimes cause serious illness for the mother and the baby during gestation and after delivery. GBS infections in the mother can cause chorioamnionitis (intra-amniotic infection or severe infection of the placental tissues) infrequently, postpartum infections (after birth) and it had been related with prematurity and fetal death.[25] GBS urinary tract infections may induce labour in pregnant women and cause premature delivery (preterm birth) and miscarriage.[5][26] ### Newborns[edit] In the western world, GBS (in the absence of effective prevention measures) is the main cause of bacterial infections in newborns, such as sepsis, pneumonia, and meningitis, which can lead to death or long-term after effects.[5][27] GBS infections in newborns are separated into two clinical types, early-onset disease (GBS-EOD) and late-onset disease (GBS-LOD). GBS-EOD manifests from 0 to 7 living days in the newborn, most of the cases of EOD being apparent within 24 h from birth. GBS-LOD starts between 7 and 90 days after birth.[5][20] The most common clinical syndromes of GBS-EOD are sepsis without apparent location, pneumonia, and less frequently meningitis. Bacteremia without a focus occurs in 80-85%, pneumonia in 10-15%, and meningitis in 5-10% of cases. The initial clinical findings are respiratory signs in more than 80% of cases. Neonates with meningitis often have an initial clinical presentation identical to presentation in those without meningeal affectation. An exam of the cerebrospinal fluid is often necessary to rule out meningitis.[5][28][29] Colonization with GBS during labour is the primary risk factor for the development of GBS-EOD. GBS-EOD is acquired vertically (vertical transmission), through exposure of the fetus or the baby to GBS from the vagina of a colonized woman, either in utero (because of ascending infection) or during birth, after rupture of membranes. Infants can also be infected during passage through the birth canal, nevertheless, newborns who acquire GBS through this route can only become colonized, and these colonized infants usually do not develop GBS-EOD.[citation needed] Roughly 50% of newborns of GBS colonized mothers are also GBS colonized and (without prevention measures) 1-2% of these newborns will develop GBS-EOD.[30] Though maternal GBS colonization is the key determinant for GBS-EOD, other factors also increase the risk. These factors are:[5][20] * Onset of labour before 37 weeks of gestation (premature birth) * Prolonged rupture of membranes (longer duration of membrane rupture) (≥18 h before delivery) * GBS bacteriuria during pregnancy * Intrapartum (during childbirth) fever (>38 °C, >100.4 °F) * Amniotic infections (chorioamnionitis) * Young maternal age * Maternal HIV-infection[31] Nevertheless, most babies who develop GBS-EOD are born to colonized mothers without any of these risk factors.[20] Heavy GBS vaginal colonization is also associated with a higher risk for GBS-EOD. Women who had one of these risk factors but who are not GBS colonized at labour are at low risk for GBS-EOD compared to women who were colonized prenatally, but had none of the aforementioned risk factors.[30] Presence of low levels of anticapsular antibodies against GBS in the mother are also of great importance for the development of GBS-EOD.[32][33] Because of that, a previous sibling with GBS-EOD is also an important risk factor for the development of the infection in subsequent deliveries, probably reflecting the lack of protective antibodies in the mother. [20] Overall, the case fatality rates from GBS-EOD have declined, from 50% observed in studies from the 1970s to between 2 and 10% in recent years, mainly as a consequence of improvements in therapy and management. Fatal neonatal infections by GBS are more frequent among premature infants. [5] [20] [34] GBS-LOD affects infants from 7 days to 3 months of age and has a lower case fatality rate (1%-6%) than GBS-EOD. Clinical syndromes of GBS-LOD are bacteremia without a focus (65%), meningitis (25%), cellulitis, osteoarthritis, and pneumonia. Prematurity has been reported to be the main risk factor. Each week of decreasing gestation increases the risk by a factor of 1.34 for developing GBS-LOD. [35] GBS-LOD is not acquired through vertical transmission during delivery; it can be acquired later from the mother from breast milk or from environmental and community sources. GBS-LOD commonly shows nonspecific signs, and diagnosis should be made obtaining blood cultures in febrile newborns. S.agalactiae neonatal meningitis does not present with the hallmark sign of adult meningitis, a stiff neck; rather, it presents with nonspecific symptoms, such as fever, vomiting and irritability, and can consequently lead to a late diagnosis. Hearing loss and mental impairment can be a long-term consequence of GBS meningitis.[5][27] ### Prevention of neonatal infection[edit] Currently, the only reliable way to prevent GBS-EOD is intrapartum antibiotic prophylaxis (IAP) - administration of intravenous (IV) antibiotics during delivery. Intravenous penicillin or ampicillin given at the onset of labour and then again every four hours until delivery to GBS colonized women have been proven to be very effective at preventing vertical transmission of GBS from mother to baby and GBS-EOD (penicillin G, 5 million units IV initial dose, then 3 million units[22] every 4 hours until delivery or ampicillin, 2 g IV initial dose, then 1 g IV every 4 hours until delivery).[5][20][22] Penicillin-allergic women without a history of anaphylaxis (angioedema, respiratory distress, or urticaria) following administration of a penicillin or a cephalosporin (low risk of anaphylaxis) could receive cefazolin (2 g IV initial dose, then 1 g IV every 8 hours until delivery) instead of penicillin or ampicillin.[20] Clindamycin (900 mg IV every 8 hours until delivery), Erythromycin is not recommended today because the high proportion of GBS resistance to erythromycin (up to 44.8%),[20][22] Neither oral nor intramuscular antibiotics are effective in reducing the risk GBS-EOD.[22] Antibiotic susceptibility testing of GBS isolates is crucial for appropriate antibiotic selection for IAP in penicillin-allergic women, because resistance to clindamycin, the most common agent used (in penicillin-allergic women), is increasing among GBS isolates. Appropriate methodologies for testing are important, because resistance to clyndamicin (antimicrobial resistance) can occur in some GBS strains that appear susceptible (antibiotic sensitivity) in certain susceptibility tests.[20] For women who are at risk of anaphylaxis after exposure to penicillin, the laboratory requisitions should indicate clearly the presence of penicillin allergy to ensure that the laboratory is aware for the need of testing GBS isolates for clindamycin susceptibility. Vancomycin (20 mg/Kg every 8 hours until delivery)[22] is used to prevent GBS-EOD in infants born to penicillin-allergic mothers.[20][22] If appropriate IAP in GBS colonized women starts at least 2 hours before the delivery, the risk of neonatal infection is also somehow reduced.[36][37][38] True penicillin allergy is rare with an estimated frequency of anaphylaxis of one to five episodes per 10,000 cases of penicillin therapy.[39] Penicillin administered to a woman with no history of β-lactam allergy has a risk of anaphylaxis of 0.04 to 4 per 100,000. Maternal anaphylaxis associated with GBS IAP occurs, but any morbidity associated with anaphylaxis is offset greatly by reductions in the incidence of GBS-EOD. [20] IAPs have been considered to be associated with the emergence of resistant bacterial strains and with an increase in the incidence of early-onset infections caused by other pathogens, mainly Gram-negative bacteria such as Escherichia coli. Nevertheless, most studies have not found an increased rate of non-GBS early-onset sepsis related to the widespread use of IAP. [20][40][41][42] Other strategies to prevent GBS-EOD have been studied, and chlorhexidine intrapartum vaginal cleansing has been proposed to help preventing GBS-EOD, nevertheless no evidence has been shown for the effectiveness of this approach.[20][22][43][44] ### Identifying candidates to receive IAP[edit] Two ways are used to select female candidates to IAP: the culture-based screening approach and the risk-based approach.[45] The culture-based screening approach identifies candidates using lower vaginal and rectal cultures obtained between 35 and 37 weeks of gestation (or 36-37[22]), and IAP is administered to all GBS colonized women. The risk-based strategy identifies candidates to receive IAP by the aforementioned risk factors known to increase the probability of GBS-EOD without considering if the mother is or is not a GBS carrier.[5][20][46] IAP is also recommended for women with intrapartum risk factors if their GBS carrier status is not known at the time of delivery, and for women with GBS bacteriuria during their pregnancy, and for women who have had an infant with GBS-EOD previously. The risk-based approach is, in general, less effective than the culture-based approach, [47] because in most cases, GBS-EOD develops among newborns who have been born to mothers without risk factors.[20][30][48] IAP is not required for women undergoing planned caesarean section in the absence of labour and with intact membranes, irrespective of the carriage of GBS.[20][22] Routine screening of pregnant women is performed in most developed countries such as the United States, France, Spain, Belgium, Canada, and Australia, and data have shown falling incidences of GBS-EOD following the introduction of screening-based measures to prevent GBS-EOD.[24][48] [49] The risk-based strategy is advocated, among other counties, in the United Kingdom, the Netherlands, New Zealand, and Argentina.[24] The issue of cost-effectiveness of both strategies for identifying candidates for IAP is less clear-cut, and some studies have indicated that testing low risk women, plus IAP administered to high-risk women, and to those found to carry GBS is more cost-effective than the current UK practice.[50] Other evaluations have also found the culture-based approach to be more cost-effective than the risk-based approach for the prevention of GBS-EOD.[51][52] Testing pregnant women to detect GBS carriers has also been proposed, and giving IAP to those carrying GBS and to high-risk women, is significantly more cost-effective than the use of the risk-factor approach. One research paper calculated an expected net benefit to the UK government of such an approach of around £37million a year, compared with the current RCOG approach.[50][51] It has been reported that IAP does to not prevent all cases of GBS-EOD; its efficacy is estimated at 80%. The risk-based prevention strategy does not prevent about 33% of cases with no risk factors.[53] Up to 90% of cases of GBS-EOD would be preventable if IAP were offered to all GBS carriers identified by universal screening late in pregnancy, plus to the mothers in higher risk situations.[54] Where insufficient intravenous antibiotics are given before delivery, the baby may be given antibiotics immediately after birth, although evidence is inconclusive as to whether this practice is effective or not.[20][55][56][57] Falling incidence of EOD and LOD GBS disease in US-CDC ### Home births and water birth[edit] Home births are becoming increasingly popular in the UK. Recommendations for preventing GBS infections in newborns are the same for home births as for hospital births. Around 25% of women having home births probably carry GBS in their vaginas at delivery without knowing, and it could be difficult to follow correctly the recommendations of IAP and to deal with the risk of a severe allergic reaction to the antibiotics outside of a hospital setting.[58] The RCOG and the ACOG guidelines suggest that birth in a pool is not contraindicated for GBS carriers who have been offered the appropriate IAP if no other contraindications to water immersion are present[22][59] ### Screening for colonization[edit] Approximately 10–30% of women are colonized with GBS during pregnancy. Nevertheless, during pregnancy, colonization can be temporary, intermittent, or continual.[20] Because the GBS colonization status of women can change during pregnancy, only cultures carried out ≤5 weeks before delivery predict quite accurately the GBS carrier status at delivery.[60] In contrast, if the prenatal culture is carried out more than 5 weeks before delivery, it is unreliable for accurately predicting the GBS carrier status at delivery. Because of that, testing for GBS colonization in pregnant women is recommended by the CDC at 35–37 weeks of gestation.[20][61] It is important to note that the ACOG now recommends performing universal GBS screening between 36 and 37 weeks of gestation. This new recommendation provides a 5-week window for valid culture results that includes births that occur up to a gestational age of at least 41 weeks.[22] The clinical samples recommended for culture of GBS are swabs collected from the lower vagina and rectum through the external anal sphincter. The sample should be collected swabbing the lower vagina (vaginal introitus) followed by the rectum (i.e., inserting the swab through the anal sphincter) using the same swab or two different swabs. Cervical, perianal, perirectal, or perineal specimens are not acceptable, and a speculum should not be used for sample collection.[20] Samples can be taken by healthcare professionals, or by the mother herself with appropriate instruction.[62][63][64] Instructions for the collection of a genital swab for the detection of GBS Following the recommendations of the CDC, these swabs should be placed into a non-nutritive transport medium. When feasible, specimens should be refrigerated and sent to the laboratory as soon as possible.[20] Appropriate transport systems are commercially available, and in these transport media, GBS can remain viable for several days at room temperature. However, the recovery of GBS declines over one to four days, especially at elevated temperatures, which can lead to false-negative results.[20][65] #### Culture methods[edit] Samples (vaginal, rectal, or vaginorectal swabs) should be inoculated into a selective enrichment broth, (Todd Hewitt broth with selective antibiotics, enrichment culture). This involves growing the samples in an enriched medium to improve the viability of the GBS and simultaneously impairing the growth of other naturally occurring bacteria. After incubation (18–24 hours, 35-37 °C), the enrichment broth is subcultured to blood agar plates and GBS-like colonies are identified by the CAMP test or using latex agglutination with GBS antiserum.[20][66] In the UK, this is the method described by the Public Health England's UK Standards for Microbiology Investigations[67] After incubation, the enrichment broth can also be subcultured to granada medium agar where GBS grows as pinkish-red colonies[16][17][66][68] [69] or to chromogenic agars, where GBS grows as coloured colonies.[20] Nevertheless, GBS-like colonies that develop in chromogenic media should be confirmed as GBS using additional reliable tests to avoid mis-identification.[16] Inoculating directly the vaginal and rectal swabs or the vaginorectal swab in a plate of an appropriate culture medium (blood agar, granada medium or chromogenic media) is also possible. However, this method (bypassing the selective enrichment broth step) can lead to some false-negative results, and this approach should be taken only in addition to, and not instead of, inoculation into selective broth.[20] Today, in the UK, the detection of GBS colonization using the enrichment broth technique is not offered from most laboratories serving the NHS. However, the implementation of this test seems to be a viable option. At present, culture for GBS (using enriched culture medium) at 35–37 weeks to define an at-risk group of women appears to be the most cost-effective strategy.[51][52] The charitable organization Group B Strep Support have published a list of hospitals in the UK that offer the detection of GBS using the enrichment broth culture method (enrichment culture medium, ECM).[70] This test is also available privately from around £35 per test for a home-testing pack, and it is offered by private clinics.[70] The test is also available privately, for a UK-wide postal service.[71] [72] #### Point-of-care testing[edit] No current culture-based test is both accurate enough and fast enough to be recommended for detecting GBS once labour starts. Plating of swab samples requires time for the bacteria to grow, meaning that this is unsuitable to be used as an intrapartum point-of-care test.[citation needed] Alternative methods to detect GBS in clinical samples (as vaginorectal swabs) rapidly have been developed, such are the methods based on nucleic acid amplification tests, such as polymerase chain reaction (PCR) tests, and DNA hybridization probes. These tests can also be used to detect GBS directly from broth media, after the enrichment step, avoiding the subculture of the incubated enrichment broth to an appropriate agar plate.[16][20][73] Testing women for GBS colonization using vaginal or rectal swabs at 35–37 weeks of gestation and culturing them in an enriched media is not as rapid as a PCR test that would check whether the pregnant woman is carrying GBS at delivery. PCR tests would allow starting IAP on admission to the labour ward in those women for whom it is not known if they are GBS carriers.[20] PCR testing for GBS carriage could, in the future, be sufficiently accurate to guide IAP. However, the PCR technology to detect GBS must be improved and simplified to make the method cost-effective and fully useful as a point-of-care test. These tests still cannot replace antenatal culture for the accurate detection of GBS.[20][22][74] Nevertheless, point-of-care testing may be used for women who present in labor with an unknown GBS status and without risk factors for ascertaining the use of IAP.[22] ### Missed opportunities of prevention[edit] The important factors for successful prevention of GBS-EOD using IAP and the universal screening approach are:[citation needed] * Reach most pregnant women for antenatal screens * Proper sample collection * Using an appropriate procedure for detecting GBS * Administering a correct IAP to GBS carriers Most cases of GBS-EOD occur in term infants born to mothers who screened negative for GBS colonization and in preterm infants born to mothers who were not screened, though some false-negative results observed in the GBS screening tests can be due to the test limitations and to the acquisition of GBS between the time of screening and delivery. These data show that improvements in specimen collection and processing methods for detecting GBS are still necessary in some settings. False-negative screening test, along with failure to receive IAP in women delivering preterm with unknown GBS colonization status, and the administration of inappropriate IAP agents to penicillin-allergic women account for most missed opportunities for prevention of cases of GBS-EOD.[citation needed] GBS-EOD infections presented in infants whose mothers had been screened as GBS culture-negative are particularly worrying, and may be caused by incorrect sample collection, delay in processing the samples, incorrect laboratory techniques, recent antibiotic use, or GBS colonization after the screening was carried out.[48][75][76][77][78] ### Epidemiology[edit] In 2000–2001, the reported overall incidence of GBS infection in newborn babies in the UK was 0.72 per 1,000 live births, 0.47 per 1,000 for GBS-EOD and 0.25 per 1,000 for GBS-LOD. Very marked variations were observed, the incidence in Scotland was 0.42 per 1,000, whilst in Northern Ireland, it was 0.9 per 1,000 live births. [79][80] Nevertheless, it may be a serious underestimation of the real incidence of GBS infections in newborns. A plausible explanation of this is that a considerable number of infants with probable GBS-EOD had negative cultures as a result of a previous maternal antibiotic treatment that inhibits the growth of GBS in blood and cerebrospinal fluid cultures, but does not mask clinical symptoms.[81][82] Data collected prospectively for neonates that required a septic screen in the first 72 hrs of life in the UK, indicated a combined rate of definite and probable GBS-EOD infection of 3.6 per 1,000 live births. [83] Another study on the epidemiology of invasive GBS infections in England and Wales, reported a rise in the incidence of GBS-EOD between 2000 and 2010 from 0.28 to 0.41 per 1,000 live births. Rates of GBS-LOD also increased between 1991 and 2010 from 0.11 to 0.29 per 1,000 live births in England and Wales.[84] In the past, the incidence of GBS-EOD ranged from 0.7 to 3.7 per thousand live births in the US,[5] and from 0.2 to 3.25 per thousand in Europe.[24] In 2008, after widespread use of antenatal screening and intrapartum antibiotic prophylaxis, the Centers for Disease Control and Prevention in the United States reported an incidence of 0.28 cases of GBS-EOD per thousand live births in the US.[85] From 2006 to 2015 the incidence of GBS EOD decreased to 0.37 to 0.23 per thousand live births in the US.[86] In contrast, the incidence of GBS-LOD has remained unchanged at 0.26-0.31 per 1,000 live births in the US.[86][87] Falling incidence of GBS-EOD in Spain (Castrillo Group of Hospitals) In Spain, the incidence of GBS vertical sepsis declined by 73.6%, from 1.25/1,000 live births in 1996 to 0.33/1,000 in 2008.[88] In the Barcelona area between 2004 and 2010, the incidence of GBS-EOD was 0.29 per thousand living newborns, with no significant differences along the years. The mortality rate was 8.16%.[48][89] In France since 2001, a rapid decrease in the incidence of the neonatal GBS infections has also been reported after widespread use of IAP, from 0.7 to 0.2 per 1,000 births between 1997 and 2006.[90] Since 2012 the incidence of neonatal GBS infection has been estimated as 0.53 per 1,000 births in the European region, 0.67 in America, and 0.15 in Australasia. Countries reporting no use of IAP had a 2.2-fold higher incidence of GBS-EOD compared with those reporting any use of IAP.[34][80] It has been estimated that GBS infections cause at least 409.000 maternal/fetal/infant cases and 147.000 stillbirths and infant deaths worldwide annually.[91] The following are estimates of the chances that a baby will be infected with a GBS neonatal infection if no preventive measures are taken and no other risk factors are present: [92] * One in 1,000 where the woman is not a known GBS carrier * One in 400 where the woman carries GBS during the pregnancy * One in 300 where the woman carries GBS at delivery * One in 100 where the woman had a previous baby infected with GBS If a woman who carries GBS is given IAP during labour, the baby's risk is reduced significantly: * One in 8,000 where the mother carries GBS during pregnancy; * One in 6,000 where the mother carries GBS at delivery; and * One in 2,200 where the mother has previously had a baby infected with GBS ### Guidelines[edit] #### United Kingdom[edit] ##### Royal College of Obstetricians and Gynaecologists (RCOG)[edit] The Royal College of Obstetricians and Gynaecologists (RCOG) issued their Green Top Guideline No 36 "Prevention of early onset neonatal Group B streptococcal disease" in 2003. This guideline clearly stated: "Routine bacteriological screening of all pregnant women for antenatal GBS carriage is not recommended, and vaginal swabs should not be taken during pregnancy unless there is a clinical indication to do so." But, "Intrapartum antibiotic prophylaxis should be offered if GBS is detected on a vaginal swab in the current pregnancy."[citation needed] Nevertheless, this guideline uses minimum incidence figures from a study undertaken in 2000–2001, [93] so it could not only have underestimated the true incidence of GBS infection, but it could also have underestimated the risks to babies from GBS infection. GBS infection in babies has increased in England, Wales, and Northern Ireland since 2003 (when the guideline was introduced). Voluntarily reported cases from the Communicable Disease Report/Health Protection Agency show 0.48 cases per 1,000 live births in 2003, and this figure increased to 0.64 per 1,000 in 2009.[94] In 2007, the RCOG published the findings of their audit to evaluate practice in the UK obstetric units against their recommendations.[95] The audit started out by comparing international guidelines for prevention of GBS-EOD: highlighting the fact that, in contrast to the UK and New Zealand guidelines, most of the other countries recommended identifying women for IAP by offering effective tests to all pregnant women. The audit reviewed hospitals' protocols against GBS infection in newborns. Of the 161 UK units, which submitted their protocol, four units did not even have a protocol for GBS, of those that did, 35% did not mention the 2003 RCOG guideline, and only a minority of units had protocols entirely consistent with the guideline.[citation needed] Further UK research published in 2010 looked at the opportunities for prevention of GBS-EOD following the introduction of the RCOG guideline. They found that, in the 48 cases of GBS during 2004 to 2007 (0.52/1,000 live births), only 19% of the mothers in whom risk factors were present were given adequate IAP. The researchers stated: "if all women with risk factors received prophylaxis, 23 cases (48%) may have been prevented."[53] The 2003 RCOG guideline was reviewed in July 2012, but no substantial changes were made. The most notable change being the clarification of procedure when a woman carrying GBS has PROM and the clarification that oral antibiotics are not recommended in labour against GBS infection in the baby.[citation needed] The review also dealt with a common misconception regarding vaginal cleansing stating that no evidence shows that this procedure can reduce GBS infection in the baby. New evidence and guidance in this field were reviewed by the RCOG in 2014, and it was decided that revision of the guideline would be deferred to a later date and in the meantime the version available on the website will remain valid until replaced.[citation needed] The second and final audit report into GBS (Audit of current practice in preventing GBS EOD in the UK) has been published. As a result of the audit, the RCOG have recommended that the national guidelines for preventing GBS infection in newborns should be updated.[96] In the UK, the RCOG still does not recommend bacteriological screening of pregnant women for antenatal GBS carriage in its revised new guidelines.[59] Nevertheless, it is stated that if GBS carriage is detected incidentally or by intentional testing, women should be offered IAP. And that all pregnant women should be provided with an appropriate information leaﬂet about GBS and pregnancy (published in December 2017).[97] Instead, women are treated according to their risk in labour. IAP is given to women where GBS has been found from their urine or vaginal/rectal swabs taken during the pregnancy, and to women who have previously had a baby with GBS disease. Immediate induction of labour and IAP should be offered to all women with prelabour rupture of membranes at 37 weeks of gestation or more, to women whose membranes are ruptured more than 18 hours and to those who have fever in labour. Women who are pyrexial in labour should be offered broad-spectrum antibiotics including an antibiotic appropriate for preventing EOD-GBS.[59] In the UK, it has also been suggested that: "For women known to carry GBS where it is not expected that the intravenous antibiotics can be given for at least 4 hours before delivery, an intramuscular injection of 4.8 MU (2.9 g) of Penicillin G at about 35 weeks of pregnancy may be useful in addition to intravenous antibiotics given from the onset of labour or membranes rupturing until delivery to try to eradicate GBS carriage until after delivery". [98] However, this recommendation IS NOT supported by any of the present guidelines.[20][22][59] ##### NICE guidelines[edit] The UK's National Institute for Health and Care Excellence (NICE) does not recommend routine testing for GBS, stating: "Pregnant women should not be offered routine antenatal screening for group B streptococcus because evidence of its clinical and cost effectiveness remains uncertain."[99] Nevertheless, the NICE guideline "Neonatal infection: antibiotics for prevention and treatment" states: "Intrapartum Antibiotic Prophylaxis should be offered if group B streptococcal colonisation, bacteriuria or infection are detected in the current pregnancy".[100] ##### National Screening Committee[edit] The UK National Screening Committee's current policy position on GBS is: "screening should not be offered to all pregnant women. This policy was reviewed in 2012, and despite receiving 212 responses, of which 93% advocated screening, the NSC has decided to not recommend antenatal screening.[101] This decision was strongly criticized by the charity Group B Strep Support as ignoring both the wishes of the public and the rising incidence rates of GBS infection in the UK.[102] In May 2006, the UK National Screening Committee launched their GBS online learning package. This learning package was developed to raise awareness of GBS amongst health care professionals. Developed by the Women's Health Specialist Library (part of the National Library for Health), the learning package was based upon the current UK guidelines published by the RCOG, and it is divided into three sections – antenatal, delivery, and postnatal. Within each section, the option exists to access an introduction to GBS, different clinical scenarios, a series of quiz questions to test knowledge, and a FAQs section.[citation needed] #### United States[edit] Recommendations for IAP to prevent perinatal GBS disease were issued in 1996 by the CDC. In these guidelines, the use of one of two prevention methods was recommended: either a risk-based approach or a culture-based screening approach.[45] The CDC issued updated guidelines in 2002; these guidelines recommended the universal culture-based screening of all pregnant women at 35–37 weeks' gestation to optimize the identification of women who must receive IAP. CDC also recommended that women with unknown GBS colonization status at the time of delivery be managed according to the presence of intrapartum risk factors. Because of this strategy, the US has seen a major reduction in the incidence of GBS-EOD. [103] The CDC issued updated guidelines again in 2010, however, the foundations of prevention in the CDC's 2010 guidelines remained unchanged.[20] The following were the main additions in the 2010 guidelines:[citation needed] * Expanded options for laboratory detection of GBS include the use of pigmented media and PCR assays. * A revised colony count threshold was set for laboratories to report GBS in the urine of pregnant women. * Revised algorithms for GBS screening and use of IAP for women with threatened preterm delivery include one algorithm for preterm labor and one for preterm premature rupture of membranes. * Recommendations for IAP agents are presented in an algorithm format in an effort to promote the use of the most appropriate antibiotic for penicillin-allergic women. * A minor change has been made to penicillin dosing to facilitate implementation in facilities with different packaged penicillin products. * The neonatal management algorithm's scope was expanded to apply to all newborns. * Management recommendations depend upon clinical appearance of the neonate and other risk factors such as maternal chorioamnionitis, adequacy of IAP if indicated for the mother, gestational age, and duration of membrane rupture. * Changes were made to the algorithm to reduce unnecessary evaluations in well-appearing newborns at relatively low risk for GBS-EOD. In 2018, the task of revising and updating the GBS prophylaxis guidelines were transferred from the CDC to ACOG (American College of Obstetricians and Gynecologists) (ACOG) and to the American Academy of Pediatrics.[citation needed] The ACOG committee issued an updated document on Prevention of Group B Streptococcal Early-Onset Disease in Newborns in 2019.[22] ACOG's guidance replaced the 2010 guidelines published by CDC.[104] This document does not introduce important changes from the CDC guidelines. The key measures necessary for preventing neonatal GBS early onset disease continue to be universal prenatal screening by culture of GBS from swabs collected from the lower vagina and rectum, correct collection and microbiological processing of the samples, and proper implementation of intrapartum antibiotic prophylaxis. It is also important to note that the ACOG recommended performing universal GBS screening between 36 and 37 weeks of gestation. This new recommendation provides a 5-week window[60] for valid culture results that includes births that occur up to a gestational age of at least 41 weeks. In 2019, American Academy of Pediatrics (AAP) published a new clinical report—Management of Infants at Risk for GBS neonatal disease.[105] AAP's Clinical Report replaced the 2010 guidelines published by CDC. #### Other guidelines[edit] National guidelines in most developed countries advocate the use of universal screening of pregnant women late in pregnancy to detect GBS carriage and use of IAP in all colonized mothers. e.g. Canada,[106] Spain,[107] Switzerland,[108] Germany,[109] Poland,[110] Czech Republic,[111] France,[112] Norway, and Belgium.[113] In contrast, risk factor-based guidelines were issued in the Netherlands,[114] New Zealand, Argentina,[115] and Queensland. [116] Nevertheless, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists does not recommend clearly one of both prevention strategies -either the risk-based or the culture-based approach to identify pregnant women for IAP, and allow practitioners to choose according jurisdictional guidelines.[117] ## Adults[edit] GBS is also an important infectious agent able to cause invasive infections in adults. Serious life-threatening invasive GBS infections are increasingly recognized in the elderly and in individuals compromised by underlying diseases such as diabetes, cirrhosis and cancer. GBS infections in adults include urinary tract infection, skin and soft-tissue infection (skin and skin structure infection) bacteremia without focus, osteomyelitis, meningitis and endocarditis.[14] GBS infection in adults can be serious, and mortality is higher among adults than among neonates.[118] In general, penicillin is the antibiotic of choice for treatment of GBS infections. Erythromycin or clindamycin should not be used for treatment in penicillin-allergic patients unless susceptibility of the infecting GBS isolate to these agents is documented. Gentamicin plus penicillin (for antibiotic synergy) in patients with life-threatening GBS infections may be used.[119][120][121] Toxic shock syndrome (TSS) is an acute multisystem life-threatening disease resulting in multiple organ failure. The severity of this disease frequently warrants immediate medical treatment. TSS is caused primarily by some strains of Staphylococcus aureus and Streptococcus pyogenes that produce exotoxins. Nevertheless, invasive GBS infection can be complicated, though quite infrequently, by streptococcal toxic shock-like syndrome (STLS)[122] ## Society and culture[edit] July has been recognised as Group B Strep Awareness Month,[123] a time when information about group B Strep aimed at families and health professionals is shared, predominantly in the UK and the US. In the UK, this is led by Group B Strep Support[124] ## Vaccine[edit] Though the introduction of national guidelines to screen pregnant women for GBS carriage and the use of IAP has significantly reduced the burden of GBS-EOD disease, it has had no effect on preventing either GBS-LOD in infants or GBS infections in adults.[125] Because of this if an effective vaccine against GBS were available, it would be an effective means of controlling not only GBS disease in infants, but also infections in adults.[citation needed] There are a number of problems with giving antibiotics to women in labor. Such antibiotic exposure risks included severe allergic reactions and difficulties screening pregnant women for GBS. If pregnant women could be given a vaccine against GBS, this could potentially prevent most cases of GBS without the need for antibiotics or screening. Vaccination is considered an ideal solution to prevent not only early- and late-onset disease but also GBS infections in adults at risk.[126] Development of GBS vaccines for maternal immunization has been identified as a priority by the World Health Organization on the basis of high unmet need.[127] It has been estimated that such a vaccine could potentially prevent 231,000 infant and maternal GBS cases.[128] As early as 1976,[32] low levels of maternal antibodies against the GBS capsular polysaccharide were shown to be correlated with susceptibility to GBS-EOD and GBS-LOD. Maternal-specific antibodies, transferred from the mother to the newborn, were able to confer protection to babies against GBS infection.[129] The capsular polysaccharide of GBS, which is an important virulence factor, is also an excellent candidate for the development of an effective vaccine.[130][129][131][132] GBS protein-based vaccines are also in development.[133][134][135] At present, the licensing of GBS vaccines is difficult because of the challenge in conducting clinical trials in humans due to the low incidence of GBS neonatal diseases.[24][131][136] Nevertheless, though research and clinical trials for the development of an effective vaccine to prevent GBS infections are underway, no vaccine is available as of 2019.[133][137] ## Nonhuman infections[edit] GBS has been found in many mammals and other animals such as camels, dogs, cats, seals, dolphins, and crocodiles.[138] ### Cattle[edit] In cattle, GBS causes mastitis, an infection of the udder. It can produce an acute febrile disease or a subacute, more chronic disease. Both lead to diminishing milk production (hence its name: agalactiae meaning "no milk"). Mastitis associated with GBS can have an important effect on the quantity and quality of milk produced, and is also associated with elevated somatic cell count and total bacteria count in the milk.[139] Outbreaks in herds are common, and as this is of major significance for the dairy industry, programs to reduce the impact of GBS have been enforced in many countries[140] ### Fish[edit] GBS it is also an important pathogen in a diversity of fish species, leading to serious economic losses in many species of fish worldwide. GBS causes severe epidemics in farmed fish, causing sepsis and external and internal hemorrhages. 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PMID 31751658.CS1 maint: multiple names: authors list (link) ## External links[edit] * UK Group B Strep Association * CDC—Group B Strep (GBS) Classification D * ICD-10: B95.1, P36.0 External resources * eMedicine: article/229091 * v * t * e * Firmicutes (low-G+C) Infectious diseases * Bacterial diseases: G+ Bacilli Lactobacillales (Cat-) Streptococcus α optochin susceptible * S. pneumoniae * Pneumococcal infection optochin resistant * Viridans streptococci: S. mitis * S. mutans * S. oralis * S. sanguinis * S. sobrinus * S. anginosus group β A * bacitracin susceptible: S. pyogenes * Group A streptococcal infection * Streptococcal pharyngitis * Scarlet fever * Erysipelas * Rheumatic fever B * bacitracin resistant, CAMP test+: S. agalactiae * Group B streptococcal infection ungrouped * Streptococcus iniae * Cutaneous Streptococcus iniae infection γ * D * BEA+: Streptococcus bovis Enterococcus * BEA+: Enterococcus faecalis * Urinary tract infection * Enterococcus faecium Bacillales (Cat+) Staphylococcus Cg+ * S. aureus * Staphylococcal scalded skin syndrome * Toxic shock syndrome * MRSA Cg- * novobiocin susceptible * S. epidermidis * novobiocin resistant * S. saprophyticus Bacillus * Bacillus anthracis * Anthrax * Bacillus cereus * Food poisoning Listeria * Listeria monocytogenes * Listeriosis Clostridia Clostridium (spore-forming) motile: * Clostridium difficile * Pseudomembranous colitis * Clostridium botulinum * Botulism * Clostridium tetani * Tetanus nonmotile: * Clostridium perfringens * Gas gangrene * Clostridial necrotizing enteritis Finegoldia (non-spore forming) * Finegoldia magna Mollicutes Mycoplasmataceae * Ureaplasma urealyticum * Ureaplasma infection * Mycoplasma genitalium * Mycoplasma pneumoniae * Mycoplasma pneumonia Anaeroplasmatales * Erysipelothrix rhusiopathiae * Erysipeloid * 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 * t * e Vertically transmitted infections Gestational * Viruses * Congenital rubella syndrome * Congenital cytomegalovirus infection * Neonatal herpes simplex * Hepatitis B * Congenital varicella syndrome * HIV * Fifth disease * Bacteria * Congenital syphilis * Other * Toxoplasmosis * transplacental * TORCH complex During birth * transcervical * Candidiasis * Gonorrhea * Listeriosis Late pregnancy * Listeriosis * Congenital cytomegalovirus infection By breastfeeding * Breastfeeding * Tuberculosis * HIV [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Group B streptococcal infection	c2020625	5,030	wikipedia	https://en.wikipedia.org/wiki/Group_B_streptococcal_infection	2021-01-18T18:49:19	{"mesh": ["D013290"], "umls": ["C2020625"], "icd-10": ["P36.0", "B95.1"], "wikidata": ["Q3500350"]}
For a phenotypic description and a discussion of genetic heterogeneity of systemic lupus erythematosus (SLE), see 152700. Pathogenesis Relative deficiency of pentraxin proteins is implicated in the pathogenesis of SLE. The C-reactive protein (CRP; 123260) response is defective in patients with acute flares of disease, and mice with targeted deletions of the APCS (104770) gene develop a lupus-like illness. In humans, the CRP and APCS genes are both within the chromosome 1q23-q24 interval that has been linked to SLE. Among 586 simplex SLE families, Russell et al. (2004) found that basal levels of CRP were influenced independently by a synonymous change at codon 144 designated CRP2 (rs1800947) and a 3-prime flanking region SNP designated CRP4 (rs1205), and the latter was associated with SLE and antinuclear autoantibody production. Russell et al. (2004) hypothesized that defective disposal of potentially immunogenic material may be a contributory factor in lupus pathogenesis. Mapping Edberg et al. (2008) analyzed SNPs in the proximal 5-prime promoter region of the CRP gene on chromosome 1q21-q23 in SLE patients and controls and found the strongest association for -707A-G (CRP-707, rs3093061; corrected p = 8.75 x 10(-5) and 2.66 x 10(-5) for Caucasian and African American case-control samples, respectively). The authors noted that linkage disequilibrium (LD) exists between SNPs in the proximal promoter, but that association of functional haplotypes containing CRP-409/CRP-390 (-409G-A, rs3091244; -390C-T-A, rs3093062) appeared to be driven by the CRP-707 association; however, they also noted CRP-707 is not predicted to lie within a transcription factor-binding site. There was also a high degree of LD between the promoter SNPs studied by Edberg et al. (2008) and CRP2 and CRP4, which the authors suggested might explain the previously reported association between the latter SNPs and CRP levels. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, 14	c2751054	5,031	omim	https://www.omim.org/entry/613145	2019-09-22T15:59:34	{"omim": ["613145"]}
Interictal dysphoric disorder (IDD) is a mood disorder sometimes found in patients with epilepsy, at a prevalence rate of approximately 17%.[1] The most common symptom of IDD is intermittent dysphoric mood in between seizures. Interictal dysphoric disorder can often be treated with a combination of antidepressant and anticonvulsant medication.[2] ## History[edit] Emil Kraepelin in 1923 first outlined a set of symptoms common in people with chronic epilepsy, the most prominent of which is intermittent depressive episodes.[3] These mood changes occur without any external triggers, during the interictal phase (between seizures). In 1949, Bleuler note a similar syndrome and in 1955, Gastaut confirmed both these observations.[4] Later, Blumer coined the term interictal dysphoric disorder to describe a similar pleomorphic presentation of symptoms exhibited by his patients.[5] Blumer and Altshuler outlined eight affective-somatoform symptoms that characterize IDD: depressive moods, irritability, anergia, insomnia, pains, phobic fears, and euphoric moods.[6] The diagnosis of IDD should be made when at least three of the eight symptoms are present.[7] ## References[edit] 1. ^ Kōhō Miyoshi (9 August 2010). Neuropsychiatric Disorders. Springer. pp. 107–. ISBN 978-4-431-53871-4. 2. ^ Steven C. Schachter; Gregory L. Holmes, MD; Dorothée Kasteleijn-Nolst Trenité (2008). Behavioral Aspects of Epilepsy: Principles and Practice. Demos Medical Publishing. pp. 213–. ISBN 978-1-933864-04-4. 3. ^ Jerome Engel; Timothy A. Pedley; Jean Aicardi (2008). Epilepsy: A Comprehensive Textbook. Lippincott Williams & Wilkins. pp. 2199–. ISBN 978-0-7817-5777-5. 4. ^ Andres Kanner; Steven C. Schachter (28 July 2010). Psychiatric Controversies in Epilepsy. Elsevier. pp. 54–. ISBN 978-0-08-055959-9. 5. ^ Michael R. Trimble; Bettina Schmitz (9 June 2011). The Neuropsychiatry of Epilepsy. Cambridge University Press. pp. 82–. ISBN 978-1-139-49789-3. 6. ^ Frank Gilliam; Andres M. Kanner; Yvette Sheline (8 December 2005). Depression and Brain Dysfunction. Taylor & Francis. pp. 219–. ISBN 978-1-84214-214-1. 7. ^ Gregory P. Lee Professor of Adult Neuropsychology Medical College of Georgia (30 January 2010). Neuropsychology of Epilepsy and Epilepsy Surgery. Oxford University Press. pp. 147–. ISBN 978-0-19-970699-0. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Interictal dysphoric disorder	None	5,032	wikipedia	https://en.wikipedia.org/wiki/Interictal_dysphoric_disorder	2021-01-18T18:54:29	{"wikidata": ["Q17142111"]}
Equine infectious anemia virus Virus classification (unranked): Virus Realm: Riboviria Kingdom: Pararnavirae Phylum: Artverviricota Class: Revtraviricetes Order: Ortervirales Family: Retroviridae Genus: Lentivirus Species: Equine infectious anemia virus Equine infectious anemia or equine infectious anaemia (EIA), also known by horsemen as swamp fever, is a horse disease caused by a retrovirus (Equine infectious anemia virus) and transmitted by bloodsucking insects. The virus (EIAV) is endemic in the Americas, parts of Europe, the Middle and Far East, Russia, and South Africa. The virus is a lentivirus, like human immunodeficiency virus (HIV). Like HIV, EIA can be transmitted through blood, milk, and body secretions. Transmission is primarily through biting flies, such as the horse-fly and deer-fly.[1] The virus survives up to 4 hours in the vector. Contaminated surgical equipment and recycled needles and syringes, and bits[2] can transmit the disease. Mares can transmit the disease to their foals via the placenta. The risk of transmitting the disease is greatest when an infected horse is ill, as the blood levels of the virus are then highest. ## Contents * 1 Stages * 2 Prevention and treatment * 3 Diagnosis * 4 References * 5 External links ## Stages[edit] Acute: The acute form is a sudden onset of the disease at full-force. Symptoms include high fever, anemia (due to the breakdown of red blood cells), weakness, swelling of the lower abdomen and legs, weak pulse, and irregular heartbeat. The horse may die suddenly. Subacute: A slower, less severe progression of the disease. Symptoms include recurrent fever, weight loss, an enlarged spleen (felt during a rectal examination), anemia, and swelling of the lower chest, abdominal wall, penile sheath, scrotum, and legs. Chronic: The horse tires easily and is unsuitable for work. The horse may have a recurrent fever and anemia, and may relapse to the subacute or acute form even several years after the original attack. A horse may also not appear to have any symptoms, yet still tests positive for EIA antibodies. Such a horse can still pass on the disease. According to most veterinarians, horses diagnosed EIA positive usually do not show any sign of sickness or disease. EIA may cause abortion in pregnant mares. This may occur at any time during the pregnancy if there is a relapse when the virus enters the blood. Most infected mares will abort, however some give birth to healthy foals. Foals are not necessarily infected. Studies indicate that there are breeds with a tolerance to EIA.[3] Recent studies in Brazil on living wild horses have shown that in the Pantanal, about 30% of domesticated and about 5.5% of the wild horses are chronically infected with EIA.[4] ## Prevention and treatment[edit] A vaccine is available, called "Chinese Live Attenuated EIA vaccine", developed in China and widely used there since 1983. Another attenuated live virus vaccine is in development in the United States.[5] Reuse of syringes and needles is a risk factor for transfer of the disease. Currently in the United States, all horses that test positive must be reported to federal authorities by the testing laboratory. EIA-positive horses are infected for life. Options for the horse include sending the horse to a recognized research facility, branding the horse and quarantining it at least 200 yards from other horses for the rest of its life, and euthanizing the horse. Very few quarantine facilities exist, which usually leads to the option of euthanizing the horse. The Florida Research Institute for Equine Nurturing, Development and Safety (a.k.a. F.R.I.E.N.D.S.) is one of the largest such quarantine facilities and is located in south Florida.[6] The horse industry and the veterinary industry strongly suggest that the risks posed by infected horses, even if they are not showing any clinical signs, are enough of a reason to impose such stringent rules. The precise impacts of the disease on the horse industry are unknown. ## Diagnosis[edit] The Coggins test submission form, which requires identification of the horse's physical appearance. This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2016) (Learn how and when to remove this template message) The Coggins test (agar immunodiffusion) is a sensitive diagnostic test for equine infectious anemia developed by Dr. Leroy Coggins in the 1970s. Currently, the US does not have an eradication program due to the low rate of incidence. However, many states require a negative Coggins test for interstate travel. In addition, most horse shows and events require a negative Coggins test. Most countries require a negative test result before allowing an imported horse into the country. Horse owners should verify that all the horses at a breeding farm and or boarding facility have a negative Coggins test before using the services of the facility. A Coggins test should be done on an annual basis. Tests every 6 months are recommended if there is increased traveling. ## References[edit] 1. ^ "Equine Infectious Anemia: Introduction". The Merck Veterinary Manual. 2006. Retrieved 2007-06-23. 2. ^ Equine Infectious Anemia (EIA) Archived 2009-07-27 at the Wayback Machine, North Carolina Department of Agriculture and Consumer Services, retrieved December 19, 2008. 3. ^ "Agricultural Biological Diversity"[permanent dead link], Convention on Biological Diversity, referenced August 12, 2008. 4. ^ R.A.M.S. Silva; U.G.P. De Abreu; A.M.R. Dávila; L. Ramirez (1999). "Swamp fever in wild horses from the Pantanal, Brazil" (PDF). Revue d'Élevage et de Médecine Vétérinaire des Pays Tropicaux. 52 (2): 99–101. Retrieved 2010-10-17. 5. ^ Craigo JK, Li F, Steckbeck JD, Durkin S, Howe L, Cook SJ, Issel C, Montelaro RC (2005). "Discerning an effective balance between equine infectious anemia virus attenuation and vaccine efficacy". J. Virol. 79 (5): 2666–77. doi:10.1128/JVI.79.5.2666-2677.2005. PMC 548432. PMID 15708986. 6. ^ "FRIENDS HORSE RESCUE". FRIENDS HORSE RESCUE. Retrieved 17 January 2019. ## External links[edit] * The short film Equine Infectious Anemia: A Status Report (1996) is available for free download at the Internet Archive * v * t * e Virus: Retroviruses ssRNA-RT virus Retroviridae Alpharetrovirus * Avian sarcoma leukosis virus * Rous sarcoma virus Betaretrovirus * Mouse mammary tumor virus * Jaagsiekte sheep retrovirus Deltaretrovirus * Human T-lymphotropic virus (HTLV-1 * HTLV-2, 3, 4) * Simian-T-lymphotropic virus (types 1-4) * Bovine leukemia virus Epsilonretrovirus * Walleye epidermal hyperplasia virus Gammaretrovirus * Murine leukemia virus * Abelson murine leukemia virus * Friend virus * Feline leukemia virus * Koala retrovirus (KoRV) * Xenotropic murine leukemia virus-related virus Lentivirus * HIV (human immunodeficiency viruses) * Simian immunodeficiency virus (SIV) * Feline immunodeficiency virus (FIV) * Puma lentivirus (PLV) * Equine infectious anemia virus (EIAV) * Bovine immunodeficiency virus (BIV) * Caprine arthritis encephalitis virus * Visna-maedi virus Spumavirus * Simian foamy virus * Human foamy virus Other * Metaviridae * Pseudoviridae dsDNA-RT virus * Hepadnaviridae (Hepatitis B virus) * Caulimoviridae Endogenous * ERVWE1 * HCP5 * Human teratocarcinoma-derived virus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Equine infectious anemia	c0014661	5,033	wikipedia	https://en.wikipedia.org/wiki/Equine_infectious_anemia	2021-01-18T19:05:20	{"mesh": ["D004859"], "wikidata": ["Q19000458"]}
A number sign (#) is used with this entry because of evidence that odontochondrodysplasia (ODCD) is caused by compound heterozygous mutation in the TRIP11 gene (604505) on chromosome 14q32. Description Odontochondrodysplasia is characterized by mesomelic shortening of tubular bones, ligamentous laxity, and scoliosis, in association with dentinogenesis imperfecta involving both primary and secondary dentition. Affected individuals show variable severity. Radiologic features include trident pelvis, posteriorly flattened vertebrae, and brachydactyly with cone-shaped epiphyses (Maroteaux et al., 1996). Clinical variability and extraskeletal manifestations have been observed (Wehrle et al., 2019). Mutation in the TRIP11 gene also causes a more severe chondrodysplasia, achondrogenesis type IA (ACG1A; 200600). Clinical Features In a 3.5-year-old boy of mixed Australian/Thai parentage, Goldblatt et al. (1991) described a form of spondylometaphyseal dysplasia associated with joint laxity and dentinogenesis imperfecta. The disorder appeared to be different from the spondyloepimetaphyseal dysplasia with joint laxity described by Beighton et al. (1984) (see 271640) as well as from the forms of spondylometaphyseal dysplasia known as the Irapa (271650) and Strudwick (184250) types. The dentinogenesis imperfecta resembled that seen with osteogenesis imperfecta but there were no signs of that disorder. The father's age was not given. X-linked spondylometaphyseal dysplasia (313420) is not associated with dentinogenesis imperfecta. Bonaventure et al. (1992) presented the cases of 2 additional patients: a brother and sister with short limb dwarfism, joint laxity, and dentinogenesis imperfecta, born to healthy nonconsanguineous parents. Electron microscopic studies revealed large vacuoles of dilated rough endoplasmic reticulum within the cytoplasm of chondrocytes. Gel electrophoresis of pepsin-soluble collagen extracted from cartilage demonstrated type II collagen chains with abnormal mobility. A quantitative decrease in COL1A1 and COL1A2 mRNA was also observed. Overmodification of type II collagen peptides, suggested by the findings, was consistent with the presence of a single base substitution in the COL2A1 gene (120140). Maroteaux et al. (1996) studied 4 unrelated children with growth retardation, ligamentous laxity, and scoliosis, including the brother and sister previously reported by Bonaventure et al. (1992). Mild facial dysmorphism was present, and 1 patient was referred for evaluation of thoracic deformity, but the most striking feature was shortening of the limbs, especially the hands and feet. Radiographs showed short tubular bones, particularly of the middle segment, with irregular metaphyses, as well as cone-shaped epiphyses of the hands, square iliac wings, horizontal acetabular roofs, and posterior wedging of vertebral bodies. The authors proposed the designation 'odontochondrodysplasia' for the disorder, which they noted was of variable severity. Unger et al. (2008) reported 6 additional patients with Goldblatt syndrome, including a second sib pair (brother and sister). The main clinical features included short stature, joint laxity, narrow chest, and dentinogenesis imperfecta. Two patients required spinal surgery to correct progressive scoliosis at age 4.5 years and 7 years. Intellectual development was normal but motor delays occurred in some patients. The main radiographic features included congenital platyspondyly with coronal clefts, severe metaphyseal changes (especially hands, wrists, and knees), mesomelic limb shortening, and coxa valga. The occurrence of a second sib pair suggests autosomal recessive inheritance, although none of the reported families (including those with sib recurrence) were consanguineous. One patient was initially suspected of having Torrance type platyspondylic lethal skeletal dysplasia (PLSDT; 151210). Wehrle et al. (2019) studied 10 patients from 7 families with ODCD, including the 6 patients previously reported by Unger et al. (2008), who were all compound heterozygous for mutations in the TRIP11 gene. The authors observed considerable clinical variability, with early lethality and milder postnatal phenotypes occurring within the same family (family 1), in which a brother died at age 4 months with severe ODCD, whereas his sister was alive at age 16 years with mild disease. In addition, there were extraskeletal disease manifestations, including pulmonary hypoplasia in 3 patients, polycystic kidneys in 1, nephronophthisis in 1, and hydrocephaly in 1. Inheritance Maroteaux et al. (1996) noted that the occurrence of odontochondrodysplasia in a brother and sister reported by Bonaventure et al. (1992) suggested autosomal recessive inheritance, although parental mosaicism could not be excluded with certainty. Wehrle et al. (2019) confirmed autosomal recessive inheritance of OCDC in 7 families. Molecular Genetics Wehrle et al. (2019) analyzed the TRIP11 gene in 10 patients from 7 families with ODCD and identified compound heterozygous mutations in all 10 (see, e.g., 604505.0001 and 604505.0005-604505.0012). The unaffected parents were each heterozygous for 1 of the mutations, and unaffected sibs were heterozygous or wildtype. None of the variants were found in public exome databases. Wehrle et al. (2019) noted that all patients carried both a TRIP11 null allele as well as a splice variant that was translated into low-abundance GMAP protein; they concluded that hypomorphic mutations of TRIP11 are the genetic basis for a range of ODCD phenotypes. ### Exclusion Studies Unger et al. (2008) performed complete sequencing of several genes, including the COL2A1 gene, in one or more of the patients they reported with Goldblatt syndrome and identified no pathogenic mutations. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Relative macrocephaly Face \- Narrow face \- Long philtrum \- Prominent forehead Teeth \- Dentinogenesis imperfecta \- Delayed tooth eruption, primary and secondary RESPIRATORY \- Respiratory distress Lung \- Pulmonary hypoplasia CHEST External Features \- Narrow thorax Ribs Sternum Clavicles & Scapulae \- Pectus carinatum GENITOURINARY Kidneys \- Polycystic kidneys (in 1 patient) \- Nephronophthisis (in 1 patient) SKELETAL \- Joint hyperextensibility \- Osteoporosis \- Chondrocytes have large vacuoles of dilated rough endoplasmic reticulum seen on electron microscopy Spine \- Biconvex vertebral bodies \- Coronal clefts (neonate) \- Scoliosis \- Platyspondyly (neonate) Pelvis \- Flared iliac wings \- Horizontal acetabular roof \- Small sciatic notch \- Lacy iliac wings (early childhood) Limbs \- Genu vara \- Genu recurvata \- Short long bones \- Broad, cupped metaphyses \- Mesomelia \- 'Banana peel' configuration of distal radius \- Small, irregular epiphyses Hands \- Brachydactyly, mild \- Short metacarpals \- Short phalanges \- Cone-shaped epiphyses \- Delayed carpal ossification NEUROLOGIC Central Nervous System \- Delayed motor milestones LABORATORY ABNORMALITIES \- Abnormal electrophoretic mobility of type II collagen MISCELLANEOUS \- Possible gonadal mosaicism in one report \- Mesomelia becomes more evident with age MOLECULAR BASIS \- Caused by mutation in the thyroid hormone receptor interactor 11 gene (TRIP11, 604505.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	ODONTOCHONDRODYSPLASIA	c2745953	5,034	omim	https://www.omim.org/entry/184260	2019-09-22T16:34:22	{"mesh": ["C535792"], "omim": ["184260"], "orphanet": ["166272"], "synonyms": ["Alternative titles", "SPONDYLOMETAPHYSEAL DYSPLASIA WITH DENTINOGENESIS IMPERFECTA", "GOLDBLATT SYNDROME"]}
Congenital dyserythropoietic anemia type III SpecialtyHematology Congenital dyserythropoietic anemia type III (CDA III) is a rare autosomal dominant disorder characterized by macrocytic anemia, bone marrow erythroid hyperplasia and giant multinucleate erythroblasts.[1] New evidence suggests that this may be passed on recessively as well. ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 Further reading * 8 External links ## Presentation[edit] The signs and symptoms of CDA type III tend to be milder than those of the other types. Most affected individuals do not have hepatosplenomegaly, and iron does not build up in tissues and organs. In adulthood, abnormalities of a specialized tissue at the back of the eye (the retina) can cause vision impairment. Some people with CDA type III also have a blood disorder known as monoclonal gammopathy, which can lead to a cancer of white blood cells (multiple myeloma).[2] ## Genetics[edit] CDA type III is transmitted autosomal dominantly. The genetic cause of CDA type III is known to be a problem with the KIF23 gene, located on the long arm of chromosome 15 at a position designated 15q22. Type OMIM Gene Locus CDAN3 105600 KIF23 15q21 ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2017) ## Treatment[edit] Treatment consists of frequent blood transfusions and chelation therapy. Potential cures include bone marrow transplantation and gene therapy. ## See also[edit] * Congenital dyserythropoietic anemia * Thalassemia * Hemoglobinopathy * List of hematologic conditions ## References[edit] 1. ^ Localization of the gene for congenital dyserythropoietic anemia type III, CDAN3, to chromosome 15q21-q25 2. ^ congenital dyserythropoietic anemia \- Genetic Home References ## Further reading[edit] * Congenital dyserythropoietic anemia at the US National Institutes of Health Home Genetic Reference ## External links[edit] Classification D * ICD-10: D64.4 * ICD-9-CM: 285.8 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Congenital dyserythropoietic anemia type III	c0271934	5,035	wikipedia	https://en.wikipedia.org/wiki/Congenital_dyserythropoietic_anemia_type_III	2021-01-18T19:06:20	{"mesh": ["D000742"], "icd-9": ["285.8"], "icd-10": ["D64.4"], "orphanet": ["98870"], "wikidata": ["Q5160425"]}
Limb body wall complex (LBWC) is characterized by severe multiple congenital anomalies in the fetus with exencephaly/encephalocele, thoraco- and/or abdominoschisis (anterior body wall defects) and limb defects, with or without facial clefts. ## Epidemiology Approximately 250 cases have been reported in the literature so far. ## Clinical description Clinical manifestations vary widely and include limb defects and visceral malformations (95% of cases), spinal abnormalities, absent diaphragm, bowel atresia and renal agenesis. LBWC generally presents as a short umbilical cord, abdominal placental attachment, persistence of an extraembryonic celom, anorectal malformations, urogenital abnormalities, lumbosacral meningomyelocele and kyphoscoliosis. A spectrum of LBWC manifestations is included in the amniotic band sequence (see this term), presenting mostly with craniofacial defects, facial clefts, amniotic bands and/or adhesions. At present, it remains unclear whether these two entities represent a single disorder. ## Etiology The etiology of LBWC remains unknown. Karyotypes have been reported as normal and no correlations with gender, parental age and teratogenic agents have been found. The principal theories are an extrinsic origin by early amniotic rupture, or a vascular origin due to an early vascular accident during embryological development. Single cases of familial occurrence have been documented. ## Diagnostic methods Diagnosis is based on the presenting features. ## Differential diagnosis LBWC should be differentiated from gastroschisis (see this term), which has better prognosis. ## Antenatal diagnosis Early antenatal diagnosis is feasible by ultrasound examination and may be followed by medical termination of the pregnancy. ## Prognosis LBWC is fatal, with death occurring antenatally or early in the neonatal period. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Limb body wall complex	c4274839	5,036	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2369	2021-01-23T18:43:57	{"gard": ["3251"], "icd-10": ["Q87.8"], "synonyms": ["Body stalk anomaly", "LBWC syndrome"]}
A number sign (#) is used with this entry because autosomal recessive deafness-48 (DFNB48) is caused by homozygous mutation in the CIB2 gene (605564) on chromosome 15q25. Description DFNB48 is an autosomal recessive form of deafness. Affected individuals have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies (summary by Riazuddin et al., 2012). Mapping By linkage analysis in 5 large consanguineous Pakistani families with nonsyndromic deafness segregating as an autosomal recessive trait, Ahmad et al. (2005) mapped the phenotype locus to chromosome 15q23-q25.1. Analysis in 1 of the families demonstrated linkage of the deafness locus, designated DFNB48, to D15S1005 (lod score of 8.6 at theta = 0), and a critical linkage interval of approximately 7 cM was defined between D15S216 and D15S1041. Affected individuals had bilateral profound congenital hearing loss. Ahmed et al. (2009) sequenced the TLE3 gene within the DFNB48 locus but did not identify any pathogenic alleles. Molecular Genetics In affected members of 54 Pakistani families with autosomal recessive deafness-48, Riazuddin et al. (2012) identified a homozygous mutation in the CIB2 gene (F91S; 605564.0001). Haplotype analysis indicated a founder effect. Two additional homozygous CIB2 mutations were found in other families with DFNB48 (C99W, 605564.0002 and I123T, 605564.0003). Transfection of the F91S and C99W mutations in COS-7 cells decreased or abolished the ability of CIB2 to decrease ATP-induced calcium release from the cell compared to wildtype, whereas transfection of the I123T mutation increased the ability of CIB2 to decrease calcium release compared to wildtype. These findings suggested that the mutations had an effect on CIB2 calcium-binding or buffering activity, and indicated that loss of this gene results in defects in calcium regulation. Population Genetics Riazuddin et al. (2012) estimated that CIB2 mutations may account for up to 7.25% of Pakistani families with autosomal recessive deafness. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, congenital, profound (250-8,000 Hz) MISCELLANEOUS \- Prelingual onset \- Hearing loss affects all frequencies MOLECULAR BASIS \- Caused by mutation in the calcium- and integrin-binding protein 2 gene (CIB2, 605564.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	DEAFNESS, AUTOSOMAL RECESSIVE 48	c1836199	5,037	omim	https://www.omim.org/entry/609439	2019-09-22T16:06:03	{"doid": ["0110505"], "mesh": ["C563720"], "omim": ["609439"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"]}
## Clinical Features In man, hair is commonly present on all the basal segments of the digits and invariably absent from all the terminal ones. On the middle segments, there is wide fluctuation with apparent familial and racial tendencies. Hair is present on the middle segment of the fingers more frequently than on the middle segment of the toes. Hair is most often found on the middle segment of the fourth finger (summary by Danforth, 1921). Egesi and Rashid (2010) reviewed the subject of middigital hair. Inheritance The genetic determination of presence or absence of hair on the dorsal aspect of the middle phalanx was first suggested by Danforth (1921). From a study of 80 families with a total of 178 children, he suggested that 'a phylogenetically progressive loss of hair is brought about through the action of one or more recessive genes, or of one primary recessive gene with several modifying factors that regulate the distribution of hair when it is present.' Stated conversely, 'despite the fact that in evolutionary progress hair is disappearing from the mid-digital region, its presence...may be regarded as the manifestation of a dominant trait.' Bernstein and Burks (1942) suggested that 5 allelic genes, A-0 to A-4, 'control the inheritance and distribution of middigital hair involving but a single gene substitution (the subscript denoting the number of fingers affected with middigital hair),' and that the genes for the presence of hair are dominant over the genes for its absence (summary by Bernstein, 1949). From a literature review and their own study in Brazil, Saldanha and Guinsburg (1961) suggested that lack of middle phalangeal hair may be determined by a pair of recessive genes, but noted that the occurrence of sex, age, and possibly environmental differences make genetic analysis of the trait difficult. Population Genetics Danforth (1921) reported that middigital hair was present in men more often than in women. Caucasians were found to have a higher incidence of middle phalangeal hair than other ethnic groups, including African Americans, American Indians, and Japanese. Saldanha and Guinsburg (1961) studied the presence or absence of middigital hair in a white population of Sao Paulo, Brazil, including 131 males and 158 females, and compared their findings with those of previous reports. The frequencies of individuals without midphalangeal hair showed striking population differences. The range among northern Europeans varied from 20 to 30%, and among Mediterraneans, from 30 to 50%. Among Japanese, American Indians, and blacks, the figures varied between about 60% and 90%. The trait was virtually absent among Eskimos. History Willier (1974) quoted Danforth as stating that 'the hair follicle is a kind of biological microcosm in which almost any problem relating to growth, differentiation, decline and rejuvenescence of tissue can be studied to advantage....' While riding on a streetcar in Wilkes-Barre one summer, Danforth observed, in his own words, that 'a man in front of me draped his arm over the back of the seat and I noticed that while his arm was very hairy the middle segments of his fingers were free of hair and so, I observed, were my own; but I knew this was not generally true.' So far as he was aware, no one before had recognized this variation as possibly hereditary. Hair \- Hair on dorsum of middle phalanx Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	MIDPHALANGEAL HAIR	c1834876	5,038	omim	https://www.omim.org/entry/157200	2019-09-22T16:38:08	{"mesh": ["C537471"], "omim": ["157200"], "synonyms": ["Alternative titles", "MIDDIGITAL HAIR"]}
Imperforate oropharynx-costovertebral anomalies syndrome is a dysostosis with predominant vertebral and costal involvement characterized by oropharyngeal atresia, mild mandibulofacial dysostosis, auricular malformations, and costovertebral anomalies (hemivertebrae, block vertebra, partial fusion of the ribs, absent ribs). There have been no further descriptions in the literature since 1989. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Imperforate oropharynx-costovertebral anomalies syndrome	None	5,039	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2759	2021-01-23T17:58:56	{"gard": ["2989"], "synonyms": ["Seghers syndrome"]}
Blau syndrome (BS) is a rare systemic inflammatory disease characterized by early onset granulomatous arthritis, uveitis and skin rash. BS now refers to both the familial and sporadic (formerly early-onset sarcoidosis) form of the same disease. The proposed term pediatric granulomatous arthritis is currently questioned since it fails to represent the systemic nature of the disease. ## Epidemiology Exact prevalence is unknown. From a Danish registry, the annual incidence was estimated to be 1/1,670,000/ year for children <5 years of age. ## Clinical description Skin rash (of tiny red/tan dots) is usually the first manifestation and appears as early as the age of 1 month on the face and then spreads to the trunk. Patients can have intermittent episodes of skin lesions that resolve without treatment. Joint manifestations usually begin before the age of 10 with painless cyst-like swellings on the back of feet and wrists. Symmetric arthritis (with boggy inflammatory synovitis and tenosynovitis) of the wrists, ankles, knees and sometimes elbows follows. Camptodactyly due to hypertrophic tenosynovitis is often described as the disease progresses. Severe handicap is not usually experienced until the age of 40-50. An insidious granulomatous iridocyclitis and posterior uveitis (see this term) can evolve into a severe destructive panuveitis. Over time, characteristic iris nodules, focal synechiae, cataract, increased intraocular pressure and characteristic clumpy keratic precipitates at the limbus ensue. Posterior involvement includes vitritis, multifocal choroiditis, retinal vasculopathy and optic nerve edema. Significant visual loss is observed in 20-30% of the affected individuals. The spectrum of clinical manifestations includes fever, malignant systemic and pulmonary hypertension, granulomatous large-vessel vasculitis and granulomatous inflammation of the liver, kidneys and lung. ## Etiology BS is due to an inherited or de novo mutation in the NOD2 gene (16q12), responsible for alterations in the innate immune response, inflammation and cell death. From transfection studies, it has been proposed that NOD2 mutations cause activation of nuclear factor kappa B which is in turn an up-regulator of pro-inflammatory cytokine transcription. ## Diagnostic methods Diagnosis relies greatly on the demonstration of noncaseating granulomatous inflammation with epithelioid cells and multinucleated giant cells on a skin, synovial or conjunctival biopsy, and genetic testing for mutations in the NOD2 gene. ## Differential diagnosis Differential diagnoses include polyarthritis and systemic juvenile idiopathic arthritis (JIA; see this term), granulomatous inflammation associated with primary immunodeficiencies, and systemic granulomatous vasculitis. In patients with granulomatous inflammation, chronic infections especially with mycobacteria and fungi must be excluded. ## Antenatal diagnosis Antenatal diagnosis and prenatal genetic testing is rarely performed. ## Genetic counseling BS is an autosomal dominant disorder in the familial form and genetic counseling is advised. ## Management and treatment There is no evidence-based data on the optimal treatment of BS. Moderate to low-dose daily corticosteroid therapy is effective in controlling uveitis and joint disease but the side effects of prolonged use may become unacceptable. Methotrexate at a dosage of 10-15 mg/m2 once weekly is effective in suppressing disease activity and allowing corticosteroid tapering. The introduction of anti-TNF monoclonal antibody agents (infliximab and adalimumab) may constitute a major therapeutic advance in the treatment of BS; however, the effect on uveitis activity may be less convincing. ## Prognosis BS is a chronic and progressive disease with a variable and often unpredictable spectrum of severity. In cases with expanded manifestations, life expectancy may be reduced. Uveitis has a poor prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Blau syndrome	c1861303	5,040	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90340	2021-01-23T18:50:23	{"gard": ["304"], "mesh": ["C538157"], "omim": ["186580"], "umls": ["C1861303"]}
Disease of cellular proliferation that results in abnormal growths in the body which lack the ability to metastasize Benign tumor Normal epidermis and dermis with intradermal nevus, 10x-cropped SpecialtyPathology A benign tumor is a mass of cells (tumor) that lacks the ability to either invade neighboring tissue or metastasize (spread throughout the body). When removed, benign tumors usually do not grow back, whereas malignant tumors sometimes do. Unlike most benign tumors elsewhere in the body, benign brain tumors can be life-threatening.[1] Benign tumors generally have a slower growth rate than malignant tumors and the tumor cells are usually more differentiated (cells have more normal features).[2][3][4] They are typically surrounded by an outer surface (fibrous sheath of connective tissue) or stay contained within the epithelium.[5] Common examples of benign tumors include moles and uterine fibroids. Although benign tumors will not metastasize or locally invade tissues, some types may still produce negative health effects. The growth of benign tumors produces a "mass effect" that can compress tissues and may cause nerve damage, reduction of blood flow to an area of the body (ischaemia), tissue death (necrosis) and organ damage. The health effects of the tumor may be more prominent if the tumor is within an enclosed space such as the cranium, respiratory tract, sinus or inside bones. Tumors of endocrine tissues may overproduce certain hormones. Examples include thyroid adenomas and adrenocortical adenomas.[2] Although most benign tumors are not life-threatening, many types of benign tumors have the potential to become cancerous (malignant) through a process known as tumor progression.[6] For this reason and other possible negative health effects, some benign tumors are removed by surgery.[7] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 PTEN hamartoma syndrome * 2.2 Other syndromes * 2.3 Familial adenomatous polyposis * 2.4 Tuberous sclerosis complex * 2.5 Von Hippel-Lindau disease * 3 Mechanism * 3.1 Benign vs malignant * 3.2 Multistage carcinogenesis * 4 Diagnosis * 4.1 Classification * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] Benign tumors are very diverse; they may be asymptomatic or may cause specific symptoms, depending on their anatomic location and tissue type. They grow outward, producing large, rounded masses which can cause what is known as a "mass effect". This growth can cause compression of local tissues or organs, leading to many effects, such as blockage of ducts, reduced blood flow (ischaemia), tissue death (necrosis) and nerve pain or damage.[2] Some tumors also produce hormones that can lead to life-threatening situations. Insulinomas can produce large amounts of insulin, causing hypoglycemia.[8][9] Pituitary adenomas can cause elevated levels of hormones such as growth hormone and insulin-like growth factor-1, which cause acromegaly; prolactin; ACTH and cortisol, which cause Cushings disease; TSH, which causes hyperthyroidism; and FSH and LH.[10] Bowel intussusception can occur with various benign colonic tumors.[11] Cosmetic effects can be caused by tumors, especially those of the skin, possibly causing psychological or social discomfort for the person with the tumor.[12] Vascular tissue tumors can bleed, in some cases leading to anemia.[13] ## Causes[edit] ### PTEN hamartoma syndrome[edit] PTEN hamartoma syndrome consists of four distinct hamartomatous disorders characterised by genetic mutations in the PTEN gene; Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome. Although they all have distinct clinical features, the formation of hamartomas occurs in all four syndromes. PTEN is a tumor suppressor gene that is involved in cellular signalling. Absent or dysfunctional PTEN protein allows cells to over-proliferate, causing hamartomas.[14] ### Other syndromes[edit] Cowden syndrome is an autosomal dominant genetic disorder characterised by multiple benign hamartomas (trichilemmomas and mucocutaneous papillomatous papules) as well as a predisposition for cancers of multiple organs including the breast and thyroid.[15][16] Bannayan-Riley-Ruvalcaba syndrome is a congenital disorder characterised by hamartomatous intestinal polyposis, macrocephaly, lipomatosis, hemangiomatosis and glans penis macules.[14][17] Proteus syndrome is characterised by nevi, asymmetric overgrowth of various body parts, adipose tissue dysregulation, cystadenomas, adenomas, vascular malformation.[18][19] Endoscopic image of sigmoid colon of a patient with familial adenomatous polyposis. ### Familial adenomatous polyposis[edit] Familial adenomatous polyposis (FAP) is a familial cancer syndrome caused by mutations in the APC gene. In this disorder adenomatous polyps are present in the colon that will progress into colon cancer unless removed.[20] The APC gene is a tumor suppressor; its protein product is involved in many cellular processes. Inactivation of the APC gene leads to the buildup of a protein called β-catenin, which activates two transcription factors: T-cell factor (TCF) and lymphoid enhancer factor (LEF). These cause the upregulation of many genes involved in cell proliferation, differentiation, migration and apoptosis (programmed cell death), causing the growth of benign tumors.[21] ### Tuberous sclerosis complex[edit] Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in the genesTSC1 and TSC2, which produce the proteins hamartin and tuberin, respectively. This disorder presents with many benign hamartomatous tumors including angiofibromas, renal angiomyolipomas, pulmonary lymphangiomyomatosis. Tuberin and hamartin inhibit the mTOR protein in normal cellular physiology and the inactivation of the TSC tumor suppressors causes an increase in mTOR activity. This leads to the activation of genes and the production of proteins that increase cell growth.[22][23][24] ### Von Hippel-Lindau disease[edit] Von Hippel-Lindau disease is a dominantly-inherited cancer syndrome that significantly increases the risk of various tumors including benign hemangioblastomas and malignant pheochromocytomas, renal cell carcinomas, pancreatic endocrine tumors and endolymphatic sac tumors. It is caused by genetic mutations in the Von Hippel–Lindau tumor suppressor gene. The VHL protein (pVHL) is involved in cellular signalling in oxygen starved (hypoxic) cells. One role of pVHL is to cause the cellular degradation of another protein, HIF1α. Dysfunctional pVHL leads to accumulation of HIF1α, which activates several genes responsible for the production of substances involved in cell growth and blood vessel production: VEGF, PDGFβ, TGFα and erythropoietin.[25] ## Mechanism[edit] Benign (L) vs Malignant tumor (R). ### Benign vs malignant[edit] Diagram showing two epithelial tumors. The upper tumor is a benign tumor that is non-invasive. Benign tumors are usually round in shape and encapsulated by fibrous connective tissue. The lower picture depicts a malignant tumor. It is irregularly shaped, vascular, and it is invasive, crossing the basement membrane. One of the most important factors in classifying a tumor as benign or malignant is its invasive potential. If a tumor lacks the ability to invade adjacent tissues or spread to distant sites by metastasizing then it is benign, whereas invasive or metastatic tumors are malignant.[2] For this reason, benign tumors are not classed as cancer.[3] Benign tumors will grow in a contained area usually encapsulated in a fibrous connective tissue capsule. The growth rates of benign and malignant tumors also differ; benign tumors generally grow more slowly than malignant tumors. Although benign tumors pose a lower health risk than malignant tumors, they both can be life-threatening in certain situations. There are many general characteristics which apply to either benign or malignant tumors, but sometimes one type may show characteristics of the other. For example, benign tumors are mostly well differentiated and malignant tumors are often undifferentiated. However, undifferentiated benign tumors and differentiated malignant tumors can occur.[26][27] Although benign tumors generally grow slowly, cases of fast-growing benign tumors have also been documented.[28] Some malignant tumors are mostly non-metastatic such as in the case of basal cell carcinoma.[4] CT and chest radiography can be a useful diagnostic exam in visualizing a benign tumor and differentiating it from a malignant tumor. The smaller the tumor on a radiograph the more likely it is to be benign as 80% of lung nodules less than 2 cm in diameter are benign. Most benign nodules are smoothed radiopaque densities with clear margins but these are not exclusive signs of benign tumors.[29] ### Multistage carcinogenesis[edit] Tumors are formed by carcinogenesis, a process in which cellular alterations lead to the formation of cancer. Multistage carcinogenesis involves the sequential genetic or epigenetic changes to a cell's DNA, where each step produces a more advanced tumor. It is often broken down into three stages; initiation, promotion and progression, and several mutations may occur at each stage. Initiation is where the first genetic mutation occurs in a cell. Promotion is the clonal expansion (repeated division) of this transformed cell into a visible tumor that is usually benign. Following promotion, progression may take place where more genetic mutations are acquired in a sub-population of tumor cells. Progression changes the benign tumor into a malignant tumor.[6][30] A prominent and well studied example of this phenomenon is the tubular adenoma, a common type of colon polyp which is an important precursor to colon cancer. The cells in tubular adenomas, like most tumors that frequently progress to cancer, show certain abnormalities of cell maturation and appearance collectively known as dysplasia. These cellular abnormalities are not seen in benign tumors that rarely or never turn cancerous, but are seen in other pre-cancerous tissue abnormalities which do not form discrete masses, such as pre-cancerous lesions of the uterine cervix. ## Diagnosis[edit] ### Classification[edit] Tumors and cell origin Cell origin Cell type Tumor Endodermal Biliary tree Cholangioma Colon Colonic polyp Glandular Adenoma Papilloma Cystadenoma Liver Liver cell adenoma Placental Hydatiform mole Renal Renal tubular adenoma Squamous Squamous cell papilloma Stomach Gastric polyp Mesenchymal Blood vessel Hemangioma, Cardiac myxoma Bone Osteoma Cartilage Chondroma Fat tissue Lipoma Fibrous tissue Fibroma Lymphatic vessel Lymphangioma Smooth muscle Leiomyoma Striated muscle Rhabdomyoma Ectodermal Glia Astrocytoma, Schwannoma Melanocytes Nevus Meninges Meningioma Nerve cells Ganglioneuroma Reference[31] Benign neoplasms are typically but not always composed of cells which bear a strong resemblance to a normal cell type in their organ of origin. These tumors are named for the cell or tissue type from which they originate, followed by the suffix "-oma" (but not -carcinoma, -sarcoma, or -blastoma, which are generally cancers). For example, a lipoma is a common benign tumor of fat cells (lipocytes), and a chondroma is a benign tumor of cartilage-forming cells (chondrocytes). Adenomas are benign tumors of gland-forming cells, and are usually specified further by their cell or organ of origin, as in hepatic adenoma (a benign tumor of hepatocytes, or liver cells). Teratomas contain many cell types such as skin, nerve, brain and thyroid, among others, because they are derived from germ cells.[4] Hamartomas are a group of benign tumors that have relatively normal cellular differentiation but the architecture of the tissue is disorganised.[22] There are a few cancers with 'benign-sounding' names which have been retained for historical reasons, including melanoma (a cancer of pigmented skin cells, or melanocytes) and seminoma (a cancer of male reproductive cells).[32] Skin tags, vocal chord polyps and hyperplastic polyps of the colon are often referred to as benign but they are actually overgrowths of normal tissue rather than neoplasms.[4] ## Treatment[edit] Some benign tumors need no treatment; others may be removed if they cause problems such as seizures, discomfort or cosmetic concerns. Surgery is usually the most effective approach and is used to treat most benign tumors. In some case other treatments may be of use. Adenomas of the rectum may be treated with sclerotherapy, a treatment in which chemicals are used to shrink blood vessels in order to cut off the blood supply.[13] Most benign tumors do not respond to chemotherapy or radiation therapy, although there are exceptions; benign intercranial tumors are sometimes treated with radiation therapy and chemotherapy under certain circumstances.[33][34] Radiation can also be used to treat hemangiomas in the rectum.[13] Benign skin tumors are usually surgically resected but other treatments such as cryotherapy, curettage, electrodesiccation, laser therapy, dermabrasion, chemical peels and topical medication are used.[35][36] ## References[edit] 1. ^ "What Is Cancer?". National Cancer Institute. 2007-09-17. Retrieved 2017-11-26. This article incorporates text from this source, which is in the public domain. 2. ^ a b c d Wilson, Kathleen Atkins; Waugh, Anne; Chambers, Graeme; Grant, Allison; Ross, Janet (2006). Ross and Wilson anatomy and physiology in health and illness. Edinburgh: Churchill Livingstone. pp. 53–54. ISBN 0-443-10101-9. 3. ^ a b Nunn, Laura Silverstein; Silverstein, Alvin; Silverstein, Virginia B. (2006). Cancer. Brookfield, Conn: Twenty-First Century Books. pp. 11–12. ISBN 0-7613-2833-5. 4. ^ a b c d David Lowell Strayer; Raphael Rubin; Rubin, Emanuel (2008). Rubin's pathology: clinicopathologic foundations of medicine. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. pp. 138–139. ISBN 978-0-7817-9516-6. 5. ^ Ober, William B.; Martini, Frederic (2006). Fundamentals of anatomy & physiology. San Francisco: Pearson Benjamin Cummings. ISBN 0-321-31198-1. 6. ^ a b Clark WH (October 1991). "Tumour progression and the nature of cancer". Br. J. Cancer. 64 (4): 631–44. doi:10.1038/bjc.1991.375. PMC 1977704. PMID 1911211. 7. ^ Reece, Jane; Campbell, Neil; Urry, Lisa (2005). Biology. San Francisco: Pearson Benjamin Cummings. p. 232. ISBN 0-321-27045-2. 8. ^ Marks V, Teale JD (June 1991). "Tumours producing hypoglycaemia". Diabetes Metab Rev. 7 (2): 79–91. doi:10.1002/dmr.5610070202. PMID 1665409. 9. ^ Grant CS (October 2005). "Insulinoma". Best Pract Res Clin Gastroenterol. 19 (5): 783–98. doi:10.1016/j.bpg.2005.05.008. PMID 16253900. 10. ^ Charis Eng; DeLellis, Ronald A.; Lloyd, Ricardo V.; Phillipp U. Heitz (2004). Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press. ISBN 92-832-2416-7. 11. ^ Gill SS, Heuman DM, Mihas AA (October 2001). "Small intestinal neoplasms". J. Clin. Gastroenterol. 33 (4): 267–82. doi:10.1097/00004836-200110000-00004. PMID 11588539. 12. ^ Tromberg J, Bauer B, Benvenuto-Andrade C, Marghoob AA (2005). "Congenital melanocytic nevi needing treatment". Dermatol Ther. 18 (2): 136–50. doi:10.1111/j.1529-8019.2005.05012.x. PMID 15953143. S2CID 20915929. 13. ^ a b c M. Zuber; F. Harder (2001). Benign tumors of the colon and rectum. Munich: Zuckschwerdt: Surgical Treatment: Evidence-Based and Problem-Oriented. 14. ^ a b Hobert JA, Eng C (October 2009). "PTEN hamartoma tumor syndrome: an overview". Genet. Med. 11 (10): 687–94. doi:10.1097/GIM.0b013e3181ac9aea. PMID 19668082. 15. ^ Pilarski R, Eng C (May 2004). "Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome". J. Med. Genet. 41 (5): 323–6. doi:10.1136/jmg.2004.018036. PMC 1735782. PMID 15121767. 16. ^ Eng C (November 2000). "Will the real Cowden syndrome please stand up: revised diagnostic criteria". J. Med. Genet. 37 (11): 828–30. doi:10.1136/jmg.37.11.828. PMC 1734465. PMID 11073535. 17. ^ Eng C (September 2003). "PTEN: one gene, many syndromes". Hum. Mutat. 22 (3): 183–98. doi:10.1002/humu.10257. PMID 12938083. S2CID 13417857. 18. ^ Blumenthal GM, Dennis PA (November 2008). "PTEN hamartoma tumor syndromes". Eur. J. Hum. Genet. 16 (11): 1289–300. doi:10.1038/ejhg.2008.162. PMC 6939673. PMID 18781191. 19. ^ Cohen MM (August 2005). "Proteus syndrome: an update". Am J Med Genet C Semin Med Genet. 137C (1): 38–52. doi:10.1002/ajmg.c.30063. PMID 16010681. S2CID 31873101. 20. ^ Galiatsatos P, Foulkes WD (February 2006). "Familial adenomatous polyposis". Am. J. Gastroenterol. 101 (2): 385–98. PMID 16454848. 21. ^ Aoki K, Taketo MM (October 2007). "Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene". J. Cell Sci. 120 (Pt 19): 3327–35. doi:10.1242/jcs.03485. PMID 17881494. S2CID 8743. 22. ^ a b Inoki K, Corradetti MN, Guan KL (January 2005). "Dysregulation of the TSC-mTOR pathway in human disease". Nat. Genet. 37 (1): 19–24. doi:10.1038/ng1494. PMID 15624019. S2CID 205344131. 23. ^ Crino PB, Nathanson KL, Henske EP (September 2006). "The tuberous sclerosis complex". N. Engl. J. Med. 355 (13): 1345–56. doi:10.1056/NEJMra055323. PMID 17005952. S2CID 3579356. 24. ^ Kwiatkowski DJ (January 2003). "Tuberous sclerosis: from tubers to mTOR". Ann. Hum. Genet. 67 (Pt 1): 87–96. doi:10.1046/j.1469-1809.2003.00012.x. PMID 12556239. S2CID 41992893. 25. ^ Maher ER (December 2004). "Von Hippel-Lindau disease". Curr. Mol. Med. 4 (8): 833–42. doi:10.2174/1566524043359827. PMID 15579030. 26. ^ Skorić T, Korsić M, Zarković K, et al. (June 1999). "Clinical and morphological features of undifferentiated monomorphous GH/TSH-secreting pituitary adenoma". Eur. J. Endocrinol. 140 (6): 528–37. doi:10.1530/eje.0.1400528. PMID 10366409. 27. ^ Song HJ, Xue YL, Qiu ZL, Luo QY (2012). "Uncommon metastases from differentiated thyroid carcinoma" (PDF). Hellenic Journal of Nuclear Medicine. 15 (3): 233–40. doi:10.1967/s002449910059 (inactive 2021-01-11). PMID 23106056.CS1 maint: DOI inactive as of January 2021 (link) 28. ^ Sagel SS, Ablow RC (November 1968). "Hamartoma: on occasion a rapidly growing tumor of the lung". Radiology. 91 (5): 971–2. doi:10.1148/91.5.971. PMID 5681331. 29. ^ Erasmus, J.J.; Connolly, J.E.; McAdams, H.P.; Roggli, V.L. (2000). "Solitary pulmonary nodules: Part I. Morphologic evaluation for differentiation of benign and malignant lesions". Radiographics. 20 (1): 43–58. doi:10.1148/radiographics.20.1.g00ja0343. PMID 10682770. 30. ^ Barrett JC (April 1993). "Mechanisms of multistep carcinogenesis and carcinogen risk assessment". Environ. Health Perspect. 100: 9–20. doi:10.1289/ehp.931009. PMC 1519586. PMID 8354184. 31. ^ Wujcik, Debra; Yarbro, Connie Henke; Barbara H. Gobel (2011). Cancer nursing: principles and practice. Boston: Jones and Bartlett Publishers. ISBN 978-0-7637-6357-2. 32. ^ Ramzi Cotran; Vinay Kumar; Tucker Collins (1999). Robbins Pathologic Basis of Disease (6th ed.). W.B. Saunders. ISBN 0-7216-7335-X. 33. ^ Brada M (February 2013). "Radiotherapy for benign brain tumours coming of age; example of vestibular schwannoma". Radiother Oncol. 106 (2): 157–60. doi:10.1016/j.radonc.2013.01.009. PMID 23462704. 34. ^ Sioka C, Kyritsis AP (March 2009). "Chemotherapy, hormonal therapy, and immunotherapy for recurrent meningiomas". J. Neurooncol. 92 (1): 1–6. doi:10.1007/s11060-008-9734-y. PMID 19023520. S2CID 28106960. 35. ^ Luba MC, Bangs SA, Mohler AM, Stulberg DL (February 2003). "Common benign skin tumors". Am Fam Physician. 67 (4): 729–38. PMID 12613727. 36. ^ Marghoob AA, Borrego JP, Halpern AC (December 2007). "Congenital melanocytic nevi: treatment modalities and management options". Semin Cutan Med Surg. 26 (4): 231–40. doi:10.1016/j.sder.2008.03.007. PMID 18395671. ## External links[edit] Classification D * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Benign tumor	c0086692	5,041	wikipedia	https://en.wikipedia.org/wiki/Benign_tumor	2021-01-18T18:44:53	{"mesh": ["D009369"], "wikidata": ["Q1417240"]}
A solitary neurofibroma (also known as a "Solitary nerve sheath tumor,"[1] and "Sporadic neurofibroma"[1]) may be 2 to 20mm in diameter, is soft, flaccid, and pinkish-white, and frequently this soft small tumor can be invaginated, as if through a ring in the skin by pressure with the finger, a maneuver called "button-holing."[2]:619 ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Solitary neurofibroma	c0431123	5,042	wikipedia	https://en.wikipedia.org/wiki/Solitary_neurofibroma	2021-01-18T19:02:12	{"umls": ["C0431123"], "wikidata": ["Q7558254"]}
Hemolytic anemia Other namesHaemolytic anaemia SpecialtyHematology Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular).[1] This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically (prosthetic valve damage).[1] Hemolytic anemia accounts for 5% of all existing anemias.[1] It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects.[1] The general classification of hemolytic anemia is either intrinsic or extrinsic.[2] Treatment depends on the type and cause of the hemolytic anemia.[1] Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones[3] and pulmonary hypertension.[4] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Intrinsic causes * 2.2 Extrinsic causes * 3 Mechanism * 3.1 Intravascular hemolysis * 3.2 Extravascular hemolysis * 4 Diagnosis * 5 Treatment * 6 Other animals * 7 References * 8 External links ## Signs and symptoms[edit] Symptoms of hemolytic anemia are similar to the general signs of anemia.[1] General signs and symptoms include: fatigue, pallor, shortness of breath, and tachycardia.[1] In small children, failure to thrive may occur in any form of anemia.[5][6] In addition, symptoms related to hemolysis may be present such as chills, jaundice, dark urine, and an enlarged spleen.[1] Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, medication side effects, autoimmune disorders, blood transfusion reactions, the presence of prosthetic heart valve, or other medical illness.[1] Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones.[7] The continuous release of free hemoglobin has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness.[8] Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).[8] ## Causes[edit] Main articles: Congenital hemolytic anemia and Acquired hemolytic anemia They may be classified according to the means of hemolysis, being either intrinsic in cases where the cause is related to the red blood cell (RBC) itself, or extrinsic in cases where factors external to the RBC dominate.[9] Intrinsic effects may include problems with RBC proteins or oxidative stress handling, whereas external factors include immune attack and microvascular angiopathies (RBCs are mechanically damaged in circulation).[1][2] ### Intrinsic causes[edit] Hereditary (inherited) hemolytic anemia can be due to : * Defects of red blood cell membrane production (as in hereditary spherocytosis and hereditary elliptocytosis).[1] * Defects in hemoglobin production (as in thalassemia, sickle-cell disease and congenital dyserythropoietic anemia).[1] * Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency).[10][11] * Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia.[12] ### Extrinsic causes[edit] Acquired hemolytic anemia may be caused by immune-mediated causes, drugs, and other miscellaneous causes.[1] * Immune-mediated causes could include transient factors as in Mycoplasma pneumoniae infection (cold agglutinin disease)[13] or permanent factors as in autoimmune diseases like autoimmune hemolytic anemia[14] (itself more common in diseases such as systemic lupus erythematosus, rheumatoid arthritis, Hodgkin's lymphoma, and chronic lymphocytic leukemia).[1] * Spur cell hemolytic anemia [15] * Any of the causes of hypersplenism (increased activity of the spleen), such as portal hypertension.[16] * Acquired hemolytic anemia is also encountered in burns and as a result of certain infections (e.g. malaria).[14][17] * Lead poisoning resulting from the environment causes non-immune hemolytic anemia.[18] * Similarly, poisoning by arsine or stibine also causes hemolytic anemia.[19] * Runners can suffer hemolytic anemia due to "footstrike hemolysis", owing to the destruction of red blood cells in feet at foot impact.[20][21] * Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and severe hemolytic anemia occurs in 3%.[22] ## Mechanism[edit] In hemolytic anemia, there are two principal mechanisms of hemolysis; intravascular and extravascular.[23] ### Intravascular hemolysis[edit] Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature.[24] As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia[25] and increasing the risk of ensuing hyperbilirubinemia.[26] Intravascular hemolysis may occur when red blood cells are targeted by autoantibodies, leading to complement fixation, or by damage by parasites such as Babesia.[27] ### Extravascular hemolysis[edit] Extravascular hemolysis refers to hemolysis taking place in the liver, spleen, bone marrow, and lymph nodes.[24] In this case little hemoglobin escapes into blood plasma.[26] The macrophages of the reticuloendothelial system in these organs engulf and destroy structurally-defective red blood cells, or those with antibodies attached, and release unconjugated bilirubin into the blood plasma circulation.[28][29] Typically, the spleen destroys mildly abnormal red blood cells or those coated with IgG-type antibodies,[30][31] while severely abnormal red blood cells or those coated with IgM-type antibodies are destroyed in the circulation or in the liver.[30] If extravascular hemolysis is extensive, hemosiderin can be deposited in the spleen, bone marrow, kidney, liver, and other organs, resulting in hemosiderosis.[26] In a healthy person, a red blood cell survives 90 to 120 days in the circulation, so about 1% of human red blood cells break down each day.[32][unreliable medical source?] The spleen (part of the reticulo-endothelial system) is the main organ that removes old and damaged RBCs from the circulation.[1] In healthy individuals, the breakdown and removal of RBCs from the circulation is matched by the production of new RBCs in the bone marrow.[1] In conditions where the rate of RBC breakdown is increased, the body initially compensates by producing more RBCs; however, breakdown of RBCs can exceed the rate that the body can make RBCs, and so anemia can develop.[32] Bilirubin, a breakdown product of hemoglobin, can accumulate in the blood, causing jaundice.[27] In general, hemolytic anemia occurs as a modification of the RBC life cycle.[33][unreliable medical source?] That is, instead of being collected at the end of its useful life and disposed of normally, the RBC disintegrates in a manner allowing free iron-containing molecules to reach the blood.[33] With their complete lack of mitochondria, RBCs rely on glycolysis for the materials needed to reduce oxidative damage. Any limitations of glycolysis can result in more susceptibility to oxidative damage and a short or abnormal lifecycle.[34][unreliable medical source?] If the cell is unable to signal to the reticuloendothelial phagocytes by externalizing phosphatidylserine, it is likely to lyse through uncontrolled means.[35][36][37] The distinguishing feature of intravascular hemolysis is the release of RBC contents into the blood stream. The metabolism and elimination of these products, largely iron-containing compounds capable of doing damage through Fenton reactions, is an important part of the condition. Several reference texts exist on the elimination pathways, for example.[38][39][40] Free hemoglobin can bind to haptoglobin, and the complex is cleared from the circulation; thus, a decrease in haptoglobin can support a diagnosis of hemolytic anemia. Alternatively, hemoglobin may oxidize and release the heme group that is able to bind to either albumin or hemopexin. The heme is ultimately converted to bilirubin and removed in stool and urine.[38] Hemoglobin may be cleared directly by the kidneys resulting in fast clearance of free hemoglobin but causing the continued loss of hemosiderin loaded renal tubular cells for many days. Additional effects of free hemoglobin seem to be due to specific reactions with NO.[41] ## Diagnosis[edit] The diagnosis of hemolytic anemia can be suspected on the basis of a constellation of symptoms and is largely based on the presence of anemia, an increased proportion of immature red cells (reticulocytes) and a decrease in the level of haptoglobin, a protein that binds free hemoglobin. Examination of a peripheral blood smear and some other laboratory studies can contribute to the diagnosis. Symptoms of hemolytic anemia include those that can occur in all anemias as well as the specific consequences of hemolysis. All anemias can cause fatigue, shortness of breath, decreased ability to exercise when severe. Symptoms specifically related to hemolysis include jaundice and dark colored urine due to the presence of hemoglobin (hemoglobinuria). When restricted to the morning hemoglobinuria may suggest paroxysmal nocturnal haemoglobinuria. Direct examination of blood under a microscope in a peripheral blood smear may demonstrate red blood cell fragments called schistocytes, red blood cells that look like spheres (spherocytes), and/or red blood cells missing small pieces (bite cells). An increased number of newly made red blood cells (reticulocytes) may also be a sign of bone marrow compensation for anemia. Laboratory studies commonly used to investigate hemolytic anemia include blood tests for breakdown products of red blood cells, bilirubin and lactate dehydrogenase, a test for the free hemoglobin binding protein haptoglobin, and the direct Coombs test to evaluate antibody binding to red blood cells suggesting autoimmune hemolytic anemia. ## Treatment[edit] Definitive therapy depends on the cause: * Symptomatic treatment can be given by blood transfusion, if there is marked anemia. A positive Coombs test is a relative contraindication to transfuse the patient. In cold hemolytic anemia there is advantage in transfusing warmed blood. * In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary. * In steroid resistant cases, consideration can be given to rituximab or addition of an immunosuppressant (azathioprine, cyclophosphamide). * Association of methylprednisolone and intravenous immunoglobulin can control hemolysis in acute severe cases. * Sometimes splenectomy can be helpful where extravascular hemolysis, or hereditary spherocytosis, is predominant (i.e., most of the red blood cells are being removed by the spleen).[42] ## Other animals[edit] Hemolytic anemia affects nonhuman species as well as humans. It has been found, in a number of animal species, to result from specific triggers.[43] Some notable cases include hemolytic anemia found in black rhinos kept in captivity, with the disease, in one instance, affecting 20% of captive rhinos at a specific facility.[44][45][46] The disease is also found in wild rhinos.[47] Dogs and cats differ slightly from humans in some details of their RBC composition and have altered susceptibility to damage, notably, increased susceptibility to oxidative damage from consumption of onion. Garlic is less toxic to dogs than onion.[48] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p Capriotti, Theresa (2016). Pathophysiology : introductory concepts and clinical perspectives. Frizzell, Joan Parker. Philadelphia. ISBN 978-0-8036-1571-7. OCLC 900626405. 2. ^ a b Philadelphia, The Children's Hospital of (2014-03-30). "Hemolytic Anemia". chop.edu. Retrieved 2020-02-25. 3. ^ Trotman, BW (1991). "Pigment gallstone disease". Gastroenterology Clinics of North America. 20 (1): 111–26. ISSN 0889-8553. PMID 2022417. 4. ^ Machado, Roberto F.; Gladwin, Mark T. (2010). "Pulmonary Hypertension in Hemolytic Disorders". Chest. Elsevier BV. 137 (6): 30S–38S. doi:10.1378/chest.09-3057. ISSN 0012-3692. PMC 2882115. PMID 20522578. 5. ^ Kahre, Tiina; Teder, Maris; Panov, Maarja; Metspalu, Andres (2004). "Severe CF manifestation with anaemia and failure to thrive in a 394delTT homozygous patient". Journal of Cystic Fibrosis. Elsevier BV. 3 (1): 58–60. doi:10.1016/j.jcf.2003.12.009. ISSN 1569-1993. PMID 15463888. 6. ^ Hypoproteinemia, Anemia, and Failure to Thrive in an Infant 7. ^ Levitt, Robert E.; Ostrow, Donald J. (1980). "Hemolytic Jaundice and Gallstones". Gatroenterology. 78 (4): 821–830. doi:10.1016/0016-5085(80)90690-3. 8. ^ a b Schrier, R. W., & Bansal, S. (2008). Pulmonary hypertension, right ventricular failure, and kidney: different from left ventricular failure?. Clinical journal of the American Society of Nephrology : CJASN, 3(5), 1232–1237. https://doi.org/10.2215/CJN.01960408 9. ^ Current Medical Diagnosis and Treatment 2009 By Stephen J. McPhee, Maxine A. Papadakis page 436 https://books.google.com/books?id=zQlH4mXSziYC&pg=PT454&dq=hemoglobin+hemosiderin+hemolysis+bilirubin&ei=Z2P_SuzwA6D2ygT9vOz3Dg#v=onepage&q=hemoglobin%20hemosiderin%20hemolysis%20bilirubin&f=false 10. ^ Eisa, Mahmoud S.; Mohamed, Shehab F.; Ibrahim, Firyal; Shariff, Khalid; Sadik, Nagham; Nashwan, Abdulqadir; Yassin, Mohamed A. (2019-11-01). "Paroxysmal Nocturnal Hemoglobinuria with Glucose-6-Phosphate Dehydrogenase Deficiency: A Case Report and Review of the Literature". Case Reports in Oncology. 12 (3): 838–844. doi:10.1159/000503817. ISSN 1662-6575. PMC 6873095. PMID 31762758. 11. ^ Grace, Rachael F.; Bianchi, Paola; van Beers, Eduard J.; Eber, Stefan W.; Glader, Bertil; Yaish, Hassan M.; Despotovic, Jenny M.; Rothman, Jennifer A.; Sharma, Mukta; McNaull, Melissa M.; Fermo, Elisa (2018-05-17). "Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study". Blood. 131 (20): 2183–2192. doi:10.1182/blood-2017-10-810796. ISSN 0006-4971. PMID 29549173. 12. ^ Brodsky, Robert A. (2014-10-30). "Paroxysmal nocturnal hemoglobinuria". Blood. 124 (18): 2804–2811. doi:10.1182/blood-2014-02-522128. ISSN 0006-4971. PMC 4215311. PMID 25237200. 13. ^ Khoury, Tawfik; Abu Rmeileh, Ayman; Kornspan, Jonathan David; Abel, Roy; Mizrahi, Meir; Nir-Paz, Ran (2015-02-19). "Mycoplasma pneumoniae Pneumonia Associated With Methemoglobinemia and Anemia: An Overlooked Association?". Open Forum Infectious Diseases. 2 (1): ofv022. doi:10.1093/ofid/ofv022. ISSN 2328-8957. PMC 4438901. PMID 26034771. 14. ^ a b Hill, Anita; Hill, Quentin A. (2018-11-30). "Autoimmune hemolytic anemia". Hematology. 2018 (1): 382–389. doi:10.1182/asheducation-2018.1.382. ISSN 1520-4391. PMC 6246027. PMID 30504336. 15. ^ Privitera, G., & Meli, G. (2016). An unusual cause of anemia in cirrhosis: spur cell anemia, a case report with review of literature. Gastroenterology and hepatology from bed to bench, 9(4), 335–339. 16. ^ Li, Hao; Guan, Dongyao; Xu, Junqiang; Jin, Enhao; Sun, Shu (January 2020). "Atraumatic splenic rupture was attributed to intra-cystic haemorrhage and hypersplenism in a patient with cirrhosis and portal hypertension: A case report". SAGE Open Medical Case Reports. 8: 2050313X2090190. doi:10.1177/2050313X20901900. ISSN 2050-313X. PMC 6984417. PMID 32047630. 17. ^ Zahid, M. F., & Alsammak, M. S. (2018). Spurious Thrombocytosis in the Setting of Hemolytic Anemia and Microcytosis Secondary to Extensive Burn Injury. Turkish journal of haematology : official journal of Turkish Society of Haematology, 35(3), 205–206. https://doi.org/10.4274/tjh.2017.0466 18. ^ Valentine, W N; Paglia, D E; Fink, K; Madokoro, G (October 1976). "Lead poisoning: association with hemolytic anemia, basophilic stippling, erythrocyte pyrimidine 5'-nucleotidase deficiency, and intraerythrocytic accumulation of pyrimidines". Journal of Clinical Investigation. 58 (4): 926–932. doi:10.1172/JCI108545. ISSN 0021-9738. PMC 333255. PMID 965496. 19. ^ Correia, Nuno; Carvalho, Catarina; Friões, Fernando; Araújo, José P; Almeida, Jorge; Azevedo, Ana (2009-08-11). "Haemolytic anaemia secondary to arsenic poisoning: a case report". Cases Journal. 2: 7768. doi:10.4076/1757-1626-2-7768. ISSN 1757-1626. PMC 2769370. PMID 19918480. 20. ^ Telford RD, Sly GJ, Hahn AG, Cunningham RB, Bryant C, Smith JA (January 2003). "Footstrike is the major cause of hemolysis during running". J. Appl. Physiol. 94 (1): 38–42. doi:10.1152/japplphysiol.00631.2001. PMID 12391035. S2CID 5750453. 21. ^ Lippi G, Schena F, Salvagno GL, Aloe R, Banfi G, Guidi GC (July 2012). "Foot-strike haemolysis after a 60-km ultramarathon". Blood Transfus. 10 (3): 377–383. doi:10.2450/2012.0167-11. PMC 3417738. PMID 22682343. 22. ^ Wise, Donald Lee (2000). Biomaterials Engineering and Devices: Orthopedic, dental, and bone graft applications. ISBN 978-0-89603-859-2. 23. ^ Dhaliwal G, Cornett PA, Tierney LM., Jr Hemolytic anemia. Am Fam Physician. 2004;69:2599–606. [PubMed] [Google Scholar] 24. ^ a b Stanley L Schrier, MD. William C Mentzer, MD, Jennifer S Tirnauer, MD (eds.). "Diagnosis of hemolytic anemia in the adult". UpToDate. Archived from the original on 2017-12-26. Retrieved 2019-05-04. 25. ^ "Intravascular hemolysis". eClinpath. Retrieved 2019-05-08. 26. ^ a b c Muller, Andre; Jacobsen, Helene; Healy, Edel; McMickan, Sinead; Istace, Fréderique; Blaude, Marie-Noëlle; Howden, Peter; Fleig, Helmut; Schulte, Agnes (2006). "Hazard classification of chemicals inducing haemolytic anaemia: An EU regulatory perspective" (PDF). Regulatory Toxicology and Pharmacology. Elsevier BV. 45 (3): 229–241. doi:10.1016/j.yrtph.2006.04.004. hdl:10029/5596. ISSN 0273-2300. PMID 16793184\. Retrieved 2019-05-04 27. ^ a b "Bilirubin and hemolytic anemia". eClinpath. Retrieved 2019-05-08. 28. ^ Rhodes, Carl E.; Varacallo, Matthew (2019-03-04). "Physiology, Oxygen Transport". NCBI Bookshelf. PMID 30855920\. Retrieved 2019-05-04. 29. ^ Sokol RJ, Hewitt S, Stamps BK (June 1981). "Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre". Br Med J (Clin Res Ed). 282(6281): 2023–7. doi:10.1136/bmj.282.6281.2023. PMC 1505955\. PMID 6788179. 30. ^ a b BRAUNSTEIN.EVAN (2019-05-03). "Overview of Hemolytic Anemia – Hematology and Oncology". Merck Manuals Professional Edition (in Latin). Retrieved 2019-05-05. 31. ^ "Hypersplenism: MedlinePlus Medical Encyclopedia". MedlinePlus. 2019-04-30. Retrieved 2019-05-08. 32. ^ a b Bosman, Giel J. C. G. M. (2013). "Survival of red blood cells after transfusion: processes and consequences". Frontiers in Physiology. 4: 376. doi:10.3389/fphys.2013.00376. ISSN 1664-042X. PMC 3866658. PMID 24391593. 33. ^ a b Alaarg, Amr; Schiffelers, Raymond M.; van Solinge, Wouter W.; van Wijk, Richard (2013). "Red blood cell vesiculation in hereditary hemolytic anemia". Frontiers in Physiology. 4: 365. doi:10.3389/fphys.2013.00365. ISSN 1664-042X. PMC 3862113. PMID 24379786. 34. ^ Kosenko, Elena A.; Tikhonova, Lyudmila A.; Montoliu, Carmina; Barreto, George E.; Aliev, Gjumrakch; Kaminsky, Yury G. (2018-01-05). "Metabolic Abnormalities of Erythrocytes as a Risk Factor for Alzheimer's Disease". Frontiers in Neuroscience. 11: 728. doi:10.3389/fnins.2017.00728. ISSN 1662-453X. PMC 5760569. PMID 29354027. 35. ^ Kolb S, Vranckx R, Huisse MG, Michel JB, Meilhac O (July 2007). "The phosphatidylserine receptor mediates phagocytosis by vascular smooth muscle cells". The Journal of Pathology. 212 (3): 249–59. doi:10.1002/path.2190. PMID 17534843. S2CID 22923550. 36. ^ Bosman GJ, Willekens FL, Werre JM (2005). "Erythrocyte aging: a more than superficial resemblance to apoptosis?" (PDF). Cellular Physiology and Biochemistry. 16 (1–3): 1–8. doi:10.1159/000087725. hdl:2066/47441. PMID 16121027. S2CID 188974. 37. ^ Bratosin D, Mazurier J, Tissier JP, et al. (February 1998). "Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review". Biochimie. 80 (2): 173–95. doi:10.1016/S0300-9084(98)80024-2. PMID 9587675. 38. ^ a b Hematology in clinical practice: a guide to diagnosis and management By Robert S. Hillman, Kenneth A. Ault, Henry M. Rinder page 136-139 https://books.google.com/books?id=NJs1VpA8SEoC&pg=PA138&dq=hemoglobin+hemosiderin+hemolysis+bilirubin&ei=Z2P_SuzwA6D2ygT9vOz3Dg#v=onepage&q=hemoglobin%20hemosiderin%20hemolysis%20bilirubin&f=false 39. ^ Wintrobe's Clinical Hematology, Volume 1 By John P. Greer https://books.google.com/books?id=68enzUD7BVgC&pg=PA161&dq=hemoglobin+hemosiderin+hemolysis+bilirubin&ei=Z2P_SuzwA6D2ygT9vOz3Dg#v=onepage&q=hemoglobin%20hemosiderin%20hemolysis%20bilirubin&f=false page 160 40. ^ Bradencarter (21 January 2017). "What is Hemolytic Anemia?". hemolyticanemia.org. Archived from the original on 2 March 2018. Retrieved 21 January 2017. 41. ^ Boretti FS, Buehler PW, D'Agnillo F, et al. (August 2009). "Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs" (PDF). The Journal of Clinical Investigation. 119 (8): 2271–80. doi:10.1172/JCI39115. PMC 2719941. PMID 19620788. 42. ^ "Hemolytic Anemias, F. Spherocytosis". http://MedicalAssistantOnlinePrograms.org/. Retrieved 6 November 2013. External link in `\|website=` (help) 43. ^ Mary Anna Thrall, Dale C. Baker, E. Duane Lassen, Veterinary hematology and clinical chemistry, ISBN 0-7817-6850-0, 2004. 44. ^ Edward F. Gibbons, Barbara Susan Durrant, Jack Demarest, Conservation of endangered species in captivity: an interdisciplinary approach, page 324, 2005, ISBN 0-7914-1911-8 45. ^ Oliver A. Ryder, Zoological Society of San Diego, Rhinoceros biology and conservation, Zoological Society of San Diego, 1993, page 312, 335. 46. ^ Texas Monthly, Oct 1992, Vol. 20, No. 10, ISSN 0148-7736, page 98-100. 47. ^ Jutta Meister, ed. Catharine E. Bell, Encyclopedia of the world's zoos, Volume 3, page 1008, ISBN 1-57958-174-9, 2001. 48. ^ Kovalkovičová N, Sutiaková I, Pistl J, Sutiak V (2009). "Some food toxic for pets". Interdisciplinary Toxicology. 2 (3): 169–76. doi:10.2478/v10102-009-0012-4. PMC 2984110. PMID 21217849. ## External links[edit] Classification D * ICD-10: D55-D59 * ICD-9-CM: 282, 283, 773 * MeSH: D000743 * DiseasesDB: 5534 External resources * MedlinePlus: 000571 * eMedicine: med/979 * v * t * e Diseases of red blood cells ↑ Polycythemia * Polycythemia vera ↓ Anemia Nutritional * Micro-: Iron-deficiency anemia * Plummer–Vinson syndrome * Macro-: Megaloblastic anemia * Pernicious anemia Hemolytic (mostly normo-) Hereditary * enzymopathy: Glucose-6-phosphate dehydrogenase deficiency * glycolysis * pyruvate kinase deficiency * triosephosphate isomerase deficiency * hexokinase deficiency * hemoglobinopathy: Thalassemia * alpha * beta * delta * Sickle cell disease/trait * Hereditary persistence of fetal hemoglobin * membrane: Hereditary spherocytosis * Minkowski–Chauffard syndrome * Hereditary elliptocytosis * Southeast Asian ovalocytosis * Hereditary stomatocytosis Acquired AIHA * Warm antibody autoimmune hemolytic anemia * Cold agglutinin disease * Donath–Landsteiner hemolytic anemia * Paroxysmal cold hemoglobinuria * Mixed autoimmune hemolytic anemia * membrane * paroxysmal nocturnal hemoglobinuria * Microangiopathic hemolytic anemia * Thrombotic microangiopathy * Hemolytic–uremic syndrome * Drug-induced autoimmune * Drug-induced nonautoimmune * Hemolytic disease of the newborn Aplastic (mostly normo-) * Hereditary: Fanconi anemia * Diamond–Blackfan anemia * Acquired: Pure red cell aplasia * Sideroblastic anemia * Myelophthisic Blood tests * Mean corpuscular volume * normocytic * microcytic * macrocytic * Mean corpuscular hemoglobin concentration * normochromic * hypochromic Other * Methemoglobinemia * Sulfhemoglobinemia * Reticulocytopenia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hemolytic anemia	c0002878	5,043	wikipedia	https://en.wikipedia.org/wiki/Hemolytic_anemia	2021-01-18T18:40:56	{"mesh": ["D000743"], "umls": ["C0002878"], "icd-9": ["283", "773", "282"], "orphanet": ["98363"], "wikidata": ["Q1145668"]}
Intermittent claudication Other namesVascular claudication, claudicatio intermittens SpecialtyCardiology, vascular surgery Intermittent claudication, also known as vascular claudication, is a symptom that describes muscle pain on mild exertion (ache, cramp, numbness or sense of fatigue),[1] classically in the calf muscle, which occurs during exercise, such as walking, and is relieved by a short period of rest. It is classically associated with early-stage peripheral artery disease, and can progress to critical limb ischemia unless treated or risk factors are modified. Claudication derives from the Latin verb claudicare, "to limp". ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] One of the hallmarks of arterial claudication is that it occurs intermittently. It disappears after a very brief rest and the patient can start walking again until the pain recurs. The following signs are general signs of atherosclerosis of the lower extremity arteries: * cyanosis * atrophic changes like loss of hair, shiny skin * decreased temperature * decreased pulse * redness when limb is returned to a "dependent" position (part of Buerger's test) The six "P"s of ischemia * Pain * Pallor (increased) * Pulse (decreased) * Perishing cold * Paraesthesia * Paralysis ## Causes[edit] Most commonly, intermittent (or vascular or arterial) claudication is due to peripheral arterial disease which implies significant atherosclerotic blockages resulting in arterial insufficiency. Other uncommon causes are Trousseau disease,[medical citation needed] Beurger's disease (Thromboangiitis obliterans),[medical citation needed] in which vasculitis occurs. Raynaud's phenomenon functional vasospasm.[clarification needed] It is distinct from neurogenic claudication, which is associated with lumbar spinal stenosis. It is strongly associated with smoking, hypertension, and diabetes.[2] ## Diagnosis[edit] Intermittent claudication is a symptom and is by definition diagnosed by a patient reporting a history of leg pain with walking relieved by rest. However, as other conditions such as sciatica can mimic intermittent claudication, testing is often performed to confirm the diagnosis of peripheral artery disease. Magnetic resonance angiography and duplex ultrasonography appear to be slightly more cost-effective in diagnosing peripheral artery disease among people with intermittent claudication than projectional angiography.[3] ## Treatment[edit] Exercise can improve symptoms, as can revascularization.[4] Both together may be better than one intervention of its own.[4] In people with stable leg pain, exercise, such as strength training, polestriding and upper or lower limb exercises, compared to usual care or placebo improves maximum walking time, pain-free walking distance and maximum walking distance.[5] Alternative exercise modes, such as cycling, strength training and upper-arm ergometry compared to supervised walking programmes showed no difference in maximum walking distance or pain-free walking distance for people with intermittent claudication.[6] Pharmacological options exist, as well. Medicines that control lipid profile, diabetes, and hypertension may increase blood flow to the affected muscles and allow for increased activity levels. Angiotensin converting enzyme inhibitors, adrenergic agents such as alpha-1 blockers and beta-blockers and alpha-2 agonists, antiplatelet agents (aspirin and clopidogrel), naftidrofuryl, pentoxifylline, and cilostazol (selective PDE3 inhibitor) are used for the treatment of intermittent claudication.[7] However, medications will not remove the blockages from the body. Instead, they simply improve blood flow to the affected area.[8] Catheter-based intervention is also an option. Atherectomy, stenting, and angioplasty to remove or push aside the arterial blockages are the most common procedures for catheter-based intervention. These procedures can be performed by interventional radiologists, interventional cardiologists, vascular surgeons, and thoracic surgeons, among others. Surgery is the last resort; vascular surgeons can perform either endarterectomies on arterial blockages or perform an arterial bypass. However, open surgery poses a host of risks not present with catheter-based interventions. ## Epidemiology[edit] Atherosclerosis affects up to 10% of the Western population older than 65 years and for intermittent claudication this number is around 5%. Intermittent claudication most commonly manifests in men older than 50 years. One in five of the middle-aged (65–75 years) population of the United Kingdom have evidence of peripheral arterial disease on clinical examination, although only a quarter of them have symptoms. The most common symptom is muscle pain in the lower limbs on exercise—intermittent claudication.[9] ## See also[edit] * Peripheral artery disease ## References[edit] 1. ^ "intermittent claudication" at Dorland's Medical Dictionary 2. ^ Dr Hicks, Rob. "Intermittent Claudication". BBC Health. 3. ^ Visser K, Kuntz KM, Donaldson MC, Gazelle GS, Hunink MG (2003). "Pretreatment imaging workup for patients with intermittent claudication: a cost-effectiveness analysis". J Vasc Interv Radiol. 14 (1): 53–62. PMID 12525586. 4. ^ a b Frans, FA; Bipat, S; Reekers, JA; Legemate, DA; Koelemay, MJ (January 2012). "Systematic review of exercise training or percutaneous transluminal angioplasty for intermittent claudication". The British Journal of Surgery. 99 (1): 16–28. doi:10.1002/bjs.7656. PMID 21928409. 5. ^ Lane, Risha; Harwood, Amy; Watson, Lorna; Leng, Gillian C. (26 December 2017). "Exercise for intermittent claudication". The Cochrane Database of Systematic Reviews. 12: CD000990. doi:10.1002/14651858.CD000990.pub4. ISSN 1469-493X. PMC 6486315. PMID 29278423. 6. ^ Lauret, Gert Jan; Fakhry, Farzin; Fokkenrood, Hugo JP; Hunink, M G Myriam; Teijink, Joep AW; Spronk, Sandra (2014-07-04). Cochrane Vascular Group (ed.). "Modes of exercise training for intermittent claudication". Cochrane Database of Systematic Reviews (7): CD009638. doi:10.1002/14651858.CD009638.pub2. PMID 24993079. 7. ^ Vascular, Team (2015-01-31). "Intermittent Claudication Treatment India". VascularSurgery. 8. ^ National Institute for Health and Care Excellence, (Published date: 25 May 2011). ""Cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease"". Retrieved July 28, 2016. 9. ^ Fowkes, F G R.; Housley, E.; Cawood, E H H.; MacIntyre, C C A.; Ruckley, C. V.; Prescott, R. J. (Jun 1991). "Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population". Int J Epidemiol. 20 (2): 384–92. doi:10.1093/ije/20.2.384. PMID 1917239. ## Further reading[edit] * Burns P, Gough S, Bradbury AW (March 2003). "Management of peripheral arterial disease in primary care". BMJ. 326 (7389): 584–8. doi:10.1136/bmj.326.7389.584. PMC 1125476. PMID 12637405. * Shammas NW (2007). "Epidemiology, classification, and modifiable risk factors of peripheral arterial disease". Vasc Health Risk Manag. 3 (2): 229–34. doi:10.2147/vhrm.2007.3.2.229. PMC 1994028. PMID 17580733. ## External links[edit] Classification D * ICD-10: I73.9 * ICD-9-CM: 440.21 * MeSH: D007383 * Cochrane Peripheral Vascular Diseases Review Group * QUANTAFLO Peripheral Arterial Disease Test * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Intermittent claudication	c0021775	5,044	wikipedia	https://en.wikipedia.org/wiki/Intermittent_claudication	2021-01-18T18:52:33	{"mesh": ["D007383"], "umls": ["C0021775"], "icd-9": ["440.21"], "wikidata": ["Q1097957"]}
X-linked congenital stationary night blindness is a disorder of the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing in low light (night blindness). They also have other vision problems, including loss of sharpness (reduced acuity), severe nearsightedness (high myopia), involuntary movements of the eyes (nystagmus), and eyes that do not look in the same direction (strabismus). Color vision is typically not affected by this disorder. The vision problems associated with this condition are congenital, which means they are present from birth. They tend to remain stable (stationary) over time. Researchers have identified two major types of X-linked congenital stationary night blindness: the complete form and the incomplete form. The types have very similar signs and symptoms. However, everyone with the complete form has night blindness, while not all people with the incomplete form have night blindness. The types are distinguished by their genetic cause and by the results of a test called an electroretinogram, which measures the function of the retina. ## Frequency The prevalence of this condition is unknown. It appears to be more common in people of Dutch-German Mennonite descent. However, this disorder has been reported in families with many different ethnic backgrounds. The incomplete form is more common than the complete form. ## Causes Mutations in the NYX and CACNA1F genes cause the complete and incomplete forms of X-linked congenital stationary night blindness, respectively. The proteins produced from these genes play critical roles in the retina. Within the retina, the NYX and CACNA1F proteins are located on the surface of light-detecting cells called photoreceptors. The retina contains two types of photoreceptor cells: rods and cones. Rods are needed for vision in low light. Cones are needed for vision in bright light, including color vision. The NYX and CACNA1F proteins ensure that visual signals are passed from rods and cones to other retinal cells called bipolar cells, which is an essential step in the transmission of visual information from the eyes to the brain. Mutations in the NYX or CACNA1F gene disrupt the transmission of visual signals between photoreceptors and retinal bipolar cells, which impairs vision. In people with the complete form of X-linked congenital stationary night blindness (resulting from NYX mutations), the function of rods is severely disrupted, while the function of cones is only mildly affected. In people with the incomplete form of the condition (resulting from CACNA1F mutations), rods and cones are both affected, although they retain some ability to detect light. ### Learn more about the genes associated with X-linked congenital stationary night blindness * CACNA1F * NYX ## Inheritance Pattern This condition is inherited in an X-linked recessive pattern. The NYX and CACNA1F genes are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. Carriers of an NYX or CACNA1F mutation can pass on the mutated gene, but most do not develop any of the vision problems associated with X-linked congenital stationary night blindness. However, carriers may have retinal changes that can be detected with an electroretinogram. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	X-linked congenital stationary night blindness	c3495587	5,045	medlineplus	https://medlineplus.gov/genetics/condition/x-linked-congenital-stationary-night-blindness/	2021-01-27T08:24:35	{"gard": ["3995"], "mesh": ["C536122"], "omim": ["310500", "300071"], "synonyms": []}
Intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome is a rare multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (brachycephaly resulting from craniosynostosis, frontal bossing, downslanting palpebral fissures, large and low-set ears, depressed nasal bridge, high-arched, wide palate, thin upper lip), impaired neurological development with intellectual disability, hypotonia, pyloric stenosis, pectus excavatum, bilateral cryptorchidism and short stature. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome	None	5,046	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=314575	2021-01-23T17:41:29	{}
Microcytic anaemia Microcytosis is the presence of red cells that are smaller than normal. Normal adult red cell has a diameter of 7.2 µm. Microcytes are common seen in with hypochromia in iron-deficiency anaemia, thalassaemia trait, congenital sideroblastic anaemia and sometimes in anaemia of chronic diseases. SpecialtyHematology Microcytic anaemia is any of several types of anaemia characterized by small red blood cells (called microcytes). The normal mean corpuscular volume (abbreviated to MCV on full blood count results, and also known as mean cell volume) is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic (the latter occur in macrocytic anemia). The MCV is the average red blood cell size. In microcytic anaemia, the red blood cells (erythrocytes) contain less hemoglobin and are usually also hypochromic, meaning that the red blood cells appear paler than usual. This can be reflected by a low mean corpuscular hemoglobin concentration (MCHC), a measure representing the amount of hemoglobin per unit volume of fluid inside the cell; normally about 320–360 g/L or 32–36 g/dL. Typically, therefore, anemia of this category is described as "microcytic, hypochromic anaemia". ## Contents * 1 Causes * 2 See also * 3 References * 4 External links ## Causes[edit] Typical causes of microcytic anemia include: * Childhood * Iron deficiency anemia,[1] by far the most common cause of anemia in general and of microcytic anemia in particular * Thalassemia * Sideroblastic anemia. Very rare. In congenital sideroblastic anemia the MCV (mean corpuscular volume) is either low or normal. In contrast, the MCV is usually high in the much more common acquired sideroblastic anemia. * Adulthood * Iron deficiency anemia * Thalassemia * Anemia of chronic disease,[2] (aso known as anemia of inflammation) although this can also be normocytic. Microcytic anemia has been discussed by Weng et al.[2] * Lead poisoning – very rare. * Hyperthyroidism – very rare. * Vitamin B6 (pyridoxine) deficiency – very rare. Other causes that are typically thought of as causing normocytic anemia or macrocytic anemia must also be considered, and the presence of two or more causes of anemia can distort the typical picture. There are five main causes of microcytic anemia forming the acronym TAILS.[3] Thalassemia, anemia of chronic disease, iron deficiency, lead poisoning and congenital sideroblastic anemia. Only the first three are common in most parts of the world. In theory, these three can be differentiated by their red blood cell (RBC) morphologies. Anemia of chronic disease shows unremarkable RBCs, iron deficiency shows anisocytosis, anisochromia and elliptocytosis, and thalassemias demonstrate target cells and coarse basophilic stippling. In practice though elliptocytes and anisocytosis are often seen in thalassemia and target cells occasionally in iron deficiency.[3] All three may show unremarkable RBC morphology. Basophilic stippling is one morphologic finding of thalassemia which does not appear in iron deficiency or anemia of chronic disease. The patient should be in an ethnically at risk group and the diagnosis is not confirmed without a confirmatory method such as hemoglobin HPLC, H body staining, molecular testing or another reliable method. Coarse basophilic stippling occurs in other cases as seen in Table 1.[3] ## See also[edit] * Hypochromic anemia ## References[edit] 1. ^ Iolascon A, De Falco L, Beaumont C (January 2009). "Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis". Haematologica. 94 (3): 395–408. doi:10.3324/haematol.13619. PMC 2649346. PMID 19181781. 2. ^ a b Weng, CH; Chen JB; Wang J; Wu CC; Yu Y; Lin TH (2011). "Surgically Curable Non-Iron Deficiency Microcytic Anemia: Castleman's Disease". Onkologie. 34 (8–9): 456–8. doi:10.1159/000331283. PMID 21934347. 3. ^ a b c Ford, J. (June 2013). "Red blood cell morphology". International Journal of Laboratory Hematology. 35 (3): 351–357. doi:10.1111/ijlh.12082. PMID 23480230. ## External links[edit] Classification D * ICD-10: D50.8 * MeSH: C562385 C562385, C562385 * Emedicine on chronic anemia * v * t * e Diseases of red blood cells ↑ Polycythemia * Polycythemia vera ↓ Anemia Nutritional * Micro-: Iron-deficiency anemia * Plummer–Vinson syndrome * Macro-: Megaloblastic anemia * Pernicious anemia Hemolytic (mostly normo-) Hereditary * enzymopathy: Glucose-6-phosphate dehydrogenase deficiency * glycolysis * pyruvate kinase deficiency * triosephosphate isomerase deficiency * hexokinase deficiency * hemoglobinopathy: Thalassemia * alpha * beta * delta * Sickle cell disease/trait * Hereditary persistence of fetal hemoglobin * membrane: Hereditary spherocytosis * Minkowski–Chauffard syndrome * Hereditary elliptocytosis * Southeast Asian ovalocytosis * Hereditary stomatocytosis Acquired AIHA * Warm antibody autoimmune hemolytic anemia * Cold agglutinin disease * Donath–Landsteiner hemolytic anemia * Paroxysmal cold hemoglobinuria * Mixed autoimmune hemolytic anemia * membrane * paroxysmal nocturnal hemoglobinuria * Microangiopathic hemolytic anemia * Thrombotic microangiopathy * Hemolytic–uremic syndrome * Drug-induced autoimmune * Drug-induced nonautoimmune * Hemolytic disease of the newborn Aplastic (mostly normo-) * Hereditary: Fanconi anemia * Diamond–Blackfan anemia * Acquired: Pure red cell aplasia * Sideroblastic anemia * Myelophthisic Blood tests * Mean corpuscular volume * normocytic * microcytic * macrocytic * Mean corpuscular hemoglobin concentration * normochromic * hypochromic Other * Methemoglobinemia * Sulfhemoglobinemia * Reticulocytopenia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Microcytic anemia	c0085576	5,047	wikipedia	https://en.wikipedia.org/wiki/Microcytic_anemia	2021-01-18T19:09:34	{"mesh": ["C562385"], "umls": ["C0085576"], "icd-10": ["D50.8"], "wikidata": ["Q3298999"]}
Group of autosomal recessive genetic disorders that affect Finns much more frequently A Finnish heritage disease is a genetic disease or disorder that is significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Sweden (Meänmaa) and Russia (Karelia and Ingria). There are 36 rare diseases regarded as Finnish heritage diseases.[1] The diseases are not restricted to Finns; they are genetic diseases with far wider distribution in the world, but due to founder effects and genetic isolation they are more common in Finns. Within Finland these diseases are more common in the east and north, consistent with their higher association with ethnic Finns than with ethnic Swedes.[2] The Finnish disease heritage does not extend to other ethnic groups in the region, the Sámi and Karelians other than Finnish Karelians. It is attributed to a population bottleneck among ancestors of modern Finns, estimated to have occurred about 4000 years ago, presumably when populations practicing agriculture and animal husbandry arrived in Finland.[3] In Finland about one in five persons carries a gene defect associated with at least one Finnish heritage disease, and about one in 500 children born is affected.[4] Most of the gene defects are autosomal recessives, so that if both the mother and father carry the same defect, the chance that their child will have the associated disease is 1 in 4. The molecular genetics of many of these diseases have been determined, enabling genetic testing, prenatal testing, and counseling. This has raised questions of bioethics and eugenics.[5] ## Contents * 1 Finnish heritage disease types * 2 Other genetic diseases * 3 Genetic history * 4 Etymology * 5 See also * 6 References ## Finnish heritage disease types There are 36 identified Finnish heritage diseases:[6][7] * Amyloidosis, Finnish type * Lethal arthrogryposis with anterior horn cell disease * Aspartylglucosaminuria * Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia * Cartilage–hair hypoplasia * Ceroid lipofuscinosis, neuronal, 1 * Ceroid lipofuscinosis, neuronal, 3 * Ceroid lipofuscinosis, neuronal, 5 * Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant (Synonyms: Northern epilepsy; Epilepsy, progressive, with mental retardation) * Choroideremia * Cohen syndrome * Cornea plana 2 * Diarrhea 1, secretory chloride, congenital * Diastrophic dysplasia * Epilepsy, progressive myoclonic 1A (Unverricht–Lundborg) * Glycine encephalopathy (Nonketotic hyperglycinemia) * GRACILE syndrome * Gyrate atrophy of choroid and retina * Hydrolethalus syndrome 1 * Infantile-onset spinocerebellar ataxia (Mitochondrial DNA depletion syndrome 7) * Lactase deficiency, congenital * Lethal congenital contracture syndrome 1 * Lysinuric protein intolerance * Meckel syndrome * Megaloblastic anemia-1, Finnish and Norwegian type * Mulibrey nanism * Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3 * Nephrotic syndrome, type 1 (Finnish congenital nephrosis) * Ovarian dysgenesis 1 * Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu–Hakola disease) * Progressive encephalopathy with Edema, Hypsarrhythmia and Optic atrophy * RAPADILINO syndrome * Retinoschisis 1, X-linked, juvenile * Sialuria, Finnish type (Salla disease) * Tibial muscular dystrophy, tardive * Usher syndrome, type 3A Out of these, three are rare causes of dwarfism: cartilage–hair hypoplasia, diastrophic dysplasia and Mulibrey nanism. Four genetically distinct subtypes of neuronal ceroid lipofuscinosis are found in the Finnish heritage: CLN1, CLN3, CLN5, and CLN8.[8] Names for conditions associated with these subtypes include infantile neuronal ceroid lipofuscinosis, Jansky–Bielschowsky disease and northern epilepsy syndrome. As of 2001, CLN5 and CLN8 had been reported almost exclusively in Finland.[8] Meckel syndrome type 1 (MKS1[9]), a lethal condition, is known in 48 Finnish families.[10] ## Other genetic diseases The European Organization for Rare Diseases (EURORDIS) estimates that there are between 5,000 and 7,000 distinct rare diseases, affecting between 6% and 8% of the population of the European Union.[11] The majority of genetic diseases reported in Finland are not part of the Finnish disease heritage and their prevalence is not higher in Finland than worldwide. Some genetic diseases are disproportionately rare in Finns. These include cystic fibrosis and phenylketonuria. In Finland, about 1 in 80 persons are carriers of a cystic fibrosis mutation, compared with an average of 1 in 25 elsewhere in Europe.[12] ## Genetic history Based on molecular data, a population bottleneck among ancestors of modern Finns is estimated to have occurred about 4000 years ago.[3] This bottleneck resulted in exceptionally low diversity in the Y chromosome, estimated to reflect the survival of just two ancestral male lineages.[13][14] The distribution of Y chromosome haplotypes within Finland is consistent with two separate founding settlements, in eastern and western Finland.[15] The Finnish disease heritage has been attributed to this 4000-year-old bottleneck.[3] The geographic distribution and family pedigrees associated with some Finnish heritage disease mutations has linked the enrichment in these mutations to multiple local founder effects, some associated with a period of "late settlement" in the 16th century (see History of Finland).[16] ## Etymology Although the concept is older, the English term "Finnish disease heritage" first appears in the medical literature in the 1990s. One of the earliest uses is in the translated title of a 1994 medical article,[17] soon followed by others.[3][18] ## See also * Medicine portal * Finland portal * Leena Peltonen-Palotie * Nine diseases * Population genetics * BCG disease outbreak in Finland in the 2000s * Medical genetics of Ashkenazi Jews * Finnish Association on Intellectual and Developmental Disabilities (FAIDD) * Finno-Ugrian suicide hypothesis ## References 1. ^ Norio R (May 2003). "The Finnish Disease Heritage III: the individual diseases". Human Genetics. 112 (5–6): 470–526. doi:10.1007/s00439-002-0877-1. PMID 12627297. S2CID 26741302. 2. ^ Palo JU, Ulmanen I, Lukka M, Ellonen P, Sajantila A (April 2009). "Genetic markers and population history: Finland revisited". European Journal of Human Genetics. 17 (10): 1336–46. doi:10.1038/ejhg.2009.53. PMC 2986642. PMID 19367325. 3. ^ a b c d Sajantila A, Salem AH, Savolainen P, Bauer K, Gierig C, Pääbo S (October 1996). "Paternal and maternal DNA lineages reveal a bottleneck in the founding of the Finnish population". Proceedings of the National Academy of Sciences of the United States of America. 93 (21): 12035–9. Bibcode:1996PNAS...9312035S. doi:10.1073/pnas.93.21.12035. PMC 38178. PMID 8876258. 4. ^ Kallinen J, Heinonen S, Palotie A, Mannermaa A, Ryynanen M (May 2001). "Antenatal gene tests in low-risk pregnancies: molecular screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL) in Finland". Prenatal Diagnosis. 21 (5): 409–12. doi:10.1002/pd.82. PMID 11360285. 5. ^ Seppo Poutanen (2005). "3: The first genetic screening in Finland: its execution, evaluation, and some possible implications for liberal government". In Robin Bunton; Alan Petersen (eds.). Genetic governance: Health, risk, and ethics in the biotech era. Routledge. p. 215. ISBN 0-415-35407-2. 6. ^ "The Finnish Disease Heritage". FinDis. Retrieved 4 March 2018. 7. ^ "Diseases". FinDis. Retrieved 4 March 2018. 8. ^ a b Krystyna E. Wiśniewski; Nanbert Zhong; Jeffrey C. Hall (2001). Batten disease: diagnosis, treatment, and research. Academic Press. p. 243. ISBN 0-12-017645-9. page 125 9. ^ Consugar MB, Kubly VJ, Lager DJ, Hommerding CJ, Wong WC, Bakker E, Gattone VH, Torres VE, Breuning MH, Harris PC (June 2007). "Molecular diagnostics of Meckel–Gruber syndrome highlights phenotypic differences between MKS1 and MKS3". Human Genetics. 121 (5): 591–9. doi:10.1007/s00439-007-0341-3. PMID 17377820. S2CID 11815792. 10. ^ Salonen R; Opitz, John M.; Reynolds, James F. (August 1984). "The Meckel syndrome: clinicopathological findings in 67 patients". American Journal of Medical Genetics. 18 (4): 671–89. doi:10.1002/ajmg.1320180414. PMID 6486167. 11. ^ "Rare Diseases: Understanding This Public Health Priority" (PDF). European Organisation for Rare Diseases (EURORDIS). November 2005. Retrieved 16 May 2009. 12. ^ Hytönen M, Patjas M, Vento SI, Kauppi P, Malmberg H, Ylikoski J, Kere J (December 2001). "Cystic fibrosis gene mutations deltaF508 and 394delTT in patients with chronic sinusitis in Finland". Acta Oto-Laryngologica. 121 (8): 945–7. doi:10.1080/000164801317166835. PMID 11813900. 13. ^ Kittles RA, Bergen AW, Urbanek M, Virkkunen M, Linnoila M, Goldman D, Long JC (April 1999). "Autosomal, mitochondrial, and Y chromosome DNA variation in Finland: evidence for a male-specific bottleneck" (PDF). American Journal of Physical Anthropology. 108 (4): 381–99. doi:10.1002/(SICI)1096-8644(199904)108:4<381::AID-AJPA1>3.0.CO;2-5. PMID 10229384. 14. ^ Lahermo P, Savontaus ML, Sistonen P, Béres J, de Knijff P, Aula P, Sajantila A (1999). "Y chromosomal polymorphisms reveal founding lineages in the Finns and the Saami". European Journal of Human Genetics. 7 (4): 447–58. doi:10.1038/sj.ejhg.5200316. PMID 10352935. 15. ^ Kittles RA, Perola M, Peltonen L, Bergen AW, Aragon RA, Virkkunen M, Linnoila M, Goldman D, Long JC (May 1998). "Dual origins of Finns revealed by Y chromosome haplotype variation". American Journal of Human Genetics. 62 (5): 1171–9. doi:10.1086/301831. PMC 1377088. PMID 9545401. 16. ^ Peltonen L, Jalanko A, Varilo T (1999). "Molecular genetics of the Finnish disease heritage". Human Molecular Genetics. 8 (10): 1913–23. doi:10.1093/hmg/8.10.1913. PMID 10469845. 17. ^ de la Chapelle A, Hästbacka J, Lehesjoki AE, Sulisalo T, Kere J, Tahvanainen E, Sistonen P (1994). "[Linkage and linkage disequilibrium in the Finnish disease heritage]". Duodecim; Lääketieteellinen Aikakauskirja (in Finnish). 110 (7): 654–64. PMID 8542820. 18. ^ Perheentupa J (October 1995). "The Finnish disease heritage: a personal look". Acta Paediatrica. 84 (10): 1094–9. doi:10.1111/j.1651-2227.1995.tb13501.x. PMID 8563216. S2CID 29999767. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Finnish heritage disease	None	5,048	wikipedia	https://en.wikipedia.org/wiki/Finnish_heritage_disease	2021-01-18T18:44:46	{"wikidata": ["Q2567857"]}
Cattle dead from rinderpest in South Africa, 1896 In the 1890s, an epizootic of the rinderpest virus struck Africa, considered to be "the most devastating epidemic to hit southern Africa in the late nineteenth century".[1] It killed more than 5.2 million cattle south of the Zambezi,[2] as well as domestic oxen, sheep, and goats, and wild populations of buffalo, giraffe, and wildebeest. This led to starvation resulting in the death of an estimated third of the human population of Ethiopia and two-thirds of the Maasai people of Tanzania.[3] ## History[edit] The virus is thought to have been introduced into Eritrea in 1887 by Indian cattle brought by the Italians for their campaign against Somalia. It spread throughout the Horn of Africa, and crossed the Zambezi in March of 1896.[1] ## References[edit] 1. ^ a b Phoofolo, Pule (February 1993). "Epidemics and Revolutions: The Rinderpest Epidemic in Late Nineteenth-Century Southern Africa". Past & Present. 138 (1): 112–143. doi:10.1093/past/138.1.112. 2. ^ Van den Bossche, Peter; de La Rocque, Stéphane; Hendrickx, Guy; Bouyer, Jérémy (May 2010). "A changing environment and the epidemiology of tsetse-transmitted livestock trypanosomiasis". Trends in Parasitology. 26 (5): 236–243. doi:10.1016/j.pt.2010.02.010. 3. ^ Normile, Dennis (March 2008). "Driven to Extinction". Science. 319: 1606–9. doi:10.1126/science.319.5870.1606. PMID 18356500. ## Further reading[edit] * Sunseri, Thaddeus (2018-04-26). "The African Rinderpest Panzootic, 1888–1897". Oxford Research Encyclopedia of African History. Oxford University Press. doi:10.1093/acrefore/9780190277734.013.375. This African history–related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	1890s African rinderpest epizootic	None	5,049	wikipedia	https://en.wikipedia.org/wiki/1890s_African_rinderpest_epizootic	2021-01-18T18:33:33	{"wikidata": ["Q16820343"]}
Bosworth fracture SpecialtyOrthopedic The Bosworth fracture is a rare fracture of the distal fibula with an associated fixed posterior dislocation of the proximal fibular fragment which becomes trapped behind the posterior tibial tubercle. The injury is caused by severe external rotation of the ankle.[1] The ankle remains externally rotated after the injury, making interpretation of X-rays difficult which can lead to misdiagnosis and incorrect treatment.[2] The injury is most commonly treated by open reduction internal fixation as closed reduction is made difficult by the entrapment of the fibula behind the tibia.[1] The entrapment of an intact fibula behind the tibia was described by Ashhurst and Bromer in 1922, who attributed the description of the mechanism of injury to Huguier's 1848 publication.[3] The injury involving fibular fracture with posterior dislocation was described by David M. Bosworth in 1947.[4] ## References[edit] 1. ^ a b Perry, CR; Rice S; Rao A; Burdge R. (Oct 1983). "Posterior fracture-dislocation of the distal part of the fibula. Mechanism and staging of injury". J Bone Joint Surg Am. 65 (8): 1149–57. doi:10.2106/00004623-198365080-00016. PMID 6630259. Archived from the original on 2010-11-01. Retrieved 2009-10-10. 2. ^ Hoblitzell, RM; Ebraheim NA; Merritt T; Jackson WT. (1990). "Bosworth fracture-dislocation of the ankle. A case report and review of the literature". Clin Orthop Relat Res (255): 257–62. PMID 2112075. 3. ^ Ashhurst, APC; Bromer RS (1922). "Classification and Mechanism of Fractures of the Leg Bones Involving the Ankle. Based on a Study of Three Hundred Cases from the Episcopal Hospital". Arch. Surg. 4: 51–129. doi:10.1001/archsurg.1922.01110100060003. 4. ^ Bosworth, DM (Jan 1947). "Fracture-Dislocation of the Ankle with Fixed Displacement of the Fibula behind the Tibia". J Bone Joint Surg. 29: 130–135. ## External links[edit] Classification D * ICD-10: S82.4 External resources * AO Foundation: 44-C1 * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal This article about an injury is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Bosworth fracture	None	5,050	wikipedia	https://en.wikipedia.org/wiki/Bosworth_fracture	2021-01-18T18:37:03	{"wikidata": ["Q4948376"]}
A number sign (#) is used with this entry because progressive myoclonic epilepsy-3 with or without intracellular inclusions (EPM3) is caused by homozygous or compound heterozygous mutation in the KCTD7 gene (611725) on chromosome 7q11. Description Mutations in the KCTD7 gene cause a severe neurodegenerative phenotype characterized by onset of intractable myoclonic seizures before age 2 years and accompanied by developmental regression. The initial description was consistent with a form of progressive myoclonic epilepsy (designated here as EPM3), whereas a later report identified intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis (designated CLN14). Ultrastructural findings on skin biopsies thus appear to be variable. However, clinical features are generally consistent between reports (summary by Staropoli et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800). For a general phenotypic description and a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730). Clinical Features Van Bogaert et al. (2007) reported a consanguineous Moroccan family in which 3 members had early-onset progressive myoclonic epilepsy. Multifocal myoclonic seizures began between 16 and 24 months of age after normal initial development. Two patients had secondary generalization. Neurodegeneration and regression occurred with seizure onset. Other features included mental retardation, dysarthria, truncal ataxia, and loss of fine finger movements. One patient had several episodes of myoclonic status epilepticus and developed permanent myoclonus affecting the face, tongue, and limbs. Two patients showed transient neurologic improvement when the epilepsy was controlled. EEG showed slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges, and photosensitivity. Ultrastructural analysis of a skin biopsy was normal. Staropoli et al. (2012) reported 2 Mexican sibs with onset of severe intractable myoclonic seizures at ages 9 and 8 months, respectively, after normal development. Myoclonic movements involved mainly the face and extremities, and were often precipitated or worsened by fevers. Normal development occurred until about 18 months of age, at which point motor and speech regression were noted. At ages 12 and 10 years, both sibs had microcephaly, were nonverbal, and were without spontaneous motor function. Neither showed a response to visual threat and both had diminished pupillary light reflexes; 1 also had bilateral optic atrophy without retinopathy. Brain imaging showed global cortical and cerebellar atrophy and thinning of the corpus callosum. Skin biopsy of 1 patient showed CLN-type storage material in fibroblasts, neurons, and eccrine secretory epithelial cells. Electron microscopy of lymphocytes showed lysosomal storage material containing fingerprint-like profiles and granular osmiophilic deposits. The axon of a myelinated nerve contained vacuole-bound rectilinear profiles. Immunoblot analysis of lymphocytes showed increased levels of mitochondrial ATP synthase subunit C in fingerprint, rectilinear, and curvilinear storage profiles, similar to that observed in CLN3 (204200). Both sibs died from complications of progressive disease in their mid-teens. Kousi et al. (2012) reported 9 patients from 6 unrelated Turkish families and 1 Pakistani family with EPM3. Three of the families were consanguineous. All patients were alive at the time of the study and were between 3.2 and 14 years of age. The mean age at presentation was 19 months, and most presented with myoclonic and/or tonic-clonic seizures. One patient presented with ataxia. Six of the 9 patients had a favorable response to antiepileptic drug treatment with multiple agents. Psychomotor decline, including ataxia, became evident soon after onset of seizures and resulted in severe motor and mental retardation. Some patients developed scoliosis. All patients had abnormal EEG findings in various brain regions. None had retinal findings, and none of the patients tested had evidence of neuronal ceroid lipofuscinosis on skin biopsy. Mapping By linkage mapping, Van Bogaert et al. (2007) identified a locus for EPM3 on chromosome 7q11.2 (maximum multipoint lod score of 4.0 at D7S663). Molecular Genetics In affected members of a consanguineous Moroccan family with progressive myoclonic epilepsy, Van Bogaert et al. (2007) identified a homozygous mutation in the KCTD7 gene (R99X; 611725.0001). In 2 Mexican sibs with progressive myoclonic epilepsy and pathologic findings of neuronal ceroid lipofuscinosis in multiple cell types, Staropoli et al. (2012) identified a homozygous mutation in the KCTD7 gene (R184C; 611725.0002). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. KCTD7 mutations were not found in 32 additional CLN samples. In affected members of 7 unrelated families with progressive myoclonic epilepsy-3, Kousi et al. (2012) identified 6 different mutations in the KCTD7 gene (see, e.g., 611725.0003-611725.0007). All mutations were in the homozygous or compound heterozygous state. The initial mutations were found in 2 probands by homozygosity mapping followed by candidate gene sequencing, and the other mutations were found by screening of the gene in 108 Turkish patients and 1 Pakistani patient with the phenotype. Four mutations were missense, 1 was an in-frame deletion, and 1 was truncating. None of the patients with KCTD7 mutations tested had evidence of neuronal ceroid lipofuscinosis on skin biopsy, and none of 22 additional patients with neuronal ceroid lipofuscinosis carried mutations in the KCTD7 gene. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly (in 1 family) Eyes \- Visual loss (in 1 family) \- Optic atrophy, mild (in 1 patient) NEUROLOGIC Central Nervous System \- Myoclonic seizures \- Secondary generalization \- Initial normal development \- Neurologic regression following seizure onset \- Mental retardation \- Dysarthria \- Limited expressive language \- Truncal ataxia \- Loss of motor function \- EEG shows slowed dysrhythmia and multifocal discharges \- Cerebral atrophy (in 1 family) \- Cerebellar atrophy (in 1 family) \- Thinning of the corpus callosum (in 1 family) LABORATORY ABNORMALITIES \- Granular osmiophilic cytoplasmic deposits ultrastructurally in cells \- 'Fingerprint profiles' ultrastructurally in cells \- 'Rectilinear profiles' ultrastructurally in cells MISCELLANEOUS \- Onset before age 2 years \- Two unrelated families have been reported (last curated July 2012) \- Only 1 family had ultrastructural cellular findings of neuronal ceroid lipofuscinosis \- Progressive disorder \- Severe phenotype MOLECULAR BASIS \- Caused by mutation in the potassium channel tetramerisation domain containing 7 gene (KCTD7, 611725.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITH OR WITHOUT INTRACELLULAR INCLUSIONS	c2673257	5,051	omim	https://www.omim.org/entry/611726	2019-09-22T16:02:54	{"doid": ["891"], "mesh": ["C567095"], "omim": ["611726"], "orphanet": ["263516"], "synonyms": ["Alternative titles", "CEROID LIPOFUSCINOSIS, NEURONAL, 14"]}
Symblepharon Symblepharon in lower conjunciva caused by chemical eye burn Differential diagnosistrachoma A symblepharon is a partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball. It results either from disease (conjunctival sequelae of trachoma) or trauma. Cicatricial pemphigoid[1] and, in severe cases, rosacea may cause symblepharon. It is rarely congenital.[citation needed] and its treatment is symblepharectomy. ## See also[edit] * Ankyloblepharon ## References[edit] 1. ^ Holsclaw, DS (1998). "Ocular cicatricial pemphigoid and its treatment is surgery by conjunctival rotate graft and or amniotic membran transplant (AMT)". International Ophthalmology Clinics. 38 (4): 89–106. doi:10.1097/00004397-199803840-00009. PMID 10200078. ## Further reading[edit] * Brazier, DJ; Hardman-Lea, SJ; Collin, JR (1986). "Cryptophthalmos: surgical treatment of the congenital symblepharon variant". The British Journal of Ophthalmology. 70 (5): 391–5. doi:10.1136/bjo.70.5.391. PMC 1041021. PMID 3008809. This medical symptom article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Symblepharon	c0152454	5,052	wikipedia	https://en.wikipedia.org/wiki/Symblepharon	2021-01-18T18:35:59	{"umls": ["C0152454"], "icd-10": ["H11.2"], "wikidata": ["Q2374415"]}
Bain type of X-linked syndromic intellectual disability is a genetic syndrome characterized by developmental delay, intellectual disability, autism, hypotonia, and seizures. Other symptoms may include loss of acquired skills (developmental regression), behavioral problems, stiffness or tightness of the muscles (spasticity), problems coordinating movements, small head, unusual facial features, and short stature. Some individuals also develop mental disorders such as anxiety, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and stereotyped behaviors. The syndrome has only been identified in females. It is caused by mutations in the HNRNPH2 gene which is located on the X chromosome. Treatment is symptomatic and supportive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Bain type of X-linked syndromic intellectual disability	c4310814	5,053	gard	https://rarediseases.info.nih.gov/diseases/13442/bain-type-of-x-linked-syndromic-intellectual-disability	2021-01-18T18:01:54	{"omim": ["300986"], "synonyms": ["HNRNPH2 deficiency"]}
## Summary ### Clinical characteristics. X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), is characterized by muscle weakness that ranges from severe to mild. Approximately 80% of affected males present with severe (classic) X-MTM characterized by polyhydramnios, decreased fetal movement, and neonatal weakness, hypotonia, and respiratory failure. Motor milestones are significantly delayed and most individuals fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most individuals requiring 24-hour ventilatory assistance. It is estimated that at least 25% of boys with severe X-MTM die in the first year of life, and those who survive rarely live into adulthood. Males with mild or moderate X-MTM (~20%) achieve motor milestones more quickly than males with the severe form; many ambulate independently, and may live into adulthood. Most require gastrostomy tubes and/or ventilator support. In all subtypes of X-MTM, the muscle disease is not obviously progressive. Female carriers of X-MTM are generally asymptomatic, although manifesting heterozygotes are increasingly being identified. In affected females, symptoms range from severe, generalized weakness presenting in childhood, with infantile onset similar to affected male patients, to mild (often asymmetric) weakness manifesting in adulthood. Affected adult females may experience progressive respiratory decline and ultimately require ventilatory support. ### Diagnosis/testing. The diagnosis of X-MTM is established in a proband with suggestive clinical findings and identification of a hemizygous pathogenic variant in MTM1 by molecular genetic testing. ### Management. Treatment of manifestations: Treatment is supportive. Management optimally involves a team of specialists with expertise in the long-term care of children and/or adults with neuromuscular disorders, often including a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, and clinical geneticist. Tracheostomy, G-tube feeding, and assistive communication devices are often required. Ophthalmologists, orthopedists, and orthodontists should address specific medical complications related to the underlying myopathy. Surveillance: Annual pulmonary assessment; polysomnography every one to three years; routine examination for scoliosis; annual ophthalmologic examinations to evaluate for ophthalmoplegia, ptosis, and myopia; routine assessment for dental malocclusion. ### Genetic counseling. X-MTM is inherited in an X-linked manner. The risk to sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, each sib has a 50% chance of inheriting the MTM1 pathogenic variant. Males who inherit the variant will be affected; females who inherit the variant will be carriers and will generally not be affected. To date, there are no reported males with incomplete penetrance. In simplex cases (i.e., a single occurrence in a family), there is a probability of 80%-90% that a woman is a carrier if her son has a confirmed MTM1 pathogenic variant. Thus, about 10%-20% of males who represent simplex cases have a de novo pathogenic variant in MTM1 and a mother who is not a carrier. Germline mosaicism has been reported. Carrier testing of at-risk female relatives and prenatal testing for a pregnancy at risk are possible if the MTM1 pathogenic variant has been identified in an affected male relative. ## Diagnosis ### Suggestive Findings The diagnosis of X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), should be suspected in any male with the following clinical and histopathologic features. Clinical features * Neonatal hypotonia * Neonatal respiratory failure * Significant and diffuse muscle weakness * Diminished muscle bulk * A family history suggestive of X-linked inheritance * Length and head circumference >90th centile * Cryptorchidism * Long fingers and toes * Involvement of the extraocular muscles (i.e., ophthalmoparesis) Histopathologic features on muscle biopsy [Lawlor et al 2016] * Numerous small, rounded myofibers with internally located nuclei that are present at (or very near) the center of a myofiber. The nucleus often appears very large in comparison to the small fiber size. * Aberrant accumulation of centrally located staining with oxidative stains (SDH and NADH) and glycogen stains (PAS), often in conjunction with a halo-like area of subsarcolemmal clearing on these stains * Small, predominant type I fibers * Necklace fibers on hematoxylin-eosin stained sections and with succinate dehydrogenase staining; present in some individuals with sporadic late-onset X-MTM as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei The diagnosis of X-MTM should be considered in females with the following clinical and histopathologic features: * Mild to moderate extremity weakness in a limb girdle pattern, often with prominent asymmetry * Asymmetric muscle growth * Facial weakness, ptosis, and ophthalmoparesis * A family history suggestive of X-linked inheritance (affected females may not have a family history of X-MTM) * Necklace fibers on muscle biopsy, or features of typical centronuclear myopathy ### Establishing the Diagnosis Male proband. The diagnosis of X-MTM is established in a male proband with suggestive clinical findings and identification of a hemizygous pathogenic variant in MTM1 by molecular genetic testing (see Table 1). Female proband. The diagnosis of X-MTM is usually established in a female proband with suggestive clinical findings and identification of a heterozygous pathogenic variant in MTM1 by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing, exome array) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of X-MTM is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with myopathy are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of X-MTM, molecular genetic testing approaches can include a multigene panel or single-gene testing: * A multigene panel that includes MTM1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * Single-gene testing. Rarely, single-gene testing can be considered under the appropriate circumstances. These include: (a) a male child with weakness and a positive family history of X-MTM; or (b) a severely affected male infant with physical features consistent with X-MTM, including diffuse weakness, ophthalmoparesis, and length and head circumference >90th centile. Sequence analysis of MTM1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by myopathy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in X-Linked Myotubular Myopathy View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method MTM1Sequence analysis 3, 4~90% 5, 6 Gene-targeted deletion/duplication analysis 7~10% 8 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\. de Gouyon et al [1997], Laporte et al [1997], Herman et al [2002], Tsai et al [2005] 6\. The occurrence of deep intronic pathogenic variants has been described [Tosch et al 2010, Al-Hashim et al 2017]; these inform the choice of molecular testing method. 7\. 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. 8\. Laporte et al [2000], Amburgey et al [2013b], Oliveira et al [2013] ## Clinical Characteristics ### Clinical Description The clinical characteristics and disease course of X-linked myotubular myopathy (X-MTM) have been described in two retrospective natural history studies including nearly 200 genetically confirmed probands [Amburgey et al 2017, Beggs et al 2018]. One study included a prospective one-year survey in addition to retrospective analysis [Amburgey et al 2017]. Following isolation of MTM1 in 1996, Herman et al [1999] described a clinical classification for the broader phenotype. Individuals with MTM1 pathogenic variants were classified as having one of the following: * Severe (classic) X-MTM. Characteristic facies, chronic ventilator dependence, delayed gross motor milestones, inability to independently ambulate, and high incidence of death in infancy. This is by far the most common form of the disease (~80% of all individuals with X-MTM). * Moderate X-MTM. Less severely delayed motor milestones than in the severe form, prolonged periods of decreased ventilatory support * Mild X-MTM. Ambulatory with minimally delayed motor milestones, chronic ventilatory support not required beyond the newborn period, and no/limited impact on life span Since publication of the phenotypic classification by Herman et al [1999], a rare adult-onset form with slowly progressive myopathy and no clinical manifestations in infancy has been identified [Hoffjan et al 2006]. In addition, manifesting female heterozygotes are increasingly reported [Biancalana et al 2017, Felice et al 2018]. #### Severe/Classic X-MTM In males with the severe/classic phenotype, polyhydramnios and decreased fetal movement are frequently reported. Premature delivery is described in approximately one third of males [Beggs et al 2018]. Hypotonia, extremity weakness, and respiratory distress are present during the newborn period. Ventilatory support is required due to respiratory failure [Amburgey et al 2017, Beggs et al 2018]. Hypoxic events may occur, leading to an acquired hypoxic ischemic encephalopathy. Prolonged ventilator dependence leads to an increased risk of respiratory infection, hypoventilation, and hypoxia. Affected infants often have typical myopathic facies with dolichocephaly, high forehead, long face with midface retrusion, prominent eyes, narrow high-arched palate, and severe malocclusion. Ophthalmoparesis is also frequently observed. Additional features include length greater than the 90th centile with a proportionately lower weight (60% of infants), long fingers and/toes (43%), cryptorchidism and/or undescended testicle (>50%), contractures including clubfeet (30%), and areflexia (60%). Most infants require lengthy NICU hospitalizations, with approximately 30%-50% of the first year spent in the hospital. Many infants with severe/classic X-MTM succumb to complications of the disorder. The percentage of infants that do not survive the first year of life has been difficult to determine. The reported causes of death are multifactorial, and include removal of ventilatory support. Approximately 25% of male infants die in the first year of life. Most surviving males are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy tube feedings. In one study including all forms of X-MTM, 85% of individuals required ventilatory and G-tube support, and nearly all needed wheelchair support for ambulation [Amburgey et al 2017]. The estimated rate of mortality is 10% per year after age one, with few individuals surviving to adulthood. The cause of death is usually related to respiratory failure, though very rarely may be associated with hepatic peliosis. The muscle disease may not be progressive. A prospective study of the ventilatory support requirements of 33 individuals over one year showed little change. Prospective analysis of muscle function in a small pilot group also detected no large changes over a one-year period [Amburgey et al 2017]. Interestingly, and despite the severe disability and technology dependence of the disease, the annual rate of nonelective hospitalization after the first year of life is not as high as would be expected. In a prospective study of 33 individuals, the rate was 1.1 emergency room visits per year [Amburgey et al 2017]. The rate of hospitalization is higher in very young individuals (age 1-2 years) [Amburgey et al 2017, Beggs et al 2018]. Additional features of the underlying myopathy are ophthalmoplegia, ptosis, and severe myopia. Dental malocclusion (requiring orthodontic care) may occur. Constipation is common. Scoliosis often develops in later childhood (75% of individuals in one study) and may require surgical intervention, though scoliosis surgery is documented in only a minority of individuals (≤10%). Scoliosis can exacerbate respiratory insufficiency, in some cases causing ventilator-independent males to become ventilator dependent again as it progresses. Additional orthopedic manifestations include hip dysplasia and long bone fractures [Cahill et al 2007]. Hepatic peliosis. Liver hemorrhage due to hepatic peliosis is perhaps the most serious non-muscle-related complication in X-MTM. Several individuals have died following prolonged liver hemorrhage or hemorrhage into the peritoneal cavity due to hepatic peliosis, a rare vascular lesion characterized by the presence of multiple blood-filled cysts within the liver [Motoki et al 2013]. This complication may occur in up to 5% of individuals. Growth and pubertal development. Despite chronic illness and prolonged ventilator dependence, many individuals with X-MTM have linear growth above the 50th centile, with some individuals achieving greater than the 90th centile for height. Advanced bone age and/or premature adrenarche have been documented in several young males. However, endocrinologic studies performed on several individuals have been normal. Puberty has occurred normally in the few males who have reached adulthood. Cognition. A recent natural history study identified that many children require special education for learning/cognitive impairments [Amburgey et al 2017]. This may be due to comorbid hypoxic ischemic encephalopathy, and there are rare individuals with central nervous system complications [McCrea et al 2009]. However, determination of whether there is a primary cognitive component to the disorder awaits further study. Other. Several medical problems unrelated to the muscle disorder have been reported at low frequency. It is not entirely clear if these are due to MTM1 pathogenic variants or unrelated comorbidities. They include pyloric stenosis (~5%), gastroesophageal reflux (10%), cardiac arrhthymias (10%; severity is unclear), gallstones (9%), kidney stones (10%), and elevated liver function tests (20%). Herman et al [1999] also identified some individuals with a mild form of spherocytosis and a vitamin K-responsive bleeding diathesis. These have not been recently reported and their presence in this population is unknown. #### Mild and Moderate X-MTM At least three reports of multigenerational families with MTM1 pathogenic variants and a much milder phenotype have been described [Barth & Dubowitz 1998, Biancalana et al 2003, Yu et al 2003, Hoffjan et al 2006]. In the recent natural history study, 13% of study subjects could walk independently and were thus considered in the mild/moderate category; 2% required no support for ambulation, ventilation, or feeding. Males with moderate or even mild disease are at increased risk for respiratory decompensation with intercurrent illness and may require transient or increased ventilatory support. They are also at risk for some of the same medical complications (including peliosis hepatis) as those with severe X-MTM [Herman et al 1999]. Most still require some respiratory support (which may be noninvasive), and typically also require feeding assistance. There are several case reports describing adult males with mild disease and pathogenic variants in MTM1. These include two individuals in their 60s at the time of publication who first manifested limb girdle weakness after childhood (first symptoms age 18 and 52 years, respectively) [Biancalana et al 2003, Hoffjan et al 2006]. At least one of these males had facial weakness and ophthalmoparesis. Yu et al [2003] described two males with a pathogenic variant in MTM1, age 55 and 30 years, both of whom live independently. The 30-year-old developed some muscle weakness later in life and had decreased muscle bulk that was improved by diet and weight-lifting exercises. Heterozygous females are generally asymptomatic, although symptomatic heterozygote females have been described [Savarese et al 2016, Biancalana et al 2017, Felice et al 2018]. Severity is variable, and some present with severe infantile weakness resembling that seen in affected males. More commonly, symptoms include mild/moderate asymmetric limb weakness and asymmetric reduction of muscle bulk in the correspondingly affected limbs. Facial weakness, ptosis, and ophthalmoparesis are often present. Respiratory failure is not uncommon, and can be unrecognized at the time of presentation. Histopathologic features [Lawlor et al 2016] * The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [Pierson et al 2007]. The combination of small myofiber size and central nucleation may result in the central nuclei comprising the majority of the cross-sectional area in some myofibers, which is not specific for X-MTM but is characteristic of severe centronuclear myopathies in very young individuals. * Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [Romero 2010]. In some cases, a particularly striking subsarcolemmal halo will be seen around these aggregates. * ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [Pierson et al 2005]. All fiber types tend to show some degree of decreased myofiber size in most biopsies, however, and appropriately sized or large fibers may be rare or absent. In some biopsies, ATPase staining demonstrates myofibers with central clearing that results from a focal absence of myofibrils [Romero 2010]. * The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see Differential Diagnosis) and in early-onset autosomal forms of centronuclear myopathy. X-MTM with a low percentage of central nuclei and type 1 fiber predominance can also resemble congenital fiber type disproportion [Pierson et al 2005]. Note: (1) The clinical and histopathologic features of MTM1-associated myopathies are broad, requiring that a distinction be made between central and internal nuclei [Romero 2010]. The former occur at (or very near) the exact center of a myofiber and are typical of (although not specific for) X-MTM, whereas the latter are usually eccentrically situated within the myofiber and may alternatively be associated with other centronuclear myopathies or with chronic myofiber regeneration. (2) Necklace fibers are a distinctive feature that has been described in males with sporadic late-onset X-MTM as well as in manifesting heterozygous females [Biancalana et al 2017]. Necklace fibers appear on hematoxylin-eosin-stained sections as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei. They can also be visualized with succinate dehydrogenase histochemical staining [Bevilacqua et al 2009]. Necklace fibers may be accompanied by muscle hypotrophy and type 1 fiber predominance. The percentage of myofibers with internal nuclei frequently exceeds the percentage of fibers with central nuclei and both tend to increase with age. (3) Biopsies from older individuals may feature increased connective and adipose tissues. Immunohistochemical stains on most (not all) muscle samples from individuals with X-MTM demonstrate persistence of fetal-specific muscle proteins or isoforms such as desmin, vimentin, and fetal myosin [Sarnat 1990, Sewry 1998]. Variation in the immunohistochemical expression of NCAM, utrophin, laminin, alpha 5, and HLA1 antigen has also been described [Helliwell et al 1998]. The clinical utility of these immunostains has not been systematically studied. T-tubule disorganization visualized through immunohistochemistry has been described in X-MTM [Al-Qusairi et al 2009, Dowling et al 2009]. DHPRa1, a T-tubule protein, and RyR1, a sarcoplasmic recticulum protein, are abnormally distributed in myofibers with increased immunoreactivity appearing in the center of small fibers [Dowling et al 2009]. Levels of both proteins are also diminished, as demonstrated by western blot analysis [Bachmann et al 2017]. Since other centronuclear myopathies also have T-tubule defects, the specific diagnostic utility of this finding may be limited [Toussaint et al 2011]. Electron microscopy. Ultrastructurally, X-MTM is characterized by the disorganization or decreased number of triads (interfaces between the sarcotubular reticulum and T-tubules) in longitudinal sections. This has been well demonstrated in human patients and animal models of disease [Al-Qusairi et al 2009, Dowling et al 2009, Childers et al 2014], and quantitative studies have been performed in some animal treatment studies to assist in the evaluation of therapeutic efficacy [Lawlor et al 2013, Lawlor et al 2016, Mack et al 2017]. These quantitative studies have been highly controlled in the collection and processing of the tissue, however, and quantification of triads or sarcotubular elements in the clinical diagnostic setting is not feasible. Immunologic testing using antibodies specific for myotubularin, the protein encoded by MTM1 [Laporte et al 2001b], can detect the presence or absence of myotubularin in cell lines from affected individuals. In 21/24 males with known pathogenic variants, including some missense variants, no myotubularin was detected on western blot. One out of five boys with suspected X-MTM in whom no pathogenic variant was identified also had no detectable protein by western analysis. Tosch et al [2010] demonstrated the absence of detectable protein in eight affected individuals with severe to intermediate phenotypes and a decreased amount of protein in an individual with a mild phenotype. Eight of nine individuals had confirmed MTM1 pathogenic variants; one individual had no detectable protein and an intermediate phenotype, but no MTM1 pathogenic variant was detected. While immunologic testing may be helpful in some individuals with suspected X-MTM in whom no pathogenic variant is found, such analysis is not routine, and adequate antibodies to myotubularin are not widely available. ### Genotype-Phenotype Correlations X-MTM is most frequently caused by nonsense, frameshift, and splice site variants that predict loss of function. Pathogenic variants are found throughout the gene with no concentration in any specific domain. * Nonsense and frameshift variants nearly always result in the severe/classic X-MTM phenotype. * Splice site and intronic variants may cause the severe presentation or can be associated with the milder phenotype. * Missense variants can be associated with both severe and mild/moderate phenotypes. * Variants associated with the phosphatase domain and the SET-interacting domain nearly always cause a severe phenotype. Pathogenic variants outside of these two domains are more likely to be associated with milder phenotypes [Amburgey et al 2017, Beggs et al 2018]. * A large number of pathogenic variants occur in hypermutable CpG dinucleotides; the most common is variant c.1261-10A>G in intron 11, which activates a cryptic splice site and produces an in-frame insertion of three amino acids in the core of the protein tyrosine phosphatase (PTP) site. This pathogenic variant is associated with a severe phenotype in males. ### Penetrance Penetrance is thought to be 100% in males with a pathogenic variant in MTM1, as all have shown findings of the disease. However, disease severity can range from mild to severe. Carrier females are generally asymptomatic, though an increasing number of manifesting heterozygotes are being identified [Savarese et al 2016, Biancalana et al 2017, Felice et al 2018]. ### Nomenclature X-MTM (or myotubular myopathy or X-linked centronuclear myopathy [X-CNM]) is considered a subtype of centronuclear myopathy based on the centrally located nuclei of muscle fibers on histologic examination, and based on shared pathogenic mechanisms. Autosomal dominant and autosomal recessive centronuclear myopathy should not be referred to as myotubular myopathy. Males with X-MTM with identifiable pathogenic variants in MTM1 are said to have X-linked myotubular myopathy or simply myotubular myopathy (MTM). This term should only be used to refer to individuals with documented or presumed MTM1 pathogenic variants. ### Prevalence It has been estimated that X-MTM affects approximately one in 50,000 newborn males [Laporte et al 2001a]; careful, large studies attempting complete ascertainment have not been published. ## Differential Diagnosis ### Table 2. Disorders to Consider in the Differential Diagnosis of X-Linked Myotubular Myopathy View in own window DisorderGene(s)MOIClinical Features of This Disorder Overlapping w/X-MTMDistinguishing from X-MTM Congenital myotonic dystrophy type 1DMPKAD * Polyhydramnios * Decreased fetal movements * Hypotonia * Myopathic facies * Respiratory distress * ID * Muscle biopsy possibly indistinguishable * Absence of ophthalmoparesis * AD family history DNM2-related CNM (OMIM 160150)DNM2AD * Hypotonia * Diffuse muscle weakness * Ptosis * Ophthalmoparesis * Myopathic facies * Muscle biopsy w/central nuclei * Clinical features possibly less severe * Normal/reduced growth parameters * "Spoke on wheel" changes w/oxidative stains on muscle biopsy RYR1-related CNM 1RYR1AR * Neonatal hypotonia * Weakness * Ophthalmoparesis * Ptosis * Myopathic facies * Severe respiratory compromise * Muscle biopsy w/central nuclei * Clinical features possibly less severe * Normal/reduced growth parameters * May have other non-MTM features on biopsy (cores, dystrophic changes) BIN1-related CNM (OMIM 255200)BIN1AR * Onset in infancy possible * Muscle biopsy w/central nuclei * Clinical features less severe * Normal growth parameters SPEG-related CNM (OMIM 615959)SPEG1AR * Onset in infancy * Diffuse weakness * Respiratory failure * Ophthalmoparesis * Muscle biopsy w/central nuclei * Can have prominent cardiac involvement * Biopsies may lack central nuclei Nemaline myopathy (OMIM PS161800)>10 genesAD AR * Can present w/diffuse weakness starting in infancy, often w/prominent facial weakness * Biopsies can feature myofiber hypotrophy & type I fiber predominance. * Ophthalmoparesis is rare (except in LMOD3-related nemaline myopathy). * Muscle biopsy showing nemaline rod aggregates (essentially never seen in X-MTM) * Central nuclei usually not increased Multiminicore disease (OMIM 606210, 180901)SEPN1 RYR1AR 2 * May present w/diffuse weakness starting from birth * Ophthalmoparesis in a subset of individuals * Weakness usually less than in X-MTM * Muscle biopsy showing characteristic disruptions of mitochondrial & sarcotubular organization on oxidative stains (i.e., cores) * Central nuclei usually not increased Congenital myasthenic syndromes>25 genesAD AR * Can present w/similar symptoms in early childhood, w/facial & extremity weakness & involvement of extraocular muscles * Both conditions may respond to mestinon. * Electrodiagnostic features of CMS (abnormal repetitive stimulation & jitter on single-fiber EMG) may be seen in X-MTM. * Fluctuating weakness variably present in CMS (not typical of X-MTM) * Biopsies are either normal or show nonspecific changes; the features of X-MTM are not seen on biopsy in CMS. AD = autosomal dominant; AR = autosomal recessive; CNM = centronuclear myopathy; ID = intellectual disability; MOI = mode of inheritance; MTM = myotubular myopathy 1\. Wilmshurst et al [2010], Amburgey et al [2013a] 2\. The occurrence of minicore myopathy in two generations in a few families – suggestive of autosomal dominant inheritance – has been reported. See Myopathy, centronuclear: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with X-linked myotubular myopathy (X-MTM), the following evaluations are recommended if they have not already been completed: * Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established. * Feeding/swallowing assessment, as performed by a qualified occupational therapist or equivalent allied health professional * Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established * In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis * In the presence of infantile vomiting, investigation for pyloric stenosis * Consultation with a clinical geneticist and/or genetic counselor * In older children, evaluation for orthopedic complications, including examination for scoliosis ### Treatment of Manifestations Management of individuals with X-MTM is based on supportive care measures and in large part is similar to that for other congenital myopathies [Wang et al 2012]. Management optimally involves a team of specialists with expertise in the long-term care of individuals with neuromuscular disorders. Such teams often include a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, and clinical geneticist. Once the specific diagnosis of X-MTM is confirmed, management may be guided by family decisions regarding continued ventilatory support for the affected family member. Families may benefit from the involvement of professionals familiar with the data concerning the overall prognosis for X-MTM. Talking with other families who have children with the disorder can be extremely helpful, as can discussion with members of an MTM family foundation (see Resources). There is also a patient-/family-oriented guide for care for X-MTM. * Given the risks for aspiration pneumonia and respiratory failure in infants with moderate or severe disease, tracheostomy and G-tube feeding should be seriously considered. Even individuals with mild disease are at risk for significant morbidity and mortality from intercurrent respiratory infection and hypoventilation. * For ventilator-dependent individuals, communication support incorporates speech with a capped tracheostomy or Passy-Muir valve, sign language, and/or communication devices such as writing boards. * Affected individuals older than age five years attend school, usually assisted by a dedicated nurse or aide, or have home-based teachers to limit exposure to infectious agents. Based on the emerging natural history study data, neuropsychologic evaluation may help identify learning difficulties and enable optimized educational planning. * Ophthalmologists, orthopedists specializing in scoliosis management, and orthodontists should address specific medical complications related to the underlying myopathy. * Children with X-MTM and an unexpected decline in motor skills should be evaluated for a potential abnormality in neuromuscular junction (NMJ) function. Robb et al [2011] identified one individual with mild X-MTM and unexplained decline in motor skills (i.e., lost ambulation) consistent with a disorder of NMJ transmission. On evaluation, this individual was found to have the electrodiagnostic features of NMJ disease (electrodecrement with repetitive stimulation and jitter with single-fiber EMG) but no laboratory evidence to support a co-occurring diagnosis of myasthenia gravis. Subsequent treatment with pyridostigmine resulted in rapid recovery of ambulation. * In addition, and even without signs of unexplained decline, individuals with X-MTM may have underlying abnormalities in NMJ structure and function and thus may benefit from treatment targeted at improving NMJ signaling. A preclinical study in a mouse model of X-MTM identified structural abnormalities in the NMJ and demonstrated significant improvement in muscle fatigue with pyridostigmine treatment [Dowling et al 2012]. Pyridostigmine has been used "off label" by many individuals with X-MTM, with several anecdotal reports of clinical improvement [Author, personal communication]. The drug, however, has not been systematically studied in individuals with X-MTM; a retrospective study aimed at understanding the potential impact of pyridostigmine on clinical symptoms is ongoing. ### Surveillance Appropriate surveillance includes the following: * Annual pulmonary assessment, including pulmonary function testing if able to be performed * Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history * Spinal examination for signs of scoliosis, particularly in late childhood and adolescence * Annual ophthalmologic exams for ophthalmoplegia, ptosis, myopia, and for protective assessment of the effect of impaired eyelid closure * Assessment for dental malocclusion, with referral for orthodontia if indicated Currently, the risk for non-neurologic events including bleeding diatheses and gastrointestinal complications is uncertain. Furthermore, the benefit of screening for such abnormalities has yet to be determined. Potential screening tests may include the following, though these studies have not been found to reliably identify actionable abnormalities: * Annual blood counts [Herman et al 1999] * Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis Note: No advanced screening has been found to be useful for detecting hepatic peliosis prior to the development of clinically significant hemorrhage. ### Agents/Circumstances to Avoid It is generally agreed that neuromuscular paralytics such as succinylcholine should be avoided as part of anesthesia for patients with X-MTM. However, it is important to note that individuals with X-MTM are NOT susceptible to malignant hyperthermia [Litman et al 2018]. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Gene replacement therapy is a promising treatment strategy for X-MTM. AAV-mediated delivery of MTM1 is associated with significant improvement in strength, histopathology, and survival in both murine and canine models of the disease [Childers et al 2014]. A Phase I/II clinical trial (ASPIRO) is currently under way testing the safety and efficacy of this treatment in X-MTM in boys under age four years. Several other strategies have shown promise in preclinical models of X-MTM. Lowering of DNM2, a key disease modifier, using either genetic or antisense oligonucleotide-mediated gene knockdown, resulted in increased strength and prolonged survival in a murine model of X-MTM [Cowling et al 2014, Tasfaout et al 2017]. Similarly, genetic knockdown or chemical inhibition of the lipid kinase PIK3C2B both prevented and reversed the disease course in an X-MTM murine model [Sabha et al 2016]. Additional development of treatments based on these data is under way, with a goal of translation to the clinical arena. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	X-Linked Myotubular Myopathy	c0410203	5,054	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1432/	2021-01-18T20:48:20	{"mesh": ["D020914"], "synonyms": ["Myotubular Myopathy (MTM)", "XLCNM", "X-Linked Centronuclear Myopathy", "XLMTM"]}
Form of acute myeloid leukemia Acute myelomonocytic leukemia SpecialtyHematology, oncology Acute myelomonocytic leukemia (AMML) is a form of acute myeloid leukemia that involves a proliferation of CFU-GM myeloblasts and monoblasts. AMML occurs with a rapid increase amount in white blood cell count and is defined by more than 20% of myeloblast in the bone marrow. It is classified under "M4" in the French-American-British classification (FAB).[1] It is classified under "AML, not otherwise classified" in the WHO classification.[2] Translocations have been observed.[3] Progression from myelodysplastic syndrome has been reported.[4] ## Contents * 1 Signs and Symptoms * 2 Cause * 3 Mechanism * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 Research Directions * 9 See also * 10 References * 11 External links ## Signs and Symptoms[edit] Some patients may experience:[5] * Fatigue * Easy Bruising * Abnormal Bleeding * Anemia * Thrombocytopenia * Dyspnea If the blast count gets too high and clog up blood vessels, some patients may experience:[6] * Slurred Speech * Headache * Confusion * Weakness on one side of the body * Sleepiness ## Cause[edit] The cause has not yet been determined. It has been said that acute myeloid leukemia can occur from a progression of chronic myelomonocytic leukemia type 1 and 2.[7] Normal red blood cells decrease and a rapid proliferation of the abnormal myeloblasts occur.[8] Apoptosis functional ability decreases which causes a back up of myeloblasts in the bone marrow and blood.[8] AML with a translocation or inversion is seen in different chromosomes. Specifically, AML with inversion in chromosome 16 also known as inv(16) is commonly seen in children. ## Mechanism[edit] AMML does not have an exact mechanism. The underlying pathophysiology of acute myeloid leukemia consist of maturational arrest of the bone marrow cell during the early stages of development. A myeloblast is an immature precursor cell that will change into a monocyte, healthy white blood cell. In AML, Myeloblast do not mature but grow and multiply with regulation. The abnormal cells build up in the bone marrow and prevent the development of other healthy cells.[9] This type of arrest is still under study but in most cases, a gene inactivation or activation has occurred due to chromosome translocations or inversion.[8] AML-M4 with an inversion of chromosome 16 is caused by breakage and rearrangement within itself. ## Diagnosis[edit] Criteria for AMML is confirmed if the myleoblasts and promonocytes in the bone marrow are greater than 20 percent. Also can be confirmed if the blood monocyte is 5 x 10 to the ninth power lites or higher.[10] Testing available to diagnosis AML includes a complete blood count which is characterized by blood is taken from the vein in the arm to test for leukemia, a peripheral blood smear, and a bone marrow test. During a peripheral blood smear, a sample of blood is checked for blast cells, white blood cell amount, and changes in shape of blood cells.[11] During a bone marrow test, bone marrow is taken from the hip bone in search of leukemia cells. Aspiration and Biopsy are two types of testing that can be done in order to obtain bone marrow. Further classification can be done for the type of AML from examining the cells shape and size. Generally you'll find immature cells which lack normal features of a cell. ## Treatment[edit] AMML can be treated depending on the degree of disease, age of patient, and current patient's health status. Treatment consists of a multi-drug chemotherapy regimen.[12] Chemotherapy drugs often used to treat AML are Cytarabine and an anthracycline drug. Chemotherapy is broken down into 2 phases: * Induction Therapy: first short and invasive phase of treatment with the goal to the blood of blasts and reduce the number of blasts in the bone marrow back to normal.[13] * Consolidation Therapy: second phase given in cycles that occur after the patient has recovered from induction therapy. Its objective is to kill remaining blasts that can't be seen.[13] In some cases, an allogenic bone marrow transplantation can be performed. If AML with chromosomal abnormalities such as inv(16) are often cured by the standard chemotherapy regimen. ## Prognosis[edit] With AMML being difficult to fully treat, AMML five year survival rate is about 38-72% which typically decrease to 35-60% if there's no bone marrow transplantation performed.[12] Generally older patients over 60 have a poor outlook due to prior health status before the diagnosis and the aggressive chemotherapy regimen used.[14] The aggressive Chemotherapy regimen can lead to long term side effects such as prolonged anemia, leukocytopenia, neutropenia, and thrombocytopenia.[12] The use of anthracycline drugs can cause a decrease in cardiac contractility, both short and long term. Those with AML-M4 inv(16) have a favorable prognosis with a five year overall survival rate of 61%.[12] ## Epidemiology[edit] AML is commonly seen in pediatric patients with higher pediatric incidence in Hispanics and Asians as compared to non-Hispanic Caucasian and African Americans in the USA.[12] Predisposition to AML includes but not limited to:Down syndrome, Klinefelter's syndrome, and Fanconi's anemia.[12] Acquired predisposing factors include:Aplastic anemia, Chemotherapy, prenatal exposure to tobacco, marihuana, and alcohol.[12] ## Research Directions[edit] Considering the disease is rare, not much research is being done specifically for the AML-M4 subtype. Research regarding the production of granulocyte colony stimulating factor (G-CSF) is being conducted to investigate AMML ability to secrete and synthesize G-CSF.[15] Multiple chemotherapy drugs and its effects are being research in comparison to its treatment success in AML not specifically AML-M4. ## See also[edit] * Juvenile myelomonocytic leukemia ## References[edit] 1. ^ "Acute Myeloid Leukemia - Signs and Symptoms". 2. ^ "eMedicine - Acute Myelogenous Leukemia : Article by Karen Seiter". 3. ^ Yamamoto K, Nagata K, Tsurukubo Y, et al. (2002). "Translocation (8;12)(q13;p13) during disease progression in acute myelomonocytic leukemia with t(11;19)(q23;p13.1)". Cancer Genet. Cytogenet. 137 (1): 64–7. doi:10.1016/S0165-4608(02)00555-1. PMID 12377416. 4. ^ Zhang L, Alsabeh R, Mecucci C, et al. (2007). "Rare t(1;11)(q23;p15) in therapy-related myelodysplastic syndrome evolving into acute myelomonocytic leukemia: a case report and review of the literature". Cancer Genet. Cytogenet. 178 (1): 42–8. doi:10.1016/j.cancergencyto.2007.06.012. PMID 17889707. 5. ^ "Acute myelomonocytic leukemia \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2019-11-06. 6. ^ "Signs and Symptoms of Acute Myeloid Leukemia (AML)". www.cancer.org. Retrieved 2019-11-06. 7. ^ "Survival Rates for Chronic Myelomonocytic Leukemia". www.cancer.org. Retrieved 2019-11-06. 8. ^ a b c "Acute Myeloid Leukemia (AML): Practice Essentials, Pathophysiology, Etiology". 2019-10-20. Cite journal requires `\|journal=` (help) 9. ^ "Acute Myeloid Leukemia". NORD (National Organization for Rare Disorders). Retrieved 2019-12-14. 10. ^ "Acute myelomonocytic leukemia (FAB AML M4)". www.pathologyoutlines.com. Retrieved 2019-11-06. 11. ^ "Acute Myeloid Leukemia (AML)". Cleveland Clinic. Retrieved 2019-11-06. 12. ^ a b c d e f g Verschuur, A. C. (2004, May). Acute myelomonocytic leukemia. Retrieved December 13, 2019, from https://www.orpha.net/data/patho/Pro/en/AcuteMyelomonocyticLeukemia-FRenPro8560.pdf. 13. ^ a b "Chemotherapy for Acute Myeloid Leukemia (AML)". www.cancer.org. Retrieved 2019-11-06. 14. ^ "Acute Myeloid Leukemia (AML) Subtypes and Prognostic Factors". www.cancer.org. Retrieved 2019-12-14. 15. ^ Shirafuji, Naoki; Asano, Shigetaka; Kozai, Koji; Takahashi, Satoshi; Matsuda, Satoru; Takaku, Fumimaro; Nagata, Shigekazu (1988-01-01). "Production of granulocyte colony-stimulating factor by acute myelomonocytic leukemia cells". Leukemia Research. 12 (9): 745–750. doi:10.1016/0145-2126(88)90007-0. ISSN 0145-2126. PMID 2461497. ## External links[edit] Classification D * ICD-10-CM: C92.5 * ICD-O: M9867/3 * MeSH: D015479 External resources * Orphanet: 517 * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Acute myelomonocytic leukemia	c0023479	5,055	wikipedia	https://en.wikipedia.org/wiki/Acute_myelomonocytic_leukemia	2021-01-18T19:10:49	{"gard": ["529"], "mesh": ["D015479"], "umls": ["C0023479"], "orphanet": ["517"], "wikidata": ["Q4677943"]}
Idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder characterized by too few platelets in the blood. This is because platelets are being destroyed by the immune system. Symptoms may include bruising, nosebleed or bleeding in the mouth, bleeding into the skin, and abnormally heavy menstruation. With treatment, the chance of remission (a symptom-free period) is good. Rarely, ITP may become a chronic ailment in adults and reappear, even after 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 [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Idiopathic thrombocytopenic purpura	c0398650	5,056	gard	https://rarediseases.info.nih.gov/diseases/5194/idiopathic-thrombocytopenic-purpura	2021-01-18T17:59:49	{"mesh": ["D016553"], "omim": ["188030"], "umls": ["C0043117"], "orphanet": ["3002"], "synonyms": ["ITP", "Autoimmune thrombocytopenic purpura", "Thrombocytopenic purpura autoimmune"]}
A number sign (#) is used with this entry because of evidence that oculoauricular syndrome (OCACS) is caused by homozygous mutation in the HMX1 gene (142992) on chromosome 4p16. Clinical Features Franceschetti and Valerio (1945) described a 3-year-old Swiss girl who had bilateral mild microphthalmia with marked corneal opacities similar to corneal sclerosis and increased intraocular pressure on the left, and whose vision was limited to perception of light. She also had bilateral symmetric abnormalities of the external ear, characterized by a primitive appearing intertragic notch and coloboma of the lobule. Her 6-year-old brother also had eye and ear malformations, including bilateral mild microphthalmia with microcornea, inferonasal coloboma of the iris, anteroinferior polar cataract, and microphakia. The fundus was not visible, and he could recognize objects at 30 cm. His ear findings were identical to his sister's; both sibs had normal hearing. Their mother had a bilateral mild symmetric abnormality of the ear lobes. The authors stated that there were no other anomalies in the patients or other family members. Schorderet et al. (2008) reported a developmental defect affecting the eye and external ear in 3 members of a consanguineous Swiss family, 2 of whom had been described by Franceschetti and Valerio (1945). Their proband, the great-nephew of the previously described sibs, presented at 2 months of age with congenital nystagmus, bilateral microcornea, posterior synechiae, bilateral cataract, colobomatous microphthalmia of the right eye, and anterior segment dysgenesis consisting of incomplete coloboma of the iris, stromal iris cyst of the right eye, and iridocorneal adherences in the left eye. Fundal examination revealed dysplastic macropapillae reminiscent of morning glory syndrome (see 120430), macular hypoplasia, and peripheral inferonasal chorioretinal coloboma. The cataract was rapidly progressive, requiring surgery at 11 months of age. Ophthalmoscopy at 7 years of age revealed the presence of circumferential abnormalities of the retinal pigment epithelium and chorioretinal atrophic lacunae at the equator, and the patient had rod-cone dystrophy on electroretinogram (ERG). His ears showed lobular aplasia, a narrow intertragic notch, and an abnormal bridge connecting the crus of the helix and antihelix, resulting in complete separation between the cymba and the conqua. Audiogram and vestibular function were normal. Reexamination of the great-uncle revealed an inferior chorioretinal coloboma of the right eye and lacunae of the left; the great-aunt's fundus was not visible. Other systemic findings included 3 maxillary dental rows in the great-uncle and spina bifida occulta and moderate dyscrania with flattening of the cranial base and short mandibular rami in the great-aunt. Gillespie et al. (2015) described 2 male cousins, aged 28 months and 14 years, from a consanguineous Asian family with a complex ocular developmental phenotype and malformed ears. Patient I was unable to open his eyes at birth. At 3 days of age, he was noted to have an inability to fix and follow. He had dense bilateral congenital cataracts requiring lensectomy at age 6 weeks, at which time he was found to have bilateral microcornea with high pachymetry measurements. Short axial lengths were observed, but intraocular pressure was normal. He displayed a manifest horizontal nystagmus with right divergent strabismus. Other developmental abnormalities included colobomatous microphthalmia with inferior iris coloboma, localized sclerocornea in the right eye, and posterior embryotoxon in the left. He also had nasolacrimal duct obstruction. ERGs from both eyes of the patient at age 28 months were symmetrical and well developed in the light-adapted state, but dark adaptation revealed attenuated responses, suggestive of early rod dysfunction. Loss of peripheral vision was also noted at that time. At birth, patient II had bilateral congenital cataracts, with a particularly dense central nuclear component, and significant bilateral microcornea. He also had bilateral microphthalmia that was more severe in the right eye. At age 4 months, he had a lensectomy on the left eye, but the right was inoperable due to the severity of the malformation. Other developmental abnormalities included bilateral inferior iris coloboma, left posterior embryotoxon with anterior synechiae, and sclerocornea of the right eye. His vision began to deteriorate at age 4 years; by age 14 years, his ERG results showed grossly attenuated light- and dark-adapted responses, consistent with a severe generalized retinal dystrophy. Auricular findings in both patients were malformed, low-set pinna with crumpled helix, narrow external acoustic meatus, and deficient lobule. The father of 1 patient had minor external ear abnormalities and marked bilateral posterior embryotoxon. Mapping Schorderet et al. (2008) performed homozygosity mapping in a consanguineous Swiss family with an oculoauricular syndrome and identified a unique homozygous region on chromosome 4p16 flanked by D4S2935 and D4S391, obtaining a maximum lod score of 3.37 (theta = 0) at D4S2906. SNP analysis reduced the homozygous interval to a less than 10-Mb region between D4S2935 and D4S419. By autozygosity mapping in a consanguineous Asian family in which 2 cousins had an oculoauricular syndrome, Gillespie et al. (2015) identified genomic regions identical by descent in the patients on chromosome 17 and chromosome 4; the region on chromosome 4 included the HMX1 gene. Molecular Genetics In 3 affected members of a consanguineous Swiss family with an oculoauricular syndrome mapping to chromosome 4p16, Schorderet et al. (2008) identified homozygosity for a 26-bp deletion in the HMX1 gene (142992.0001). The parents of the proband were heterozygous for the deletion, which was not found in more than 250 ethnically matched controls or in more than 500 patients with various eye diseases. By direct sequencing of the HMX1 gene in 2 male cousins from a consanguineous Asian family with oculoauricular syndrome, Gillespie et al. (2015) identified homozygosity for a missense mutation (Q217P; 142992.0002) at a highly conserved residue. The parents of 1 of the cousins were heterozygous for the mutation, but DNA from the other set of parents was not available. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Lobular aplasia \- Narrow intertragic notch \- Abnormal bridge connecting the crus of the helix and antihelix Eyes \- Nystagmus \- Microphthalmia \- Microcornea \- Cataract \- Coloboma \- Chorioretinal atrophic lacunae \- Morning glory-like dysplastic macropapillae \- Macular hypoplasia \- Microphakia \- Rod-cone dystrophy \- Sclerocornea \- Increased intraocular pressure MOLECULAR BASIS \- Caused by mutation in the homeobox (H6 family) 1 gene (HMX1, 142992.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	OCULOAURICULAR SYNDROME	c2677500	5,057	omim	https://www.omim.org/entry/612109	2019-09-22T16:02:19	{"doid": ["0060482"], "mesh": ["C567416"], "omim": ["612109"], "orphanet": ["157962"], "synonyms": ["SCHORDERET-MUNIER-FRANCESCHETTI SYNDROME", "Alternative titles", "MICROPHTHALMIA, MICROCORNEA, ANTERIOR SEGMENT DYSGENESIS, CATARACT, OCULAR COLOBOMA, RETINAL PIGMENT EPITHELIUM ABNORMALITIES, ROD-CONE DYSTROPHY, AND ANOMALIES OF THE EXTERNAL EAR"]}
A number sign (#) is used with this entry because SED congenita is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13. Description Spondyloepiphyseal dysplasia congenita is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990). Clinical Features Spranger and Wiedemann (1966, 1966) suggested the designation spondyloepiphyseal dysplasia congenita for a disorder affecting particularly the vertebrae and juxtatruncal epiphyses. Four of 6 patients had progressive myopia. Three persons (mother and 2 sons) were affected in 1 family. They collected 14 cases from the literature. Bach et al. (1967) reported an isolated case. Platyspondyly, short limbs, and cleft palate were evident at birth. Other malformations included myopia, hypoplasia of abdominal musculature, abdominal and inguinal hernias, and mental retardation. Detachment of the retina occurs in some patients even without significant myopia. Roaf et al. (1967) reported 4 sporadic cases. Severe myopia in particular was a serious problem in the cases reported by Fraser et al. (1969). Mother and 2 children were affected in 1 of their families. Spranger and Langer (1970) reported 20 cases. In the affected newborn, x-rays showed lack of ossification of the os pubis, distal femoral and proximal tibial epiphyses, talus and calcaneus, and flattening of vertebral bodies. Yang et al. (1980) demonstrated PAS-positive cytoplasmic inclusions in chondrocytes after diastase digestion to eliminate glycogen. Ultrastructural examination showed the inclusions to be accumulations of fine, granular material in dilated cisterns of rough endoplasmic reticulum. Inclusions have been found also in achondrogenesis (200600), one type of short rib-polydactyly syndrome (263520), one form of pseudoachondroplastic dysplasia (177170), and Kniest syndrome (156550). The presence of type II ('cartilage') collagen in the vitreous of the eye pointed to mutation in the COL2A1 gene as the possible basis of SED congenita. Furthermore, in connection with the deafness present in some cases (Roaf et al., 1967), the experiments of Yoo et al. (1983), demonstrating induction of sensorineural hearing loss and vestibular dysfunction in rats by a mechanism of autoimmunity to type II collagen, were noteworthy. Bilateral progressive sensorineural hearing loss has been thought to have an autoimmune etiology in some patients. Helfgott et al. (1991) reported that the presence of antibodies to type II collagen might be predictive of corticosteroid responsiveness in such patients. Sutjita et al. (1992) reviewed the difficulties with the interpretation of studies like that of Helfgott et al. (1991). In a series of 17 patients with SED congenita, Wynne-Davies and Hall (1982) delineated 2 clinical types. There was wide clinical and radiologic variability in each with overlap between them, but 12 had very short stature and grossly disorganized hips with severe coxa vara, whereas the remaining 5 patients were less severely affected with height only a little below the third percentile and only mild coxa vara. Both groups could be diagnosed at birth but not distinguished until after the age of 3 or 4 years when the hip and height differences became evident. Both forms may be autosomal dominant; all cases were sporadic except for a concordant twin-pair, presumably monozygotic. Hamidi-Toosi and Maumenee (1982) studied the ocular features of 18 cases. In 7 there was nonprogressive myopia of 5.00 or more diopters. In 6 of these 7, vitreoretinal degeneration was found and vitreous syneresis was present in all patients. Retinal detachment was found in none, contrary to the reports of a frequency as high as 50%. In an infant with SED congenita who died at age 5 months after an anoxic episode, Murray et al. (1985) found in the eye that the collagen of the vitreous had a smaller-than-normal fiber diameter. Furthermore, the vitreous had central liquefaction, was detached in multiple areas, and was exerting traction on the retina. The internal limiting membrane of the retina was thin throughout and displayed many areas of discontinuity. The findings were considered consistent with a defect of type II collagen and with an increased risk of retinal detachment in this disorder. Reconciliation with the findings of Hamidi-Toosi and Maumenee (1982)--no retinal detachment in 18 cases--was difficult. Murray and Rimoin (1985) found abnormal mobility of type II collagen cyanogen bromide peptides in cases of SED and SEMD, including cases of SED congenita and SEMD Strudwick (184250). They suggested that the abnormal mobility of multiple peptides may be the consequence of excessive posttranslational modification which in turn results from impediments in formation of the collagen helix by a variety of defects. Murray and Rimoin (1988) demonstrated abnormal type II collagen in SED congenita. Givon et al. (1999) described a 35-year-old mother and her 6-year-old daughter with SED congenita and a consistent finding of pseudarthrosis-like lesions in the middiaphysis of both humeri. The mother had minimal symptoms that resolved spontaneously and the child had no symptoms related to these lesions. In the mother the lesion had undergone complete remodeling. This finding, which Givon et al. (1999) concluded is a manifestation of SED congenita, resolves through bone remodeling with time. Terhal et al. (2015) reviewed the clinical and radiologic features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphseal dysplasia congenita or a related phenotype. Inheritance Fraser and Friedmann (1967) observed dominant inheritance (his case M 13). Harrod et al. (1984) evaluated 2 unrelated infants for short stature at age 14 and 27 months, respectively, and found clinical and radiographic features consistent with SED congenita. Both pairs of parents were healthy and not consanguineous. Both families were counseled for a new autosomal dominant mutation, but both had a second affected child. The parents in both families were in their twenties. Is this experience indicative of an autosomal recessive genocopy or is it explained by some other mechanism such as gonadal mosaicism? Spranger and Langer (1974) had noted the possible existence of a recessive form of SED congenita. Lee et al. (1989) and Tiller et al. (1989, 1990) confirmed autosomal dominant inheritance of SED congenita. Mapping In a 4-generation family, Goldberg et al. (1989) and Anderson et al. (1990) confirmed absolute linkage of SEDC and COL2A1 on chromosome 12q. Molecular Genetics In a sporadic case of SED congenita, Lumadue et al. (1988) found changes in the COL2A1 gene consistent with deletion or insertion 5-prime to exon 39. Lee et al. (1989) identified an abnormal restriction pattern in the COL2A1 gene in an affected member of a family with SED congenita. Analysis of selected genomic fragments, amplified by the polymerase chain reaction (PCR), demonstrated that all affected family members carried the same single-exon deletion in heterozygous state (120140.0001). As a consequence of the mutation, nearly 90% of the assembled type II collagen homotrimers might be expected to contain one or more procollagen subunits harboring an interstitial deletion of 36 amino acids in the triple helical domain. In a new mutation case of SED congenita, Tiller et al. (1989, 1990) found evidence of a 45-bp tandem duplication in exon 48 of the COL2A1 gene (120140.0004), adding 5 Gly-X-Y triplets to the COOH terminus of the gene. In a 4-year-old girl with clinical and radiographic features typical of SED congenita, Chan et al. (1993) identified heterozygosity for a missense mutation (R789C; 120140.0014) in the COL2A1 gene. Gunthard et al. (1995) described the case of an infant thought to represent double heterozygosity for SEDC and achondroplasia (100800). The mother had the first condition, probably due to a new mutation, and the father had achondroplasia also due to a new mutation. Ultrasound examinations during gestation showed a normal femur length up to the twenty-fourth week. At 28 weeks of gestation, the femur length was 3.8 cm (normal range 4.0 to 6.5 cm). The child was delivered by elective cesarean section at 37 weeks. The newborn showed large head, short neck, bell-shaped thorax, protruding abdomen, and short limbs. There was a prominent forehead with hypoplastic midface, depressed nasal bridge, and cleft palate. 2D-echocardiography showed signs of pulmonary hypertension with right ventricular hypertrophy. The child died at the age of 1 year with pneumonia which led to right heart failure. Radiologic signs were in part those of achondroplasia and in part those of SEDC. The absence of ossification of the epiphyses at the knees and the short tubular bones were signs of both. A decrease in the interpedicular distance from the upper to lower lumbar spine, usually appearing at 6 months of age in achondroplasia, was not seen. Ischial notch hypoplasia and trident hand deformity were less pronounced than usually seen in achondroplasia. The hypoplasia of the dens was not as pronounced as usually seen in SEDC. Lung hypoplasia was also a major complication in the ACH/SEDC double heterozygote reported by Young et al. (1992). Unger et al. (2001) reported a child with double heterozygosity for pseudoachondroplasia (177170) and spondyloepiphyseal dysplasia congenita. The child inherited pseudoachondroplasia from his mother and spondyloepiphyseal dysplasia congenita from his father. Mutations in the COMP gene (600310.0014) and the COL2A1 gene (120140.0035) were confirmed by molecular analysis. The child had clinical and radiographic findings that were more severe than those in either disorder alone. Genotype/Phenotype Correlations Murray et al. (1989) found that almost all the patients they studied with spondyloepiphyseal dysplasias or spondyloepimetaphyseal dysplasias showed abnormally slow electrophoretic mobility of type II collagen. Peptides near the amino terminus were almost always altered, while the mobility of peptides close to the carboxyl terminus were normal in all but the severely affected cases. Amino acid analysis indicated that the abnormal collagens had a higher ratio of hydroxylysine to lysine than did control collagen, suggesting that overmodification may be involved in the altered mobility. The results were considered consistent with a defect in the collagen helix that resulted in overmodification of the molecule from that point toward the amino terminus. Murray et al. (1989) proposed that some forms of SED and SEMD are associated with abnormalities in type II collagen that result in delayed helix formation and consequent overmodification of the collagen. Cases of SED fit into a continuous spectrum of clinical severity that correlated positively with both the extent of overmodification and the proximity of the defect to the carboxyl terminus. Animal Model Donahue et al. (2003) identified a naturally occurring arg1147-to-cys mutation in exon 48 of the Col2a1 gene in mice. The mutation was considered analogous to the arg789-to-cys mutation in the COL2A1 gene (R789C; 120140.0016), which had been described in 2 unrelated patients with SEDC (Chan et al. (1993, 1995)). Homozygous Sedc mice were identified at birth by their small size and short trunk. Adults had shortened noses, dysplastic vertebrae, femora, and tibias, plus retinoschisis and hearing loss. INHERITANCE \- Autosomal dominant GROWTH Height \- Dwarfism, short-trunk, identifiable at birth \- Final adult height, 84-128cm Other \- Specific growth curves are available HEAD & NECK Face \- Flat face \- Malar hypoplasia Eyes \- Myopia \- Retinal detachment \- Vitreoretinal degeneration Mouth \- Cleft palate RESPIRATORY Lung \- Respiratory distress \- Restrictive lung disease CHEST External Features \- Barrel chest Ribs Sternum Clavicles & Scapulae \- Pectus carinatum SKELETAL Spine \- Platyspondyly \- Short neck \- Odontoid hypoplasia \- Kyphosis \- Scoliosis \- Lumbar lordosis \- Ovoid vertebral bodies Pelvis \- Dislocation of hip \- Coxa vara \- Absent pubic ossification in infancy Limbs \- Flattened epiphyses \- Diminished joint mobility at elbows, knees, and hips Feet \- Talipes equinovarus \- Absent talus and calcaneal ossification in infancy NEUROLOGIC Central Nervous System \- Cervical myelopathy \- Hypotonia MISCELLANEOUS \- Gonadal mosaicism reported \- Waddling gait MOLECULAR BASIS \- Caused by mutation in the collagen II, alpha-1 polypeptide gene (COL2A1, 120140.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SPONDYLOEPIPHYSEAL DYSPLASIA CONGENITA	c2745959	5,058	omim	https://www.omim.org/entry/183900	2019-09-22T16:34:25	{"doid": ["14789"], "mesh": ["C535788"], "omim": ["183900"], "icd-10": ["Q77.7"], "orphanet": ["94068"], "synonyms": ["Alternative titles", "SED CONGENITA", "SPONDYLOEPIPHYSEAL DYSPLASIA, CONGENITAL TYPE"], "genereviews": ["NBK540447"]}
A number sign (#) is used with this entry because of evidence that congenital hydrocephalus-3 with brain anomalies (HYC3) is caused by homozygous mutation in the WDR81 gene (614218) on chromosome 17p13. For a discussion of genetic heterogeneity of congenital hydrocephalus, see 236600. Clinical Features Shaheen et al. (2017) reported 2 unrelated consanguineous Saudi families (families 13 and 26) in which at least 5 patients, including a pair of twins, had hydrocephalus apparent in utero. In the first family, the twin gestation was terminated at 18 weeks based on prenatal findings of severe hydrocephalus, a second conception showed significantly enlarged ventricles and hypoplastic cerebellum, and a third pregnancy resulted in delivery of a similarly affected fetus at age 28 weeks due to preeclampsia; this infant died 2 hours after birth. In the second family, the mother had a history of stillbirth associated with polyhydramnios, hydranencephaly, and absent cerebellum. A subsequent pregnancy resulted in delivery of a male infant with holoprosencephaly, absent cerebellum, Dandy-Walker malformation, hydrocephaly, brain atrophy, and dysmorphic facial features. Inheritance The transmission pattern of HYC3 in the families reported by Shaheen et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 unrelated patients, each conceived of consanguineous Saudi parents (families 13 and 26), with congenital hydrocephalus, Shaheen et al. (2017) identified homozygous mutations in the WDR81 gene (Q1096X, 614218.0003 and G282E, 614218.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Segregation of the disorder with the genotype was demonstrated for 1 family. Both families had histories of additional similarly affected pregnancies, but DNA from those patients was not available. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect. The patients were part of a large genetic study of 27 consanguineous Saudi families with congenital hydrocephalus. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Macrocephaly Face \- Dysmorphic facial features NEUROLOGIC Central Nervous System \- Hydrocephalus \- Enlarged ventricles \- Hydranencephaly \- Hypoplastic or absent cerebellum \- Brain atrophy \- Holoprosencephaly \- Dandy-Walker malformation PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios MISCELLANEOUS \- Onset in utero \- Most patient die in utero or shortly after birth \- Two consanguineous Saudi families have been reported (last curated May 2018) MOLECULAR BASIS \- Caused by mutation in the WD repeat-containing protein 81 gene (WDR81, 614218.0003 ) ▲ 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 [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	HYDROCEPHALUS, CONGENITAL, 3, WITH BRAIN ANOMALIES	None	5,059	omim	https://www.omim.org/entry/617967	2019-09-22T15:44:12	{"omim": ["617967"], "synonyms": ["Alternative titles", "HYDROCEPHALUS, NONSYNDROMIC, AUTOSOMAL RECESSIVE 3, FORMERLY"]}
A rare bacterial infectious disease most prominently characterized by a red, sandpaper-like rash, a strawberry-like tongue, and a flushed face with perioral pallor. Other clinical symptoms include pharyngitis, tonsillitis, fever, headaches, and swollen lymph nodes. Potential complications are sinusitis, pneumonia, rheumatic fever, glomerulonephritis, and endocarditis, among others. The disease is caused by infection with toxin producing strains of Streptococcus pyogenes and can affect people of any age, although it is most common in children. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Staphylococcal scarlet fever	None	5,060	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=36235	2021-01-23T16:56:39	{"icd-10": ["A38"]}
Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis. ## Epidemiology HS is the most common cause of inherited chronic hemolysis in North America with a prevalence of 1/5,000 births. However, osmotic fragility studies suggest the existence of extremely mild or subclinical forms, raising the prevalence to 1/2,000 in Northern Europe. ## Clinical description Jaundice is usually the first clinical manifestation in newborns (50% of cases) with anemia developing a few days after birth and requiring exchange transfusion (~10%) and transfusion support (~35%). Splenomegaly is frequently observed. Age of onset and severity vary considerably depending on the degree of anemia and hemolysis. Four HS categories have been identified: trait (normal hemoglobin (Hb), reticulocytes < 3%, bilirubin < 17micromoles/L), mild (Hb 11-15 g/dL, reticulocytes 3-6%, bilirubin 17-34 micromoles/L), moderate (Hb 8-12 g/dL, reticulocytes > 6%, bilirubin > 34 micromoles/L), and severe (Hb < 8 g/dL, reticulocytes > 10%, bilirubin > 51 micromoles/L). Aplastic crisis, often associated with viral infections, is observed in 10-15% of cases, particularly pediatric. Rare complications include poor growth, skin ulceration, chronic dermatitis, high output heart failure, and secondary iron overload. ## Etiology HS is caused by mutations in one of the following genes: SPTA1 (1q21), SPTB (14q23.3), ANK1 (8p11.21), SLC4A1 ( 17q21.31) and EPB42 (15q15-q21), that encode the red blood cell (RBC) membrane proteins erythrocytic 1 spectrin alpha chain, erythrocytic 1 spectrin beta chain, ankyrin-1, band 3 anion transport protein, and erythrocyte membrane protein band 4.2, respectively. Defects in these proteins lead to a loss in RBC membrane cohesion and membrane surface area, resulting in erythrocyte sphering, decreased deformability and premature destruction in the spleen. ## Diagnostic methods Diagnosis is based on clinical and family history, physical examination and laboratory test results. Red cell morphology, osmotic resistance, hypertonic cryohemolysis test, eosin-5-maleimide binding in flow cytometry, sodium dodecyl sulfate-poly acrylamide gel electrophoresis and ektacytometry are all used to diagnose HS. Mean cellular Hb concentration is usually above normal range (~35 g/dl), reticulocyte count normal or increased, and indirect bilirubin moderately increased. Molecular genetic testing is not routinely used to confirm diagnosis. ## Differential diagnosis Differential diagnoses include hereditary elliptocytosis, hereditary stomatocytosis, Southeast Asian ovalocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, autoimmune hemolytic anemia, and alpha-thalassemia (see these terms). ## Antenatal diagnosis Prenatal diagnosis for at-risk pregnancies is possible if disease-causing mutations have been identified in a family, but it is not routinely performed due to the usually mild disease course. ## Genetic counseling HS is inherited autosomal dominantly in 75% of cases. Autosomal recessive inheritance and de novo mutations have also been reported, but are less common. Genetic counseling is recommended in families with a history of HS. ## Management and treatment Treatment involves management of jaundice (phototherapy and even exchange blood transfusion to prevent hyperbilirubinemic encephalopathy) and RBC transfusions in case of severe, symptomatic anemia. Splenectomy usually results in disappearance of anemia and clear amelioration of hemolytic markers. It is not indicated in patients with HS trait, whereas it is usually necessary in severe cases, albeit delayed if possible until the age of 6 years. For intermediate categories the indication is less clear, being useful in moderate cases before puberty. Laparoscopic splenectomy is preferred if performed by experienced surgeons. A combined splenectomy and cholecystectomy may be beneficial in patients with gallstones. Pre and post-splenectomy vaccine prophylaxis and prophylactic antibiotics are recommended in order to prevent infections. Folate supplement is recommended particularly after infectious events. Serum ferritin levels should be checked annually. ## Prognosis The prognosis is variable and depends on the severity of the disease and any associated complications. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Hereditary spherocytosis	c0037889	5,061	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=822	2021-01-23T17:48:54	{"gard": ["6639"], "mesh": ["C536356", "D013103"], "omim": ["182900", "270970", "612653", "612690", "616649"], "umls": ["C0037889", "C0221409"], "icd-10": ["D58.0"], "synonyms": ["Minkowski-Chauffard disease"]}
STS-41 crewmembers conduct Detailed Supplementary Objective (DSO) 472, Intraocular Pressure on the middeck of Discovery, Orbiter Vehicle (OV) 103. Mission Specialist (MS) William M. Shepherd rests his head on the stowed treadmill while Pilot Robert D. Cabana, holding Shepherd's eye open, prepares to measure Shepherd's intraocular pressure using a tonometer (in his right hand). Spaceflight-induced visual impairment[1] is hypothesized to be a result of increased intracranial pressure. The study of visual changes and intracranial pressure (ICP) in astronauts on long-duration flights is a relatively recent topic of interest to Space Medicine professionals. Although reported signs and symptoms have not appeared to be severe enough to cause blindness in the near term, long term consequences of chronically elevated intracranial pressure is unknown.[2] NASA has reported that fifteen long-duration male astronauts (45–55 years of age) have experienced confirmed visual and anatomical changes during or after long-duration flights.[3] Optic disc edema, globe flattening, choroidal folds, hyperopic shifts and an increased intracranial pressure have been documented in these astronauts. Some individuals experienced transient changes post-flight while others have reported persistent changes with varying degrees of severity.[4] Although the exact cause is not known, it is suspected that microgravity-induced cephalad fluid shift and comparable physiological changes play a significant role in these changes.[4] Other contributing factors may include pockets of increased CO2 and an increase in sodium intake. It seems unlikely that resistive or aerobic exercise are contributing factors, but they may be potential countermeasures to reduce intraocular pressure (IOP) or intracranial pressure (ICP) in-flight.[3] ## Contents * 1 Causes and current studies * 1.1 CO2 * 1.2 Sodium intake * 1.3 Exercise * 1.4 Biomarkers * 1.5 One-carbon metabolism (homocysteine) * 1.6 Space obstructive syndrome * 2 Current ICP and IOP measurement * 2.1 ICP measurement * 2.1.1 Non-invasive ICP measurement * 2.2 IOP measurement * 3 Existing long-duration flight occurrences * 4 Case definition and clinical practice guidelines * 4.1 Classes * 4.2 Stages * 5 Risk factors and recommendations * 5.1 Immediate actions * 5.2 Near and long-term actions * 6 Benefits to Earth * 7 See also * 8 References * 9 Further reading ## Causes and current studies[edit] Although a definitive cause (or set of causes) for the symptoms outlined in the Existing Long-Duration Flight Occurrences section is unknown, it is thought that venous congestion in the brain brought about by cephalad-fluid shifts may be a unifying pathologic mechanism.[5] Additionally, a recent study reports changes in CSF hydrodynamics and increased diffusivity around the optic nerve under simulated microgravity conditions which may contribute to ocular changes in spaceflight.[6] As part of the effort to elucidate the cause(s), NASA has initiated an enhanced occupational monitoring program for all mission astronauts with special attention to signs and symptoms related to ICP. Similar findings have been reported among Russian Cosmonauts who flew long-duration missions on MIR. The findings were published by Mayasnikov and Stepanova in 2008.[7] Animal research from the Russian Bion-M1 mission indicates duress of the cerebral arteries may induce reduced blood flow, thereby contributing to impaired vision.[8] On 2 November 2017, scientists reported that significant changes in the position and structure of the brain have been found in astronauts who have taken trips in space, based on MRI studies. Astronauts who took longer space trips were associated with greater brain changes.[9][10] ### CO2[edit] Carbon dioxide (CO2) is a natural product of metabolism. People typically exhale around 200mL of CO2 per minute at rest and over 4.0 L at peak exercise levels.[11] In a closed environment, CO2 levels can quickly rise and can be expected to a certain degree in an environment such as the ISS. Nominal CO2 concentrations on Earth are approximately 0.23 mmHg [12] while nominal CO2 levels aboard the ISS are up to 20 times that at 2.3 to 5.3 mmHg. Those astronauts who experienced VIIP symptoms were not exposed to CO2 levels in excess of 5 mmHg.[13][14] Ventilation and heart rate increase as CO2 rise. Hypercapnia also stimulates vasodilation of cerebral blood vessels, increased cerebral blood flow and elevated ICP presumably leading to headache, visual disturbance and other central nervous system (CNS) symptoms. CO2 is a known potent vasodilator and an increase in cerebral perfusion pressure will increase the CSF fluid production by about 4%.[15] Since air movement is reduced in microgravity, local pockets of increased CO2 concentrations may form. Without proper ventilation, CO2 concentrations ppCO2 could rise above 9mmHg within 10 minutes around a sleeping astronaut's mouth and chin.[16] More data is needed to fully understand the individual and environmental factors that contribute to CO2-related symptoms in microgravity. ### Sodium intake[edit] A link between increased ICP and altered sodium and water retention was suggested by a report in which 77% of IIH patients had evidence of peripheral edema and 80% with orthostatic retention of sodium and water.[17] Impaired saline and water load excretions were noted in the upright position in IIH patients with orthostatic edema compared to lean and obese controls without IIH. However, the precise mechanisms linking orthostatic changes to IIH were not defined, and many IH patients do not have these sodium and water abnormalities. Astronauts are well known to have orthostatic intolerance upon reentry to gravity after long-duration spaceflight, and the dietary sodium on orbit is also known to be in excess of 5 grams per day in some cases. The Majority of the NASA cases did have high dietary sodium during their increment. The ISS program is working to decrease in-flight dietary sodium intake to less than 3 grams per day.[17] Prepackaged foods for the International Space Station were originally high in sodium at 5300 mg/d. This amount has now been substantially reduced to 3000 mg/d as a result of NASA reformulation of over ninety foods as a conscious effort to reduce astronaut sodium intake.[18] ### Exercise[edit] While exercise is used to maintain muscle, bone and cardiac health during spaceflight, its effects on ICP and IOP have yet to be determined. The effects of resistive exercise on the development of ICP remains controversial. An early investigation showed that the brief intrathoractic pressure increase during a Valsalva maneuver resulted in an associated rise in ICP.[19] Two other investigations using transcranial Doppler ultrasound techniques showed that resistive exercise without a Valsalva maneuver resulted in no change in peak systolic pressure or ICP.[20][21][22] The effects of resistive exercise in IOP are less controversial. Several different studies have shown a significant increase in IOP during or immediately after resistive exercise.[23][24][25][26][27][28][29] There is much more information available regarding aerobic exercise and ICP. The only known study to examine ICP during aerobic exercise by invasive means showed that ICP decreased in patients with intracranial hypertension and those with normal ICP.[30] They suggested that because aerobic exercise is generally done without Valsalva maneuvers, it is unlikely that ICP will increase during exercise. Other studies show global brain blood flow increases 20–30% during the transition from rest to moderate exercise.[31][32] More recent work has shown that an increase in exercise intensity up to 60% VO2max results in an increase in CBF, after which CBF decreases towards (and sometimes below) baseline values with increasing exercise intensity.[33][34][35][36] ### Biomarkers[edit] Several biomarkers may be used for early VIIP Syndrome detection. The following biomarkers were suggested as potential candidates by the 2010 Visual Impairment Summit:[37] * albumin * aquaporin * atrial naturetic peptide * CRP/inflammation markers * immunoglobin G index * insulin-like growth factors * myelin basic protein * oligoclonal bands * platelet count * S-100 * somatostatin * tet-transactivator (TTA) * vasopressin Also, gene expression profiling, epigenetic modifications, CO2 retaining variants, single-nucleotide polymorphisms and copy number variants should be expanded in order to better characterize the individual susceptibility to develop the VIIP syndrome. As the etiology of the symptoms is more clearly defined, the appropriate biomarkers will be evaluated. ### One-carbon metabolism (homocysteine)[edit] While the common theories regarding vision issues during flight focus on cardiovascular factors (fluid shift, intracranial hypertension, CO2 exposure, etc.), the difficulty comes in trying to explain how on any given mission, breathing the same air and exposed to the same microgravity, why some crewmembers have vision issues while others do not. Data identified as part of an ongoing nutrition experiment found biochemical evidence that the folate-dependent one-carbon metabolic pathway may be altered in those individuals who have vision issues. These data have been published[38] and summarized by the ISS Program,[39] and described in a journal sponsored pubcast.[40] In brief: serum concentrations of metabolites of the folate, vitamin B-12 dependent one carbon metabolism pathway, specifically, homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid were all significantly (P<0.001) higher (25–45%) in astronauts with ophthalmic changes than in those without such changes. These differences existed before, during, and after flight. Serum folate tended to be lower (P=0.06) in individuals with ophthalmic changes. Preflight serum concentrations of cystathionine and 2-methylcitric acid, and mean in-flight serum folate, were significantly (P<0.05) correlated with changes in refraction (postflight relative to preflight). Thus, data from the Nutrition SMO 016E provide evidence for an alternative hypothesis: that individuals with alterations in this metabolic pathway may be predisposed to anatomic and/or physiologic changes that render them susceptible to ophthalmologic damage during space flight. A follow-up project has been initiated (the "One Carbon" study) to follow up and clarify these preliminary findings. ### Space obstructive syndrome[edit] An anatomic cause of the microgravity related intracranial hypertension and visual disturbances has been proposed and is termed Space Obstructive Syndrome or SOS. This hypothesis has the possibility of linking the various symptoms and signs together through a common mechanism in a cascade phenomenon, and explaining the findings in one individual and not another due to specific anatomic variations in the structural placement of the internal jugular vein. This hypothesis was presented in May 2011 at the annual meeting of the Aerospace Medicine Association in Anchorage, Alaska, and was published in January, 2012.[41] In 1G on earth, the main outflow of blood from the head is due to gravity, rather than a pumping or vacuum mechanism. In a standing position, the main outflow from the head is through the vertebral venous system because the internal jugular veins, located primarily between the carotid artery and the sternocleidomastoid muscle are partially or completely occluded due to the pressure from these structures, and in a supine position, the main outflow is through the internal jugular veins as they have fallen laterally due to the weight of the contained blood, are no longer compressed and have greatly expanded in diameter, but the smaller vertebral system has lost the gravitational force for blood outflow. In microgravity, there is no gravity to pull the internal jugular veins out from the zone of compression (Wiener classification Zone I), and there is also no gravitational force to pull blood through the vertebral venous system. In microgravity, the cranial venous system has been put into minimal outflow and maximal obstruction. This then causes a cascade of cranial venous hypertension, which decreases CSF resorption from the arachnoid granulations, leading to intracranial hypertension and papilledema. The venous hypertension also contributes to the head swelling seen in photos of astronauts and the nasal and sinus congestion along with headache noted by many. There is also subsequent venous hypertension in the venous system of the eye which may contribute to the findings noted on ophthalmic exam and contributing to the visual disturbances noted. The astronauts afflicted with long term visual changes and prolonged intracranial hypertension have all been male, and SOS may explain this because in men, the sternocleidomastoid muscle is typically thicker than in women and may contribute to more compression. The reason that SOS does not occur in all individuals may be related to anatomic variations in the internal jugular vein. Ultrasound study has shown that in some individuals, the internal jugular vein is located in a more lateral position to Zone I compression, and therefore not as much compression will occur, allowing continued blood flow. ## Current ICP and IOP measurement[edit] ### ICP measurement[edit] Intracranial pressure (ICP) needs to be directly measured before and after long duration flights to determine if microgravity causes the increased ICP. On the ground, lumbar puncture is the standard method of measuring cerebral spinal fluid pressure and ICP,[4][42] but this carries additional risk in-flight.[2] NASA is determining how to correlate ground-based MRI with inflight ultrasound[2] and other methods of measuring ICP in space is currently being investigated.[42] To date, NASA has measured intraocular pressure (IOP), visual acuity, cycloplegic refraction, Optical Coherence Tomography (OCT) and A-scan axial length changes in the eye before and after spaceflight.[43] #### Non-invasive ICP measurement[edit] There are different approaches to non-invasive intracranial pressure measurement, which include ultrasound "time-of-flight" techniques, transcranial Doppler, methods based on acoustic properties of the cranial bones, EEG, MRI, tympanic membrane displacement, oto-acoustic emission, ophthalmodynamometry, ultrasound measurements of optic nerve sheath diameter, and Two-Depth Transorbital Doppler. Most of the approaches are "correlation based". Such approaches can not measure an absolute ICP value in mmHg or other pressure units because of the need for individual patient specific calibration. Calibration needs non-invasive "gold standard" ICP meter which does not exists. Non-invasive absolute intracranial pressure value meter, based on ultrasonic Two-Depth Transorbital Doppler technology, has been shown to be accurate and precise in clinical settings and prospective clinical studies. Analysis of the 171 simultaneous paired recordings of non-invasive ICP and the "gold standard" invasive CSF pressure on 110 neurological patients and TBI patients showed good accuracy for the non-invasive method as indicated by the low mean systematic error (0.12 mmHg; confidence level (CL) = 0.98). The method also showed high precision as indicated by the low standard deviation (SD) of the random errors (SD = 2.19 mmHg; CL = 0.98).[44] This measurement method and technique (the only non-invasive ICP measurement technique which already received EU CE Mark approval) eliminates the main limiting problem of all other non-successful "correlation based" approaches to non-invasive ICP absolute value measurement – the need of calibration to the individual patient.[45] ### IOP measurement[edit] Intraocular pressure (IOP) is determined by the production, circulation and drainage of ocular aqueous humor and is described by the equation: I O P = F C + P V {\displaystyle IOP={\frac {F}{C}}+PV} Where: F = aqueous fluid formation rate C = aqueous outflow rate PV = episcleral venous pressure In general populations IOP ranges between and 20 mmHg with an average of 15.5 mmHg, aqueous flow averages 2.9 μL/min in young healthy adults and 2.2 μL/min in octogenarians, and episcleral venous pressure ranges from 7 to 14 mmHg with 9 to 10 mmHg being typical. ## Existing long-duration flight occurrences[edit] The first U.S. case of visual changes observed on orbit was reported by a long-duration astronaut that noticed a marked decrease in near-visual acuity throughout his mission on board the ISS, but at no time reported headaches, transient visual obscurations, pulsatile tinnitus or diplopia (double vision). His postflight fundus examination (Figure 1) revealed choroidal folds below the optic disc and a single cotton-wool spot in the inferior arcade of the right eye. The acquired choroidal folds gradually improved, but were still present 3 year postflight. The left eye examination was normal. There was no documented evidence of optic-disc edema in either eye. Brain MRI, lumbar puncture, and OCT were not performed preflight or postflight on this astronaut.[3] Figure 1:Fundus examination of the first case of visual changes from long-duration spaceflight. Fundus examination revealed choroidal folds inferior to the optic disc and a single cotton-wool spot in the inferior arcade of the right eye (white arrow). The second case of visual changes during long-duration spaceflight on board the ISS was reported approximately 3 months after launch when the astronaut noticed that he could now only see Earth clearly while looking through his reading glasses. The change continued for the remainder of the mission without noticeable improvement or progression. He did not complain of transient visual obscurations, headaches, diplopia, pulsatile tinnitus or visual changes during eye movement. In the months since landing, he has noticed a gradual, but incomplete, improvement in vision.[3] Figure 2: Fundus examination of second case of visual changes from long-duration spaceflight. Fundoscopic images showing choroidal folds (white arrows) in the papillomacular bundle area in the right eye and left eye and a cotton-wool spot (bottom arrow) at the inferior arcade in the left eye. Both optic discs show grade 1 disc edema. The third case of visual changes while on board the ISS had no changes in visual acuity and no complaints of headaches, transient visual obscurations, diplopia or pulsatile tinnitus during the mission. Upon return to Earth, no eye issues were reported by the astronaut at landing. Fundus examination revealed bilateral, asymmetrical disc edema. There was no evidence of choroidal folds or cotton-wool spots, but a small hemorrhage was observed below the optic dics in the right eye. This astronaut had the most pronounced optic-disc edema of all astronauts reported to date, but had no choroidal folds, globe flattening or hyperopic shift. At 10 days post landing, an MRI of the brain and eyes was normal, but there appeared to be a mild increase in CSF signal around the right optic nerve.[3] The fourth case of visual changes on orbit was significant for a past history of transsphenoidal hypophysectomy for macroadenoma where postoperative imaging showed no residual or recurrent disease. Approximately 2 months into the ISS mission, the astronaut noticed a progressive decrease in near-visual acuity in his right eye and a scotoma in his right temporal field of vision.[3] Figure 5: On-orbit ultrasound of posterior orbit of the fourth case of visual changes from long-duration spaceflight. In-flight ultrasound image of the right eye showing posterior globe flattening and a raised optic disc consistent with optic-disc edema and raised ICP. Figure 6: On-orbit ultrasound of optic nerves of the fourth case of visual changes from long-duration spaceflight. In-flight ultrasound shows proximal kinking and increased optic nerve sheath diameter (ONSD) of approximately 12 mm that is consistent with raised ICPs. Optic nerve shown in purple and the ONSD in green. Figure 10: MRI (R+30 days) of the fourth case of visual changes from long-duration spaceflight. There is prominence of central T2-hyperintensity of the optic nerves bilaterally, right greater than left approximately 10 to 12 mm posterior to the globe (arrow) that represents an element of optic nerve congestion. Figure 11: MRI (R+30 days) of the fourth case of visual changes from long-duration spaceflight. Tortuous optic nerve and kink on left (arrow). Control orbit on the right. During the same mission, another ISS long-duration astronaut reported the fifth case of decreased near-visual acuity after 3 weeks of spaceflight. In both cases, CO2, cabin pressure and oxygen levels were reported to be within acceptable limits and the astronauts were not exposed to any toxic fumes.[3] The fifth case of visual changes observed on the ISS was noticed only 3 weeks into his mission. This change continued for the remainder of the mission without noticeable improvement or progression. He never complained of headaches, transient visual obscurations, diplopia, pulsatile tinnitus or other visual changes. Upon return to Earth, he noted persistence of the vision changes he observed in space. He never experienced losses in subjective best-corrected acuity, color vision or stereopsis. This case is interesting because the astronaut did not have disc edema or choroidal folds, but was documented to have nerve fiber layer (NFL) thickening, globe flattening, a hyperopic shift and subjective complaints of loss of near vision.[3] The sixth case of visual changes of an ISS astronaut was reported after return to Earth from a 6-month mission. When he noticed that his far vision was clearer through his reading glasses. A fundus examination performed 3 weeks postflight documented a grade 1 nasal optic-disc edema in the right eye only. There was no evidence of disc edema in the left eye or choroidal folds in either eye (Figure 13). MRI of the brain and eyes days postflight revealed bilateral flattening of the posterior globe, right greater than left, and a mildly distended right optic nerve sheath. There was also evidence of optic-disc edema in the right eye. A fundus examination postflight revealed a "new onset" cotton-wool spot in the left eye. This was not observed in the fundus photographs taken 3 weeks postflight.[3] Figure 13: Fundus examination of the sixth case of visual changes from long-duration spaceflight. Preflight images of normal optic disc. Postflight right and left optic disc showing grade 1 (superior and nasal) edema at the right optic disc. The seventh case of visual changes associated with spaceflight is significant in that it was eventually treated postflight. Approximately 2 months into the ISS mission, the astronaut reported a progressive decrease in his near and far acuity in both eyes. The ISS cabin pressure, CO2 and O2 levels were reported to be within normal operating limits and the astronaut was not exposed to any toxic substances. He never experienced losses in subjective best-corrected acuity, color vision or stereopsis. A fundus examination revealed a grade 1 bilateral optic-disc edema and choroidal folds (Figure 15).[3] Figure 15: Preflight images of the right and left optic discs (upper). Postflight images of the ONH showing in more detail the extent of the edematous optic-disc margins and glutting of the superior and inferior nerve fiber layer axons OD and OS (arrows) (lower). ## Case definition and clinical practice guidelines[edit] According to guidelines set forth by the Space Medicine Division, all long-duration astronauts with postflight vision changes should be considered a suspected case of VIIP syndrome. Each case could then be further differentiated by definitive imaging studies establishing the postflight presence of optic-disc edema, increased ONSD and altered OCT findings. The results from these imaging studies are then divided into five classes that determine what follow-up testing and monitoring is required. ### Classes[edit] The definition of the classes and Frisén scale used for optic disc edema diagnosis are listed below: Class 0 * < 0.50 diopter cycloplegic refractive change * No evidence of optic-disc edema, nerve sheath distention, choroidal folds, globe flattening, scotoma or cotton-wool spots compared to baseline Class 1 Repeat OCT and visual acuity in 6 weeks * Refractive changes ≥ 0.50 diopter cycloplegic refractive change and/or cotton-wool spot * No evidence of optic-disc edema, nerve sheath distanton, choroidal folds, globe flattening or scotoma compared to baseline * CSF opening pressure ≤ 25 cm H2O (if measured) Class 2 Repeat OCT, cycloplegic refraction, fundus examination and threshold visual field every 4 to 6 weeks × 6 months, repeat MRI in 6 months * ≥ 0.50 diopter cycloplegic refractive changes or cotton-wool spot * Choroidal folds and/or ONS distention and/or globe flattening and/or scotoma * No evidence of optic-disc edema * CSF opening pressure ≤ 25 cm H2O (if measured) Class 3 Repeat OCT, cycloplegic refraction, fundus examination and threshold visual field every 4 to 6 weeks × 6 months, repeat MRI in 6 months * ≥ 0.50 diopter cycloplegic refractive changes and/or cotton-wool spot * Optic nerve sheath distention, and/or globe flattening and/or choroidal folds and/or scotoma * Optic-disc edema of Grade 0-2 * CSF opening pressure ≤ 25 cm H2O Class 4 Institute treatment protocol as per Clinical Practice Guideline * ≥ 0.50 diopter cycloplegic refractive changes and/or cotton-wool spot * Optic nerve sheath distention, and/or globe flattening and/or choroidal folds and/or scotoma * Optic-disc edema Grade 2 or above * Presenting symptoms of new headache, pulsatile tinnitus and/or transient visual obscurations * CSF opening pressure > 25 cm H2O ### Stages[edit] Optic-disc edema will be graded based on the Frisén Scale[46] as below: Stage 0 – Normal Optic-disc Blurring of nasal, superior and inferior poles in inverse proportion to disc diameter. Radial nerve fiber layer (NFL) without NFL tortuosity. Rare obscuration of a major blood vessel, usually on the upper pole. Stage 1 – Very early optic-disc edema Obscuration of the nasal border of the disc. No elevation of the disc borders. Disruption of the normal radial NFL arrangement with grayish opacity accentuating nerve fiber layer bundles. Normal temporal disc margin. Subtle grayish halo with temporal gap (best seen with indirect ophthalmoscopy). Concentric or radial retrochoroidal folds. Stage 2 – Early optic-disc edema Obscuration of all borders. Elevation of the nasal border. Complete peripapillary halo. Stage 3 – Moderate optic-disc edema Obscurations of all borders. Increased diameter of ONH. Obscuration of one or more segments of major blood vessels leaving the disc. Peripapillary halo – irregular outer fringe with finger-like extensions. Stage 4 – Marked optic-disc edema Elevation of the entire nerve head. Obscuration of all borders. Peripapillary halo. Total obscuration on the disc of a segment of a major vessel. Stage 5 – Severe optic-disc edema Dome-shaped protrusions representing anterior expansion of the ONG. Peripapillary halo is narrow and smoothly demarcated. Total obscuration of a segment of a major blood vessel may or may not be present. Obliteration of the optic cup. ## Risk factors and recommendations[edit] Risk factors and underlying mechanisms based on anatomy, physiology, genetics and epigenetics need to be researched further.[47] The following actions have been recommended to assist in the research of vision impairment and increased intracranial pressure associated with long-duration space flight:[48] ### Immediate actions[edit] * Correlate pre-flight and post-flight MRIs with in-flight Ultrasound * Directly measure intracranial pressure through lumbar puncture pre-flight and post-flight on all long duration astronauts * Due to the normal variability in this measurement, obtain more than one pre-flight intracranial pressure measurement through lumbar puncture * Enhanced analysis of OCT findings such as RPE angle * Blinded readings of previous and future diagnostic imaging to minimize potential bias * Measurement of in-flight IOP on all astronauts * Improved in-flight fundoscopic imaging capability * Measurement of pre-flight and post-flight compliance (cranial, spinal, vascular) ### Near and long-term actions[edit] * Establish case definition based on current Medical Requirements Integration Documents (MRID) and clinical findings * Develop clinical practice guidelines * Establish a reliable and accurate non-invasive in-flight capability to measure and monitor ICP, compliance and cerebral blood flow * Develop more sophisticated in-flight neurocognitive testing * Establish risk stratification and underlying mechanisms based on anatomy and physiology * Characterization of Human Spaceflight Physiology and Anatomy (human and animal tissue studies) * Develop or utilize advance imaging modalities (Near Infrared Spectroscopy (NIRS), Transcranial Doppler (TCD), Ophthalmodynanometry, Venous Doppler Ultrasound * Genetic testing and the use of biomarkers in blood and cerebral spinal fluid (CSF) ## Benefits to Earth[edit] The development of accurate and reliable non-invasive ICP measurement methods for VIIP has the potential to benefit many patients on earth who need screening and/or diagnostic ICP measurements, including those with hydrocephalus, intracranial hypertension, intracranial hypotension, and patients with cerebrospinal fluid shunts. Current ICP measurement techniques are invasive and require either a lumbar puncture, insertion of a temporary spinal catheter,[49] insertion of a cranial ICP monitor, or insertion of a needle into a shunt reservoir.[50] ## See also[edit] * Effect of spaceflight on the human body * Intracranial Pressure and its Effect on Vision in Space and on Earth * Papilledema ## References[edit] 1. ^ Chang, Kenneth (27 January 2014). "Beings Not Made for Space". New York Times. Retrieved 27 January 2014. 2. ^ a b c "The Visual Impairment Intracranial Pressure Summit Report" (PDF). NASA. p. 5. Retrieved 13 June 2012. 3. ^ a b c d e f g h i j Otto, C.; Alexander, DJ; Gibson, CR; Hamilton, DR; Lee, SMC; Mader, TH; Oubre, CM; Pass, AF; Platts, SH; Scott, JM; Smith, SM; Stenger, MB; Westby, CM; Zanello, SB (12 July 2012). "Evidence Report: Risk of spaceflight-induced intracranial hypertension and vision alterations" (PDF). 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"Exercise increases blood flow to locomotor, vestibular, cardiorespiratory and visual regions of the brain in miniature swine". The Journal of Physiology. 533 (3): 849–59. doi:10.1111/j.1469-7793.2001.t01-1-00849.x. PMC 2278667. PMID 11410640. 33. ^ Jørgensen, LG; Perko, G; Secher, NH (November 1992). "Regional cerebral artery mean flow velocity and blood flow during dynamic exercise in humans". Journal of Applied Physiology. 73 (5): 1825–30. doi:10.1152/jappl.1992.73.5.1825. PMID 1474058. 34. ^ Jørgensen, LG; Perko, M; Hanel, B; Schroeder, TV; Secher, NH (March 1992). "Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans". Journal of Applied Physiology. 72 (3): 1123–32. doi:10.1152/jappl.1992.72.3.1123. PMID 1568967. 35. ^ Hellström, G; Fischer-Colbrie, W; Wahlgren, NG; Jogestrand, T (July 1996). "Carotid artery blood flow and middle cerebral artery blood flow velocity during physical exercise". Journal of Applied Physiology. 81 (1): 413–8. doi:10.1152/jappl.1996.81.1.413. PMID 8828693. 36. ^ Moraine, J. J.; Lamotte, M.; Berré, J.; Niset, G.; Leduc, A.; Naeije, R. (1993). "Relationship of middle cerebral artery blood flow velocity to intensity during dynamic exercise in normal subjects". European Journal of Applied Physiology and Occupational Physiology. 67 (1): 35–8. doi:10.1007/BF00377701. PMID 8375362. 37. ^ "The Visual Impairment Intracranial Pressure Summit Report" (PDF). NASA. 38. ^ Zwart, S. R.; Gibson, C. R.; Mader, T. H.; Ericson, K.; Ploutz-Snyder, R.; Heer, M.; Smith, S. M. (2012). "Vision Changes after Spaceflight Are Related to Alterations in Folate- and Vitamin B-12-Dependent One-Carbon Metabolism". Journal of Nutrition. 142 (3): 427–31. doi:10.3945/jn.111.154245. PMID 22298570. 39. ^ Keith, L. "New Findings on Astronaut Vision Loss". International Space Station. NASA. 40. ^ Zwart, S; Gibson, CR; Mader, TH; Ericson, K; Ploutz-Snyder, R; Heer, M; Smith, SM. "Vision Changes after Spaceflight Are Related to Alterations in Folate– and Vitamin B-12–Dependent One-Carbon Metabolism". SciVee. PMID 22298570. 41. ^ Wiener, TC (January 2012). "Space obstructive syndrome: intracranial hypertension, intraocular pressure, and papilledema in space". Aviation, Space, and Environmental Medicine. 83 (1): 64–66. doi:10.3357/ASEM.3083.2012. PMID 22272520. 42. ^ a b "The Visual Impairment Intracranial Pressure Summit Report" (PDF). NASA. p. 2. Retrieved 13 June 2012. 43. ^ "The Visual Impairment Intracranial Pressure Summit Report" (PDF). NASA. p. 3. Retrieved 13 June 2012. 44. ^ Ragauskas A, Matijosaitis V, Zakelis R, Petrikonis K, Rastenyte D, Piper I, Daubaris G; Matijosaitis; Zakelis; Petrikonis; Rastenyte; Piper; Daubaris (May 2012). "Clinical assessment of noninvasive intracranial pressure absolute value measurement method". Neurology. 78 (21): 1684–91. doi:10.1212/WNL.0b013e3182574f50. PMID 22573638.CS1 maint: multiple names: authors list (link) 45. ^ News-Medical.net. http://www.news-medical.net/news/20120705/Non-invasive-absolute-intracranial-pressure-value-meter-shown-to-be-accurate-in-clinical-settings.aspx[full citation needed] 46. ^ Frisén, L (January 1982). "Swelling of the optic nerve head: a staging scheme". Journal of Neurology, Neurosurgery, and Psychiatry. 45 (1): 13–8. doi:10.1136/jnnp.45.1.13. PMC 491259. PMID 7062066. 47. ^ "The Visual Impairment Intracranial Pressure Summit Report" (PDF). NASA. p. 6. Retrieved 13 June 2012. 48. ^ "The Visual Impairment Intracranial Pressure Summit Report" (PDF). NASA. pp. 9–10. Retrieved 13 June 2012. 49. ^ Torbey, MT; Geocadin RG; Razumovsky AY; Rigamonti D; Williams MA (2004). "Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache". Cephalalgia. 24 (6): 495–502. doi:10.1111/j.1468-2982.2004.00688.x. PMID 15154860. 50. ^ Geocadin, RG; Varelas PN; Rigamonti D; Williams MA (April 2007). "Continuous intracranial pressure monitoring via the shunt reservoir to assess suspected shunt malfunction in adults with hydrocephalus". Neurosurg Focus. 22 (4): E10. doi:10.3171/foc.2007.22.4.12. PMID 17613188. This article incorporates public domain material from the National Aeronautics and Space Administration document: "The Visual Impairment Intracranial Pressure Summit Report" (PDF). This article incorporates public domain material from the National Aeronautics and Space Administration document: "Evidence Report: Risk of Spaceflight-Induced Intracranial Hypertension and Vision Alterations" (PDF). ## Further reading[edit] * Brandon R Macias, John HK Liu, Christian Otto, Alan R Hargens (2017). "Intracranial Pressure & its Effect on Vision in Space and on Earth". * Mader TH, Gibson CR, Pass AF, et al. (October 2011). "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight". Ophthalmology. 118 (10): 2058–69. doi:10.1016/j.ophtha.2011.06.021. PMID 21849212. * "What's New in Space Medicine – Can you say "VIIP"?" (PDF). The Lifetime Surveillance of Astronaut Health. 18 (1). Spring 2012. * Geeraerts T, Merceron S, Benhamou D, Vigué B, Duranteau J; Merceron; Benhamou; Vigué; Duranteau (November 2008). "Non-invasive assessment of intracranial pressure using ocular sonography in neurocritical care patients". Intensive Care Med. 34 (11): 2062–7. doi:10.1007/s00134-008-1149-x. PMC 4088488. PMID 18509619.CS1 maint: multiple names: authors list (link) * Dallas, Mary Elizabeth. "Space Travel Might Lead to Eye Trouble: Study". philly.com. Retrieved 15 June 2012. * "Space missions may damage eyes". American Medical Network. Retrieved 15 June 2012. * "Eye Problems Common in Astronauts". Discovery.com. March 2012. Retrieved 15 June 2012. * "Space flight linked to eye, brain problems". CBC News. March 2012. * Matthews, Mark K. (September 2011). "Blurred vision plagues astronauts who spend months in space". Orlando Sentinel. * Love, Shayla (9 July 2016). "The mysterious syndrome impairing astronauts' sight". Washington Post. * Kinyoun, JL; Chittum, ME; Wells, CG (15 May 1988). "Photocoagulation treatment of radiation retinopathy". American Journal of Ophthalmology. 105 (5): 470–8. doi:10.1016/0002-9394(88)90237-1. PMID 3369516. * Zhang, LF; Hargens, AR (January 2014). "Intraocular/Intracranial pressure mismatch hypothesis for visual impairment syndrome in space". Aviation, Space, and Environmental Medicine. 85 (1): 78–80. doi:10.3357/asem.3789.2014. PMID 24479265. * v * t * e Space medicine Main areas * Artificial gravity * Astronautical hygiene * Bioastronautics * Neuroscience in space * Space exposure * Space food * Space nursing * Space weather * Weightlessness Illness and injuries * Asthenization * Ebullism * Illness and injuries during spaceflight * Medical treatment during spaceflight * Space adaptation syndrome * Space and survival * Spaceflight osteopenia Organizations * Aerospace Medical Association * National Space Biomedical Research Institute * Rubicon Foundation * Space Nursing Society Other topics * Adverse health effects from lunar dust exposure * Cardiac rhythm problems during space flight * Central nervous system effects from radiation exposure during spaceflight * Effect of spaceflight on the human body * Effects of sleep deprivation in space * Epidemiology data for low-linear energy transfer radiation * Sleep in space * Health threat from cosmic rays * Intervertebral disc damage and spaceflight * List of microorganisms tested in outer space * Psychological and sociological effects of spaceflight * Radiobiology evidence for protons and HZE nuclei * Reduced muscle mass, strength and performance in space * Renal stone formation in space * Spaceflight radiation carcinogenesis * Team composition and cohesion in spaceflight missions * Visual impairment due to intracranial pressure [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Visual impairment due to intracranial pressure	None	5,062	wikipedia	https://en.wikipedia.org/wiki/Visual_impairment_due_to_intracranial_pressure	2021-01-18T19:06:44	{"wikidata": ["Q17088850"]}
The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA. MDS is phenotypically heterogeneous, and can affect a specific organ or a combination of organs, with the main presentations described being either hepatocerebral (i.e. hepatic dysfunction, psychomotor delay), myopathic (i.e. hypotonia, muscle weakness, bulbar weakness), encephalomyopathic (i.e. hypotonia, muscle weakness, psychomotor delay) or neurogastrointestinal (i.e gastrointestinal dysmotility, peripheral neuropathy). Additional phenotypes include fatal infantile lactic acidosis with methylmalonic aciduria, spastic ataxia (early-onset spastic ataxia-neuropathy syndrome), and Alpers syndrome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Mitochondrial DNA depletion syndrome	c0342782	5,063	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35698	2021-01-23T17:21:14	{"umls": ["C0342782"], "synonyms": ["mtDNA depletion syndrome"]}
Rare genetic disorder caused by part of the father's chromosome 15 being missing Prader–Willi syndrome Other namesLabhart–Willi syndrome, Prader's syndrome, Prader–Labhart–Willi-Fanconi syndrome[1] Eight-year-old with Prader–Willi syndrome, exhibiting characteristic obesity[2] Pronunciation * /ˈprɑːdər ˈvɪli/, /ˈpreɪdər wɪli/, /ˈprɑːdər ˈwɪli/ SpecialtyMedical genetics, psychiatry, pediatrics SymptomsBabies: weak muscles, poor feeding, slow development[3] Children: constantly hungry, intellectual impairment, behavioural problems[3] ComplicationsObesity, type 2 diabetes[3] DurationLifelong[4] CausesGenetic disorder (typically new mutation)[3] Differential diagnosisSpinal muscular atrophy, congenital myotonic dystrophy, familial obesity[5] TreatmentFeeding tubes, strict food supervision, exercise program, counseling[6] MedicationGrowth hormone therapy[6] Frequency1 in 10,000–30,000 people[3] Prader–Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15.[3] In newborns, symptoms include weak muscles, poor feeding, and slow development.[3] Beginning in childhood, those affected become constantly hungry, which often leads to obesity and type 2 diabetes.[3] Mild to moderate intellectual impairment and behavioral problems are also typical of the disorder.[3] Often, affected individuals have a narrow forehead, small hands and feet, short height, light skin and hair. Most are unable to have children.[3] About 74% of cases occur when part of the father's chromosome 15 is deleted.[3] In another 25% of cases, the affected person has two copies of the maternal chromosome 15 from the mother and lacks the paternal copy.[3] As parts of the chromosome from the mother are turned off through imprinting, they end up with no working copies of certain genes.[3] PWS is not generally inherited, but rather the genetic changes happen during the formation of the egg, sperm, or in early development.[3] No risk factors are known for the disorder.[7] Those who have one child with PWS have less than a 1% chance of the next child being affected.[7] A similar mechanism occurs in Angelman syndrome, except the defective chromosome 15 is from the mother, or two copies are from the father.[8][9] Prader–Willi syndrome has no cure.[4] Treatment may improve outcomes, especially if carried out early.[4] In newborns, feeding difficulties may be supported with feeding tubes.[6] Strict food supervision is typically required, starting around the age of three, in combination with an exercise program.[6] Growth hormone therapy also improves outcomes.[6] Counseling and medications may help with some behavioral problems.[6] Group homes are often necessary in adulthood.[6] PWS affects between 1 in 10,000 and 1 in 30,000 people.[3] The condition is named after Swiss physicians Andrea Prader and Heinrich Willi who, together with Alexis Labhart, described it in detail in 1956.[1] An earlier description was made in 1887 by British physician John Langdon Down.[10][11] ## Contents * 1 Signs and symptoms * 1.1 Uterus and birth * 1.2 Childhood * 1.3 Adulthood * 1.4 Physical appearance * 1.5 Neurocognitive * 1.6 Behavioral * 1.7 Endocrine * 1.8 Ophthalmologic * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 Society and culture * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Prader-Willi syndrome phenotype at 15 years of age: Note absence of typical PWS facial features and presence of mild truncal obesity. PWS has many signs and symptoms. The symptoms can range from poor muscle tone during infancy to behavioral problems in early childhood. Some symptoms that are usually found in infants, besides poor muscle tone, are a lack of eye coordination, some are born with almond-shaped eyes, and due to poor muscle tone, some may not have a strong sucking reflex. Their cries are weak, and they have difficulty waking up. Another sign of this condition is a thin upper lip.[12] More aspects seen in a clinical overview include hypotonia and abnormal neurologic function, hypogonadism, developmental and cognitive delays, hyperphagia and obesity, short stature, and behavioral and psychiatric disturbances.[13] Holm et al. (1993) describe the following features and signs as indicators of PWS, although not all will be present.[citation needed] ### Uterus and birth[edit] * Reduced fetal movement * Frequent abnormal fetal position * Occasional polyhydramnios (excessive amniotic fluid) * Often breech or caesarean births * Lethargy * Hypotonia * Feeding difficulties (due to poor muscle tone affecting sucking reflex) * Difficulties establishing respiration * Hypogonadism ### Childhood[edit] * Delayed milestones/intellectual delay * Excessive sleeping * Strabismus (crossed eyes) * Scoliosis (often not detected at birth) * Cryptorchidism * Speech delay * Poor physical coordination * Hyperphagia (overeating) begins between the ages of 2 and 8, and continues on throughout adulthood. * Excessive weight gain * Sleep disorders * Delayed puberty * Short stature * Obesity * Extreme flexibility ### Adulthood[edit] * Infertility (males and females) * Hypogonadism * Sparse pubic hair * Obesity * Hypotonia (low muscle tone) * Learning disabilities/borderline intellectual functioning (but some cases of average intelligence) * Prone to diabetes mellitus * Extreme flexibility ### Physical appearance[edit] * Prominent nasal bridge * Small hands and feet with tapering of fingers * Soft skin, which is easily bruised * Excess fat, especially in the central portion of the body * High, narrow forehead * Thin upper lip * Downturned mouth * Almond-shaped eyes * Light skin and hair relative to other family members * Lack of complete sexual development * Frequent skin picking * Stretch marks * Delayed motor development ### Neurocognitive[edit] Individuals with PWS are at risk of learning and attention difficulties. Curfs and Fryns (1992) conducted research into the varying degrees of learning disability found in PWS.[14] Their results, using a measure of IQ, were as follows:[citation needed] * 5%: IQ above 85 (high to low average intelligence) * 27%: IQ 70–85 (borderline intellectual functioning) * 39%: IQ 50–70 (mild intellectual disability) * 27%: IQ 35–49 (moderate intellectual disability) * 1%: IQ 20–34 (severe intellectual disability) * <1%: IQ <20 (profound intellectual disability) Cassidy found that 40% of individuals with PWS have borderline/low average intelligence,[15] a figure higher than the 32% found in Curfs and Fryns' study.[14] However, both studies suggest that most individuals (50–65%) fall within the mild/borderline/low average intelligence range. Children with PWS show an unusual cognitive profile. They are often strong in visual organization and perception, including reading and vocabulary, but their spoken language (sometimes affected by hypernasality) is generally poorer than their comprehension. A marked skill in completing jigsaw puzzles has been noted,[16][17] but this may be an effect of increased practice.[18] Auditory information processing and sequential processing are relatively poor, as are arithmetic and writing skills, visual and auditory short-term memory, and auditory attention span. These sometimes improve with age, but deficits in these areas remain throughout adulthood.[16] PWS may be associated with psychosis.[19] ### Behavioral[edit] PWS is frequently associated with a constant insatiable appetite, which persists no matter how much the patient eats, often resulting in morbid obesity. Caregivers need to strictly limit the patients' access to food, usually by installing locks on refrigerators and on all closets and cabinets where food is stored.[20] It is the most common genetic cause of morbid obesity in children.[21] Currently, no consensus exists as to the cause for this symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the hypothalamus.[15] Given that the hypothalamic arcuate nucleus regulates many basic processes, including appetite, a link may well exist. In the hypothalamus of people with PWS, nerve cells that produce oxytocin, a hormone thought to contribute to satiety, have been found to be abnormal.[citation needed] People with PWS have high ghrelin levels, which are thought to directly contribute to the increased appetite, hyperphagia, and obesity seen in this syndrome.[22] Cassidy states the need for a clear delineation of behavioral expectations, the reinforcement of behavioural limits, and the establishment of regular routines. The main mental health difficulties experienced by people with PWS include compulsive behaviour (usually manifested in skin picking) and anxiety.[16][23] Psychiatric symptoms, for example, hallucinations, paranoia and depression, have been described in some cases[16] and affect about 5–10% of young adults.[15] Patients are also often extremely stubborn and prone to anger.[20] Psychiatric and behavioural problems are the most common cause of hospitalization.[24] Typically, 70–90% of affected individuals develop behavioral patterns in early childhood.[13] Aspects of these patterns can include stubbornness, temper tantrums, controlling and manipulative behavior, difficulty with change in routine, and compulsive-like behaviors.[13] ### Endocrine[edit] Several aspects of PWS support the concept of a growth hormone deficiency. Specifically, individuals with PWS have short stature, are obese with abnormal body composition, have reduced fat-free mass, have reduced lean body mass and total energy expenditure, and have decreased bone density. PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature adrenarche in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy. ### Ophthalmologic[edit] PWS is commonly associated with development of strabismus. In one study,[25] over 50% of patients had strabismus, mainly esotropia. ## Genetics[edit] PWS is related to an epigenetic phenomenon known as imprinting. Normally, a fetus inherits an imprinted maternal copy of PW genes and a functional paternal copy of PW genes. Due to imprinting, the maternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the paternal copies of the genes.[26][27] In PWS, however, there is mutation/deletion of the paternal copies of PW genes, leaving the fetus with no functioning PW genes. The PW genes are the SNRPN and NDN necdin genes, along with clusters of snoRNAs: SNORD64, SNORD107, SNORD108 and two copies of SNORD109, 29 copies of SNORD116 (HBII-85) and 48 copies of SNORD115 (HBII-52). These genes are located on chromosome 15 located in the region 15q11-13.[28][29][30][31] This so-called PWS/AS region in the paternal chromosome 15 may be lost by one of several genetic mechanisms, which in the majority of instances occurs through chance mutation. Other, less common mechanisms include uniparental disomy, sporadic mutations, chromosome translocations, and gene deletions. Region 15q11-13 is implicated in both PWS and Angelman syndrome (AS). While PWS results from the loss of PW genes within this region on the paternal chromosome, loss of a different gene (UBE3A) within the same region on the maternal chromosome causes AS.[32] PWS and AS represent the first reported instances of disorders related to imprinting in humans. The risk to the sibling of an affected child of having PWS depends upon the genetic mechanism which caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control region, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms. A microdeletion in one family of the snoRNA HBII-52 has excluded it from playing a major role in the disease.[33] Studies of human and mouse model systems have shown deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) to be the primary cause of PWS.[34][35][36][37][38] ## Diagnosis[edit] It is traditionally characterized by hypotonia, short stature, hyperphagia, obesity, behavioral issues (specifically obsessive–compulsive disorder-like behaviors), small hands and feet, hypogonadism, and mild intellectual disability.[39] However, with early diagnosis and early treatment (such as with growth hormone therapy), the prognosis for persons with PWS is beginning to change. Like autism, PWS is a spectrum disorder and symptoms can range from mild to severe and may change throughout the person's lifetime. Various organ systems are affected. Traditionally, PWS was diagnosed by clinical presentation. Currently, the syndrome is diagnosed through genetic testing; testing is recommended for newborns with pronounced hypotonia. Early diagnosis of PWS allows for early intervention and the early prescription of growth hormone. Daily recombinant growth hormone (GH) injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain. The mainstay of diagnosis is genetic testing, specifically DNA-based methylation testing to detect the absence of the paternally contributed PWS/AS region on chromosome 15q11-q13. Such testing detects over 97% of cases. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings. PWS is often misdiagnosed as other syndromes due to many in the medical community's unfamiliarity with it.[21] Sometimes it is misdiagnosed as Down syndrome, simply because of the relative frequency of Down syndrome compared to PWS.[21] ## Treatment[edit] PWS has no cure; several treatments are available to lessen the condition's symptoms. During infancy, subjects should undergo therapies to improve muscle strength. Speech and occupational therapy are also indicated. During the school years, children benefit from a highly structured learning environment and extra help. The largest problem associated with the syndrome is severe obesity. Access to food must be strictly supervised and limited, usually by installing locks on all food-storage places including refrigerators.[20] Physical activity in individuals with PWS for all ages is needed to optimize strength and promote a healthy lifestyle.[13] Prescription of daily recombinant GH injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain.[40][41][42] Because of severe obesity, obstructive sleep apnea is a common sequela, and a positive airway pressure machine is often needed. A person who has been diagnosed with PWS may have to undergo surgical procedures. One surgery that has proven to be unsuccessful for treating the obesity is gastric bypass.[43] Behavior and psychiatric problems should be detected early for the best results. These issues are best when treated with parental education and training. Sometimes medication is introduced, as well. Serotonin agonists have been most effective in lessening temper tantrums and improving compulsivity.[13] ## Epidemiology[edit] PWS affects one in 10,000 to one in 25,000 newborns.[39] More than 400,000 people live with PWS.[44] ## Society and culture[edit] A 1680 painting by Juan Carreño de Miranda of Eugenia Martínez Vallejo, a girl presumed to have PWS[45] Despite its rarity, PWS has been often referenced in popular culture, partly due to curiosity surrounding the insatiable appetite and fascination with the trademark obesity symptomatic of the syndrome. The syndrome has been depicted and documented several times in television. A fictional individual with PWS featured in the episode "Dog Eat Dog" of the television series CSI: Crime Scene Investigation, which aired in the US on 24 November 2005.[46] In July 2007 Channel 4 aired a 2006 documentary called Can't Stop Eating, surrounding the everyday lives of two people with PWS, Joe and Tamara.[47] In a 2010 episode of Extreme Makeover: Home Edition, Sheryl Crow helped Ty Pennington rebuild a home for a family whose youngest son, Ethan Starkweather, was living with the syndrome.[48] In a 2012 episode of Mystery Diagnosis on the Discovery Health channel, Conor Heybach, who has Prader–Willi syndrome, shared how he was diagnosed with it.[49] ## See also[edit] * Epigenetics * Genomic imprinting * ROHHAD ## References[edit] 1. ^ a b "Prader-Labhardt-Willi syndrome". Whonamedit?. Archived from the original on August 21, 2016. Retrieved August 20, 2016. 2. ^ Cortés M, F; Alliende R, MA; Barrios R, A; Curotto L, B; Santa María V, L; Barraza O, X; Troncoso A, L; Mellado S, C; Pardo V, R (January 2005). "[Clinical, genetic and molecular features in 45 patients with Prader-Willi syndrome]". Revista Médica de Chile. 133 (1): 33–41. doi:10.4067/s0034-98872005000100005. PMID 15768148. 3. ^ a b c d e f g h i j k l m n o "Prader-Willi syndrome". Genetics Home Reference. June 2014. Archived from the original on August 27, 2016. Retrieved August 19, 2016. 4. ^ a b c "Is there a cure for Prader-Willi syndrome (PWS)?". NICHD. January 14, 2014. Archived from the original on August 27, 2016. Retrieved August 20, 2016. 5. ^ Teitelbaum, Jonathan E. (2007). In a Page: Pediatrics. Lippincott Williams & Wilkins. p. 330. ISBN 9780781770453. 6. ^ a b c d e f g "What are the treatments for Prader-Willi syndrome (PWS)?". NICHD. January 14, 2014. Archived from the original on August 10, 2016. Retrieved August 20, 2016. 7. ^ a b "How many people are affected/at risk for Prader-Willi syndrome (PWS)?". NICHD. January 14, 2014. Archived from the original on August 27, 2016. Retrieved August 20, 2016. 8. ^ "Prader-Willi Syndrome (PWS): Other FAQs". NICHD. January 14, 2014. Archived from the original on July 27, 2016. Retrieved August 19, 2016. 9. ^ "Angelman syndrome". Genetic Home Reference. May 2015. Archived from the original on August 27, 2016. Retrieved August 20, 2016. 10. ^ Mia, Md Mohan (2016). Classical and Molecular Genetics. American Academic Press. p. 195. ISBN 978-1-63181-776-2. Archived from the original on September 11, 2017. 11. ^ Jorde, Lynn B.; Carey, John C.; Bamshad, Michael J. (2015). Medical Genetics (5 ed.). Elsevier Health Sciences. p. 120. ISBN 978-0-323-18837-1. 12. ^ "Mayo Clinic, Diseases and Conditions". Prader-Willi Syndrome, Symptoms and Causes. Retrieved February 6, 2019. 13. ^ a b c d e Cassidy, Suzanne B; Driscoll, Daniel J (September 10, 2008). "Prader–Willi syndrome". European Journal of Human Genetics. 17 (1): 3–13. doi:10.1038/ejhg.2008.165. PMC 2985966. PMID 18781185. 14. ^ a b Curfs LM, Fryns JP (1992). "Prader-Willi syndrome: a review with special attention to the cognitive and behavioral profile". Birth Defects Orig. Artic. Ser. 28 (1): 99–104. PMID 1340242. 15. ^ a b c Cassidy SB (1997). "Prader-Willi syndrome". Journal of Medical Genetics. 34 (11): 917–23. doi:10.1136/jmg.34.11.917. PMC 1051120. PMID 9391886. 16. ^ a b c d Udwin O (November 1998). "Prader-Willi syndrome: Psychological and behavioural characteristics". Contact a Family. Archived from the original on July 16, 2011. 17. ^ Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F (1993). "Prader-Willi syndrome: consensus diagnostic criteria". Pediatrics. 91 (2): 398–402. PMC 6714046. PMID 8424017. 18. ^ Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H (February 2004). "Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome". J Intellect Disabil Res. 48 (Pt 2): 172–87. doi:10.1111/j.1365-2788.2004.00556.x. PMID 14723659. 19. ^ Boer, H; Holland, A; Whittington, J; Butler, J; Webb, T; Clarke, D (January 12, 2002). "Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy". Lancet. 359 (9301): 135–6. doi:10.1016/S0140-6736(02)07340-3. PMID 11809260. S2CID 21083489. 20. ^ a b c "What are the treatments for Prader-Willi syndrome (PWS)?". Archived from the original on July 6, 2016. Retrieved June 16, 2016. 21. ^ a b c Nordqvist, Christian (March 15, 2010). "What Is Prader-Willi Syndrome? What Causes Prader-Willi Syndrome?". Medical News Today. MediLexicon International. Archived from the original on January 16, 2013. Retrieved December 4, 2012. 22. ^ Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS (July 2002). "Elevated plasma ghrelin levels in Prader Willi syndrome". Nature Medicine. 8 (7): 643–4. doi:10.1038/nm0702-643. PMID 12091883. S2CID 5253679. 23. ^ Clark DJ, Boer H, Webb T (1995). "General and behavioural aspects of PWS: a review". Mental Health Research. 8 (195): 38–49. 24. ^ Cassidy SB, Devi A, Mukaida C (1994). "Aging in PWS: 232 patients over age 30 years". Proc. Greenwood Genetic Centre. 13: 102–3. 25. ^ Hered RW, Rogers S, Zang YF, Biglan AW (1988). "Ophthalmologic features of Prader-Willi syndrome". J Pediatr Ophthalmol Strabismus. 25 (3): 145–50. PMID 3397859. 26. ^ Buiting, K; Saitoh, S; Gross, S; Dittrich, B; Schwartz, S; Nicholls, RD; Horsthemke, B (April 1995). "Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15". Nature Genetics. 9 (4): 395–400. doi:10.1038/ng0495-395. PMID 7795645. S2CID 7184110. 27. ^ "Major breakthrough in understanding Prader-Willi syndrome, a parental imprinting disorder". Medicalxpress.com. Archived from the original on April 28, 2015. Retrieved June 18, 2015. 28. ^ Online Mendelian Inheritance in Man (OMIM): Prader-Willi Syndrome; PWS - 17627 29. ^ de los Santos T, Schweizer J, Rees CA, Francke U (November 2000). "Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which is highly expressed in brain". American Journal of Human Genetics. 67 (5): 1067–82. doi:10.1086/303106. PMC 1288549. PMID 11007541. 30. ^ Cavaillé J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, Bachellerie JP, Brosius J, Hüttenhofer A (December 2000). "Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14311–6. Bibcode:2000PNAS...9714311C. doi:10.1073/pnas.250426397. PMC 18915. PMID 11106375. 31. ^ "Prader-Willi Syndrome - MeSH - NCBI." National Center for Biotechnology Information. U.S. National Library of Medicine, n.d. Web. November 1, 2016. <"Prader-Willi Syndrome - MeSH - NCBI". Archived from the original on November 3, 2016. Retrieved November 1, 2016.>. 32. ^ Cassidy, SB; Dykens, E (2000). "Prader-Willi and Angelman syndromes: sister imprinted disorders". Am J Med Genet. 97 (2): 136–146. doi:10.1002/1096-8628(200022)97:2<136::aid-ajmg5>3.0.co;2-v. PMID 11180221. 33. ^ Runte M, Varon R, Horn D, Horsthemke B, Buiting K (2005). "Exclusion of the C/D box snoRNA gene cluster HBII-52 from a major role in Prader-Willi syndrome". Hum Genet. 116 (3): 228–30. doi:10.1007/s00439-004-1219-2. PMID 15565282. S2CID 23190709. 34. ^ Skryabin BV, Gubar LV, Seeger B, Pfeiffer J, Handel S, Robeck T, Karpova E, Rozhdestvensky TS, Brosius J (2007). "Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation". PLOS Genet. 3 (12): e235. doi:10.1371/journal.pgen.0030235. PMC 2323313. PMID 18166085. 35. ^ Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL (2008). "Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster". Nat Genet. 40 (6): 719–21. doi:10.1038/ng.158. PMC 2705197. PMID 18500341. 36. ^ Ding F, Li HH, Zhang S, Solomon NM, Camper SA, Cohen P, Francke U (March 2008). "SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice". PLOS ONE. 3 (3): e1709. Bibcode:2008PLoSO...3.1709D. doi:10.1371/journal.pone.0001709. PMC 2248623. PMID 18320030. 37. ^ Ding F, Prints Y, Dhar MS, Johnson DK, Garnacho-Montero C, Nicholls RD, Francke U (2005). "Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models". Mamm Genome. 16 (6): 424–31. doi:10.1007/s00335-005-2460-2. PMID 16075369. S2CID 12256515. 38. ^ de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, Brady AF, Fairbrother UL, Dattani M, Keogh JM, Henning E, Yeo GS, O'Rahilly S, Froguel P, Farooqi IS, Blakemore AI (June 2009). "A Deletion of the HBII-85 Class of Small Nucleolar RNAs (snoRNAs) is Associated with Hyperphagia, Obesity and Hypogonadism". Hum. Mol. Genet. 18 (17): 3257–65. doi:10.1093/hmg/ddp263. PMC 2722987. PMID 19498035. 39. ^ a b Killeen, Anthony A. (2004). "Genetic Inheritance". Principles of Molecular Pathology. Humana Press. p. 41. ISBN 978-1-58829-085-4. Archived from the original on June 29, 2014. 40. ^ Davies PS, Evans S, Broomhead S, Clough H, Day JM, Laidlaw A, Barnes ND (May 1998). "Effect of growth hormone on height, weight, and body composition in Prader-Willi syndrome". Arch. Dis. Child. 78 (5): 474–6. doi:10.1136/adc.78.5.474. PMC 1717576. PMID 9659098. 41. ^ Carrel AL, Myers SE, Whitman BY, Allen DB (April 2002). "Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study". J. Clin. Endocrinol. Metab. 87 (4): 1581–5. doi:10.1210/jc.87.4.1581. PMID 11932286. 42. ^ Höybye C, Hilding A, Jacobsson H, Thorén M (May 2003). "Growth hormone treatment improves body composition in adults with Prader-Willi syndrome". Clin. Endocrinol. 58 (5): 653–61. doi:10.1046/j.1365-2265.2003.01769.x. PMID 12699450. S2CID 6941937. 43. ^ Scheimann, AO; Butler, MG; Gourash, L; Cuffari, C; Klish, W (January 2008). "Critical analysis of bariatric procedures in Prader-Willi syndrome". Journal of Pediatric Gastroenterology and Nutrition. 46 (1): 80–3. doi:10.1097/01.mpg.0000304458.30294.31. PMC 6815229. PMID 18162838. 44. ^ Tweed, Katherine (September 2009). "Shawn Cooper Struggles with Prader Willi Syndrome". AOL Health. Archived from the original on September 9, 2009. Retrieved September 9, 2009. 45. ^ Mary Jones. "Case Study: Cataplexy and SOREMPs Without Excessive Daytime Sleepiness in Prader Willi Syndrome. Is This the Beginning of Narcolepsy in a Five Year Old?". European Society of Sleep Technologists. Archived from the original on April 13, 2009. Retrieved April 6, 2009. 46. ^ "Dog Eat Dog". Csifiles.com. Archived from the original on June 4, 2009. Retrieved June 12, 2009. 47. ^ "Can't Stop Eating". Channel4.com. 2006. Archived from the original on July 25, 2009. Retrieved June 12, 2009. 48. ^ "Extreme Makeover: Home Edition Articles on AOL TV". Aoltv.com. Archived from the original on September 23, 2015. Retrieved June 18, 2015. 49. ^ [1] Archived July 14, 2014, at the Wayback Machine ## External links[edit] Wikimedia Commons has media related to Prader-Willi syndrome. * Prader–Willi syndrome at Curlie Classification D * ICD-10: Q87.1 * ICD-9-CM: 759.81 * OMIM: 176270 * MeSH: D011218 * DiseasesDB: 10481 * SNOMED CT: 89392001 External resources * MedlinePlus: 001605 * eMedicine: ped/1880 * Patient UK: Prader–Willi syndrome * GeneReviews: Prader-Willi syndrome * Orphanet: 739 * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 * v * t * e Disorders due to genomic imprinting Chromosome 15 * Angelman syndrome ♀ / Prader-Willi syndrome ♂ Chromosome 11 * Beckwith–Wiedemann syndrome ♀ / Silver–Russell syndrome ♂ * Myoclonic dystonia Chromosome 20 * Pseudohypoparathyroidism ♀ / Pseudopseudohypoparathyroidism ♂ Chromosome 6 * Transient neonatal diabetes mellitus Authority control * GND: 4201277-6 * NDL: 01179976 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Prader–Willi syndrome	c0032897	5,064	wikipedia	https://en.wikipedia.org/wiki/Prader%E2%80%93Willi_syndrome	2021-01-18T19:05:07	{"gard": ["5575"], "mesh": ["D011218"], "umls": ["C0032897"], "orphanet": ["739"], "wikidata": ["Q594013"]}
Ledderhose disease is a type of plantar fibromatosis characterized by the growth of hard and round or flattened nodules (lumps) on the soles of the feet. It is generally seen in middle-aged and elderly people, and occurs in men about 10 times more often than in women. It typically affects both feet and progresses slowly, but not indefinitely. The nodules are often painless at first, but may cause pain when walking as they grow. People with Ledderhose disease may also have other conditions associated with the formation of excess fibrous connective tissue such as Dupuytren contracture, knuckle pads, or Peyronie disease. Repeated trauma, long-term alcohol consumption, chronic liver disease, diabetes, and epilepsy have also been reported in association with this condition. The exact cause of Ledderhose disease is not known, but heredity is thought to play a role in many cases. Treatment, if needed, may involve conservative management, steroid injections, radiotherapy, or surgery (fasciectomy and removal of the fibrous tissue). The condition has a good prognosis, although slow progression is not uncommon. Fasciectomy has been shown to reduce the rate of recurrence. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Ledderhose disease	c0158360	5,065	gard	https://rarediseases.info.nih.gov/diseases/6873/ledderhose-disease	2021-01-18T17:59:29	{"mesh": ["D000071380"], "umls": ["C0158360"], "orphanet": ["199251"], "synonyms": ["Lederhose disease"]}
Epidermal nevus syndrome Other namesSolomon's syndrome SpecialtyDermatology, medical genetics Epidermal nevus syndrome (also known as "Feuerstein and Mims syndrome",[1][2] and "Solomon's syndrome"[1]:775[3]) is a rare disease that was first described in 1968 and consists of extensive epidermal nevi with abnormalities of the central nervous system (CNS), skeleton, skin, cardiovascular system, genitourinary system and eyes.[2]:634 However, since the syndrome's first description, a broader concept for the "epidermal nevus" syndrome has been proposed, with at least six types being described:[1]:776[4] * Schimmelpenning syndrome * Nevus comedonicus syndrome * Pigmented hairy epidermal nevus syndrome * Proteus syndrome * CHILD syndrome * Phakomatosis pigmentokeratotica ## See also[edit] * Epidermis * List of cutaneous conditions ## References[edit] 1. ^ a b c Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ a b James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 4. ^ Happle, R. "Epidermal nevus syndrome." Semin Dermatol. 1995;14:111. ## External links[edit] Classification D * ICD-10: Q85.8 External resources * Orphanet: 35125 * 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 This Epidermal nevi, neoplasms, cysts article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Epidermal nevus syndrome	c0334082	5,066	wikipedia	https://en.wikipedia.org/wiki/Epidermal_nevus_syndrome	2021-01-18T19:10:32	{"mesh": ["C580062"], "umls": ["C0334082"], "orphanet": ["35125"], "wikidata": ["Q5382842"]}
Dysdiadochokinesia Other namesDysdiadochokinesis, dysdiadokokinesia, dysdiadokokinesis SpecialtyNeurology Dysdiadochokinesia (DDK) is the medical term for an impaired ability to perform rapid, alternating movements (i.e., diadochokinesia). Complete inability is called adiadochokinesia. The term is from Greek δυς dys "bad", διάδοχος diadochos "succeeding", κίνησις kinesis "movement".[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 References * 4 External links ## Signs and symptoms[edit] Abnormalities in diadochokinesia can be seen in the upper extremity, lower extremity and in speech. The deficits become visible in the rate of alternation, the completeness of the sequence, and in the variation in amplitude involving both motor coordination and sequencing.[2][3] Average rate can be used as a measure of performance when testing for dysdiadochokinesia.[4] Dysdiadochokinesia is demonstrated clinically by asking the patient to tap the palm of one hand with the fingers of the other, then rapidly turn over the fingers and tap the palm with the back of them, repeatedly. This movement is known as a pronation/supination test of the upper extremity. A simpler method using this same concept is to ask the patient to demonstrate the movement of trying a doorknob or screwing in a light bulb. When testing for this condition in legs, ask the patient to tap your hand as quickly as possible with the ball of each foot in turn. Movements tend to be slow or awkward. The feet normally perform less well than the hands.[5] When testing for dysdiadochokinesia with speech the patient is asked to repeat syllables such as /pə/, /tə/, and /kə/; variation, excess loudness, and irregular articular breakdown are signs of dysdiadochokinesia.[4] ## Causes[edit] Dysdiadochokinesia is a feature of cerebellar ataxia and may be the result of lesions to either the cerebellar hemispheres or the frontal lobe (of the cerebrum), it can also be a combination of both.[2] It is thought to be caused by the inability to switch on and switch off antagonising muscle groups in a coordinated fashion due to hypotonia, secondary to the central lesion.[6] Dysdiadochokinesia is also seen in Friedreich's ataxia and multiple sclerosis, as a cerebellar symptom (including ataxia, intention tremor and dysarthria). It is also a feature of ataxic dysarthria. Dysdiadochokinesia often presents in motor speech disorders (dysarthria), therefore testing for dysdiadochokinesia can be used for a differential diagnosis.[4] Dysdiadochokinesia has been linked to a mutation in SLC18A2, which encodes vesicular monoamine transporter 2 (VMAT2).[7] ## References[edit] 1. ^ "dysdiadochokinesia". Farlex Partner Medical Dictionary. 2012. 2. ^ a b Deshmukh, A; Rosenbloom, MJ; Pfefferbaum, A; Sullivan EV (2002). "Clinical signs of cerebellar dysfunction in schizophrenia, alcoholism, and their comorbidity". Schizophr. Res. 57 (2–3): 281–291. doi:10.1016/s0920-9964(01)00300-0. PMID 12223260. S2CID 3198795. 3. ^ Diener, HC; Dichgans, J (1992). "Pathophysiology of Cerebellar Ataxia". Movement Disorders. 7 (2): 95–109. doi:10.1002/mds.870070202. PMID 1584245. 4. ^ a b c Wang, YT; Kent, RD; Duffy, JR; Thomas, JE (2008). "Analysis of diadochokinesis in ataxic dysarthria using the motor speech profile program". Folia Phoniatrica et Logopaedica. 61 (1): 11. doi:10.1159/000184539. PMC 2790744. PMID 19088478. 5. ^ Bates Guide to Physical Examination, 8th Ed. 6. ^ "Dysdiadochokinesia"[permanent dead link], UBM Medica, United States. (2011). Retrieved May 11, 2011. 7. ^ Rilstone, Jennifer; Alkhater, R; Minassian, B (2013). "Brain Dopamine-Serotonic Vesicular Transport Disease and Its Treatment". New England Journal of Medicine. 368 (6): 543–550. doi:10.1056/NEJMoa1207281. PMID 23363473. ## External links[edit] Classification D * ICD-10: R27 * ICD-9-CM: 781.3 * v * t * e Symptoms and signs relating to movement and gait Gait * Gait abnormality * CNS * Scissor gait * Cerebellar ataxia * Festinating gait * Marche à petit pas * Propulsive gait * Stomping gait * Spastic gait * Magnetic gait * Truncal ataxia * Muscular * Myopathic gait * Trendelenburg gait * Pigeon gait * Steppage gait * Antalgic gait Coordination * Ataxia * Cerebellar ataxia * Dysmetria * Dysdiadochokinesia * Pronator drift * Dyssynergia * Sensory ataxia * Asterixis Abnormal movement * Athetosis * Tremor * Fasciculation * Fibrillation Posturing * Abnormal posturing * Opisthotonus * Spasm * Trismus * Cramp * Tetany * Myokymia * Joint locking Paralysis * Flaccid paralysis * Spastic paraplegia * Spastic diplegia * Spastic paraplegia * Syndromes * Monoplegia * Diplegia / Paraplegia * Hemiplegia * Triplegia * Tetraplegia / Quadruplegia * General causes * Upper motor neuron lesion * Lower motor neuron lesion Weakness * Hemiparesis Other * Rachitic rosary * Hyperreflexia * Clasp-knife response [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Dysdiadochokinesia	c0234979	5,067	wikipedia	https://en.wikipedia.org/wiki/Dysdiadochokinesia	2021-01-18T18:57:46	{"umls": ["C0234979"], "icd-9": ["781.3"], "icd-10": ["R27"], "wikidata": ["Q1280963"]}
Group of genetic connective tissues disorders Ehlers–Danlos syndromes Individual with EDS displaying skin hyperelasticity Pronunciation * ey-lerz dan-los SpecialtyMedical genetics, rheumatology SymptomsOverly flexible joints, stretchy skin, abnormal scar formation[1] ComplicationsAortic dissection, joint dislocations, osteoarthritis[1] Usual onsetChildhood or teens depending on type.[2] DurationLifelong[3] TypesHypermobile, classic, vascular, kyphoscoliosis, arthrochalasia, dermatosparaxis, brittle cornea syndrome, others[4] CausesGenetic[1] Risk factorsFamily history[1] Diagnostic methodGenetic testing, skin biopsy[3] Differential diagnosisMarfan syndrome, cutis laxa syndrome, familial joint hypermobility syndrome,[3] Loeys-Dietz syndrome, hypermobility spectrum disorder TreatmentSupportive[5] PrognosisDepends on specific disorder[3] Frequency1 in 5,000[1] Ehlers–Danlos syndromes are a group of rare genetic connective tissue disorders.[1] Symptoms may include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation.[1] These can be noticed at birth or in early childhood.[2] Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.[1][3] EDS occurs due to variations of more than 19 different genes which are present at birth.[1] The specific gene affected determines the type of EDS.[1] Some cases result from a new variation occurring during early development, while others are inherited in an autosomal dominant or recessive manner.[1] Typically, these variations result in defects in the structure or processing of the protein collagen.[1] Diagnosis is often based on symptoms and confirmed with genetic testing or skin biopsy.[3] However, people may initially be misdiagnosed with hypochondriasis, depression, or chronic fatigue syndrome.[3] A large number of signs and symptoms still remain to be identified and linked to EDS, and ignorance on the part of physicians is, according to rehabilitation medicine physician Claude Hamonet, "at the origin of therapeutic errors accompanied by the iatrogenic effects of prejudice towards these patients."[6] There is no known cure.[5] Treatment is supportive in nature.[3] Physical therapy and bracing may help strengthen muscles and support joints.[3] While some forms of EDS result in a normal life expectancy, those that affect blood vessels generally decrease life expectancy.[5] The hypermobile type of EDS (hEDS) affects at least one in 5,000 people globally,[1][7] however other types occur at rarer frequencies.[8][9] The prognosis depends on the specific disorder.[3] Excess mobility was first described by Hippocrates in 400 BC.[10] The syndromes are named after two physicians, Edvard Ehlers from Denmark and Henri-Alexandre Danlos from France, who described them at the turn of the 20th century.[11] ## Contents * 1 Signs and symptoms * 1.1 Musculoskeletal * 1.2 Skin * 1.3 Cardiovascular * 1.4 Other manifestations * 2 Genetics * 3 Diagnosis * 3.1 Classification * 3.1.1 Hypermobile EDS * 3.1.2 Classical EDS * 3.1.3 Vascular variant of Ehlers–Danlos syndrome * 3.1.4 Kyphoscoliosis EDS * 3.1.5 Arthrochalasia EDS * 3.1.6 Dermatosparaxis EDS * 3.1.7 Brittle cornea syndrome * 3.1.8 Classical-like EDS * 3.1.9 Spondylodysplastic EDS * 3.1.10 Musculocontractural EDS * 3.1.11 Myopathic EDS * 3.1.12 Periodontal EDS * 3.1.13 Cardiac-valvular EDS * 3.2 History * 3.3 Differential diagnosis * 4 Management * 4.1 Pain management * 4.1.1 Medications * 4.2 Surgery * 5 Prognosis * 5.1 Complications * 5.1.1 Vascular * 6 Epidemiology * 7 Society and culture * 7.1 Notable cases * 8 Other species * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] This group of disorders affects connective tissues across the body, with symptoms most typically present in the joints, skin, and blood vessels. Effects may range from mildly loose joints to life-threatening cardiovascular complications.[12] Due to the diversity of subtypes within the EDS family, symptoms may vary widely between individuals diagnosed with EDS. ### Musculoskeletal[edit] Musculoskeletal symptoms include hyperflexible joints that are unstable and prone to sprain, dislocation, subluxation, and hyperextension.[3][11] There can be an early onset of advanced osteoarthritis,[13] chronic degenerative joint disease,[13] swan-neck deformity of the fingers,[14] and Boutonniere deformity of the fingers. Tearing of tendons or muscles may occur.[15] Deformities of the spine, such as scoliosis (curvature of the spine), kyphosis (a thoracic hump), tethered spinal cord syndrome, craniocervical instability, and occipitoatlantoaxial hypermobility may also be present.[16][17] There can also be myalgia (muscle pain) and arthralgia (joint pain),[18] which may be severe and disabling. Trendelenburg's sign is often seen, which means that when standing on one leg, the pelvis drops on the other side.[19] Osgood–Schlatter disease, a painful lump on the knee, is common as well.[20] In infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs.[21] * Individual with EDS showing hypermobile fingers, including the "swan-neck" malformation on the 2nd–5th digits, and a hypermobile thumb * Individual with EDS displaying hypermobile thumb * Individual with EDS displaying hypermobile metacarpophalangeal joints * Kyphoscoliosis of the back of someone with kyphoscoliosis EDS. * Severe joint hypermobility in a girl with EDS arthrochalasia type. ### Skin[edit] The weak connective tissue causes abnormal skin. This may present as stretchy or in other types simply be velvet soft. In all types there is some increased fragility but the degree varies depending on the underlying subtype. Skin may tear and bruises easily, and may heal with abnormal atrophic scars[13] and atrophic scars that look like cigarette paper are a sign seen including in those whose skin might appear otherwise normal.[1][11][22] In some sub-types, although not in the hypermobile subtype, redundant skin folds occur, especially on the eyelids. Redundant skin folds are areas of excess skin lying in folds.[13][23] Other skin symptoms include molluscoid pseudotumors,[24] especially on pressure points, petechiae,[25] subcutaneous spheroids,[24] livedo reticularis, and piezogenic papules are less common.[26] In vascular EDS, skin can also be thin and translucent. In dermatosparaxis EDS, the skin is extremely fragile and saggy.[1] * Atrophic scar in a case of EDS * Translucent skin in vascular EDS * Individual with EDS displaying skin hyperelasticity * Piezogenic papules on the heel of an individual with hypermobile EDS ### Cardiovascular[edit] * Thoracic outlet syndrome[27] * Arterial rupture[11] * Valvular heart disease, such as mitral valve prolapse, creates an increased risk for infective endocarditis during surgery. This may progress to a life-threatening degree.[28] Heart conduction abnormalities have been found in those with hypermobility form of EDS.[29] * Dilation and/or rupture (aneurysm) of ascending aorta[30] * Cardiovascular autonomic dysfunction such as postural orthostatic tachycardia syndrome[31][32] * Raynaud's phenomenon * Varicose veins[33] * Heart murmur * Heart conduction abnormalities ### Other manifestations[edit] * Hiatal hernia[24] * Gastroesophageal reflux[34] * Poor gastrointestinal motility[35] * Dysautonomia[36] * Gorlin's sign (touch tongue to nose)[37] * Anal prolapse[24] * Flat feet * Tracheobronchomalacia * Collapsed lung (spontaneous pneumothorax)[13] * Nerve disorders (carpal tunnel syndrome, acroparesthesia, neuropathy, including small fiber neuropathy)[38] * Insensitivity to local anesthetics[39] * Arnold–Chiari malformation[40] * Platelet aggregation failure (platelets do not clump together properly)[41] * Mast cell disorders (including mast cell activation syndrome and mastocytosis)[42] * Pregnancy complications: increased pain, mild to moderate peripartum bleeding, cervical insufficiency, uterine tearing,[15] or premature rupture of membranes[43] * Hearing loss may occur in some types[44] * Eye: Nearsightedness, retinal tearing and retinal detachment, keratoconus, blue sclera, dry eye, Sjogren's syndrome, lens subluxation, angioid streaks, epicanthal folds, strabismus, corneal scarring, brittle cornea syndrome, cataracts, carotid-cavernous sinus fistulas, macular degeneration[45] * Craniocervical instability: caused by trauma(s) to the head and neck areas such as concussion and whiplash. Ligaments in neck are unable to heal properly, therefore, the neck structure does not have the ability to support the skull, which can then sink into the brain stem blocking the normal flow of cerebrospinal fluid, leading to issues related to the autonomic nervous system failing to work properly.[46][47] * Celiac disease may be associated with EDS. Also, it can be misdiagnosed as EDS due to common symptoms, including fatigue, pain, gastrointestinal complaints, or cardiovascular autonomic dysfunction.[28] * Osteoporosis and osteopenia are associated with EDS and symptomatic joint hypermobility[48][49] * Gorlin's sign in a case of EDS. * A case of keratoglobus in a case of Brittle cornea syndrome Because it is often undiagnosed or misdiagnosed in childhood, some instances of EDS have been mischaracterized as child abuse.[50] The pain may also be misdiagnosed as a behavior disorder or Munchausen by proxy.[51] The pain associated with EDS ranges from mild to debilitating.[52] * psychiatric disorders [53] Almost half of EDS patients have psychiatric disorders[citation needed]. ADHD is common in hypermobility spectrum disorder but not in EDS patients. ## Genetics[edit] The collagen fibril and EDS: (a) Normal collagen fibrils are of uniform size and spacing. Fibrils from a person with dermatosparaxis (b) show dramatic alterations in fibril morphology with severe effects on tensile strength of connective tissues. Person with classical EDS (c) show composite fibrils. Fibrils from a TNX-deficient person (d) are uniform in size and no composite fibrils are seen. TNX-null (e) fibrils are less densely packed and not as well aligned to neighboring fibrils. Every type of EDS, except the hypermobile type, can be positively tied to specific genetic variation. Variations in these genes can cause EDS:[9] * Collagen primary structure and collagen processing: ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2 * Collagen folding and collagen cross-linking: PLOD1, FKBP14 * Structure and function of myomatrix: TNXB, COL12A1 * Glycosaminoglycan biosynthesis: B4GALT7, B3GALT6, CHST14, DSE * Complement pathway: C1R, C1S * Intracellular processes: SLC39A13, ZNF469, PRDM5 Variations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. Collagen provides structure and strength to connective tissue. A defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder.[1] Inheritance patterns depend on the specific syndrome. Most forms of EDS are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. A few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected by a disorder. It can also be an individual (de novo or "sporadic") variation. Sporadic variations occur without any inheritance.[54] ## Diagnosis[edit] A diagnosis can be made by an evaluation of medical history and clinical observation. The Beighton criteria are widely used to assess the degree of joint hypermobility. DNA and biochemical studies can help identify affected individuals. Diagnostic tests include collagen gene-variant testing, collagen typing via skin biopsy, echocardiogram, and lysyl hydroxylase or oxidase activity. However, these tests are not able to confirm all cases, especially in instances of an unmapped variation, so clinical evaluation remains important. If multiple individuals in a family are affected, performing prenatal diagnosis may be possible using a DNA information technique known as a linkage study.[55] Knowledge about EDS among all kinds of practitioners is poor.[56][57] Research is ongoing to identify genetic markers for all types.[58] ### Classification[edit] In 2017, 13 subtypes of EDS were classified using specific diagnostic criteria.[4] According to The Ehlers-Danlos Society, the syndromes can also be grouped by the symptoms determined by specific gene mutations. Group A disorders are those which affect primary collagen structure and processing. Group B disorders affect collagen folding and crosslinking. Group C are disorders of structure and function of myomatrix. Group D disorders are those that affect glycosaminoglycan biosynthesis. Group E disorders are characterized by defects in the complement pathway. Group F are disorders of intracellular processes, and Group G is considered to be unresolved forms of EDS.[59] #### Hypermobile EDS[edit] finger hypermobility Hypermobile EDS (formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint subluxations (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle and/or bone pain.[4] It affects the skin less than other forms. It has no available genetic test.[28] Hypermobility EDS (hEDS) is the most common of the 19 types of connective tissue disorders. Since there is no known genetic test, providers have to diagnose hEDS based on what they already know about the condition and the physical attributes that the patient shows. Other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. Along with these general signs and side effects, patients can have trouble healing.[60] Women who are pregnant should be warned about things such as pre-labor rupture of membranes, drop in blood pressure with anesthesia, precipitate birth (very fast active labor), malposition of bleeding, and more. New mothers with hEDS should pay extra attention to taking care of their new baby. Mothers may have trouble taking care of the baby because of the risk of dropping the baby due to weak connective tissue in arms and legs, falling, postpartum depression (more than the general population), and healing from the birthing process.[61] #### Classical EDS[edit] Classical EDS (formerly categorized as type 1) is characterized by extremely elastic skin that is fragile and bruises easily; and hypermobility of the joints. Molluscoid pseudotumors (calcified hematomas that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) also are seen often. A side complication of the hyperelasticity presented in many cases of EDS makes it more difficult for wounds to close on their own.[22] Sometimes, motor development is delayed and hypotonia occurs.[4] The variation causing this type of EDS is in the genes COL5A2, COL5A1, and less frequently COL1A1. It involves the skin more than hypermobile EDS.[62] In classical EDS there is often large variation in symptom presentation from patient to patient. Because of this variance EDS has often been an under diagnosed disorder.[63] Without genetic testing healthcare professionals may be able to provide a provisional diagnosis based on careful examination of the mouth, skin, and bones. As well as through neurological assessments.[64] The hyperelasticity of skin in EDS patients can be difficult to use in diagnosis because there is no good standardized way to measure and assess the elasticity of the skin. However, hyperelasticity is still a good indicator as something that may point towards EDS along with other symptoms. A good way to begin the diagnosis process is looking at family history, EDS is an autosomal dominant condition and so is often inherited from family members.[22] Genetic testing remains the most reliable way for an EDS diagnosis to be made.[65] While there is no cure for type 1 EDS, a course of non weight bearing exercising can help with muscular tension which can help correct some of the symptoms of EDS. Anti inflammatory drugs as well as lifestyle changes can help with joint pain. Lifestyle choices should also be made with children that have EDS to try and prevent wounds to the skin. Wearing protective garments can help with this. In the event of a wound often deep stitches are used and left in place for a longer period of time than normal.[22] #### Vascular variant of Ehlers–Danlos syndrome[edit] Vascular EDS (formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. It is also characterized by fragile blood vessels and organs that can easily rupture. Affected people are frequently short, and have thin scalp hair. It also has characteristic facial features including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes.[66] Joint hypermobility is present, but generally confined to the small joints (fingers, toes). Other common features include club foot, tendon and/or muscle rupture, acrogeria (premature aging of the skin of the hands and feet), early onset varicose veins, pneumothorax (collapse of a lung), recession of the gums, and a decreased amount of fat under the skin.[4] It can be caused by the variations in the COL3A1 gene.[66] Rarely, COL1A1 variations can also cause it.[67] #### Kyphoscoliosis EDS[edit] Kyphoscoliosis EDS (formerly categorized as type 6) is associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility. People may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and osteopenia (low bone density). Other common features include a "marfanoid habitus" which is characterized by long, slender fingers (arachnodactyly), unusually long limbs, and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum).[4] It can be caused by variations in the gene PLOD1, or rarely, in the FKBP14 gene.[68] #### Arthrochalasia EDS[edit] Arthrochalasia EDS (formerly categorized as types 7A & B) is characterized by severe joint hypermobility and congenital hip dislocation. Other common features include fragile, elastic skin with easy bruising, hypotonia, kyphoscoliosis (kyphosis and scoliosis), and mild osteopenia.[4] Type-I collagen is usually affected. It is very rare, with about 30 cases reported. It is more severe than the hypermobility type. Variations in the genes COL1A1 and COL1A2 cause it.[69] #### Dermatosparaxis EDS[edit] Dermatosparaxis EDS (formerly categorized as type 7C) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. Variations in the ADAMTS2 gene cause it. It is extremely rare, with around 11 cases reported.[70] #### Brittle cornea syndrome[edit] Brittle cornea syndrome is characterized by the progressive thinning of the cornea, early-onset progressive keratoglobus or keratoconus, nearsightedness, hearing loss, and blue sclerae.[4][71] Classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often.[72] It has two types. Type 1 occurs due to variations in the ZNF469 gene. Type 2 is due to variations in the PRDM5 gene.[71] #### Classical-like EDS[edit] Classical-like EDS is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath).[4] It can be caused by variations in the TNXB gene.[67] #### Spondylodysplastic EDS[edit] Spondylodysplastic EDS is characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital, to mild later-onset), and bowing of limbs.[4] It can be caused by variations in both copies of the B4GALT7 gene. Other cases can be caused by variations in the B3GALT6 gene. People with variations in this gene can have kyphoscoliosis, tapered fingers, osteoporosis, aortic aneurysma, and problems with the lungs. Other cases can be caused by the SLC39A13 gene. Those with variations in this gene have protuberant eyes, wrinkled palms of the hands, tapering fingers, and distal joint hypermobility.[73] #### Musculocontractural EDS[edit] Musculocontractural EDS is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling.[4] It can be caused by variations in the CHST14 gene. Some other cases can be caused by variations in the DSE gene.[74] #### Myopathic EDS[edit] Myopathic EDS (mEDS) is characterized by three major criteria: congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures of the knee, hip, and elbow, and hypermobility of distal joints (ankles, wrists, feet, and hands).[4] There are also four minor criteria that may contribute to a diagnosis of mEDS. This disorder can be inherited through either an autosomal dominant or an autosomal recessive pattern.[59] Molecular testing must be completed to verify that mutations in the COL12A1 gene are present; if not, other collagen-type myopathies should be considered.[59] #### Periodontal EDS[edit] Periodontal EDS (pEDS) is an inherited autosomal dominant disorder[59] characterized by four major criteria of severe and intractable periodontitis of early onset (childhood or adolescence), lack of attached gingiva, pretibial plaques, and family history of a first-degree relative who meets clinical criteria.[4] Eight minor criteria may also contribute to the diagnosis of pEDS. Molecular testing may reveal mutations in C1R or C1S genes affecting the C1r protein.[59] #### Cardiac-valvular EDS[edit] Cardiac-valvular EDS (cvEDS) is characterized by three major criteria: severe progressive cardiac-valvular problems (affecting aortic and mitral valves), skin problems such as hyperextensibility, atrophic scarring, thin skin, and easy bruising, and joint hypermobility (generalized or restricted to small joints).[4] There are also four minor criteria which may aid in diagnosis of cvEDS.[59] Cardiac-valvular EDS is an autosomal recessive disorder, inherited through variation in both alleles of the gene COL1A2.[75] ### History[edit] Until 1997, the classification system for EDS included 10 specific types, and also acknowledged that other extremely rare types existed. At this time, the classification system underwent an overhaul and was reduced to six major types using descriptive titles. Genetic specialists recognize that other types of this condition exist, but have only been documented in single families. Except for hypermobility (type 3), the most common type of all ten types, some of the specific variations involved have been identified and they can be precisely identified by genetic testing; this is valuable due to a great deal of variation in individual cases. However, negative genetic test results do not rule out the diagnosis, since not all of the variations have been discovered; therefore, the clinical presentation is very important.[76] Forms of EDS in this category may present with soft, mildly stretchable skin, shortened bones, chronic diarrhea, joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns in this group include X-linked recessive, autosomal dominant, and autosomal recessive. Examples of types of related syndromes other than those above reported in the medical literature include:[77] * 305200: type 5 * 130080: type 8 – unspecified gene, locus 12p13 * 225310: type 10 – unspecified gene, locus 2q34 * 608763: Beasley–Cohen type * 130070: progeroid form – B4GALT7 * 130090: type unspecified * 601776: D4ST1-deficient Ehlers–Danlos syndrome (adducted thumb-clubfoot syndrome) CHST14 ### Differential diagnosis[edit] Several disorders share some characteristics with EDS. For example, in cutis laxa, the skin is loose, hanging, and wrinkled. In EDS, the skin can be pulled away from the body, but is elastic and returns to normal when let go. In Marfan syndrome, the joints are very mobile and similar cardiovascular complications occur. People with EDS tend to have a "marfanoid" appearance (e.g., tall, skinny, long arms and legs, "spidery" fingers). However, physical appearance and features in several types of EDS also have characteristics including short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. The palate can have a high arch, causing dental crowding. Blood vessels can sometimes be easily seen through translucent skin, especially on the chest. The genetic connective tissue disorder, Loeys–Dietz syndrome, also has symptoms that overlap with EDS.[78] In the past, Menkes disease, a copper metabolism disorder, was thought to be a form of EDS. People are not uncommonly misdiagnosed with fibromyalgia, bleeding disorders, or other disorders that can mimic EDS symptoms. Because of these similar disorders and complications that can arise from an unmonitored case of EDS, a correct diagnosis is important.[79] Pseudoxanthoma elasticum (PXE) is worth consideration in diagnosis.[80] ## Management[edit] There is no known cure for Ehlers–Danlos syndromes and treatment is supportive. Close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing, casting) may be helpful. This can help stabilize the joints and prevent injury. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances, although individuals are advised not to become dependent on them until other mobility options have been exhausted. People should avoid activities that cause the joint to lock or overextend.[81] A physician may prescribe casting to stabilize joints. Physicians may refer a person to an orthotist for orthotic treatment (bracing). Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints.[82][83] Aquatic therapy promotes muscular development and coordination.[84] With manual therapy, the joint is gently mobilized within the range of motion and/or manipulations.[82][83] If conservative therapy is not helpful, surgical joint repair may be necessary. Medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. To decrease bruising and improve wound healing, some people have responded to vitamin C.[85] Special precautions are often taken by medical care workers because of the sheer number of complications that tend to arise in people with EDS. In vascular EDS, signs of chest or abdominal pain are considered trauma situations.[86] Cannabinoids and medical marijuana have shown some efficacy in reducing pain levels.[87] In general, medical intervention is limited to symptomatic therapy. Before pregnancy, people with EDS should have genetic counseling and familiarize themselves with the risks to their own bodies that pregnancy poses. Children with EDS should be provided with information about their disorder so they can understand why they should avoid contact sports and other physically stressful activities. Children should be taught that demonstrating the unusual positions that they can maintain due to loose joints should not be done, as this may cause early degeneration of the joints. Emotional support along with behavioral and psychological therapy can be useful. Support groups can be immensely helpful for people dealing with major lifestyle changes and poor health. Family members, teachers, and friends should be informed about EDS so they can accept and assist the child.[88] ### Pain management[edit] Successfully treating chronic pain in EDS needs a multidisciplinary team. The ways to manage pain can be to modify pain management techniques used in the normal population. Chronic pain has two types. The first type is the nociceptive type, which is caused by injury sustained to tissues. The second type is neuropathic pain. It is caused by abnormal signals by the nervous system. In most cases, the pain is an unequal mix of the two. Physiotherapy (exercise rehabilitation), has evidence of positive effect. It is primarily stabilizing the core of the body and the joints. Stretching exercises must be reduced to slow and gentle stretching to reduce the risks of dislocations or subluxations. Usable methods may include posture re-education, muscle release, joint mobilization, trunk stabilization, and manual therapy for overworked muscles. Cognitive behavioural therapy (CBT) is used in all chronic pain patients, especially those who have severe, chronic, life-controlling pain that is unresponsive to treatment. It had not been checked for efficiency in clinical trials as to date. The current state of pain management with EDS is considered insufficient.[51] #### Medications[edit] Nonsteroidal anti-inflammatory drugs (NSAIDs) may help if the pain is caused by inflammation. However, long-term use is NSAIDs is often a risk factor of gastrointestinal, renal, and blood-related side effects. It can worsen symptoms of mast cell activation syndrome, a disease that may be associated with EDS. Acetaminophen can be used to avoid the bleeding-related side effects of NSAIDs.[51] Opioids can be an option for extreme short-term pain, but only for short-term use. Opioids are addictive, and long-term use is associated with increased central pain sensitivity and is therefore not a good option. They can worsen gastrointestinal symptoms like nausea and constipation and mast cell activation syndrome, which may occur with EDS.[51] Lidocaine can be applied topically after subluxations and painful gums. It can also be injected into painful areas in the case of musculoskeletal pain.[51] If the pain is neuropathic in origin, tricyclic antidepressants in low doses, anticonvulsants, and selective norepinephrine reuptake inhibitors can be used.[51] ### Surgery[edit] The instability of joints, leading to subluxations and joint pain, often requires surgical intervention in people with EDS. Instability of almost all joints can happen, but appears most often in the lower and upper extremities, with the wrist, fingers, shoulder, knee, hip, and ankle being most common.[82] Common surgical procedures are joint debridement, tendon replacements, capsulorrhaphy, and arthroplasty. After surgery, the degree of stabilization, pain reduction, and people's satisfaction can improve, but surgery does not guarantee an optimal result: affected peoples and surgeons report being dissatisfied with the results. Consensus is that conservative treatment is more effective than surgery,[29] particularly since people have extra risks of surgical complications due to the disease. Three basic surgical problems arise due to EDS: the strength of the tissues is decreased, which makes the tissue less suitable for surgery; the fragility of the blood vessels can cause problems during surgery; and wound healing is often delayed or incomplete.[82] If considering surgical intervention, seeking care from a surgeon with extensive knowledge and experience in treating people with EDS and joint hypermobility issues would be prudent.[89] Local anesthetics, arterial catheters, and central venous catheters cause a higher risk of bruise formation in people with EDS. Some people with EDS also show a resistance to local anaesthetics.[90] Resistance to lidocaine and bupivacaine is not uncommon, and mepivacaine tends to work better in people with EDS. There are special recommendations for anesthesia in people with EDS.[91] Detailed recommendations for anesthesia and perioperative care of people with EDS should be used to improve safety.[89] Surgery in people with EDS requires careful tissue handling and a longer immobilization afterward.[92] ## Prognosis[edit] The outcome for individuals with EDS depends on the specific type of EDS they have. Symptoms vary in severity, even in the same disorder, and the frequency of complications varies. Some people have negligible symptoms, while others are severely restricted in daily life. Extreme joint instability, chronic musculoskeletal pain, degenerative joint disease, frequent injuries, and spinal deformities may limit mobility. Severe spinal deformities may affect breathing. In the case of extreme joint instability, dislocations may result from simple tasks such as rolling over in bed or turning a doorknob. Secondary conditions such as autonomic dysfunction or cardiovascular problems, occurring in any type, can affect prognosis and quality of life. Severe mobility-related disability is seen more often in hypermobile EDS than in classical EDS or vascular EDS.[93] Although all types of EDS are potentially life-threatening, most people have a normal lifespan. However, those with blood-vessel fragility have a high risk of fatal complications, including spontaneous arterial rupture, which is the most common cause of sudden death. The median life expectancy in the population with vascular EDS is 48 years.[94] ### Complications[edit] #### Vascular[edit] * Pseudoaneurysm[95] * Vascular lesions (nature is disputed) due to tears in the lining of the arteries or deterioration of congenitally thin and fragile tissue[95] * Enlarged arteries[95] Gastrointestinal * 50% risk of colonic perforation[95] Obstetric * Pregnancy increases the likelihood of uterine rupture[95] * Maternal mortality around 12%[95] * Uterine hemorrhage during the postpartum recovery[95] ## Epidemiology[edit] Ehlers–Danlos syndromes are inherited disorders estimated to occur in about one in 5,000 births worldwide. Initially, prevalence estimates ranged from one in 250,000 to 500,000 people, but these estimates were soon found to be too low, as more was studied about the disorders, and medical professionals became more adept at diagnosis. EDS may be far more common than the currently accepted estimate due to the wide range of severities with which the disorder presents.[96] The prevalence of the disorders differs dramatically. The most commonly occurring is hypermobile EDS, followed by classical EDS. The others are very rare. For example, fewer than 10 infants and children with dermatosparaxis EDS have been described worldwide. Some types of EDS are more common in Ashkenazi Jews. For example, the chance of being a carrier for dermatosparaxis EDS is one in 248 in Ashkenazi Jews, whereas the prevalence of this variation in the general population is one in 2,000.[97] ## Society and culture[edit] Gary "Stretch" Turner showing his extreme Ehlers–Danlos syndrome EDS may have contributed to the virtuoso violinist Niccolò Paganini's skill, as he was able to play wider fingerings than a typical violinist.[98] Many sideshow performers have EDS. Several of them were billed as the Elastic Skin Man, the India Rubber Man, and Frog Boy. They included such well-known individuals (in their time) as Felix Wehrle, James Morris, and Avery Childs. Two performers with EDS currently hold world records. Contortionist Daniel Browning Smith has hypermobile EDS and holds the current Guinness World Record for the most flexible man as of 2018, while Gary "Stretch" Turner (shown right), sideshow performer in the Circus Of Horrors, has held the current Guinness World Record for the most elastic skin since 1999, for his ability to stretch the skin on his stomach 6.25 inches.[99] ### Notable cases[edit] Stevie Boebi and Annie Elainey who have EDS stood with walking aids on the red carpet Pageant contestant Victoria Graham has EDS * Actress Cherylee Houston, hypermobile EDS. She uses a wheelchair and was the first full-time disabled actress on Coronation Street.[100] * Drag queen and winner of the eleventh season of RuPaul's Drag Race Yvie Oddly[101] * Eric the Actor, a regular caller to The Howard Stern Show[102] * Actress and activist Jameela Jamil, hypermobile EDS[103] * Writer and actress Lena Dunham[104] * Australian singer Sia[105] * YouTuber and disability rights activist Annie Elainey[106] * Miss America 2020 Camille Schrier[107] ## Other species[edit] Ehlers–Danlos-like syndromes have been shown to be hereditary in Himalayan cats, some domestic shorthair cats,[108] and certain breeds of cattle.[109] It is seen as a sporadic condition in domestic dogs. It has a similar treatment and prognosis. Animals with the condition should not be bred, as the condition can be inherited.[110] * Animal EDS * EDS in a dog * Same dog with EDS * EDS in same dog showing an atrophic scar Degenerative suspensory ligament desmitis (DSLD) is a similar condition seen in many breeds of horses.[111] It was originally notated in the Peruvian Paso and thought to be a condition of overwork and older age. However, DSLD is being recognized in all age groups and all activity levels. It has been noted in newborn foals. ## See also[edit] * Medicine portal * Ehlers-Danlos Society * Hypermobility spectrum disorder ## References[edit] 1. ^ a b c d e f g h i j k l m n o p "Ehlers–Danlos syndrome". Genetics Home Reference. Archived from the original on 8 May 2016. Retrieved 8 May 2016. 2. ^ a b Anderson BE (2012). The Netter Collection of Medical Illustrations - Integumentary System E-Book (2 ed.). Elsevier Health Sciences. p. 235. ISBN 978-1455726646. 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Retrieved 2018-04-17. 87. ^ "Topics in Pain Management: pain management in patients with hyper mobility disorders: frequently missed causes of chronic pain" (PDF). Topics in Pain Management. 88. ^ Giroux CM, Corkett JK, Carter LM (2016). "The Academic and Psychosocial Impacts of Ehlers-Danlos Syndrome on Postsecondary Students: An Integrative Review of the Literature" (PDF). Journal of Postsecondary Education and Disability. 29 (4): 414. 89. ^ a b Wiesmann T, Castori M, Malfait F, Wulf H (July 2014). "Recommendations for anesthesia and perioperative management in patients with Ehlers-Danlos syndrome(s)". Orphanet Journal of Rare Diseases. 9: 109. doi:10.1186/s13023-014-0109-5. PMC 4223622. PMID 25053156. 90. ^ Parapia LA, Jackson C (April 2008). "Ehlers-Danlos syndrome--a historical review". British Journal of Haematology. 141 (1): 32–5. doi:10.1111/j.1365-2141.2008.06994.x. PMID 18324963. S2CID 7809153. 91. ^ OrphanAnesthesia Guidelines harvnb error: no target: CITEREFOrphanAnesthesia_Guidelines (help) 92. ^ Shirley ED, Demaio M, Bodurtha J (September 2012). "Ehlers-danlos syndrome in orthopaedics: etiology, diagnosis, and treatment implications". Sports Health. 4 (5): 394–403. doi:10.1177/1941738112452385. PMC 3435946. PMID 23016112. 93. ^ "What are the Ehlers-Danlos Syndromes?". The Ehlers Danlos Society. Retrieved 2019-09-10. 94. ^ Pepin M, Schwarze U, Superti-Furga A, Byers PH (March 2000). "Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type". The New England Journal of Medicine. 342 (10): 673–80. CiteSeerX 10.1.1.603.1293. doi:10.1056/NEJM200003093421001. PMID 10706896. 95. ^ a b c d e f g Pepin M, Schwarze U, Superti-Furga A, Byers PH (March 2000). "Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type". The New England Journal of Medicine. 342 (10): 673–80. doi:10.1056/NEJM200003093421001. PMID 10706896. 96. ^ "Ehlers–Danlos Syndrome: Epidemiology". Medscape.com. Archived from the original on 2013-04-24. Retrieved 2014-02-27. 97. ^ "Ehlers-Danlos syndrome type VIIc". geneaware.clinical.bcm.edu. Archived from the original on 2017-08-14. Retrieved 2017-07-24. 98. ^ Yücel D (January 1995). "Was Paganini born with Ehlers-Danlos syndrome phenotype 4 or 3?". Clinical Chemistry. 41 (1): 124–5. doi:10.1093/clinchem/41.1.124. PMID 7813066. 99. ^ "Stretchiest skin". Guinness World Records. Retrieved 2019-06-22. 100. ^ "Houston hits out at 'preconceived ideas' – Coronation Street News – Soaps". Digital Spy. 2010-05-22. Archived from the original on 2013-05-09. Retrieved 2014-02-27. 101. ^ Drag Race's Yvie Oddly On Living with Ehlers Danos Syndrome 102. ^ Rosenberg P (30 September 2014). "Eric the Actor: A Eulogy". Rolling Stone. Retrieved 23 July 2019. 103. ^ Gillespie, Claire. "Jameela Jamil Confirms She Has Ehlers-Danlos Syndrome". SELF. Retrieved 9 August 2019. 104. ^ "Lena Dunham goes on Instagram to reveal she has Ehlers-Danlos syndrome" 105. ^ Doherty, Jennifer (2019-10-05). "Ehlers-Danlos syndrome: Singer Sia's condition explained". Newsweek. Retrieved 2019-11-11. 106. ^ "Here's What YouTuber Annie Elainey Wants You to Know About Being Disabled". Brit + Co. 2017-09-01. Retrieved 2019-11-11. 107. ^ "Living with little-known disorder Ehlers-Danlos sparked Miss Virginia's love of science". VCU School of Pharmacy News. Retrieved 2020-03-01. 108. ^ Scott DV (October 1974). "Cutaneous asthenia in a cat, resembling Ehlers-Danlos syndrome in man". Veterinary Medicine, Small Animal Clinician. 69 (10): 1256–8. doi:10.3906/vet-1203-64. PMID 4496767. 109. ^ Scott DW (2008). "Congenital and hereditary skin diseases". Color Atlas of Farm Animal Dermatology. Wiley Online Library. p. 61. doi:10.1002/9780470344460. ISBN 9780470344460. 110. ^ "Ehler-Danlos Syndrome (Cutaneous asthenia, dermatosparaxis)". veterinary-practice.com. 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PMID 24443030. ## External links[edit] Wikimedia Commons has media related to Ehlers-Danlos syndrome. * Ehlers–Danlos syndromes at Curlie Classification D * ICD-10: Q79.6 (ILDS Q82.817) * ICD-9-CM: 756.83 * MeSH: D004535 * DiseasesDB: 4131 External resources * MedlinePlus: 001468 * eMedicine: derm/696 ped/654 * Patient UK: Ehlers–Danlos syndromes * GeneReviews: Ehlers–Danlos Syndrome, Classic TypeVascular Ehlers–Danlos SyndromeEhlers–Danlos Syndrome, Hypermobility TypeEhlers–Danlos Syndrome, Kyphoscoliotic Form * Orphanet: 98249 * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous proteins * v * t * e Disorders of translation and posttranslational modification Translation * Ribosome: Diamond–Blackfan anemia * FMR1 * Fragile X syndrome * Fragile X-associated tremor/ataxia syndrome * Premature ovarian failure 1 * Initiation factor: Leukoencephalopathy with vanishing white matter * snRNP: Retinitis pigmentosa 33 Posttranslational modification Protein folding * Alzheimer's disease * Huntington's disease * Creutzfeldt–Jakob disease * chaperonins: 3-Methylglutaconic aciduria 5 Protein targeting * I-cell disease Ubiquitin * E1: X-linked spinal muscular atrophy 2 * E3: Johanson–Blizzard syndrome * Von Hippel–Lindau disease * 3-M syndrome * Angelman syndrome * Deubiquitinating enzyme: Machado–Joseph disease * Aneurysmal bone cyst * Multiple familial trichoepithelioma 1 SUMO * OFC10 Other * Multiple sulfatase deficiency * Hyperproinsulinemia * Ehlers–Danlos syndrome 6 * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Ehlers–Danlos syndromes	c0013720	5,068	wikipedia	https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndromes	2021-01-18T19:01:42	{"gard": ["6322"], "mesh": ["D004535"], "umls": ["C0013720"], "orphanet": ["98249"], "wikidata": ["Q1141499"]}
3M syndrome is a growth disorder that causes short stature, characteristic facial features, and skeletal abnormalities. Intelligence is normal. The name comes from the initials of three researchers who first identified it: Miller, McKusick, and Malvaux. 3M syndrome is caused by mutations in one of three genes: CUL7, OBSL1, and CCDC8. It is inherited in an autosomal recessive pattern. Diagnosis is based on the presence of clinical features. Genetic testing can confirm the diagnosis and identify the specific gene involved. Treatment is aimed at addressing the growth and skeletal problems and may include surgical bone lengthening, adaptive aids, and physical therapy. An endocrinologist may assist with growth hormone replacement and appropriate evaluations during puberty. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	3M syndrome	c1851996	5,069	gard	https://rarediseases.info.nih.gov/diseases/5667/3m-syndrome	2021-01-18T18:02:25	{"mesh": ["C535725"], "orphanet": ["2616"], "synonyms": ["Three M syndrome", "Gloomy face syndrome", "3M1", "Dolichospondylic dysplasia", "Le Merrer syndrome", "3-MSBN", "Three-M slender-boned nanism", "Yakut short stature syndrome", "3-M syndrome"]}
Central nervous system tumor SpecialtyOncology, neurology A central nervous system tumor (CNS tumor) is an abnormal growth of cells from the tissues of the brain or spinal cord.[1] CNS tumor is a generic term encompassing over 120 distinct tumor types.[2] Common symptoms of CNS tumors include vomiting, headache, changes in vision, nausea, and seizures.[3] A CNS tumor can be detected and classified via neurological examination, medical imaging, such as x-ray imaging, magnetic resonance imaging (MRI) or computed tomography (CT), or after analysis of a biopsy.[4] ## Contents * 1 Types * 2 Symptoms * 3 Causes * 3.1 Inheritance * 4 Diagnosis * 4.1 Imaging * 4.1.1 Magnetic Resonance Imaging * 4.1.2 Magnetic Resonance Spectroscopy * 4.1.3 Computed tomography * 4.2 Biopsy * 4.3 Blood tests * 5 Treatment * 5.1 Surgery * 5.2 Radiation therapy * 5.3 Chemotherapy * 5.4 Targeted therapy * 5.5 Active surveillance * 6 References * 7 Sources ## Types[edit] The list below is based on the WHO classification of CNS tumors and on http://www.kinderkrebsregister.de/[5] and http://www.seer.cancer.gov/.[6] The American Cancer Society estimated the number of new cases of CNS tumors in the US in 2019 to be 23,820, and the number of deaths attributable to CNS tumors to be 17,760.[7] Tumor classification Frequency as % of total CNS tumors Pilocytic astrocytomas ~30% Diffuse astrocytomas ~12% Anaplastic astrocytomas ~2% Glioblastomas ~3% Oligodendroglial tumors ~1.5% Ependymal tumor ~9% Medulloblastomas ~20% Pineal tumors ~1.5% Meningeal tumors ~1.2% Germ cell tumors ~3% ## Symptoms[edit] The most common symptoms of CNS tumors are headache, vomiting, and nausea. Symptoms vary depending on the tumor and may include unsteady gait, slowed speech, memory loss, loss of hearing and vision, problems with memory, narrowing of visual field, and back pain. Symptoms may also vary greatly between individuals with the same tumor type. In pediatric patients, symptoms may include:[8] * Headache * Changes in vision * Nausea and vomiting * Balance problems * Seizures * Behavioral changes * Abnormal head position * Delayed puberty * Abnormal growth * Excessive thirst * Reduced consciousness Some symptoms in adults are specific to the location of the tumor: * Tumors in the cerebrum, which controls movement, may cause weakness or numbness to the body. This weakness is often limited to one side of the body. * Tumors in the Broca's area of the cerebrum can cause speech difficulties. In extreme cases, the patient may have problems understanding words. * Tumors in the premotor cortex and the primary motor cortex, which are located at the front and top of the cerebrum, may cause sloppy movements, trouble walking, difficulties in moving arms, hands, fingers, and legs. In severe cases, such tumors may even cause wallowing and abnormal eye movements. * Tumors located in the lower part of the cerebrum near the primary visual cortex can cause blurred vision, double vision, or loss of vision. * Tumors located in the spinal cord usually have symptoms that start with back pain that spreads towards the arms or legs. These tumors can cause trouble urinating or walking. ## Causes[edit] The causes of CNS tumors are poorly understood. A few risk factors are known, including radiation exposure, genetic disorder, a family history of CNS tumors, immunodeficiency, stress and a history of previous cancers. As with all cancers, the risk of developing a CNS tumor increases with age.[9] ### Inheritance[edit] A number of genetic disorders increase the risk of specific types of CNS tumors. These include tuberous sclerosis, Von Hippel-Lindau disease, Li-Fraumeni syndrome, Gorlin syndrome, Turcot syndrome, Cowden Syndrome and neurofibromatosis types 1 and 2 (NF1/NF2).[10] Patients suffering from NF1 have higher risks of having schwannomas, meningiomas, and some types of gliomas. NF2 is correlated with vestibular schwannomas. ## Diagnosis[edit] There are no recommended tests to diagnose CNS tumors.[11] The tumor is usually found when patients develop symptoms and visit the doctor. The first step in diagnosis is usually a neurological exam, including tests for reflexes, muscle strength, vision and eye movements, and balance and alertness. If the results are abnormal, additional tests carried out by a specialist such as a neurosurgeon or a neurologist may be recommended. Adults and children both undergo a similar set of tests to diagnose CNS tumors, including: * Medical history * Blood test * Urine test * Medical imaging * X-ray * CT scan * MRI * Biopsy Most patients who have CNS tumors do not have a family record of the disease. ### Imaging[edit] Imaging is an important method for diagnosing CNS tumors and determining their location. The location is informative both for identifying the type of tumor and for determining how to treat it. Magnetic resonance imaging (MRI) and computed tomography (CT) scans are the most commonly used imaging technologies for diagnosis of CNS tumors. MRI provides better detail and detection of tumor-infiltrated areas.[12] Examples of CNS tumors imaged using positron emission tomography (PET). #### Magnetic Resonance Imaging[edit] Magnetic resonance imaging uses strong magnetic fields, magnetic field gradients, and radio waves to generate images of the structure of the brain. In perfusion MRI a contrast agent, such as gadolinium compounds, may be used to study the structure of the blood vessels around the tumor that provide nutrients and remove waste.[12] The contrast agent may be taken by mouth or injected into the patient before the scan. #### Magnetic Resonance Spectroscopy[edit] Magnetic resonance spectroscopy (MRS) is a variant of MRI used to measure biochemical changes in the brain. Comparing the metabolites detected in normal brain tissue with those in affected brain tissue can help determine the type of tumor and estimate how quickly it is growing.[12] #### Computed tomography[edit] Computed tomography (CT) technologies include X-ray CT, positron emission tomography (PET) and single-photon emission computed tomography (SPECT). X-ray CT scans take many X-ray measurements from different angles to produce virtual "slices" of specific areas of a scanned object that can then be reassembled into a complete image of the object. Such scans can detect tumors by the swelling and anatomical distortion they cause, or by surrounding edema. While CT scans are widely available and produce images rapidly, MRI scans provide better anatomic detail of brain structures and detection of tumor-infiltrated areas.[12] ### Biopsy[edit] A biopsy is the definitive way to diagnose CNS tumors. Because of the difficulty of accessing brain tissue, and the risk of damage to the brain, biopsies may be guided by computer and imaging in a stereotactic surgery procedure. A stereotactic biopsy is performed under local anesthesia or general anesthesia. After the MRI or a CT scan, the scalp or scalp contours are marked to show the position of where to drill or cut the scalp. An image guidance system is then used to provide assistance in directing a needle into the tumor to collect a small tissue sample. The sample is analyzed by a pathologist or neuropathologist to determine whether the tumor is benign or malignant and identify the type of tumor. Biopsies can also be performed as part of an operation to remove the tumor mass.[13] ### Blood tests[edit] Blood tests such as a complete blood count (CBC) can provide insight into the progress of a tumor by measuring the number of blood cell types such as white blood cells, red blood cells and platelets. Blood chemistry is also used to check the health of the liver, kidneys and other organs. Many tumors shed microscopic extracellular vesicles into the bloodstream that can be used to monitor the progress of a cancer or its response to therapy.[14] ## Treatment[edit] CNS tumors are typically treated using one or more of the following options: * Surgery * Radiation Therapy * Chemotherapy * Targeted therapy * Active surveillance Treatment of CNS tumors frequently involves a team of doctors working together, including neurosurgeons, neurologists, medical oncologists, radiation oncologists and endocrinologists. ### Surgery[edit] Surgeries are used both to diagnose and to treat CNS tumors. Removal of tumor tissues helps decrease the pressure of the tumor on nearby parts of the brain.[15] The main goal of surgery is to remove as much as possible of the tumor mass while preserving normal brain function, and to relieve the symptoms caused by the tumor such as headache, nausea and vomiting.[16] Some tumors are deep-seated and unsafe to remove, and in these cases the role of surgery may be limited to obtaining a diagnostic biopsy.[16] After the surgery, chemotherapy or radiation therapy may be used to destroy the remaining cancer cells. ### Radiation therapy[edit] Radiation therapy uses high energy rays to destroy cancer cells or to shrink tumors. The kind of rays used are x-rays, gamma rays, electron beams or protons. According to the National Cancer Institute,[1] there are two types of radiation therapy: * external radiation therapy * internal radiation therapy External radiation therapy or teletherapy uses a machine that sends a focused beam of radiation directed at the location of the tumor in the body. The radiation may be delivered from several angles or in a shaped beam to maximize the dose delivered to the tumor while reducing the harm to healthy parts of the body.[1] Treatment is commonly given daily for 4-8 weeks.[17] In internal radiation therapy, the source of radiation is inserted into the patient's body. This may be done by placing a solid source of radiation adjacent to the tumor in the form of a seed, ribbon or capsule (brachytherapy)[1] or by giving the patient a liquid source of radiation that travels through the body and kills cancer cells (system therapy). In this case the radiation is usually given in the form of injections, ingesting a capsule or through an intravenous line.[citation needed] ### Chemotherapy[edit] Chemotherapy is a treatment that uses a tumor-killing drug to prevent the growth of cancer cells by stopping them from dividing. It is often used after surgery or as the first line of treatment. The drug may be given systemically, by injection into a vein or by mouth, or may be injected into the fluid that surrounds the brain and spinal cord to allow the drug to reach the tumor without crossing the blood–brain barrier (intrathecal administration).[1] Common side effects of chemotherapy include: * Hair loss * Mouth sores * Loss of appetite * Nausea * Diarrhea * Increased rate of infections * Easy bruising and bleeding * Fatigue ### Targeted therapy[edit] An increasing number of drugs are available that promise to target a tumor specifically, reducing harm to normal cells. These therapies are matched to the specific tumor, and include antibodies that bind to specific surface molecules found primarily on the tumor, or small molecules that target proteins mutated in the tumor. Targeted therapies may block enzymes or other proteins necessary for cancer cell proliferation, deliver toxic substances directly to cancer cells, help with immune system function, or prevent the tumor from obtaining the nutrients it needs.[18] For example, bevacizumab is a targeted therapy drug used against various cancers, including glioblastoma, that blocks the blood supply to and therefore the proliferation of cancerous tumors.[citation needed] Checkpoint inhibitors, which prevent the tumor from blocking the action of tumor-killing cells of the immune system. are also being tested for CNS tumor therapy.[19] Although targeted therapy may have fewer side effects than other forms of cancer treatment, side effects are still frequent and may include high blood pressure, fatigue, increased risk of infection, or diarrhea.[citation needed] ### Active surveillance[edit] All treatments for CNS tumors have significant risks and side-effects. In cases where tumors are slow growing and do not cause symptoms, it may be preferable to closely watch the patient's condition without any treatment, until new test results or symptoms indicate that the patient's condition has worsened.[15] ## References[edit] 1. ^ a b c d e "Adult Central Nervous System Tumors Treatment". National Cancer Institute. 1980-01-01. Retrieved 2019-06-28. 2. ^ "Tumor Types". National Brain Tumor Society. Retrieved 2019-06-28. 3. ^ "Signs and Symptoms of Adult Brain and Spinal Cord Tumors". www.cancer.org. Retrieved 2019-06-28. 4. ^ "Brain tumor - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2019-06-28. 5. ^ "Übersicht- Deutsches Kinderkrebsregister". www.kinderkrebsregister.de. Retrieved 2019-05-15. 6. ^ "Surveillance, Epidemiology, and End Results Program". SEER. Retrieved 2019-05-15. 7. ^ PDQ Adult Treatment Editorial Board (2002), "Adult Central Nervous System Tumors Treatment (PDQ®): Health Professional Version", PDQ Cancer Information Summaries, National Cancer Institute (US), PMID 26389419, retrieved 2019-11-11 8. ^ "Child brain tumor symptoms \| The Brain Tumor Charity". www.thebraintumourcharity.org. Retrieved 2019-06-28. 9. ^ "Risks and causes of brain tumors \| Brain tumor (primary) \| Cancer Research UK". www.cancerresearchuk.org. Retrieved 2019-06-28. 10. ^ "Risk Factors for Brain and Spinal Cord Tumors". www.cancer.org. Retrieved 2019-06-28. 11. ^ "Signs and Symptoms of Adult Brain and Spinal Cord Tumors". www.cancer.org. Retrieved 2019-05-25. 12. ^ a b c d Pope, Whitney B.; Brandal, Garth (September 2018). "Conventional and advanced magnetic resonance imaging in patients with high-grade glioma". The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 62 (3): 239–253. doi:10.23736/S1824-4785.18.03086-8. PMC 6123261. PMID 29696946. 13. ^ "Brain Tumor - Diagnosis". Cancer.Net. 2012-06-25. Retrieved 2019-11-11. 14. ^ Jaiswal, Ritu; Sedger, Lisa M. (6 March 2019). "Intercellular Vesicular Transfer by Exosomes, Microparticles and Oncosomes - Implications for Cancer Biology and Treatments". Frontiers in Oncology. 9: 125. doi:10.3389/fonc.2019.00125. PMC 6414436. PMID 30895170. 15. ^ a b "Adult Central Nervous System Tumors Treatment (PDQ®)–Patient Version". National Cancer Institute. 2019-10-11. Retrieved 2019-11-11. 16. ^ a b Widhalm, Georg; Traub-Weidinger, Tatjana; Hainfellner, Johannes A.; Bienkowski, Michal; Wolfsberger, Stefan; Czech, Thomas (2018). "Bioimaging and surgery of brain tumors". Neuropathology. Handbook of Clinical Neurology. 145. pp. 535–545. doi:10.1016/B978-0-12-802395-2.00033-X. ISBN 978-0-12-802395-2. PMID 28987192. 17. ^ "Cancer treatment: Radiotherapy". International Atomic Energy Agency. 2016-04-13. Retrieved 2019-11-12. 18. ^ "Targeted Cancer Therapies Fact Sheet". National Cancer Institute. Retrieved 2019-9-22. 19. ^ Sampson, John H.; Maus, Marcela V.; June, Carl H. (2017-06-22). "Immunotherapy for Brain Tumors". Journal of Clinical Oncology. 35 (21): 2450–2456. doi:10.1200/JCO.2017.72.8089. ISSN 0732-183X. PMID 28640704. S2CID 28346352. ## Sources[edit] * Frühwald, Michael C; Rutkowski, Stefan (2011). "Tumors of the Central Nervous System in Children and Adolescents". Deutsches Ärzteblatt International. 108 (22): 390–397. doi:10.3238/arztebl.2011.0390. PMC 3123765. PMID 21712972. * PDQ Adult Treatment Editorial, Board (2002). "Adult Central Nervous System Tumors Treatment (PDQ®): Patient Version". PMID 26389458. Cite journal requires `\|journal=` (help) * "Adult Central Nervous System Tumors Treatment (PDQ®)–Patient Version". National Cancer Institute. 15 November 2019. * Brain and other central nervous system tumors \| Cancer Australia Children's Cancers. (2019). Retrieved from https://childrenscancer.canceraustralia.gov.au/types-childrens-cancers/brain-and-cns-tumors * Signs and Symptoms of Adult Brain and Spinal Cord Tumors. (2019). Retrieved from https://www.cancer.org/cancer/brain-spinal-cord-tumors-adults/detection-diagnosis-staging/signs-and-symptoms.html * Momota, Hiroyuki; Holland, Eric C. (27 October 2009). "Mouse models of CNS embryonal tumors". Brain Tumor Pathology. 26 (2): 43–50. doi:10.1007/s10014-009-0253-0. PMID 19856214. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Central nervous system tumor	c0085136	5,070	wikipedia	https://en.wikipedia.org/wiki/Central_nervous_system_tumor	2021-01-18T18:41:26	{"mesh": ["D016543"], "wikidata": ["Q4335557"]}
Autosomal dominant optic atrophy and cataract is an eye disorder that is characterized by impaired vision. Most affected individuals have decreased sharpness of vision (visual acuity) from birth, while others begin to experience vision problems in early childhood or later. In affected individuals, both eyes are usually affected equally. However, the severity of the vision loss varies widely, even among affected members of the same family, ranging from nearly normal vision to complete blindness. Several abnormalities contribute to impaired vision in people with autosomal dominant optic atrophy and cataract. In the early stages of the condition, affected individuals experience a progressive loss of certain cells within the retina, which is a specialized light-sensitive tissue that lines the back of the eye. The loss of these cells (known as retinal ganglion cells) is followed by the degeneration (atrophy) of the nerves that relay visual information from the eyes to the brain (optic nerves), which contributes to vision loss. Atrophy of these nerves causes an abnormally pale appearance (pallor) of the optic nerves, which can be seen only during an eye examination. Most people with this disorder also have clouding of the lenses of the eyes (cataracts). This eye abnormality can develop anytime but typically appears in childhood. Other common eye problems in autosomal dominant optic atrophy and cataract include involuntary movements of the eyes (nystagmus), or problems with color vision (color vision deficiency) that make it difficult or impossible to distinguish between shades of blue and green. Some people with autosomal dominant optic atrophy and cataract develop disturbances in the function of other nerves (neuropathy) besides the optic nerves. These disturbances can lead to problems with balance and coordination (cerebellar ataxia), an unsteady style of walking (gait), prickling or tingling sensations (paresthesias) in the arms and legs, progressive muscle stiffness (spasticity), or rhythmic shaking (tremors). In some cases, affected individuals have hearing loss caused by abnormalities of the inner ear (sensorineural deafness). ## Frequency Autosomal dominant optic atrophy and cataract is one form of autosomal dominant optic atrophy, a group of conditions that are estimated to affect 1 in 30,000 people worldwide, and approximately 1 in 10,000 people in Denmark. A form of optic atrophy called optic atrophy type 1 accounts for most cases, while autosomal dominant optic atrophy and cataract is thought to represent only a few percent of autosomal dominant optic atrophy cases. ## Causes Autosomal dominant optic atrophy and cataract is caused by mutations in a gene called OPA3. The protein produced from this gene is made in cells and tissues throughout the body. The OPA3 protein is found within mitochondria, which are the energy-producing centers of cells. While the exact function of the protein is unknown, it is thought to play a role in the organization of the shape and structure of the mitochondria and in controlled cell death (apoptosis). Mutations in the OPA3 gene lead to abnormal mitochondrial function. The mitochondria become misshapen and disorganized and have reduced energy-producing capabilities. Cells that contain these poorly functioning mitochondria seem to be more susceptible to apoptosis. In particular, affected cells that have high energy demands, such as retinal ganglion cells, are likely to die prematurely. Specialized extensions of retinal ganglion cells, called axons, form the optic nerves, so when retinal ganglion cells die, the optic nerves atrophy and cannot transmit visual information to the brain. Together, these effects reduce vision in affected individuals. It is likely that nerve cells in other parts of the body are similarly affected by dysfunctional mitochondria, resulting in the signs and symptoms of neuropathy in individuals with autosomal dominant optic atrophy and cataract. It is unclear how OPA3 gene mutations lead to cataracts and other eye problems that can occur in autosomal dominant optic atrophy and cataracts. ### Learn more about the gene associated with Autosomal dominant optic atrophy and cataract * OPA3 ## 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. In most cases, an affected person has one parent with the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Autosomal dominant optic atrophy and cataract	c1833809	5,071	medlineplus	https://medlineplus.gov/genetics/condition/autosomal-dominant-optic-atrophy-and-cataract/	2021-01-27T08:24:58	{"gard": ["10203"], "mesh": ["C537128"], "omim": ["165300"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that Schuurs-Hoeijmakers syndrome (SHMS) is caused by heterozygous mutation in the PACS1 gene (607492) on chromosome 11q13. Description Schuurs-Hoeijmakers syndrome is an autosomal dominant disorder characterized by mental retardation, distinct craniofacial features, and variable additional congenital abnormalities (summary by Schuurs-Hoeijmakers et al., 2016). Clinical Features Schuurs-Hoeijmakers et al. (2012) reported 2 unrelated boys from a cohort of 5,000 individuals with intellectual disability who had remarkable similarity in facial features. Both had a low anterior hairline, hypertelorism with downslanting palpebral fissures, mild synophrys with highly arched eyebrows, long eyelashes, bulbous nose, flat philtrum, large low-set ears, wide mouth with downturned corners, thin upper lip, and diastema of the teeth. One boy had an IQ of less than 50; the other boy had an IQ of 53. The first boy had a single umbilical artery, unilateral cryptorchidism, malrotation, as well as widely spaced nipples, slender fingers with broad thumbs, clubbed nails, a single transverse palmar cleft on the left hand, and pes planus. MRI showed a cavum septum pellucidum but was otherwise normal. The second boy was large at birth and had strikingly similar dysmorphic facial features. He also had cryptorchidism. On neurologic examination he had some balance problems and mild dysarthric speech. He was hypotonic. MRI showed partial agenesis of the cerebellum vermis and hypoplasia of the cerebellar hemispheres, more pronounced on the right side. Schuurs-Hoeijmakers et al. (2016) reported the clinical features of 19 patients with genetically confirmed SHMS, including the 2 patients reported by Schuurs-Hoeijmakers et al. (2012) and 1 reported by Gadzicki et al. (2015). All had a distinctive facial appearance with full and arched eyebrows, long eyelashes, hypertelorism, downslanting palpebral fissures, ptosis, low-set simple ears, bulbous nasal tip, wide mouth with downturned corners, thin upper lip, flat philtrum, and diastema of the teeth. All had delayed psychomotor development with mild to moderate intellectual disability and poor or absent speech; most had hypotonia. Fifteen patients had additional variable congenital anomalies, including cardiac septal defects and eye abnormalities, such as coloboma, high myopia, nystagmus, and strabismus. Feeding difficulties were common, and many patients showed oromotor sensitivity with problems eating solid food. Gastric reflux and constipation were also noted in some patients. Motor development was delayed, with walking achieved between 2 and 3 years in most patients, and some had persistent gait difficulties. Twelve patients had seizures that could be controlled with medication. Twelve of 16 individuals who underwent brain imaging had variable abnormalities, including cerebellar hypoplasia, enlarged ventricles, and nonspecific white matter changes. Three patients had kidney abnormalities and 6 males had cryptorchidism. Although most had a pleasant demeanor, some had behavioral difficulties, such as aggression or increased frustration. Six had autistic features. Martinez-Monseny et al. (2018) described a 12-year-old girl with genetically confirmed SHMS. Clinical features included overgrowth from birth, with height and head circumference greater than the 97th centile and hand and foot length greater than the 99th centile. She also had fifth finger clinodactyly and camptodactyly, high plantar arches without evidence of a neuropathy, and dysmorphic facial features, including hypertelorism, downslanting palpebral fissures, eversion of the lateral third of lower eyelids, a bulbous nasal tip, long philtrum, thin upper vermilion, a wide mouth with downturned corners, and low-set ears. She also had a persistent ductus arteriosus, patent foramen ovale, and bicuspid aortic valve. She had partial seizures since the age of 3 years, treated with carbamazepine, and she had laughing episodes since the age of 10 years, treated with aripiprazole. She had 3 episodes of ataxia lasting a few hours during periods when she had recurrent mycoplasma respiratory tract infections involving the right upper lobe of the lung. The ataxia resolved spontaneously. Laboratory testing showed a maintained decrease in complement factor C3 (less than 110 U/ml; normal, 890-1950). In contrast to previously reported patients, she had no digestive or feeding disturbances and her communication skills were only mildly impaired. Molecular Genetics In 2 unrelated boys with mental retardation and similar dysmorphic facial features, Schuurs-Hoeijmakers et al. (2012) identified identical de novo heterozygous mutations in the PACS1 gene (R203W; 607492.0001). The mutation was not identified in 150 alleles from the Dutch population, in 2,304 alleles from the local variant database, or in 7,020 alleles of European American origin from the NHLBI Exome Sequencing Project database. Expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects most likely in a dominant-negative fashion. The phenotype was driven by aberrant specification and migration of SOX10 (602229)-positive cranial, but not enteric, neural crest cells. In a 3-year-old boy with SHMS, Gadzicki et al. (2015) identified the same de novo heterozygous R203W mutation in the PACS1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. Schuurs-Hoeijmakers et al. (2016) reported 16 additional patients with SHMS resulting from the recurrent de novo heterozygous R203W mutation in the PACS1 gene. All patients were diagnosed by exome sequencing. Functional studies of the variant were not performed. In a 12-year-old girl with SHMS, Martinez-Monseny et al. (2018) identified the recurrent de novo R203W mutation in the PACS1 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Flat philtrum Ears \- Low-set ears \- Simple ears Eyes \- Full, arched eyebrows \- Long eyelashes \- Hypertelorism \- Downslanting palpebral fissures \- Ptosis \- Nystagmus \- Strabismus \- Myopia Nose \- Bulbous tip Mouth \- Wide mouth \- Downturned corners of the mouth \- Thin upper lip \- Oromotor sensitivity Teeth \- Diastema CARDIOVASCULAR Heart \- Septal defects (in some patients) \- Patent ductus arteriosus \- Patent foramen ovale \- Bicuspid aortic valve ABDOMEN Gastrointestinal \- Feeding difficulties \- Difficulty eating solid food Gastric reflux \- Constipation GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Renal defects (in some patients) SKELETAL Hands \- Large hands (in 1 patient) Feet \- Large feet (in 1 patient) \- High plantar arches (in 1 patient) \- Pes planus MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability \- Language delay \- Poor or absent speech \- Seizures \- Cerebellar hypoplasia (in some patients) \- Ventricular abnormalities (in some patients) \- White matter defects (in some patients) Behavioral Psychiatric Manifestations \- Behavioral abnormalities \- Aggressive behavior \- Autistic features \- Laughing episodes IMMUNOLOGY \- Decrease in complement factor C3 (in 1 patient) MISCELLANEOUS \- Recurrent de novo mutation MOLECULAR BASIS \- Caused by mutation in the phosphofurin acidic cluster sorting protein 1 gene (PACS1, 607492.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	SCHUURS-HOEIJMAKERS SYNDROME	c3554343	5,072	omim	https://www.omim.org/entry/615009	2019-09-22T15:53:28	{"doid": ["0070047"], "omim": ["615009"], "orphanet": ["329224"], "synonyms": ["Alternative titles", "MENTAL RETARDATION, AUTOSOMAL DOMINANT 17"]}
Ocular melanoma (OM) is a cancer in pigment-producing cells of the eye called melanocytes. Melanocytes are cells that produce the pigment melanin that colors the skin, hair, and eyes, as well as forms moles. There are four tissues in the eye in which melanoma can develop: the uveal tract (uvea); conjunctiva; eyelid; and orbit. The uvea - the middle layer within the eye - is divided into three main parts: the iris, ciliary body, and choroid. Uveal melanoma, also called intraocular melanoma, is the most common ocular melanoma. Conjunctival melanoma manifests on the surface of the eye and has been increasing in incidence. Eyelid and primary orbital melanoma are the least common variants. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Ocular melanoma	c0558356	5,073	gard	https://rarediseases.info.nih.gov/diseases/7236/ocular-melanoma	2021-01-18T17:58:38	{"umls": ["C0558356"], "synonyms": []}
An extremely rare, autosomal dominant immunological disorder characterized by variable enteropathy, endocrine disorders (e.g. type 1 diabetes mellitus, hypothyroidism), immune dysregulation with pulmonary and blood-borne bacterial infections, and fungal infections (chronic mucocutaneous candidiasis) developing in infancy. Other manifestations include short stature, eczema, hepatosplenomegaly, delayed puberty, and osteoporosis/osteopenia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome	c3279990	5,074	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391487	2021-01-23T17:09:03	{"omim": ["614162"], "icd-10": ["K63.9"]}
Ectomesenchymoma is a rare, fast-growing tumor of the nervous system or soft tissue that occurs mainly in children, although cases have been reported in patients up to age 60.[1] Ectomesenchymomas may form in the head and neck, abdomen, perineum, scrotum, or limbs. Also called malignant ectomesenchymoma. Malignant ectomesenchymoma (MEM) is a rare tumor of soft tissues or the CNS, which is composed of both neuroectodermal elements [represented by ganglion cells and/or well-differentiated or poorly differentiated neuroblastic cells such as ganglioneuroma, ganglioneuroblastoma, neuroblastoma, peripheral primitive neuroectodermal tumors – PNET] and one or more mesenchymal neoplastic elements, usually rhabdomyosarcoma . The most accepted theory suggests that this tumor arises from remnants of migratory neural crest cells and thus from the ectomesenchyme.[2] ## Contents * 1 Clinical picture * 2 Histopathology * 3 Research * 4 Historic background * 5 References * 6 External links ## Clinical picture[edit] The tumor largely affects children under 15 years of age and about 20% only are found in adults with nearly 60% involving males and 40% females (1). The most frequent locations are head and neck (orbit and nasopharynx), central nervous system, abdomen and retroperitoneum, pelvis, perineum, scrotum and prostate(1). Clinical symptoms are not specific and usually caused by local tumor compression and infiltration. ## Histopathology[edit] The main features of this tumor is to comprise either ectodermal derivatives (neuroblasts and ganglion cells) or mesenchymal components mostly represented by plump, elongated cells in interlacing bundles often showing rhabdomyoblastic differentiation, including strap-like and racket-shaped cells (2-6). A myofibril-like structure and cross striations can be identified. Liposarcoma-like and chondroid foci can be an additional finding. Fibrosarcoma-like and fibrous histiocytoma-like areas can be observed as well as neurofibromatous and neuroblastic components with rosette formation. Ganglion cells can appear immature and atypical, they can be bi- or multinucleated and showing evidence of Nissl substance (2-6). Rhabdomyoblasts and poorly differentiated small cells display positivity for desmin and myosin while neural areas are variably sensitive to S-100. Ganglion cells are strongly positive for NSE. It is important to point out that the ectodermal component may be sometimes scanty and can be overlooked whereas in specimens after chemotherapy the ganglioneuroma component is increased and even overwhelming. Differential diagnosis should consider rhabdomyosarcoma, Triton tumor, teratoma, Wilms tumor and benign, mature ectomesenchymoma (ectomesenchymal hamartoma). ## Research[edit] Goldsby et al. reported an ectomesenchymoma of the kidney showing hyperdiploid count and a translocation between chromosomes 12 and 15 (8). Floris et al. found in their reported case hyperploidism in a subset of cells as well as gains of chromosomes 2, 11 and 20, a finding in common with alveolar rhabdomyosarcoma. They found as well 2 distinctive chromosome 6p21.32-p21.2 and 6p11.2 amplification regions in the primary tumor which disappeared in the postchemotherapy specimen. Furthermore, the pretreatment biopsy showed strong expression of HMGA1 and HMGA2 proteins by immunohistochemistry and loss of expression after therapy thereby crediting the HMGA family of proteins for oncogenic expansion (9). ## Historic background[edit] MEM comprises a heterogeneous group of neoplasms believed to originate from the neural crest. First hints to this type of tumor were probably from Shuangshoti and Nestky (1971) and from Holimon and Rosenblum (1971) (2-3). Additional contributions were provided thereafter by Naka et al. (1975), Karcioglu et al. (1977), Cozzutto et al. (1982) and Kawamoto et al. (1987). Kosem et al. collected 44 cases of MEM in a 2004 review and examined management data finding out that resection with pre- or post-surgery chemotherapy yielded the best results with one death only in 13. In the five cases reported by Mouton et al. an aggressive chemotherapy and adequate surgical excision granted a disease-free interval for 7 to 50 months. The attainability of radical surgical ablation seems the most important prognostic factor (10). ## References[edit] 1\. Kösen M, Ibiloglu I, Bakan V, Köseloglu B (2004) Ectomesenchymoma: Case report and review of the literature. Turk J Pediat 46:82-87. 2\. Shuangshoti S, Nestky MG (1971) Neoplasms of mixed mesenchymal and neuroepithelial origin. J Neuropathol Exp Neurol 30:290-309. 3\. Holimon JL, Rosenblum WI (1971) "Gangliorhabdomyosarcoma": a tumor of ectomesenchyme. J Neurosurg 34:417-422. 4\. Naka M, Matsumoto S, Shirai T, Itoh T (1975) Ganglioneuroblastoma associated with malignant mesenchymoma. Cancer 36:1050-1056. 5\. Karcioglu Z, Semeren A, Mathes SJ (1977) Ectomesenchymoma. A malignant tumor of migratory neural crest (ectomesenchyme) remnants showing ganglionic, schwannian, melanocytic and rhabdomyoblastic differentiation. Cancer 39:2486-2496. 6\. Cozzutto C, Comelli A, Bandelloni R (1982) Ectomesenchymoma. Report of two cases. Virchows Arch A Pathol Anat Histopathol 398:185-195. 7\. Kawamoto EH, Weidner N, Agostini RM jr, Jaffe R (1987) Malignant ectomesenchymoma of soft tissue. Report of two cases and review of the literature. Cancer 59:1791-1802. 8\. Goldsby RE, Bruggers CS, Brothman AR, Sorensen PH, Beckwith JB, Pysher TJ (1998) Spindle cell sarcoma of the kidney with ganglionic elements (Malignnt ectomesenchymoma) associated with chromosomal abnormalities and a review of the literature. J Pediat Hematol Oncol 20(2):160-164. 9\. Floris G, Debiec-Rychter M, Wozniak KA, Magrini S, Maffioletti G, De Wever I, Tellini G, Sciot R (2007) Malignant ectomesenchymoma: genetic profile reflects rhabdomyosarcomatous differentiation. Diagn Mol Pathol 16(4):243-248. 10\. Mouton SC, Rosenberg HS, Cohen MC, Drut R, Emms M, Kaschula RO (1996) Malignant ectomesenchymoma in childhood. Pediat Pathol Lab Med 16(4):607-624. 1. ^ "Archived copy". Archived from the original on 2007-07-13. Retrieved 2008-11-22.CS1 maint: archived copy as title (link) 2. ^ [1] ## External links[edit] * Ectomesenchymoma entry in the public domain NCI Dictionary of Cancer Terms This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms". [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Ectomesenchymoma	c0431111	5,075	wikipedia	https://en.wikipedia.org/wiki/Ectomesenchymoma	2021-01-18T18:44:28	{"umls": ["C0431111"], "wikidata": ["Q5334252"]}
An exceedingly rare form of brachyolmia, characterized by mild platyspondyly, broad ilia, elongated femoral necks with coxa valga, scoliosis, and short trunked short stature associated with amelogenesis imperfecta of both primary and permanent dentition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Brachyolmia-amelogenesis imperfecta syndrome	c1832594	5,076	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2899	2021-01-23T18:37:26	{"gard": ["5478"], "mesh": ["C536538"], "omim": ["601216"], "umls": ["C1832594"], "icd-10": ["Q76.3"], "synonyms": ["Platyspondyly-amelogenesis imperfecta syndrome", "Verloes-Bourguignon syndrome"]}
Esophageal carcinoma (EC) is a tumor arising in the epithelial cells lining the esophagus and can be divided into two subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ## Epidemiology The estimated annual incidence of EC in Europe is approximately 1/13,300. ## Clinical description The disease usually presents between the ages of 50-70 years. It is often asymptomatic until it has reached an advanced disease stage with the first symptoms usually being difficulty in swallowing (dysphagia), especially present when swallowing dry foods. Unintentional weight loss is also common. Manifestations of back or chest pain, hoarseness of voice, unexplained coughing, protracted hiccups, and severe reflux may be presenting or associated symptoms. More rarely, neck swelling from adenopathies may be the initial manifestation. ## Etiology The etiology is unknown but many risk factors for esophageal cancer have been identified. Alcohol abuse, smoking, lye ingestion, radiation therapy and achalasia are associated with ESCC. EAC is associated with Barrett's esophagus (see this term), which is intestinal metaplasia (replacement of normal esophageal epithelia by intestinal epithelia), associated with chronic gastroesophageal reflux disease. EAC has also been associated with obesity, in particular visceral obesity and metabolic syndromes which are more common in men than in women. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Carcinoma of esophagus	c0014859	5,077	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70482	2021-01-23T18:50:18	{"mesh": ["D004938"], "umls": ["C0014859", "C0152018", "C0546837"], "synonyms": ["Esophageal carcinoma"]}
A number sign (#) is used with this entry because of the occurrence of cerebral arteriovenous malformations in several genetic disorders including hereditary hemorrhagic telangiectasia (HHT; 187300) and hereditary neurocutaneous angioma (106070). A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to intracranial hemorrhage in brain arteriovenous malformations. Somatic activating mutations in the KRAS gene (190070) have been identified as a cause of arteriovenous malformations of the brain. Clinical Features Cerebral arteriovenous malformations are considered to be distinct from cerebral cavernous malformations (116860), which are venous and usually arteriographically 'silent' (Rigamonti, 1993). Snead et al. (1979) reported cerebral arteriovenous malformations in 3 sibs with the same mother. Two were by one father and the third by another. HHT and von Hippel-Lindau disease were excluded. They found reports of 4 instances of familial aggregation. Aberfeld and Rao (1981) reported affected brother and sister. Yokoyama et al. (1991) described 6 cases in 3 families. These included a father-son pair, a mother-son pair, and male and female first cousins. They commented on the report by Boyd et al. (1985) of affected father and 3 sons and another father and daughter combination. Biochemical Features Chen et al. (2009) found increased levels of soluble endoglin (ENG; 131195) in vascular surgical specimens from 33 patients with arteriovenous malformations of the brain compared to similar specimens from 8 epileptic patients. However, there was no difference in expression of membrane-bound endoglin and no difference in plasma soluble endoglin between BAVM patients and controls. Transduction of soluble endoglin in mouse brain resulted in the formation of abnormal and dysplastic capillary structures, and was associated with increased levels of matrix metalloproteinase activity and oxidative radicals. Chen et al. (2009) suggested that soluble endoglin may play a role in the formation of sporadic BAVM by acting as a decoy receptor, resulting in inhibition of TGF-beta (TGFB1; 190180) signaling and functional haploinsufficiency of ENG, as observed in patients with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300). Molecular Genetics ### Association with IL6 Promoter Polymorphism Among 180 patients with brain arteriovenous malformations (BAVM), Pawlikowska et al. (2004) found an association between a promoter polymorphism in the IL6 gene (-174G/C; 147620.0001) and intracranial hemorrhage. Patients who were homozygous for the G allele had an increased risk intracranial bleed (odds ratio of 2.62) compared to carriers of the C allele. In brain tissue from patients with BAVM, Chen et al. (2006) found that the highest IL6 protein and mRNA levels were associated with the IL6 -174GG genotype compared to the GC and CC genotypes. IL6 protein levels were increased in BAVM tissue from patients with hemorrhagic presentation compared to those without hemorrhage. In vivo studies demonstrated that IL6 enhanced expression and activity of IL1B (147720), TNFA (191160), IL8 (146930), and several matrix metalloproteinases, MMP3 (185250), MMP9 (120361), and MMP12 (601046). IL6 also increased proliferation and migration of cultured human cerebral endothelial cells. Chen et al. (2006) suggested that IL6 expression may modulate downstream inflammatory and angiogenic targets that contribute to intracranial hemorrhage in BAVMs. ### Somatic Mutation in KRAS Nikolaev et al. (2018) analyzed tissue and blood samples from patients with BAVM to detect somatic mutations. They performed exome DNA sequencing of tissue samples of BAVM from 26 patients in the main study group and of paired blood samples from 17 of these patients, and confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. Nikolaev et al. (2018) detected somatic activating KRAS mutations gly12 to asp (190070.0025) and gly12 to val (190070.0026) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, Nikolaev et al. (2018) detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (190198) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see 176872). Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells. Animal Model Murphy et al. (2008) found that mice with constitutively active Notch4 (164951) expression in endothelial cells from birth developed hallmarks of brain arteriovenous malformations by 3 weeks of age, including cerebral arteriovenous shunting and vessel enlargement. Most died by 5 weeks of age. Approximately 25% of the mutant mice showed signs of neurologic dysfunction, including ataxia and seizures. Imaging studies detected cerebral arteriovenous malformations. Repression of Notch4 resolved ataxia and reversed the disease progression, demonstrating that Notch4 is not only sufficient to induce but also required to sustain the disease. Postmortem examination showed hemorrhage and neuronal cell death within the cerebral cortex and cerebellum, as well as widespread enlargement of the cerebral microvasculature, which coincided with a reduction in capillary density. These findings suggested that vessel enlargement underlies the development of BAVM and linked this pathology to the known function of the NOTCH pathway as an inhibitor of vessel sprouting. Inheritance \- Autosomal dominant Vascular \- Cerebral arteriovenous malformation ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	ARTERIOVENOUS MALFORMATIONS OF THE BRAIN	c0917804	5,078	omim	https://www.omim.org/entry/108010	2019-09-22T16:44:46	{"doid": ["0060688"], "mesh": ["D002538"], "omim": ["108010"], "icd-10": ["Q28.2"], "orphanet": ["46724"], "synonyms": ["Alternative titles", "BAVM", "CEREBRAL ARTERIOVENOUS MALFORMATIONS"]}
A number sign (#) is used with this entry because of evidence that Ogden syndrome (OGDNS) is caused by mutation in the NAA10 gene (300013) on chromosome Xq28. Description Ogden syndrome is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Most patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015). Clinical Features Rope et al. (2011) reported 2 families segregating an X-linked recessive condition characterized by postnatal growth failure with severe delays and dysmorphic features characterized by wrinkled forehead, prominent eyes, widely opened anterior and posterior fontanels, downsloping palpebral fissures, thickened lids, large ears, flared nares, hypoplastic alae, short columella, protruding upper lip, and microretrognathia. There were also delayed closing of fontanels and broad great toes. Skin was characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals, all males. Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Arrhythmias included torsade de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernia, and the majority had unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scoliosis. Death occurred prior to 2 years in all cases and prior to 1 year in the majority. ### Clinical Variability Popp et al. (2015) reported 2 unrelated patients, a 10-year-old Swiss boy and a 4-year-old German girl, with a severe neurodevelopmental disorder with additional features reminiscent of those reported by Rope et al. (2011). Both had postnatal growth retardation, but the girl was more severely affected with significant short stature (-4.38 SD) and microcephaly (-3.04 SD). Psychomotor development was significantly delayed: the girl could not walk or speak and had poor eye contact with stereotypic behavior, whereas the boy learned to walk at age 6 years, never achieved continence, and had severe intellectual disability with autistic features. Both patients had variable dysmorphic facial features: the boy had prominent forehead, deep-set eyes, long eyelashes, downslanting palpebral fissures, large ears, and high-arched palate, whereas the girl had delayed closure of the fontanels, long eyelashes, thin arched eyebrows, broad nasal bridge, and thin upper lip. Both patients had truncal hypotonia and hypertonia of the extremities. The girl also had prolonged QT interval, atrial septal defect, pulmonary artery stenosis, delayed bone age, and pectus carinatum. The boy had hypoplastic scrotum, small hands and feet, and epileptiform activity on EEG; he did not have cardiac abnormalities. The boy had previously been reported in a large exome sequencing study of patients with nonspecific severe intellectual disability (Rauch et al., 2012). Casey et al. (2015) reported 2 young adult Irish brothers with a complex neurodevelopmental disorder characterized by delayed psychomotor development, dysmorphic facial features, scoliosis, and cardiac dysfunction with long QT syndrome. The phenotype differed somewhat between the brothers: 1 was more intellectually impaired, whereas the other was more physically disabled. Both had failure to thrive and poor growth early in life, as well as delayed walking and speech acquisition and waddling gait. Dysmorphic features included coarse facies, low anterior hairline, hypertelorism, epicanthal folds, prominent forehead and philtrum, high cheek bones, depressed midface, flat nasal bridge, low-set and small crumpled ears, dental anomalies, and coarse hair. Additional features included recurrent infections, inguinal hernia, small hands and feet, and acetabular dysplasia; one had valgus foot deformities. EEG in 1 brother showed a diffusely slowed background, consistent with an encephalopathy. As young adults, both developed arrhythmias with long QT syndrome; 1 had 2 myocardial infarctions. The mother was mildly affected with intellectual disability, coarse facial features, small hands and feet, cardiac arrhythmia, prolonged QT, premature coronary artery disease, and ventricular tachycardia. Inheritance The transmission pattern of Ogden syndrome in the family reported by Rope et al. (2011) was consistent with X-linked recessive inheritance; the pattern in the family reported by Casey et al. (2015) suggested X-linked dominant inheritance as the carrier mother was mildly affected. Molecular Genetics Rope et al. (2011) used X chromosome exon sequencing to identify a missense mutation (S37P; 300013.0001) in the NAA10 gene, encoding the catalytic subunit of the major human N-terminal acetyltransferase. The ser37-to-pro mutation was not identified in any unaffected family members or in 401 participants in the ClinSeq project, 180 genomes in the 1000 Genomes Project, the 10Gen dataset, 184 Danish exomes, or 40 whole genomes from the Complete Genomics Diversity Panel. There was no evidence of identity by descent between the families, and Rope et al. (2011) concluded that the mutation arose independently in each family. Serine-37 and its surrounding residues are conserved among eukaryotes. Acetylation assays demonstrated significantly impaired biochemical activity of the mutant NAA10 protein. Genotype/Phenotype Correlations In 2 living unrelated children, a boy and a girl, with severe developmental delay and additional features reminiscent of Ogden syndrome, Popp et al. (2015) identified different de novo missense mutations in the NAA10 gene: a hemizygous A116W substitution (300013.0003) in the boy, and a heterozygous V107F substitution (300013.0004) in the girl. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the A116W protein had a small but significant reduction in catalytic activity (15% reduction compared to wildtype), whereas the V107F mutant had almost no catalytic activity (about 5% residual activity). Popp et al. (2015) noted that the residual NAA10 activity in their male Swiss patient was significantly higher than that reported by Rope et al. (2011) in the male patients with the S37P mutation (30-70% reduction), which correlated with the less severe phenotype in the Swiss boy. In 2 young adult brothers, born of unrelated Irish parents, with a variant of Ogden syndrome, Casey et al. (2015) identified a hemizygous missense mutation in the NAA10 gene (Y43S; 300013.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the mildly affected mother. In vitro functional expression studies showed that the mutant protein had reduced stability and an 85% reduction in catalytic activity. Casey et al. (2015) noted that although the Y43S mutation resulted in a more severe impairment in catalytic activity compared to the S37P mutation, the Irish brothers had a less severe phenotype than the patients reported by Rope et al. (2011), indicating that in vitro NAA10 activity in itself may not be sufficient to explain the resulting phenotype. INHERITANCE \- X-linked recessive \- X-linked dominant GROWTH Height \- Short stature Other \- Postnatal growth failure HEAD & NECK Head \- Microcephaly Face \- Prominent forehead \- Wrinkled forehead \- Depressed midface \- Microretrognathia \- Coarse facial features \- Prominent philtrum Ears \- Large ears \- Low-set ears Eyes \- Prominent eyes \- Downslanting palpebral fissures \- Thick eyelids \- Epicanthal folds \- Sparse eyebrows Nose \- Flared nares \- Hypoplastic alae nasi \- Short columella \- Broad nasal bridge \- Flat nasal bridge Mouth \- Protruding upper lip \- Thin upper lip \- High-arched palate Teeth \- Dental abnormalities CARDIOVASCULAR Heart \- Ventral septal defect (VSD) \- Atrial septal defect (ASD) \- Arrhythmias \- Torsade de pointes \- Premature ventricular contraction (PVC) \- Premature atrial contraction (PAC) \- Supraventricular tachycardia (SVtach) \- Ventricular tachycardia (Vtach) Vascular \- Pulmonary artery stenosis GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism \- Inguinal hernia SKELETAL Skull \- Delayed closure of fontanels Spine \- Scoliosis (in some patients) Feet \- Broad great toes SKIN, NAILS, & HAIR Skin \- Cutis laxa \- Redundant skin \- Wrinkled forehead \- Cutaneous capillary malformations Hair \- Fine hair (in some patients) \- Sparse eyebrows \- Long eyelashes MUSCLE, SOFT TISSUES \- Minimal subcutaneous fat NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Hypotonia progressing to hypertonia \- Cerebral atrophy Behavioral Psychiatric Manifestations \- Autistic feature \- Stereotypic behaviors IMMUNOLOGY \- Recurrent infections MISCELLANEOUS \- Onset at birth \- Variable phenotype \- Variable severity \- Early death may occur from cardiogenic shock preceded by arrhythmia \- Two affected females have been reported (last curated November 2015) MOLECULAR BASIS \- Caused by mutation in the NatA catalytic subunit N-alpha-acetyltransferase-10 gene (NAA10, 300013.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	OGDEN SYNDROME	c3275447	5,079	omim	https://www.omim.org/entry/300855	2019-09-22T16:19:29	{"doid": ["0050781"], "omim": ["300855"], "orphanet": ["276432"], "synonyms": ["Alternative titles", "N-TERMINAL ACETYLTRANSFERASE DEFICIENCY", "Premature aging appearance-developmental delay-cardiac arrhythmia syndrome"]}
A number sign (#) is used with this entry because of evidence that renal hypomagnesemia-5 with ocular involvement (HOMG5) is caused by homozygous or compound heterozygous mutation in the claudin-19 gene (CLDN19; 610036) on chromosome 3q28. Description HOMG5 is an autosomal recessive disorder characterized by severe renal magnesium wasting, progressive renal failure, nephrocalcinosis, and severe visual impairment (Konrad et al., 2006). Amelogenesis imperfecta may also be present in some patients (Yamaguti et al., 2017). For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014. Clinical Features In the son and daughter of consanguineous parents, Meier et al. (1979) described nephrocalcinosis with idiopathic hypercalciuria dating from the first years of life and bilateral chorioretinal 'scars' in the macula interpreted as colobomata. Nystagmus and malignant myopia were present. Both children had inguinal hernias. Konrad et al. (2006) clinically characterized 1 Swiss and 8 Spanish/Hispanic families affected with severe hypomagnesemia due to renal wasting, nephrocalcinosis, and progressive renal failure. The Swiss patient had been described by Meier et al. (1979), and 4 of the Hispanic patients by Rodriguez-Soriano and Vallo (1994). Despite similarities to patients with HOMG3 (248250), in whom mutations in the CLDN16 gene (603959) had been identified, no CLDN16 mutations were found in these cases. Affected individuals in these families also had severe visual impairment, characterized by macular colobomata, significant myopia, and horizontal nystagmus. Yamaguti et al. (2017) characterized the enamel phenotype of 9 patients from 6 unrelated families with HOMG5, including 3 Brazilian families (families 1, 2, and 3), and 3 French families (families 4, 5, and 6) that were previously studied by Godron et al. (2012) (patients 16, 15, and 11.1, respectively). All 9 patients exhibited amelogenesis imperfecta with varying degrees of severity, even among individual teeth within the same patient. Dental features included yellow-brownish discoloration consistent with hypomature enamel, linear and diffuse opacities, hypoplastic enamel with pits and grooves, and generalized reduction in enamel thickness as well as areas of total enamel absence. Some patients also showed microfractures and tooth wear. In addition, the authors noted normal vision in 3 of the Brazilian patients, including the proband from family 1 and 2 of 3 affected sibs from family 2, and suggested that ocular defects are incompletely penetrant in HOMG5. Molecular Genetics Konrad et al. (2006) demonstrated 2 different homozygous missense mutations in the CLDN19 gene in families with renal magnesium wasting, renal failure, and severe ocular involvement. In 7 of 8 Spanish/Hispanic families they found a gly20-to-asp substitution (G20D; 610036.0001) in the first transmembrane domain of claudin-19. In the Swiss family they detected a gln57-to-glu substitution (Q57E; 610036.0002) in the first extracellular loop. They subsequently identified a consanguineous Turkish family and found a homozygous leu90-to-pro substitution (L90P; 610036.0003) in the 2 affected children. Haplotype analysis indicated that G20D was a founder mutation. Godron et al. (2012) identified homozygous or compound heterozygous mutations in affected members of 18 families with HOMG5, including 15 members from 14 families of French or Spanish descent with the G20D founder mutation (see, e.g., 610036.0001 and 610036.0005). In 6 patients from 3 unrelated Brazilian families with HOMG and amelogenesis imperfecta, Yamaguti et al. (2017) identified homozygous or compound heterozygous mutations in the CLDN19 gene (see, e.g., 610036.0001 and 610036.0004). Genotype/Phenotype Correlations Godron et al. (2012) retrospectively reviewed 32 patients from 26 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis due to CLDN16 or CLDN19 mutations. Ocular abnormalities were found only in patients with CLDN19 mutations, who also displayed more severe renal impairment than patients with CLDN16 mutations. The risk of end-stage renal disease in patients with CLDN19 mutations was twice that in patients with CLDN16 mutations. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Myopia \- Nystagmus \- Strabismus \- Astigmatism \- Tapetoretinal degeneration \- Macular coloboma Teeth \- Amelogenesis imperfecta (in some patients) \- Yellow-brownish discoloration of teeth \- Hypoplastic enamel \- Cusp malformation \- Diffuse opacities \- Hypomineralized linear demarcated opacities \- Hypoplastic pits \- Hypoplastic grooves \- Areas of total enamel absence \- Microfractures \- Tooth wear GENITOURINARY Kidneys \- Nephrolithiasis \- Nephrocalcinosis \- Progressive renal failure \- Renal calcium wasting \- Renal magnesium wasting Bladder \- Recurrent urinary tract infections LABORATORY ABNORMALITIES \- Hypomagnesemia \- Normal serum calcium \- Hypermagnesiuria \- Hypercalciuria MISCELLANEOUS \- Some patients have normal vision \- Variable severity of amelogenesis imperfecta, even within the same patient MOLECULAR BASIS \- Caused by mutation in the claudin 19 (CLDN19, 610036.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	HYPOMAGNESEMIA 5, RENAL, WITH OR WITHOUT OCULAR INVOLVEMENT	c2931121	5,080	omim	https://www.omim.org/entry/248190	2019-09-22T16:25:43	{"doid": ["0060881"], "mesh": ["C536148"], "omim": ["248190"], "orphanet": ["2196"], "synonyms": ["Alternative titles", "HYPOMAGNESEMIA, RENAL, WITH OCULAR INVOLVEMENT", "HYPOMAGNESEMIA, FAMILIAL, WITH HYPERCALCIURIA, NEPHROCALCINOSIS, AND SEVERE OCULAR INVOLVEMENT", "FHHNC WITH SEVERE OCULAR INVOLVEMENT", "MACULAR COLOBOMA, BILATERAL, WITH HYPERCALCIURIA"]}
High ankle sprain Other namesSyndesmotic ankle sprain, syndesmotic ankle injury SpecialtyOrthopedics A high ankle sprain, also known as a syndesmotic ankle sprain (SAS), is a sprain of the syndesmotic ligaments that connect the tibia and fibula in the lower leg, thereby creating a mortise and tenon joint for the ankle. High ankle sprains are described as high because they are located above the ankle. They comprise approximately 15% of all ankle sprains.[1] Unlike the common lateral ankle sprains, when ligaments around the ankle are injured through an inward twisting, high ankle sprains are caused when the lower leg and foot externally rotates (twists out). ## Contents * 1 Mechanism * 2 Diagnosis * 3 Treatment * 4 See also * 5 References ## Mechanism[edit] The ankle joint consists of the talus resting within the mortise created by the tibia and fibula as previously described. Since the talus is wider anteriorly (in the front) than posteriorly (at the back), as the front of the foot is raised (dorsiflexed) reducing the angle between the foot and lower leg to less than 90°, then the mortise is confronted with an increasingly wider talus. The force is heightened when the foot is simultaneously forced into external rotation (turned outward). This chain of events may occur when the front of a hockey player's skate strikes the boards and the foot is forced outward. It may also occur in football, for example, when a player is on the ground with their leg behind them, the foot at right angles, and a rotational force is suddenly applied to the heel, as when someone falls on their foot. Overall, the most common mechanism is external rotation and may occur with sufficient rapidity that the actual mechanism is unrecognized.[citation needed] In this sequence of events, the most vulnerable structure is the anterior inferior tibio-fibular ligament, uniting the lower end of the tibia and fibula and playing an important role in the maintenance of the mortise. The injury to this ligament may vary from simple stretch to complete rupture. Some restraint to further injury is offered by the structures on the inside of the ankle, the medial malleolus and the medial collateral ligament. However, should these structures fail, then the force will be transmitted beyond the anterior inferior tibiofibular ligament to the strong membrane that holds the tibia and fibula together for most of their length. This force may then exit through the upper end of the fibula, creating a so-called Maisonneuve fracture.[citation needed] ## Diagnosis[edit] Those who sustain high ankle sprains usually present with pain in the outside-front of the leg above the ankle, with increased discomfort when twisting (external rotation) is applied. In some cases, the diagnosis is only made after treatment for the more common, lateral, ankle sprain fails.[2] Diagnosis may also be delayed because swelling is usually minor or nonexistent and the true nature of the injury unappreciated.[3] A variety of diagnostic tests have been described such as the 'squeeze' (compressing the tibia and fibula above the midpoint of the calf), 'dorsiflexion with compression' (patient dorsiflexes the foot while the examiner compresses the internal and external malleolus), and 'external rotation' (patient sits with leg dangling and ankle at 90° and external rotation then applied to the foot) etc. None of them performs sufficiently well to allow diagnosis to be made on the basis of a single test,[4] and is usually made by combining multiple tests supplemented with appropriate imaging when indicated. Plain radiographs, Ultrasound[5] or MRI may be used for diagnosis. In the case of X-rays, demonstration of widening of the tibia and fibula 'mortise', a fracture of the medial malleolus, or a Maisonneuve fracture, will indicate an unstable or potentially unstable injury. However, 'normal' x-rays do not exclude significant ligament injury, and in one study, the ratio of diagnostic X-ray to known syndesmotic injury was only one in 17. By contrast, ultrasound may permit the injury to be visualized while the mortise is being stressed.[5] Consequently, a diagnostic modality such as ultrasound or magnetic resonance imaging (MRI)[4] that demonstrates the ligament itself may be helpful, if clinical suspicion remains.[6] ## Treatment[edit] Treatment depends on severity and convalescence may be as short as a few days or as long as six months.[7] Rest, icing, compression, and elevation is often recommended.[citation needed] Two important issues should be addressed early. First, a determination of whether the ankle is stable or unstable. This is usually answered by clinical assessment together with results of the imaging modalities previously described. In the case of suspected instability, specialist referral is indicated as surgery and some form of internal fixation may be an option, if not a requirement.[8] Second, a decision of degree of weight bearing, if any, to be permitted. The answer to this is partly related to stability, partly to the clinical estimate of ligament injury together with imaging findings, and partly related to discomfort when weight bearing. The final decision is largely individualized depending on the circumstances. An alternative measure consists of H.E.M. (Healthy blood flow, Eliminate swelling and Mobility). This treatment suggests increasing healthy blood flow to the ankle, including immune cells required for healing. The treatment also suggests improving healthy range of motion, stability and strength in the ankle to aid in a full recovery. Recent research suggests that macrophages (immune cells responsible for muscle repair and growth) are necessary for muscle to grow back to its pre-injured state.[9] The H.E.M. ankle rehab treatment suggests not icing the injury, and instead, following more proactive rehab techniques for recovery: "when ice is applied to a body part for a prolonged period, nearby lymphatic vessels begin to dramatically increase their permeability (lymphatic vessels are ‘dead-end’ tubes which ordinarily help carry excess tissue fluids back into the cardiovascular system). As lymphatic permeability is enhanced, large amounts of fluid begin to pour from the lymphatics ‘in the wrong direction’ (into the injured area), increasing the amount of local swelling and pressure and potentially contributing to greater pain."[10] Rehabilitation is important. A significant percentage of these sprains also involve medial and/or lateral ankle ligament injury and slow recovery and continuing symptoms are common.[1] However, limiting external rotation to protect healing ligaments is a primary concern and can usually be achieved by short leg casts, walking boots, and custom orthoses. The degree of permitted weight bearing can be individualized dependent on tolerance and those with less injury are able to ambulate with full weight-bearing. Nevertheless, most use crutches to reduce the burden to some extent and those with more discomfort may be limited to "toe touch" on the affected side for one to two weeks. Some advocate the ability to climb and descend stairs with minimal discomfort as an indication to permit full, or at least progressive, weight-bearing.[7] Early resistance exercise minimizes muscle atrophy and weakness and a variety of exercises—elastic bands, ankle weights, heel raise exercises—may be used in conjunction with a calf stretch. In the early stages, isometric strengthening and electrical stimulation will combat muscle atrophy and developing weakness.[citation needed] ## See also[edit] * Sprained ankle ## References[edit] 1. ^ a b Gerber JP, Williams GN, Scoville CR, Arciero RA, Taylor DC (1998). "Persistent disability associated with ankle sprains: a prospective examination of an athletic population". Foot Ankle Int. 19 (10): 653–660. doi:10.1177/107110079801901002. PMID 9801078. 2. ^ Ankle Syndesmosis Injuries – Orthogate – Improving orthopedic care, education and research with Internet technologies 3. ^ Syndesmotic Sprain – Wheeless' Textbook of Orthopaedics 4. ^ a b Sman AD, Hiller CE, Refshauge KM (2013). "Diagnostic accuracy of clinical tests for diagnosis of ankle syndesmosis injury: a systematic review". Br J Sports Med. 47 (10): 620–628. doi:10.1136/bjsports-2012-091702. 5. ^ a b Mei-Dan O, Kots E, Barchilon V, Massarwe S, Nyska M, Mann G (May 2009). "A dynamic ultrasound examination for the diagnosis of ankle syndesmotic injury in professional athletes: a preliminary study". The American Journal of Sports Medicine. 37 (5): 1009–16. doi:10.1177/0363546508331202. PMID 19336613. 6. ^ Nielson JH, Gardner MJ, Peterson MG, Sallis JG, Potter HG, Helfet DL, Lorich DG (July 2005). "Radiographic measurements do not predict syndesmotic injury in ankle fractures: an MRI study". Clinical Orthopaedics and Related Research (436): 216–21. doi:10.1097/01.blo.0000161090.86162.19. PMID 15995444. 7. ^ a b Williams GN, Allen EJ (November 2010). "Rehabilitation of syndesmotic (high) ankle sprains". Sports Health. 2 (6): 460–70. doi:10.1177/1941738110384573. PMC 3438867. PMID 23015976. 8. ^ Polzer H, Kanz KG, Prall WC, Haasters F, Ockert B, Mutschler W, Grote S (Jan 2012). "Diagnosis and treatment of acute ankle injuries: development of an evidence-based algorithm". Orthop Rev (Pavia). 4 (1): e5. doi:10.4081/or.2012.e5. PMC 3348693. PMID 22577506. 9. ^ Tidball JG, Wehling-Henricks M (2007). "Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo". The Journal of Physiology. 578 (1): 327–336. doi:10.1113/jphysiol.2006.118265. PMC 2075127. PMID 17038433. 10. ^ Meeusen R, Lievens P (1986). "The use of cryotherapy in sports injuries". Sports Medicine (Auckland, N.Z.). 3 (6): 398–414. doi:10.2165/00007256-198603060-00002. PMID 3538270. * v * t * e Dislocations/subluxations, sprains and strains Joints and ligaments Head and neck * Dislocation of jaw * Whiplash Shoulder and upper arm * GH (Dislocated shoulder) * AC (Separated shoulder) * ALPSA lesion * SLAP tear * Bankart lesion Elbow and forearm * Pulled elbow * Gamekeeper's thumb Hip and thigh * Hip dislocation Knee and leg * Tear of meniscus * Anterior cruciate ligament injury * Unhappy triad * Patellar dislocation * Knee dislocation Ankle and foot * Sprained ankle (High ankle sprain) * Turf toe Muscles and tendons Shoulder and upper arm * Rotator cuff tear Hip and thigh * Pulled hamstring Knee and leg * Patellar tendon rupture * Achilles tendon rupture * Shin splints [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	High ankle sprain	None	5,081	wikipedia	https://en.wikipedia.org/wiki/High_ankle_sprain	2021-01-18T19:05:57	{"wikidata": ["Q5757498"]}
Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a severe disorder affecting the muscles that line the bladder and intestines. It is characterized by impairment of the muscle contractions that move food through the digestive tract (peristalsis) and empty the bladder. Some of the major features of MMIHS can be recognized before birth using ultrasound imaging. Affected fetuses have an enlarged bladder (megacystis) because it does not empty. In addition, the large intestine (colon) is abnormally narrow (microcolon) because of a shortage of functional muscle lining it. Intestinal and bladder problems persist throughout life. After birth, the continued impairment of peristalsis (hypoperistalsis) often causes a digestive condition called intestinal pseudo-obstruction. This condition, which mimics a physical blockage (obstruction) of the intestines but without an actual blockage, leads to a buildup of partially digested food in the intestines. This buildup can cause abdominal swelling (distention) and pain, nausea, and vomiting. The vomit usually contains a green or yellow digestive fluid called bile. Because digestion is impeded and the body does not get the nutrients from food, nutritional support is usually needed, which is given through intravenous feedings (parenteral nutrition). While some affected individuals rely solely on intravenous feedings, others require it only on occasion. Long-term use of parenteral nutrition can lead to liver problems. The reduced ability to pass urine also contributes to painful distention of the abdomen. Many people with MMIHS require placement of a tube (urinary catheter) to remove urine from the bladder. Another abnormality in some people with MMIHS is intestinal malrotation, in which the intestines do not fold properly. Instead, they twist abnormally, often causing a blockage. Individuals with MMIHS can also develop problems with the kidneys or the ureters, which are the ducts that carry urine from the kidneys to the bladder. The life expectancy of people with MMIHS is shorter than normal, often due to malnutrition, overwhelming infection (sepsis), or the failure of multiple organs. ## Frequency MMIHS is a rare disorder. More than 200 cases have been reported in the medical literature. ## Causes MMIHS can be caused by mutations in one of several genes, the most studied of which is ACTG2. The ACTG2 gene provides instructions for making a protein called gamma (γ)-2 actin. The γ-2 actin proteins organize into filaments that are important for the tensing of muscle fibers (muscle contraction), specifically contraction of smooth muscles of the urinary and intestinal tracts. These contractions empty urine from the bladder and move food through the intestines. ACTG2 gene mutations lead to production of an altered γ-2 actin protein. These changes hinder the formation of actin filaments, which impairs the ability of smooth muscle in the bladder and intestines to contract. These problems with muscle contractions impair the release of urine and the movement of food through the intestines, leading to the key features of MMIHS. Mutations in other genes have been found to cause rare cases of MMIHS. The proteins produced from these genes are also involved in smooth muscle contraction. Approximately 10 percent of people with MMIHS do not have a mutation in one of the identified genes. It is likely that additional genes that have not been identified are also involved in the disorder. ### Learn more about the genes associated with Megacystis-microcolon-intestinal hypoperistalsis syndrome * ACTG2 * MYH11 Additional Information from NCBI Gene: * LMOD1 * MYLK ## Inheritance Pattern When caused by ACTG2 gene mutations, MMIHS follows an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. These cases result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. In these cases, affected individuals have no history of the disorder in their family. When caused by mutations in other identified genes, MMIHS is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Megacystis-microcolon-intestinal hypoperistalsis syndrome	c1608393	5,082	medlineplus	https://medlineplus.gov/genetics/condition/megacystis-microcolon-intestinal-hypoperistalsis-syndrome/	2021-01-27T08:25:42	{"gard": ["12743", "3442"], "mesh": ["C536138"], "omim": ["155310"], "synonyms": []}
Oppenheimer and Andrews (1959) reported 2 cases: a 4-year-old white male from West Virginia who died from liver failure and had ceroid deposits of liver, spleen and intestinal mucosa, and a white 22-month-old female who at autopsy had ceroid limited largely to hepatic macrophages. The sister and 2 brothers reported by Nelson et al. (1961) may have had the same condition. The isolated case reported by Jonas (1966) may have had the same or a related condition. Menkes (1982) reviewed the paper by Ryan et al. (1970) and suggested, mainly on clinical grounds because the electron microscopy was unsatisfactory, that the correct diagnosis was the Finnish or Santavuori type of infantile neuronal ceroid lipofuscinosis (256730). Inheritance \- ? Autosomal recessive Liver \- Macrophage ceroid deposits \- Liver failure GI \- Mucosal ceroid deposits Spleen \- Ceroid deposits ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	CEROID STORAGE DISEASE	c0268281	5,083	omim	https://www.omim.org/entry/214200	2019-09-22T16:29:48	{"mesh": ["D009472"], "omim": ["214200"], "icd-10": ["E75.4"], "orphanet": ["79263"], "synonyms": ["Alternative titles", "LIPOFUSCIN STORAGE DISEASE"]}
A number sign (#) is used with this entry because tyrosinemia type II (TYRSN2) is caused by homozygous or compound heterozygous mutation in the tyrosine aminotransferase gene (TAT; 613018) on chromosome 16q22. Description Tyrosinemia type II is an autosomal recessive disorder characterized by keratitis, painful palmoplantar hyperkeratosis, mental retardation, and elevated serum tyrosine levels. The disorder is caused by deficiency of hepatic tyrosine aminotransferase (Natt et al., 1992). Clinical Features Richner (1938) and Hanhart (1947) described an oculocutaneous syndrome characterized by herpetiform corneal ulcers and painful punctate keratoses of digits, palms, and soles. Richner (1938) described skin lesions in brother and sister. Only the brother had corneal lesions. Hanhart (1947) reported that the parents of this patient were second cousins. Hanhart (1947) also described associated severe mental and somatic retardation. The pedigree he reported was reproduced by Waardenburg et al. (1961). Waardenburg et al. (1961) described children of a first-cousin marriage, one with the full syndrome and one with only corneal changes. Ventura et al. (1965) described the syndrome in 2 sons of first-cousin parents. Buist (1967) referred to studies of a child with tyrosinemia and tyrosine transaminase deficiency, but normal p-hydroxyphenylpyruvic acid oxidase. Phenylalanine level was normal. Hydroxyphenylpyruvic acid was elevated in the urine. Fellman et al. (1969) reported chemical studies on the same patient. Only the mitochondrial form of tyrosine aminotransferase was present in the liver. The soluble form of tyrosine aminotransferase was lacking. The patient had markedly elevated tyrosine blood levels and an increase in urinary p-hydroxyphenylpyruvate and p-hydroxyphenyllactate. Goldsmith et al. (1973) demonstrated tyrosinemia and phenylacetic acidemia in this disorder. Their patient was the 14-year-old son of consanguineous Italian parents. The urine contained excessive P-hydroxyphenylactic acid. Urinary P-hydroxyphenylpyruvic acid was normal. Clinical and biochemical improvement accompanied low phenylalanine-low tyrosine diet. They suggested that soluble TAT may be deficient. Mitochondrial tyrosine transaminase was normal. Bienfang et al. (1976) described the ophthalmologic findings in the patient reported by Goldsmith et al. (1973). This condition is also known as tyrosinemia with palmar and plantar keratosis and keratitis. Garibaldi et al. (1977) observed this disorder, which they called oculocutaneous tyrosinosis, in a 42-month-old girl and her maternal aunt. The parents of the maternal aunt were first cousins. They emphasized the importance of early diagnosis in order to prevent mental retardation by means of a diet restricted in phenylalanine and tyrosine. Hunziker (1980) reported brother and sister with unusually late onset (about age 15). Their patients' skin lesions were improved with a diet restricted in phenylalanine and tyrosine. In a consanguineous sibship, Rehak et al. (1981) reported 4 cases of Richner-Hanhart syndrome. Cutaneous manifestations were typical but the eyes were not involved, suggesting heterogeneity in this disorder. Bohnert and Anton-Lamprecht (1982) reported unique ultrastructural changes: thickening of the granular layer and increased synthesis of tonofibrils and keratohyalin; in the ridged palmar or plantar skin, large numbers of microtubules and unusually tight packing of tonofibrillar masses, which contained tubular channels or inclusions of microtubules. The authors assumed that increased cohesion and tight packing of tonofilaments prevent normal spreading of keratohyalin and result in its globular appearance. Further, they suggested that excessive amounts of intracellular tyrosine enhance crosslinks between aggregated tonofilaments. In an Ashkenazi Jewish family, Chitayat et al. (1992) observed 2 adult sibs, offspring of a first-cousin marriage, with persistent hypertyrosinemia. A curious feature was that the affected female sib, aged 41 years, had hypertyrosinemia and characteristic oculocutaneous signs; the brother, aged 39 years, had hypertyrosinemia but no oculocutaneous disease. Both sibs had 2 children; none had signs of metabolic fetopathy. Tallab (1996) described 2 brothers with Richner-Hanhart syndrome from Saudi Arabia. They were sons of consanguineous parents. They showed typical symptoms and signs of the disease. Physical examination revealed patchy hyperkeratotic yellow-white papules and plaques on palms and soles and linear and star-like corneal opacities. Their IQs were 61 and 75. Serum tyrosine levels were markedly elevated with excessive excretion of tyrosine and its metabolites in the urine. A low tyrosine and low phenylalanine diet was given. Cerone et al. (2002) reported a female patient with tyrosinemia type II who underwent 2 untreated pregnancies. The patient presented at 28 years of age for reevaluation. She was 34 weeks pregnant with a plasma tyrosine of 1302 micro mol/L and phenylalanine of 37 micro mol/L; all other amino acids were within the normal range. Her protein intake ranged from 60 to 90 grams per day. Her first child was evaluated at age 1 year and 4 months. The boy was born at term after an uneventful labor and delivery with a birth weight of 1.9 kg. At 26 months of age he was 66 cm (-3.5 SD), weight was 6.5 kg (-4.3 SD), and head circumference was 43 cm (-2.4 SD). Physical examination showed unremarkable results except for microcephaly and maxillary hypoplasia. Developmental testing indicated a DQ of 72. The second child was evaluated at the age of 12 months with a length of 74 cm (25th percentile), weight of 8.3 kg (3rd percentile), and head circumference of 45 cm (3rd percentile). He also had microcephaly and was not able to walk. Speech delay was also noted. Both children had plasma tyrosine levels in the normal range. The experience from these 2 pregnancies suggested that maternal tyrosinemia has an adverse effect on the developing fetus. Cytogenetics In an addendum in proof, Natt et al. (1986) reported that a patient with multiple congenital anomalies, including tyrosinemia II, showed a small interstitial deletion with breakpoints at 16q22.1 and 16q22.3. Natt et al. (1987) presented the full report of this patient, who had multiple congenital anomalies and severe mental retardation in addition to typical symptoms of tyrosinemia II. Southern blot analysis using a human TAT cDNA probe showed complete deletion of both TAT alleles in the patient. Molecular and cytogenetic analysis of the patient and his family showed one deletion to have been inherited from the mother, extending over at least 27 kb and including the complete TAT structural gene, whereas loss of the second TAT allele resulted from a small de novo interstitial deletion, del 16(pter-q22::q22.3-qter), in the chromosome 16 inherited from the father. The haptoglobin locus (140100) was codeleted on the chromosome inherited from the father; no HP allele was inherited by the proband from the father. In situ hybridization likewise was consistent with loss of one haptoglobin gene. On the other hand, 2 metallothionein genes, MT1 (156350) and MT2 (156360), as well as the LCAT gene (606967), were not deleted. Diagnosis ### Prenatal Diagnosis Westphal et al. (1988) described MspI and HaeIII RFLPs associated with the TAT locus. The authors used the 2 polymorphisms, which have a combined polymorphism information content (PIC) of 0.44, to perform haplotype analysis of the TAT locus in a French family with tyrosinemia type II. The polymorphisms gave a clear delineation of the mutant alleles in each parent and thus provided the opportunity for prenatal diagnosis of this condition in this family. Molecular Genetics In patients with tyrosinemia II, Natt et al. (1992) identified homozygous and compound heterozygous mutations in the TAT gene (613018.0001-613018.0005). Eyes \- Herpetiform corneal ulcers Neuro \- Mental retardation Inheritance \- Autosomal recessive Lab \- Tyrosinemia \- Tyrosine transaminase deficiency \- Normal p-hydroxyphenylpyruvic acid oxidase \- Normal phenylalanine level \- Hydroxyphenylpyruvic aciduria \- Soluble tyrosine aminotransferase (TAT) deficiency \- Phenylaceticacidemia Growth \- Growth retardation Skin \- Painful punctate keratoses of digits, palms, and soles ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	TYROSINEMIA, TYPE II	c0268487	5,084	omim	https://www.omim.org/entry/276600	2019-09-22T16:21:28	{"doid": ["0050725"], "mesh": ["D020176"], "omim": ["276600"], "orphanet": ["28378"], "synonyms": ["Alternative titles", "RICHNER-HANHART SYNDROME", "TYROSINE AMINOTRANSFERASE DEFICIENCY", "TAT DEFICIENCY", "TYROSINE TRANSAMINASE DEFICIENCY", "KERATOSIS PALMOPLANTARIS WITH CORNEAL DYSTROPHY", "OREGON TYPE TYROSINEMIA", "TYROSINOSIS, OCULOCUTANEOUS TYPE"]}
Negative socio-psychological effects of consumerism For diseases correlating with affluence, see Diseases of affluence. For other uses, see Affluenza (disambiguation). Part of series on Anti-consumerism Theories and ideas * Affluenza * Alternative culture * Anti-capitalism * Autonomous building * Billboard hacking * Bioeconomics * Buddhist economics * Buy Nothing Day * Collaborative consumption * Collapsology * Commodification * Commodity fetishism * Commons * Commune * Compulsive buying disorder * Conspicuous consumption * Consumer capitalism * Consumerism * Criticism of advertising * Culture jamming * Degrowth * Do it yourself * DIY ethic * Downshifting * Earth Overshoot Day * Ecological economics * Ecovillage * Ethical consumerism * Environmental justice * Feminist political ecology * Freeganism * Gift economy * Green consumption * Hyperconsumerism * Local food * Microgeneration * Overconsumption * Planned obsolescence * Political ecology * Post-consumerism * Post-growth * Post-normal science * Right to repair * Self-organization * Simple living * Slow Food * Spectacle * Steady-state economy * Subvertising * Sustainable consumer behaviour * Sustainable consumption Notable works * Walden * The Theory of the Leisure Class * Brave New World * The Affluent Society * One-Dimensional Man * The Society of the Spectacle (book · film) * The Consumer Society: Myths and Structures [fr] * Steal This Book * Small Is Beautiful * To Have or to Be? * Future Primitive and Other Essays * Fight Club (novel · film) * Escape from Affluenza * No Logo * Profit over People: Neoliberalism and Global Order * The Cultural Creatives * Affluenza: The All-Consuming Epidemic * Evasion * The Corporation * Surplus: Terrorized into Being Consumers * So, What's Your Price? * What Would Jesus Buy? Organizations and groups * Adbusters * Crass * CrimethInc. * Deep Green Resistance * Democracy Now! * Earth Liberation Front * Fifth Estate * Freecycle * Green Anarchy * Institute for Social Ecology * Monthly Review * Rage Against the Machine * Reverend Billy * The Venus Project * The Yes Men * 350.org People * André Amar * André Gorz * Bruno Clémentin * Donella Meadows * Edward Goldsmith * E. F. Schumacher * Erich Fromm * Federico Demaria * Filka Sekulova * François Schneider * Giacomo D’Alisa * Giorgios Kallis * Henry David Thoreau * Ivan Illich * Ivo Rens * Jacques Grinevald * Jean Baudrillard * John Ruskin * Mauro Bonaiuti * Nicholas Georgescu-Roegen * Noam Chomsky * Paul Ariès * Paul Goodman * Pierre Rabhi * Serge Latouche * Vincent Cheynet Related social movements * Alter-globalization * Amateurism * Anarcho-communism * Anarcho-primitivism * Anarcho-punk * Anti-capitalism * Anti-corporate activism * Anti-globalization movement * Diggers (theater) * Ecofeminism * Eco-socialism * Environmentalism * Feminism * Food Not Bombs * Green anarchism * Green left * Green politics * Hippie * Libertarian socialism * Neo-Luddism * New Left * Occupy Wall Street * Postmodernism * Punk * Situationists * Slow movement * Social anarchism * Social ecology See also * Works about consumerism * Advanced capitalism * Advertising * Barter * Capitalism * Consumer behaviour * Consumption (economics) * Consumption (sociology) * Cooperative * Counterculture * Cultural hegemony * Ecological economics * Economic materialism * Economic problems * Frugality * Green economy * Gross National Happiness * Heterodox economics * Influence of mass media * Informal sector * Intentional community * Left-wing politics * McDonaldization * Mutual aid * Natural resource economics * Non-monetary economy * Permaculture * Post-materialism * Productivism * Shopping * Social movements * Subsistence economy * Sustainability * Sweatshops * Veblen good * Workaholic * v * t * e Affluenza is a psychological malaise supposedly affecting wealthy young people. It is a portmanteau of affluence and influenza, and is used most commonly by critics of consumerism. It is not a medically recognized disease. It is thought to have been first used in 1954,[1] but was popularised in 1997 with a PBS documentary of the same name[2] and the subsequent book Affluenza: The All-Consuming Epidemic (2001, revised in 2005, 2014). These works define affluenza as "a painful, contagious, socially transmitted condition of overload, debt, anxiety, and waste resulting from the dogged pursuit of more". A more informal definition of the term would describe it as "a quasi-illness caused by guilt for one's own socio-economic superiority". [3] The term "affluenza" has also been used to refer to an inability to understand the consequences of one's actions because of financial privilege. The term "affluenza" was re-popularized in 2013 with the arrest of Ethan Couch, a Texas teen, for driving while intoxicated and killing four pedestrians and injuring several others. Testimony from a psychologist in court referred to Couch as having a case of affluenza as his defense, sparking a media frenzy and victim family outrage. ## Contents * 1 Theory * 2 See also * 3 References * 4 Further reading * 5 External links ## Theory[edit] In 2007, British psychologist Oliver James asserted that there was a correlation between the increasing occurrence of affluenza and the resulting increase in material inequality: the more unequal a society, the greater the unhappiness of its citizens.[4] Referring to Vance Packard's thesis The Hidden Persuaders on the manipulative methods used by the advertising industry, James related the stimulation of artificial needs to the rise in affluenza. To highlight the spread of affluenza in societies with varied levels of inequality, James interviewed people in several cities including Sydney, Singapore, Auckland, Moscow, Shanghai, Copenhagen and New York. In 2008 James wrote that higher rates of mental disorders were the consequence of excessive wealth-seeking in consumerist nations.[5] In a graph created from multiple data sources, James plotted "Prevalence of any emotional distress" and "Income inequality", attempting to show that English-speaking nations have nearly twice as much emotional distress as mainland Europe and Japan: 21.6 percent vs 11.5 percent.[6] James defined affluenza as "placing a high value on money, possessions, appearances (physical and social) and fame", which was the rationale behind the increasing mental illness in English-speaking societies. He explained the greater incidence of affluenza as the result of 'selfish capitalism', the market liberal political governance found in English-speaking nations as compared to the less selfish capitalism pursued in mainland Europe. James asserted that societies can remove the negative consumerist effects by pursuing real needs over perceived wants, and by defining themselves as having value independent of their material possessions. Clive Hamilton and Richard Denniss's book, Affluenza: When Too Much is Never Enough, poses the question: "If the economy has been doing so well, why are we not becoming happier?"[7]:vii They argue that affluenza causes overconsumption, "luxury fever", consumer debt, overwork, waste, and harm to the environment. These pressures lead to "psychological disorders, alienation and distress",[7]:179 causing people to "self-medicate with mood-altering drugs and excessive alcohol consumption".[7]:180 They note that a number of Australians have reacted by "downshifting"—they decided to "reduce their incomes and place family, friends and contentment above money in determining their life goals". Their critique leads them to identify the need for an "alternative political philosophy", and the book concludes with a "political manifesto for wellbeing".[8] ## See also[edit] * Brock Turner – Criminal case in which Brock Allen Turner was convicted of three counts of felony sexual assault * Christian views on poverty and wealth * Conspicuous consumption – Concept in sociology and economy * Diseases of affluence * Escape from Affluenza * Ethan Couch – American killer by manslaughter * Lifestyle disease – Diseases linked with the way people live their life * O. J. Simpson murder case – Criminal trial decided October 3, 1995, in United States * Simple living – lifestyle category * Status anxiety * Affluenza (film) ## References[edit] 1. ^ de Graaf, John (14 December 2013). "Co-Author of Affluenza: "I'm Appalled by the Ethan Couch Decision"". Time Magazine. Archived from the original on 31 December 2017. Retrieved 29 May 2018. 2. ^ "Escape from Affluenza", KCTS 3. ^ Affluenza: The All-Consuming Epidemic, John de Graaf, David Wann & Thomas H. Naylor, 2001 ISBN 1-57675-199-6 4. ^ James, Oliver (2007). Affluenza: How to Be Successful and Stay Sane. Vermilion. ISBN 978-0-09-190011-3. 5. ^ James, Oliver (2008). The Selfish Capitalist. Vermilion. ISBN 978-0-09-192381-5. 6. ^ James, Oliver (2007). "Appendix 2: Emotional Distress and Inequality: Selfish vs Unselfish Capitalist Nations". Affluenza: How to be Successful and Stay Sane. London: Vermilion. p. 344. ISBN 978-0-09-190010-6. "1\. The mean prevalence of emotional distress for the six English-speaking nations combined was 21.6%. The mean for the other nations, mainland Western Europe plus Japan, was 11.5%." 7. ^ a b c Clive Hamilton; Richard Denniss (2005). Affluenza: When Too Much Is Never Enough. Allen & Unwin. ISBN 978-1-74115-624-9. 8. ^ "A Manifesto For Wellbeing". Wellbeingmanifesto.net. The Australia Institute. 7 May 2005. Archived from the original on 7 May 2005. Retrieved 29 May 2018. (Archive is the same work, but on a different website) ## Further reading[edit] * The Circle of Simplicity, Cecile Andrews, ISBN 0-06-092872-7 * The Golden Ghetto: The Psychology of Affluence, Jessie H. O'Neill, ISBN 978-0-9678554-0-0 * Voluntary Simplicity, Duane Elgin, ISBN 0-688-12119-5 * Voluntary Simplicity, Daniel Doherty & Amitai Etzioni, ISBN 0-7425-2066-8 * How Much Is Too Much? Raising Likeable, Responsible, Respectful Children-From Toddler to Teens-In an Age of Overindulgence, Clarke, Jean Illsley, Bredehoft, David & Dawson, Connie, ISBN 978-0-7382-1681-2 ## External links[edit] Look up affluenza in Wiktionary, the free dictionary. * "Affluenza". pbs.org. * Macquarie Dictionary Word of the Year Winners: Affluenza * The Affluenza Project * Affluenza issues in the USA * Affluenza video * A film clip "The Open Mind - Affluenza (1984)" is available at the Internet Archive * v * t * e Extreme wealth Concepts * Capital accumulation * Overaccumulation * Economic inequality * Elite * Oligarchy * Overclass * Plutocracy * Plutonomy * Upper class * Nouveau riche (new money) * Vieux riche (old money) * Veblen goods * Conspicuous consumption * Conspicuous leisure People * Billionaire * Captain of industry * High-net-worth individual * UHNWI * Magnate * Business * Millionaire * Oligarch * Business * Russian * Ukrainian * Robber baron Wealth * Concentration * Distribution * Dynastic * Effect * Geography * Inherited * Management * National * Paper * Religion * Tax Lists People * Forbes list of billionaires * Female billionaires * Richest royals * Wealthiest Americans * Wealthiest families * Wealthiest historical figures Organizations * Largest companies by revenue * Largest corporate profits and losses * Largest financial services companies by revenue * Largest manufacturing companies by revenue * Largest software companies by revenue * Largest information technology companies by revenue * Public corporations by market capitalization * Charities * Philanthropists * Universities * Endowment * Number of billionaire alumni Other * Cities by number of billionaires * Countries by number of billionaires * Countries by total wealth * Most expensive items * by category * Wealthiest animals See also * Diseases of affluence * Affluenza * Argumentum ad crumenam * Prosperity theology Philanthropy * Gospel of Wealth * The Giving Pledge * Philanthrocapitalism * Venture philanthropy Sayings * The rich get richer and the poor get poorer * Socialism for the rich and capitalism for the poor * Too big to fail Media * Capitalism and Freedom * Plutus * Greek god of wealth * Superclass * List * The Theory of the Leisure Class * Wealth * The Wealth of Nations * Category * By Country * Commons * Search * Commons [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Affluenza	None	5,085	wikipedia	https://en.wikipedia.org/wiki/Affluenza	2021-01-18T19:07:24	{"wikidata": ["Q1349829"]}
Spinocerebellar ataxia with epilepsy is a rare, mitochondrial DNA maintenance syndrome characterized by cerebellar ataxia, sensory peripheral neuropathy, myoclonus, epilepsy, progressive cognitive impairment, late-onset ptosis and external ophthalmoplegia. Liver failure may also occur, most often in association with the use of antiepileptic drug sodium valproate. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Spinocerebellar ataxia with epilepsy	c1843851	5,086	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254881	2021-01-23T17:28:15	{"mesh": ["C537583"], "omim": ["607459"], "umls": ["C1843851", "C1843852"], "icd-10": ["G11.0"], "synonyms": ["MSCAE", "Mitochondrial spinocerebellar ataxia with epilepsy", "SCAE"]}
Micrograph of psammoma body in the centre of the field in a meningioma of brain. H&E stain. A psammoma body is a round collection of calcium, seen microscopically. The term is derived from the Greek word ψάμμος (psámmos), meaning "sand". ## Contents * 1 Cause * 2 Association with lesions * 3 Benign lesions * 4 Appearance * 5 References * 6 External links ## Cause[edit] Psammoma bodies are associated with the papillary (nipple-like) histomorphology and are thought to arise from, 1. Infarction and calcification of papillae tips. 2. Calcification of intralymphatic tumor thrombi.[1] ## Association with lesions[edit] Psammoma bodies are commonly seen in certain tumors such as: * Papillary thyroid carcinoma * Papillary renal cell carcinoma * Ovarian papillary serous cystadenoma and cystadenocarcinoma[2] * Endometrial adenocarcinomas (Papillary serous carcinoma ~3%-4%) * Meningiomas, in the central nervous system[3] * Peritoneal and Pleural Mesothelioma * Somatostatinoma (pancreas)[4] * Prolactinoma of the pituitary [5] * Glucagonoma * Micropapillary subtype of Lung Adenocarcinoma[6] ## Benign lesions[edit] Micrograph of a psammomatous melanotic schwannoma with a psammoma body, as may be seen in Carney complex. H&E stain. Psammoma bodies may be seen in: * Endosalpingiosis[7] * Psammomatous melanotic schwannoma * Melanocytic nevus[8] ## Appearance[edit] Psammoma bodies usually have a laminar appearance, are circular, acellular and basophilic. ## References[edit] 1. ^ Johannessen JV, Sobrinho-Simões M (September 1980). "The origin and significance of thyroid psammoma bodies". Lab. Invest. 43 (3): 287–96. PMID 7401638. 2. ^ Ovarian papillary serous cystadenocarcinoma at WebPath, The Internet Pathology Laboratory for Medical Education at Mercer University School of Medicine. Retrieved July 2011 3. ^ http://spinwarp.ucsd.edu/neuroweb/Text/br-300b.htm 4. ^ Lewis RB (2010). "Pancreatic Endocrine Tumors: Radiologic-Clinicopathologic Correlation". RadioGraphics. 30: 1445–1464. doi:10.1148/rg.306105523. 5. ^ Robbin's Pathology, Eight Ed 6. ^ Emoto K, Eguchi T, Tan KS, Takahashi Y, Aly RG, Rekhtman N, Travis WD, Adusumilli PS (2019). "Expansion of the Concept of Micropapillary Adenocarcinoma to Include a Newly Recognized Filigree Pattern as Well as the Classical Pattern Based on 1468 Stage I Lung Adenocarcinomas". J Thorac Oncol. 14: 1948–1961. doi:10.1016/j.jtho.2019.07.008. PMID 31352072.CS1 maint: multiple names: authors list (link) 7. ^ Hallman KB, Nahhas WA, Connelly PJ (September 1991). "Endosalpingiosis as a source of psammoma bodies in a Papanicolaou smear. A case report". J Reprod Med. 36 (9): 675–8. PMID 1774734. 8. ^ Rapini, Ronald. Practical Dermatopathology. Elsevier Mosby, 2005, p. 10. ## External links[edit] Look up papillary in Wiktionary, the free dictionary. Slides: * Meningioma * Thyroid cancer * Endometriosis (peritoneum) * Video of psammoma bodies in meningioma This article related to pathology is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Psammoma body	None	5,087	wikipedia	https://en.wikipedia.org/wiki/Psammoma_body	2021-01-18T18:54:11	{"umls": ["C0391863"], "wikidata": ["Q487813"]}
Opsismodysplasia is a rare skeletal dysplasia characterized by congenital short stature and characteristic craniofacial abnormalities. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel (the space between the front bones of the skull), and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Children with opsismodysplasia are at an increased risk for respiratory infections and respiratory failure. This condition is caused by mutations in the INPPL1 the gene. It is inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Opsismodysplasia	c0432219	5,088	gard	https://rarediseases.info.nih.gov/diseases/4098/opsismodysplasia	2021-01-18T17:58:35	{"mesh": ["C537122"], "omim": ["258480"], "umls": ["C0432219"], "orphanet": ["2746"], "synonyms": []}
A rare group of primary bone dysplasia disorders characterized by the association of epiphyseal anomalies of long bones causing joint pain early in life, recurrent osteochondritis and early arthrosis. This group contains an heterogeneous group of diseases with variable expression. Common reported clinical signs include waddling gait and pain at onset, and moderate short stature. Some forms are mainly limited to the femoral epiphyses, while several other syndromes are characterized by the association of multiple epiphyseal dysplasia with other clinical manifestations such as myopia, deafness and facial dysmorphism. Diagnosis relies on identification of the radiological 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 [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Multiple epiphyseal dysplasia	c0026760	5,089	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251	2021-01-23T18:57:26	{"gard": ["10756"], "mesh": ["D010009"], "umls": ["C0026760"], "icd-10": ["Q77.3"], "synonyms": ["EDM", "MED", "Polyepiphyseal dysplasia"]}
A number sign (#) is used with this entry because of evidence that Keutel syndrome (KTLS) is caused by homozygous mutation in the gene encoding the human matrix Gla protein (MGP; 154870) on chromosome 12p12. Description Keutel syndrome is an autosomal recessive disorder characterized by multiple peripheral pulmonary stenoses, brachytelephalangy, inner ear deafness, and abnormal cartilage ossification or calcification (summary by Khosroshahi et al., 2014). Clinical Features Among the children of first cousins once removed, Keutel et al. (1972) found a brother and sister with an apparently distinctive syndrome: multiple peripheral pulmonary stenoses, neural hearing loss, short terminal phalanges, and calcification and/or ossification of the cartilage in the external ears, nose, larynx, trachea and ribs. Fryns et al. (1984) reported a single case. In the case reported by Cormode et al. (1986), calcifications were first noted at 13 months as stippled epiphyses at the knees and elbows. Tracheobronchial, laryngeal, pinnal and nasal calcifications were noted earlier. The tracheobronchial calcification was dramatically evident on chest x-ray. The facies was characterized by midface hypoplasia, depressed nasal bridge and small alae nasi. They reviewed 6 cases in 5 families. Both sexes are affected. Of the 5 families, 3 had consanguinity. Khosroshahi et al. (1989) reported 4 affected sisters out of 5 offspring of consanguineous parents. They presented x-rays demonstrating calcification in the cartilages of the ear, epiglottis, thyroid, trachea, and ala nasi. The mother had pulmonic stenosis. Khosroshahi et al. (2014) reported a 26-year follow-up of the 4 affected sisters. Long-term complications primarily involved the respiratory system. All of the sisters suffered from recurrent upper and lower respiratory tract diseases such as chronic sinusitis, chronic obstructive pulmonary disease, asthma, and bullous emphysema. One sister died at age 37 due to respiratory failure after general anesthesia. Another sister required tracheostomy after resection of papillary thyroid carcinoma because of respiratory failure. Pulmonary CT scans in all 4 showed progressive laryngotracheobronchial ossification and calcification, which was thought to be the cause of these complications. Permanent multiple erythematous, irregularly bordered macular lesions without induration on the dorsum of hands, elbows, neck, and trunk developed in all 4 after age 30. All developed arterial hypertension and thyroid nodules. Other findings were short-term memory loss and progressive hearing loss; one sister was unable to conceive. Teebi et al. (1998) reported a case of Keutel syndrome in a 15-year-old boy in whom cerebral calcifications had been identified in the course of investigations for a seizure disorder. The parents were phenotypically normal first cousins. The vertebral bodies showed severe end-plate irregularities and Schmorl nodes. Calcification of cartilage was diffuse and involved nose, pinnae, larynx, epiglottis, trachea, bronchial rings, and costochondral junctions. Calcification of the brain was a new finding in this case of Keutel syndrome. Brachytelephalangism was present, giving the fingers a drumstick appearance with some distal interphalangeal stiffness and short nails. Teebi et al. (1998) stated that 13 cases in 9 families (including their case) had been published. Six families were consanguineous, 2 had multiple affected sibs (males and females), and 4 families originated from the Middle East. The cardinal features of Keutel syndrome, midfacial hypoplasia and ectopic abnormal calcification, are present in a number of acquired and genetic disorders. Environmental factors include prenatal exposure to phenytoin or warfarin. Genetic disorders include autosomal recessive vitamin K epoxide reductase deficiency (277450) and some forms of chondrodysplasia punctata. Phenotypic similarities between the effects of environmental and genetic factors appear to reflect the involvement of a common metabolic pathway. The gamma-carboxylation of MGP depends on vitamin K as a cofactor. Both phenytoin and warfarin interfere with vitamin K synthesis by inhibiting vitamin K reductase activity. The X-linked recessive form of chondrodysplasia punctata (CDPX1; 302950) had been found to be due to a deficiency of arylsulfatase E (300180), the expression of which is inhibited by warfarin. Munroe et al. (1999) noted that the phenotypic similarities in these conditions could, therefore, be explained by the effect of defects in a vitamin K-dependent metabolic pathway on skeletal development, and suggested that Binder syndrome (maxillonasal dysplasia; 155050) might be an allelic variant of Keutel syndrome. Munroe et al. (1999) compared the findings in patients with Keutel syndrome with those in the Mgp knockout mouse model described by Luo et al. (1997). Patients with Keutel syndrome display several of the same features as the knockout mice, including abnormal calcification of cartilage affecting auricles, nose, and respiratory tract. This may account for the recurrent respiratory tract infections and hearing loss observed in some patients with Keutel syndrome. Patients with Keutel syndrome do not appear to have problems with fractures, premature osteoporosis, or short stature. They do have short phalanges and maxillonasal hypoplasia, however, which may be the result of decreased growth secondary to abnormal calcification. Keutel syndrome patients appear to have normal life expectancy with no increased incidence of coronary arterial disease or rupture of abdominal aortic aneurysm. The most consistent arterial abnormality in Keutel syndrome is peripheral pulmonary stenosis; however, histologic or pathologic examination of arteries had not been reported. The lack of arterial calcification in Keutel syndrome suggests that other calcification regulators or mechanisms may be involved in the process of extracellular matrix (ECM) calcification in different organs. Hur et al. (2005) described 3 sibs from a consanguineous Kuwaiti family with cartilage calcification, brachytelephalangism, and the characteristic facies of Keutel syndrome. Two of the sibs also had abnormalities in the white matter of the brain, 1 had optic nerve atrophy, and 1 had middermal elastosis. Nanda et al. (2006) examined the Kuwaiti sibs with Keutel syndrome previously reported by Hur et al. (2005) and noted lax and doughy skin in all 3 sibs, 2 of whom had prominent abdominal skin folds. Skin biopsy from the latter 2 patients showed reduction of elastic fibers in the papillary dermis with marked fragmentation and focal clumping of elastic fibers in the reticular dermis. On electron microscopy, the elastic fibers were widely spaced, irregular, fragmented, and surrounded by collagen that appeared normal; elastin was aggregated in dense irregular masses with clumping of microfibrils. Noting that several of the reported findings in this family, including leukodystrophy, optic nerve atrophy, and cutis laxa, are features not previously reported as part of Keutel syndrome, whereas some of their findings, including lax skin, leukodystrophy, hydronephrosis, and pulmonary stenosis, have been reported in autosomal recessive cutis laxa (219100), Nanda et al. (2006) suggested that there might be a second mutation in this family. In response, Cohen and Boyadjiev (2006) stated that their biopsy of the abnormal skin, which developed in the youngest sib after the appearance of red, indurated plaques, showed a loss of elastic material in the middermis, whereas elastic fibers of the reticular and papillary dermis were present and appeared normal; they concluded that the history of prior inflammation and microscopic findings were most consistent with a diagnosis of middermal elastosis. Mapping By a genomewide search using homozygosity mapping in 2 consanguineous Turkish families and in a Belgian family segregating Keutel syndrome, Munroe et al. (1999) found evidence for linkage of the disorder to 12p13.1-p12.3 (maximum multipoint lod score = 4.06). The Turkish families had been reported by Fryns et al. (1984) and Khosroshahi et al. (1989). Population Genetics Khosroshahi et al. (2014) stated that the estimated prevalence of Keutel syndrome is 1 in 1 million. Molecular Genetics Munroe et al. (1999) studied the gene for matrix Gla protein as a candidate for Keutel syndrome because of its localization to the same chromosomal region as the disorder and the known function of its protein product. By mutation analysis of the MGP gene in the 3 unrelated probands of the Turkish and Belgian families, they identified 3 different mutations (154870.0001-154870.0003), all of which predicted a nonfunctional protein. Hur et al. (2005) identified homozygosity for a splice site mutation in the MGP gene (154870.0004) in 3 sibs from a consanguineous Kuwaiti family with Keutel syndrome. The unaffected parents were heterozygous for the mutation. Animal Model In an examination of the molecular determinants regulating calcification of the extracellular matrix, Luo et al. (1997) studied Mgp, which is synthesized by vascular smooth muscle cells and chondrocytes, 2 cell types that produce an uncalcified ECM. To investigate Mgp function in vivo, they generated mice with a disrupted Mgp allele by gene targeting in embryonic stem cells. Heterozygous mice that were viable were intercrossed to generate homozygous Mgp-deficient mice. These mice developed to term but died within 2 months as a result of arterial calcification which led to blood vessel rupture. Chondrocytes that elaborated a typical cartilage matrix could be seen in the affected arteries. Mgp-deficient mice additionally exhibited inappropriate calcification of various cartilages, including the growth plate, which eventually led to short stature, osteopenia, and fractures. The results indicated that ECM calcification must be actively inhibited in soft tissues. Marulanda et al. (2017) found that Mgp -/- mice showed severe blunting of the snout and more rounded and wider face than wildtype. Mutant animals showed severe dental malocclusion characterized by by anterior crossbite and progressive ectopic mineralization of the nasal septum. Amorphous calcium phosphate was the main mineral species in Mgp-deficient nasal septum. A TUNEL assay showed a marked increase in apoptosis in immature chondrocytes of calcified nasal septum. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by Mgp deficiency. INHERITANCE \- Autosomal recessive GROWTH Height \- Stature below 25th percentile HEAD & NECK Face \- Deep philtrum \- Long face \- Midface hypoplasia, mild Ears \- Hearing loss (sensorineural, mixed, and conductive) \- Large, prominent pinnae \- Pale, stiff pinnae \- Progressive cartilaginous ossification of pinnae \- Recurrent episodes of otitis media Nose \- Small alae nasi \- Depressed nasal bridge \- Cartilaginous ossification of nose CARDIOVASCULAR Heart \- Ventricular septal defect Vascular \- Pulmonary artery hypoplasia \- Peripheral pulmonary stenosis \- Arterial hypertension RESPIRATORY Nasopharynx \- Chronic sinusitis Larynx \- Cartilaginous ossification of larynx \- Tracheobronchial stenosis Airways \- Cartilaginous ossification of trachea and bronchi \- Recurrent bronchitis \- Bullous emphysema \- Obstructive lung disease CHEST Ribs Sternum Clavicles & Scapulae \- Cartilaginous ossification of rib SKELETAL \- Abnormal cartilage ossification (nose, pinnae, larynx, epiglottis, trachea, bronchial rings, costochondral junctions) Limbs \- Epiphyseal stippling (infancy) Hands \- Variable shortening of terminal phalanges (brachytelephalangy) \- Premature fusion of phalangeal epiphyses \- Short thumbs \- Interdigital webbing, mild Feet \- Short halluces SKIN, NAILS, & HAIR Skin \- Erythematous, irregular macular lesions without induration on dorsum of hands, neck, and trunk Skin Histology \- Absence of elastic fibers in dermis NEUROLOGIC Central Nervous System \- Normal intelligence \- Mental retardation, mild \- Cerebral calcifications \- Seizures VOICE \- Nasal speech PRENATAL MANIFESTATIONS Delivery \- Increased risk of spontaneous abortion MOLECULAR BASIS \- Caused by mutation in the matrix Gla protein gene (MGP, 154870.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	KEUTEL SYNDROME	c1855607	5,090	omim	https://www.omim.org/entry/245150	2019-09-22T16:26:05	{"mesh": ["C536167"], "omim": ["245150"], "orphanet": ["85202"], "synonyms": ["Alternative titles", "PULMONIC STENOSIS, BRACHYTELEPHALANGISM, AND CALCIFICATION OF CARTILAGES"]}
Chromosomal disorder in which there are three copies of chromosome 18 Edwards syndrome Other namesTrisomy 18 (T18[1]), chromosome 18 duplication,[2] trisomy E syndrome[3] Chromosome 18 SpecialtyMedical genetics, pediatrics SymptomsSmall head, small jaw, clenched fists with overlapping fingers, profound intellectual disability[3] ComplicationsHeart defects[3] Usual onsetPresent at birth[3] CausesThird copy of chromosome 18 (usually new mutation)[3] Risk factorsOlder mother[3] Diagnostic methodUltrasound, amniocentesis[2] TreatmentSupportive care[2] Prognosis5–10% survive past a year old[3] Frequency1 per 5,000 births[3] Edwards syndrome, also known as trisomy 18, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18.[3] Many parts of the body are affected.[3] Babies are often born small and have heart defects.[3] Other features include a small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability.[3] Most cases of Edwards syndrome occur due to problems during the formation of the reproductive cells or during early development.[3] The rate of disease increases with the mother's age.[3] Rarely, cases may be inherited from a person's parents.[3] Occasionally, not all cells have the extra chromosome, known as mosaic trisomy, and symptoms in these cases may be less severe.[3] An ultrasound during pregnancy can increase suspicion for the condition, which can be confirmed by amniocentesis.[2] Treatment is supportive.[2] After having one child with the condition, the risk of having a second is typically around one percent.[2] It is the second-most common condition due to a third chromosome at birth, after Down syndrome.[4] Edwards syndrome occurs in around 1 in 5,000 live births.[3] Some studies suggest that more babies that survive to birth are female.[2] Many of those affected die before birth.[3] Survival beyond a year of life is around 5–10%.[3] It is named after English geneticist John Hilton Edwards, who first described the syndrome in 1960.[5] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Prognosis * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Clenched hand and overlapping fingers: index finger overlaps third finger and fifth finger overlaps fourth finger, characteristically seen in trisomy 18. This is caused by congenital joint contracture.[6] Children born with Edwards syndrome may have some or all of these characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, intellectual disability, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).[7][8] Some physical malformations associated with Edwards syndrome include small head (microcephaly) accompanied by a prominent back portion of the head (occiput), low-set, malformed ears, abnormally small jaw (micrognathia), cleft lip/cleft palate, upturned nose, narrow eyelid openings (blepharophimosis), widely spaced eyes (ocular hypertelorism), drooping of the upper eyelids (ptosis), a short breast bone, clenched hands, choroid plexus cysts, underdeveloped thumbs and/or nails, absent radius, webbing of the second and third toes, clubfoot or rocker bottom feet, and in males, undescended testicles.[7][8] In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common intracranial anomaly is the presence of choroid plexus cysts, which are pockets of fluid on the brain. These are not problematic in themselves, but their presence may be a marker for trisomy 18.[9][10] Sometimes, excess amniotic fluid or polyhydramnios is exhibited.[7] Although uncommon in the syndrome, Edwards syndrome causes a large portion of prenatal cases of Dandy–Walker malformation.[11][12] ## Genetics[edit] Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations, but is more prevalent in female offspring.[13] A healthy egg and/or sperm cell contains individual chromosomes, each of which contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.[14] Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo has 47 chromosomes, with three copies of chromosome 18.[citation needed] A small percentage of cases occur when only some of the body's cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.[citation needed] ## Diagnosis[edit] Ultrasound can increase suspicion for the condition, which can be confirmed by amniocentesis.[2] Levels of PAPP-A, AFP, uE3, free β-hCG, all of which are generally decreased during pregnancy.[15] ## Prognosis[edit] About 95% of pregnancies that are affected do not result in a live birth.[13] Major causes of death include apnea and heart abnormalities. It is impossible to predict an exact prognosis during pregnancy or the neonatal period.[13] Half of the live infants do not survive beyond the first week of life.[16] The median lifespan is five to 15 days.[17][18] About 8–12% of infants survive longer than 1 year.[19][20][better source needed] One percent of children live to age 10.[13] However, these estimates may be pessimistic; a retrospective Canadian study of 254 children with trisomy 18 demonstrated ten-year survival of 9.8%,[20] and another found that 68.6% of children with surgical intervention survived infancy.[21] ## Epidemiology[edit] Edwards syndrome occurs in about one in 5,000 live births, but more conceptions are affected by the syndrome because the majority of those diagnosed with the condition prenatally will not survive to birth.[3] Although women in their 20s and early 30s may conceive babies with Edwards syndrome, the risk of conceiving a child with it increases with a woman's age. The average maternal age for conceiving a child with this disorder is 32½.[22] ## See also[edit] * 18q deletion syndrome ## References[edit] 1. ^ https://www.gov.uk/government/publications/trisomy-18-description-in-brief 2. ^ a b c d e f g h "Trisomy 18". Orphanet. May 2008. Archived from the original on 3 October 2016. Retrieved 1 October 2016. 3. ^ a b c d e f g h i j k l m n o p q r s t "trisomy 18". GHR. March 2012. Archived from the original on 2 October 2016. Retrieved 1 October 2016. 4. ^ Jorde, Lynn B.; Carey, John C.; Bamshad, Michael J. (2009). Medical Genetics (4 ed.). Elsevier Health Sciences. p. 109. ISBN 978-0323075763. Archived from the original on 2016-10-02. 5. ^ "Edwards syndrome (John Hilton Edwards)". WhoNamedIt.com. Archived from the original on 2008-07-09. Retrieved 2008-07-24. 6. ^ Cereda, Anna; Carey, John C (2012-10-23). "The trisomy 18 syndrome". Orphanet Journal of Rare Diseases. 7: 81. doi:10.1186/1750-1172-7-81. ISSN 1750-1172. PMC 3520824. PMID 23088440. 7. ^ a b c "What is Trisomy 18?". Trisomy 18 Foundation. Archived from the original on 2009-03-23. Retrieved 2008-07-24. 8. ^ a b "Trisomy 18". Medline. Archived from the original on 2008-10-01. Retrieved 2008-07-24. 9. ^ Hurt K, Sottner O, Záhumenský J, et al. (2007). "[Choroid plexus cysts and risk of trisomy 18. Modifications regarding maternal age and markers]". Ceska Gynekol (in Czech). 72 (1): 49–52. PMID 17357350. 10. ^ Papp C, Ban Z, Szigeti Z, Csaba A, Beke A, Papp Z (2007). "Role of second trimester sonography in detecting trisomy 18: a review of 70 cases". J Clin Ultrasound. 35 (2): 68–72. doi:10.1002/jcu.20290. PMID 17206726. 11. ^ Imataka, George; Yamanouchi, Hideo; Arisaka, Osamu (2007). "Dandy–Walker syndrome and chromosomal abnormalities". Congenital Anomalies. 47 (4): 113–118. doi:10.1111/j.1741-4520.2007.00158.x. ISSN 1741-4520. PMID 17988252. S2CID 32024323. 12. ^ Stambolliu, Emelina; Ioakeim-Ioannidou, Myrsini; Kontokostas, Kimonas; Dakoutrou, Maria; Kousoulis, Antonis A. (2017-09-01). "The Most Common Comorbidities in Dandy-Walker Syndrome Patients: A Systematic Review of Case Reports" (PDF). Journal of Child Neurology. 32 (10): 886–902. doi:10.1177/0883073817712589. ISSN 0883-0738. PMID 28635420. S2CID 20046766. 13. ^ a b c d Chen, MD, Harold. "Introduction to Trisomy 18". EMedicine. Archived from the original on 2008-08-04. Retrieved 2008-07-24. 14. ^ For a description of human karyotype see Mittleman, A., ed. (1995). "An International System for Human Cytogenetic Nomenclature". Archived from the original on 2006-07-07. Retrieved 2006-06-04. 15. ^ "Prenatal Diagnose". Archived from the original on 2018-08-17. Retrieved 2018-08-17. 16. ^ "Trisomy 18: MedlinePlus Medical Encyclopedia". Nlm.nih.gov. 2011-12-14. Archived from the original on 2012-01-21. Retrieved 2012-01-04. 17. ^ Rodeck, Charles H.; Whittle, Martin J. (1999). Fetal Medicine: Basic Science and Clinical Practice. Elsevier Health Sciences. ISBN 0-443-05357-X. 18. ^ Zoler, Mitchel L. (March 1, 2003). "Trisomy 13 survival can exceed 1 year". OB/GYN News. Retrieved 2008-07-24. 19. ^ "Trisomy 13 survival can exceed 1 year \| OB/GYN News". Find Articles. 2003-03-01. Retrieved 2012-01-04. 20. ^ a b Nelson, Katherine E.; Rosella, Laura C.; Mahant, Sanjay; Guttmann, Astrid (2016). "Survival and Surgical Interventions for Children With Trisomy 13 and 18". JAMA. 316 (4): 420–8. doi:10.1001/jama.2016.9819. PMID 27458947. Archived from the original on 17 November 2016. Retrieved 3 December 2016. 21. ^ Nelson, Katherine E.; Rosella, Laura C.; Mahant, Sanjay; Guttman, Astrid (26 July 2016). "Survival and Surgical Interventions for Children With Trisomy 13 and 18". JAMA. 316 (4): 420–428. doi:10.1001/jama.2016.9819. Retrieved 15 January 2021. 22. ^ "Prevalence and Incidence of Edwards Syndrome". Diseases Center-Edwards Syndrome. Adviware Pty Ltd. 2008-02-04. Archived from the original on 2004-06-25. Retrieved 2008-02-17. "mean maternal age for this disorder is 32½" ## External links[edit] Classification D * ICD-10: Q91.0-Q91.3 * ICD-9-CM: 758.2 * MeSH: D000073842 * DiseasesDB: 13378 External resources * MedlinePlus: 001661 * eMedicine: ped/652 * Patient UK: Edwards syndrome * Orphanet: 3380 * Edwards syndrome at Curlie * Perinatal Hospice Care - Preparing for birth and death" * Humpath #5389 * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 Authority control * GND: 1046751034 * NDL: 01161959 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Edwards syndrome	c0152096	5,091	wikipedia	https://en.wikipedia.org/wiki/Edwards_syndrome	2021-01-18T18:44:40	{"gard": ["6321"], "mesh": ["D000073842"], "umls": ["C0152096"], "orphanet": ["3380"], "wikidata": ["Q457737"]}
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-54 (EIEE54) is caused by heterozygous mutation in the HNRNPU gene (602869) on chromosome 1q44. For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). Description Early infantile epileptic encephalopathy-54 is a severe neurodevelopmental disorder characterized by delayed psychomotor development, early-onset refractory seizures that are often initially febrile but later afebrile, and severe intellectual disability (summary by de Kovel et al., 2016). Clinical Features Carvill et al. (2013) reported a 33-year-old man (patient T162) with EIEE54. He had delayed development before seizure onset as well as severe intellectual disability with regression. He had onset of atonic seizures at age 2 years, followed by atypical absence seizures, myoclonic jerks, nonconvulsive status epilepticus, and tonic and tonic-clonic seizures. EEG showed multiple abnormalities, including generalized spike and polyspike waves, diffuse slowing, slow spike waves, and generalized paroxysmal fast activity. Hamdan et al. (2014) identified reported a 3.5-year-old boy (patient 1464.524) with EIEE54. Clinical details were sparse, but the child was noted to have severe intellectual disability, borderline microcephaly, autistic features, and seizures. He was hypotonic and was unable to speak or walk. Brain imaging showed enlarged ventricles and myelination delay. De Kovel et al. (2016) reported a girl (patient 2012D06376) with EIEE54. She had developmental delay in early infancy and presented with febrile seizures at age 8 months. At age 2 years, she did not speak. Other features included hypotonia, hyperlaxity, deep-set eyes with epicanthal folds, narrow palate, gray sclerae, and a short second digit on each hand. Brain imaging suggested delayed myelination, and EEG showed epileptiform activity. Molecular Genetics In a 33-year-old man (patient T162) with EIEE54, Carvill et al. (2013) identified a heterozygous nonsense mutation in the HNRNPU gene (Y805X; 602869.0001). The mutation was not present in the mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes. In a 3.5-year-old boy (patient 1464.524) with EIEE54, Hamdan et al. (2014) identified a de novo heterozygous nonsense mutation in the HNRNPU gene (Q171X; 602869.0002). The mutation was not found in the Exome Variant Server database; functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing. In a girl (patient 2012D06376) with EIEE54, de Kovel et al. (2016) identified a de novo frameshift mutation in the HNRNPU gene (602869.0003). The mutation was found by sequencing candidate genes for epileptic encephalopathy in 359 patients and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes. In an 11-year-old girl (trio hv) with EIEE54, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous small insertion/deletion in a splice acceptor site of the HNRNPU gene, predicted to result in a modified protein. The patient was part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. The patient had previously been reported by Need et al. (2012) as also carrying a de novo heterozygous mutation in the SMAD1 gene (601595). Functional studies of the variants and studies of patient cells were not performed. The patient had delayed development before onset of febrile seizures at age 9 months. She later developed multiple types of refractory afebrile seizures. At age 11, she was nonverbal with severe intellectual disability, autistic features, aggressive behavior, and incontinence. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Small head circumference Face \- Dysmorphic features, nonspecific (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures, multiple types \- Delayed psychomotor development \- Intellectual disability \- Mental retardation \- Poor or absent speech \- Abnormal EEG \- Enlarged ventricles \- Delayed myelination Behavioral Psychiatric Manifestations \- Autistic features MISCELLANEOUS \- Onset in infancy \- Seizures are refractory to treatment \- Febrile seizures may occur in infancy, followed by afebrile seizures later \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the heterogeneous nuclear ribonucleoprotein U gene (HNRNPU, 602869.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 54	c0393706	5,092	omim	https://www.omim.org/entry/617391	2019-09-22T15:46:04	{"doid": ["0080418"], "omim": ["617391"], "orphanet": ["1934"]}
A rare, congenital cardiac anomaly characterized by a common atrioventricular junction with a common AV valve, an interatrial communication just above the common AV valve (ostium primum defect), a posterior interventricular communication (inlet VSD), that results in shunting at both the atrial and ventricular level. Morphologically, the common atrioventricular valve has 4 or 5 leaflets including superior and inferior bridging leaflets with a single annulus. ## Epidemiology Prevalence at birth of complete atrioventricular septal defect (CAVSD) is suggested to be 1/5,000 in Europe. Both sexes are equally affected. ## Clinical description Infants typically present within the first year of life with symptoms of congestive heart failure which may include feeding difficulties, excessive sweating, tachycardia, tachypnea, mild wheezing, failure to thrive, and poor peripheral blood perfusion. If untreated, affected individuals develop irreversible pulmonary hypertension which improves signs of congestive heart failure but worsens tolerance to effort and results in cyanosis and Eisenmenger syndrome. Recurrent pulmonary infections are common. Morphologically, the ventricles may be equal or nearly equal in size (balanced) or one of the ventricles may be significantly larger than the other (unbalanced). The balanced form is typically observed in Down syndrome. Unbalanced ventricles are associated with varying degrees of malalignment of the common atrioventricular valve over the hypoplastic ventricle and hypoplasia of the arterial valve above. Tetralogy of Fallot (TOF) is observed in 5-10% of CAVSD. ## Etiology CAVSD is strongly associated with Down syndrome and heterotaxy. Cilia gene mutations could be involved in isolated AVSD. A small fraction of CAVSD cases have been associated with NR2F2 (15q26.2), GATA4 (8p23.1), GATA6 (18q11.2) and CRELD1 (3p25.3) mutations. ## Diagnostic methods Echocardiography is used for postnatal diagnosis. Typical findings include a left and superior QRS axis in the frontal plane and counterclockwise depolarization. Chest X-ray may show ventricular enlargement and a greater anterior position of the left atrioventricular valve due to the inlet septal defect, which gives a ''goose neck'' appearance to le left ventricular outflow tract. ## Differential diagnosis Differential diagnosis includes other congenital cardiac anomalies that result in early heart failure including partial atrioventricular canal, atrial septal defects and large ventricular septal defects. ## Antenatal diagnosis CAVSD can be detected with fetal echocardiography; the detection rate is approximately 67%. ## Genetic counseling Atrioventricular septal defects (AVSD) can occur in the offspring of mothers with CAVSD. ## Management and treatment Digoxin, diuretics and angiotensin-converting enzymes may be used to treat congestive heart failure prior to surgery. Surgical repair is advised at 3 months of age and is typically performed between 3 and 6 months of age. The three classical techniques are single patch technique, two patch technique (most frequent), and the modified single patch technique. To avoid surgically induced AV block, the position of the AV node and bundle of His must be considered, with the AV node positioned more posteriorly and inferiorly, the non-branching bundle running slightly on the left side of the septal crest with the branching bundle being exposed. Pulmonary artery banding can be proposed before 3 months in very ill patients despite optimal medical therapy. Combined repair of other cardiac anomalies is often performed with desirable results. In case of associated tetralogy of Fallot, complete repair is usually delayed up until 1 year of age. Lifelong follow-up every 2 to 3 years is recommended. ## Prognosis Without surgery, many of the affected individuals will die in infancy. Prognosis after surgical repair is good; however, patients who weigh less the 3 kg or are less than 2.5 years old have a higher risk of mortality during surgery. Pregnancy increases the risk of developing left AVV regurgitation, arrhythmias, deterioration of heart failure, and is not recommended for women with severe pulmonary hypertension. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Complete atrioventricular septal defect	c0344787	5,093	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1329	2021-01-23T18:43:21	{"gard": ["1454"], "umls": ["C0221215", "C0344787"], "icd-10": ["Q21.2"], "synonyms": ["CAVC", "Complete AVSD", "Complete atrioventricular canal", "Complete atrioventricular canal defect", "Complete atrioventricular septal defect with atrial and ventricular components"]}
"Low T" redirects here. It is not to be confused with LOWT or T Low. Endocrine disease Hypogonadism Other namesInterrupted stage 1 puberty SpecialtyEndocrinology Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen (e.g., estradiol) as hypoestrogenism. These are responsible for the observed signs and symptoms. Hypogonadism can decrease other hormones secreted by the gonads including progesterone, DHEA, anti-Müllerian hormone, activin, and inhibin. Sperm development (spermatogenesis) and release of the egg from the ovaries (ovulation) may be impaired by hypogonadism, which, depending on the degree of severity, may result in partial or complete infertility. In January 2020, the American College of Physicians issued clinical guidelines for testosterone treatment in adult men with age-related low levels of testosterone. The guidelines are supported by the American Academy of Family Physicians. The guidelines include patient discussions regarding testosterone treatment for sexual dysfunction; annual patient evaluation regarding possible notable improvement and, if none, to discontinue testosterone treatment; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar; and, testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.[1][2] ## Contents * 1 Classification * 1.1 Affected system * 1.2 Primary or secondary * 1.3 Congenital vs. acquired * 1.4 Hormones vs. fertility * 2 Signs and symptoms * 2.1 Hypogonadotrophic hypogonadism * 3 Diagnosis * 3.1 Men * 3.2 Women * 4 Screening * 5 Treatment * 6 See also * 7 References * 8 External links ## Classification[edit] Main articles: Hypergonadotropic hypogonadism, Hypogonadotropic hypogonadism, and Isolated hypogonadotropic hypogonadism Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism usually means permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective. Physicians measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles (hyper-gonatropic hypogonadism); whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain (hypo-gonatropic hypogonadism).[citation needed] ### Affected system[edit] * Hypogonadism resulting from defects of the gonads is traditionally referred to as "primary hypogonadism". Examples include Klinefelter syndrome and Turner syndrome. Mumps is known to cause testicular failure, and in recent years has been immunized against in the US. A varicocele can reduce hormonal production as well.[citation needed] * Hypogonadism resulting from hypothalamic or pituitary defects are termed "secondary hypogonadism" or "central hypogonadism" (referring to the central nervous system).[citation needed] * Examples of hypothalamic defects include Kallmann syndrome. * Examples of pituitary defects include hypopituitarism and pituitary hypoplasia. * An example of a hypogonadism resulting from the lack of hormone response is androgen insensitivity syndrome, where there are inadequate receptors to bind the testosterone, resulting in varying clinical phenotypes of sexual characteristics despite XY chromosomes.[citation needed] ### Primary or secondary[edit] * Primary - defect is inherent within the gonad: e.g. Noonan syndrome, Turner syndrome (45X,0), Klinefelter syndrome (47XXY), XY with SRY gene-immunity[citation needed] * Secondary - defect lies outside of the gonad: e.g. Polycystic ovary syndrome, and Kallmann syndrome, also called hypogonadotropic hypogonadism.[3] Hemochromatosis and diabetes mellitus can be causes of this as well.[citation needed] ### Congenital vs. acquired[edit] * Examples of congenital causes of hypogonadism, that is, causes that are present at birth:[citation needed] * Turner syndrome and Klinefelter syndrome. It is also one of the signs of CHARGE syndrome. * Examples of acquired causes of hypogonadism:[citation needed] * Opioid Induced Androgen Deficiency (resulting from the prolonged use of opioid class drugs, e.g. codeine, Dihydrocodeine, morphine, oxycodone, methadone, fentanyl, hydromorphone, etc.) * Anabolic steroid-induced hypogonadism (ASIH) * Childhood mumps * Children born to mothers who had ingested the endocrine disruptor diethylstilbestrol for potential miscarriage * Traumatic brain injury, even in childhood * In males, normal aging causes a decrease in androgens, which is sometimes called "male menopause" (also known by the coinage "manopause"), late-onset hypogonadism (LOH), and "andropause" or androgen decline in the aging male (ADAM), among other names. * It is a symptom of hereditary hemochromatosis[4] ### Hormones vs. fertility[edit] Hypogonadism can involve just hormone production or just fertility, but most commonly involves both.[citation needed] * Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement. * Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome. ## Signs and symptoms[edit] Women with hypogonadism do not begin menstruating and it may affect their height and breast development. Onset in women after puberty causes cessation of menstruation, lowered libido, loss of body hair, and hot flashes. In men it causes impaired muscle and body hair development, gynecomastia, decreased height, erectile dysfunction, and sexual difficulties. If hypogonadism is caused by a disorder of the central nervous system (e.g., a brain tumor), then this is known as central hypogonadism. Signs and symptoms of central hypogonadism may involve headaches, impaired vision, double vision, milky discharge from the breast, and symptoms caused by other hormone problems.[5] ### Hypogonadotrophic hypogonadism[edit] The symptoms of hypogonadotrophic hypogonadism, a subtype of hypogonadism, include late, incomplete or lack of development at puberty, and sometimes short stature or the inability to smell; in females, a lack of breasts and menstrual periods, and in males a lack of sexual development, e.g., facial hair, penis and testes enlargement, deepening voice.[citation needed] ## Diagnosis[edit] ### Men[edit] Low testosterone can be identified through a simple blood test performed by a laboratory, ordered by a health care provider. Blood for the test must be taken in the morning hours, when levels are highest, as levels can drop by as much as 13% during the day and all normal reference ranges are based on morning levels.[6] However, low testosterone in the absence of any symptoms does not clearly need to be treated.[citation needed] Normal total testosterone levels depend on the man's age but generally range from 240 to 950 ng/dL (nanograms per deciliter) or 8.3-32.9 nmol/L (nanomoles per liter).[7] According to American Urological Association, the diagnosis of low testosterone can be supported when the total testosterone level is below 300 ng/dl.[8] Some men with normal total testosterone have low free or bioavailable testosterone levels which could still account for their symptoms. Men with low serum testosterone levels should have other hormones checked, particularly luteinizing hormone to help determine why their testosterone levels are low and help choose the most appropriate treatment (most notably, testosterone is usually not appropriate for secondary or tertiary forms of male hypogonadism, in which the LH levels are usually reduced).[citation needed] Treatment is often prescribed for total testosterone levels below 230 ng/dL with symptoms.[9] If the serum total testosterone level is between 230 and 350 ng/dL, free or bioavailable testosterone should be checked as they are frequently low when the total is marginal. The standard range given is based on widely varying ages and, given that testosterone levels naturally decrease as humans age, age-group specific averages should be taken into consideration when discussing treatment between doctor and patient.[10] In men, testosterone falls approximately 1 to 3 percent each year.[11] Blood testing A position statement by the Endocrine Society expressed dissatisfaction with most assays for total, free, and bioavailable testosterone.[12] In particular, research has questioned the validity of commonly administered assays of free testosterone by radioimmunoassay.[12] The free androgen index, essentially a calculation based on total testosterone and sex hormone-binding globulin levels, has been found to be the worst predictor of free testosterone levels and should not be used.[13] Measurement by equilibrium dialysis or mass spectroscopy is generally required for accurate results, particularly for free testosterone which is normally present in very small concentrations.[citation needed] ### Women[edit] Testing serum LH and FSH levels are often used to assess hypogonadism in women, particularly when menopause is believed to be happening. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels. In any case, the LH and FSH levels will rise in cases of primary hypogonadism or menopause, while they will be low in women with secondary or tertiary hypogonadism.[citation needed] Hypogonadism is often discovered during evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women.[citation needed] ## Screening[edit] Screening males who do not have symptoms for hypogonadism is not recommended as of 2018.[14] ## Treatment[edit] Male primary or hypergonadotropic hypogonadism is often treated with testosterone replacement therapy if they are not trying to conceive.[9] Adverse effects of testosterone replacement therapy include increased cardiovascular events (including strokes and heart attacks) and death.[15] The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging.[16][17] The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke.[16][17] While historically, men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth.[18] Other side effects can include an elevation of the hematocrit to levels that require blood withdrawal (phlebotomy) to prevent complications from excessively thick blood. Gynecomastia (growth of breasts in men) sometimes occurs. Finally, some physicians worry that obstructive sleep apnea may worsen with testosterone therapy, and should be monitored.[19] Another treatment for hypogonadism is human chorionic gonadotropin (hCG).[20] This stimulates the LH receptor, thereby promoting testosterone synthesis. This will not be effective in men who simply cannot make testosterone anymore (primary hypogonadism) and the failure of hCG therapy is further support for the existence of true testicular failure in a patient. It is particularly indicated in men with hypogonadism who wish to retain their fertility, as it does not suppress spermatogenesis like testosterone replacement therapy does. For both men and women, an alternative to testosterone replacement is low-dose clomifene treatment, which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects that can result from direct hormone replacement therapy.[21] Clomifene blocks estrogen from binding to some estrogen receptors in the hypothalamus, thereby causing an increased release of gonadotropin-releasing hormone and subsequently LH from the pituitary. Clomifene is a selective estrogen receptor modulator (SERM). Generally, clomifene does not have adverse effects at the doses used for this purpose. Clomifene at much higher doses is used to induce ovulation and has significant adverse effects in such a setting. * v * t * e Androgen replacement therapy formulations and dosages used in men Route Medication Major brand names Form Dosage Oral Testosteronea – Tablet 400–800 mg/day (in divided doses) Testosterone undecanoate Andriol, Jatenzo Capsule 40–80 mg/2–4x day (with meals) Methyltestosteroneb Android, Metandren, Testred Tablet 10–50 mg/day Fluoxymesteroneb Halotestin, Ora-Testryl, Ultandren Tablet 5–20 mg/day Metandienoneb Dianabol Tablet 5–15 mg/day Mesteroloneb Proviron Tablet 25–150 mg/day Buccal Testosterone Striant Tablet 30 mg 2x/day Methyltestosteroneb Metandren, Oreton Methyl Tablet 5–25 mg/day Sublingual Testosteroneb Testoral Tablet 5–10 mg 1–4x/day Methyltestosteroneb Metandren, Oreton Methyl Tablet 10–30 mg/day Intranasal Testosterone Natesto Nasal spray 11 mg 3x/day Transdermal Testosterone AndroGel, Testim, TestoGel Gel 25–125 mg/day Androderm, AndroPatch, TestoPatch Non-scrotal patch 2.5–15 mg/day Testoderm Scrotal patch 4–6 mg/day Axiron Axillary solution 30–120 mg/day Androstanolone (DHT) Andractim Gel 100–250 mg/day Rectal Testosterone Rektandron, Testosteronb Suppository 40 mg 2–3x/day Injection (IM or SC) Testosterone Andronaq, Sterotate, Virosterone Aqueous suspension 10–50 mg 2–3x/week Testosterone propionateb Testoviron Oil solution 10–50 mg 2–3x/week Testosterone enanthate Delatestryl Oil solution 50–250 mg 1x/1–4 weeks Xyosted Auto-injector 50–100 mg 1x/week Testosterone cypionate Depo-Testosterone Oil solution 50–250 mg 1x/1–4 weeks Testosterone isobutyrate Agovirin Depot Aqueous suspension 50–100 mg 1x/1–2 weeks Testosterone phenylacetateb Perandren, Androject Oil solution 50–200 mg 1x/3–5 weeks Mixed testosterone esters Sustanon 100, Sustanon 250 Oil solution 50–250 mg 1x/2–4 weeks Testosterone undecanoate Aveed, Nebido Oil solution 750–1,000 mg 1x/10–14 weeks Testosterone buciclatea – Aqueous suspension 600–1,000 mg 1x/12–20 weeks Implant Testosterone Testopel Pellet 150–1,200 mg/3–6 months Notes: Men produce about 3 to 11 mg testosterone per day (mean 7 mg/day in young men). Footnotes: a = Never marketed. b = No longer used and/or no longer marketed. Sources: See template. ## See also[edit] * Congenital adrenal hyperplasia due to 21-hydroxylase deficiency * Delayed puberty and infertility * Hypergonadism (hyperandrogenism and hyperestrogenism) * Hypergonadotropic hypogonadism * Hypoandrogenism and hypoestrogenism * Kallmann syndrome ## References[edit] 1. ^ Qaseem, Amir; et al. (6 January 2020). "Testosterone Treatment in Adult Men With Age-Related Low Testosterone: A Clinical Guideline From the American College of Physicians". Annals of Internal Medicine. 172 (2): 126–133. doi:10.7326/M19-0882. PMID 31905405. Retrieved 7 January 2020. 2. ^ Parry, Nicola M. (7 January 2020). "New Guideline for Testosterone Treatment in Men With 'Low T'". Medscape.com. Retrieved 7 January 2020. 3. ^ MedlinePlus Encyclopedia: Hypogonadotropic hypogonadism 4. ^ "Symptoms". irondisorders.org. Retrieved 21 March 2018. 5. ^ MedlinePlus Encyclopedia: Hypogonadism 6. ^ Crawford ED, Barqawi AB, O'Donnell C, Morgentaler A (September 2007). "The association of time of day and serum testosterone concentration in a large screening population". BJU International. 100 (3): 509–13. doi:10.1111/j.1464-410X.2007.07022.x. PMID 17555474. S2CID 23740125. Lay summary – UroToday (12 July 2007). 7. ^ "Testosterone, Total, Bioavailable, and Free, Serum". Mayo Medical Laboratories. Mayo Clinic. 2016. Retrieved 19 Dec 2016. 8. ^ Mulhall, John P.; Trost, Landon W.; Brannigan, Robert E.; Kurtz, Emily G.; Redmon, J. Bruce; Chiles, Kelly A.; Lightner, Deborah J.; Miner, Martin M.; Murad, M. Hassan (August 2018). "Evaluation and Management of Testosterone Deficiency: AUA Guideline". Journal of Urology. 200 (2): 423–432. doi:10.1016/j.juro.2018.03.115. ISSN 0022-5347. PMID 29601923. 9. ^ a b Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC (2006). "Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations". Journal of Andrology. 27 (2): 135–7. doi:10.2164/jandrol.05047. PMID 16474020. 10. ^ Hildebrandt, Brian. "Normal Testosterone Levels In Men - Average Ranges By Age". mens-hormonal-health.com. Retrieved 21 March 2018. 11. ^ School, Florence Comite, MD; Foreword by Abraham Morgentaler, MD associate clinical professor of urology, Harvard Medical (2013). Keep it up : the power of precision medicine to conquer low T and revitalize your life. Rodale Books. p. 14. ISBN 978-1609611019. 12. ^ a b Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H (February 2007). "Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement". The Journal of Clinical Endocrinology and Metabolism. 92 (2): 405–13. doi:10.1210/jc.2006-1864. PMID 17090633. 13. ^ Morris PD, Malkin CJ, Channer KS, Jones TH (August 2004). "A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men". European Journal of Endocrinology. 151 (2): 241–9. doi:10.1530/eje.0.1510241. PMID 15296480. 14. ^ Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA (May 2018). "Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism. 103 (5): 1715–1744. doi:10.1210/jc.2018-00229. PMID 29562364. 15. ^ Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF, Hoover RN (January 2014). "Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men" (PDF). PLOS ONE. 9 (1): e85805. Bibcode:2014PLoSO...985805F. doi:10.1371/journal.pone.0085805. PMC 3905977. PMID 24489673. Archived from the original (PDF) on 2016-03-04. Retrieved 2015-08-25. 16. ^ a b Staff (3 March 2015). "Testosterone Products: Drug Safety Communication - FDA Cautions About Using Testosterone Products for Low Testosterone Due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack And Stroke". FDA. Retrieved 5 March 2015. 17. ^ a b Tavernise, Sabrina (March 3, 2015). "Drugs Using Testosterone Will Label Heart Risks". New York Times. Retrieved March 19, 2015. 18. ^ Morgentaler A (November 2006). "Testosterone and prostate cancer: an historical perspective on a modern myth". European Urology. 50 (5): 935–9. doi:10.1016/j.eururo.2006.06.034. PMID 16875775. 19. ^ Matsumoto AM, Sandblom RE, Schoene RB, Lee KA, Giblin EC, Pierson DJ, Bremner WJ (June 1985). "Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep". Clinical Endocrinology. 22 (6): 713–21. doi:10.1111/j.1365-2265.1985.tb00161.x. hdl:1773/4497. PMID 4017261. S2CID 1790630. 20. ^ Chudnovsky A, Niederberger CS (2007). "Gonadotropin therapy for infertile men with hypogonadotropic hypogonadism". Journal of Andrology. 28 (5): 644–6. doi:10.2164/jandrol.107.003400. PMID 17522414. 21. ^ Whitten SJ, Nangia AK, Kolettis PN (December 2006). "Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate". Fertility and Sterility. 86 (6): 1664–8. doi:10.1016/j.fertnstert.2006.05.042. PMID 17007848. ## External links[edit] * Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview at National Center for Biotechnology Information. * MedlinePlus Encyclopedia: Hypogonadism * Hypogonadism at eMedicine Classification D * ICD-10: E28.3, E29.1, E23.0 * ICD-9-CM: 257.2 * OMIM: 146110 * MeSH: D007006 * DiseasesDB: 21057 External resources * MedlinePlus: 001195 * eMedicine: article/922038 * GeneReviews: Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency Overview * v * t * e Gonadal disorder Ovarian * Polycystic ovary syndrome * Premature ovarian failure * Estrogen insensitivity syndrome * Hyperthecosis Testicular Enzymatic * 5α-reductase deficiency * 17β-hydroxysteroid dehydrogenase deficiency * aromatase excess syndrome Androgen receptor * Androgen insensitivity syndrome * Familial male-limited precocious puberty * Partial androgen insensitivity syndrome Other * Sertoli cell-only syndrome General * Hypogonadism * Delayed puberty * Hypergonadism * Precocious puberty * Hypoandrogenism * Hypoestrogenism * Hyperandrogenism * Hyperestrogenism * Postorgasmic illness syndrome * Cytochrome P450 oxidoreductase deficiency * Cytochrome b5 deficiency * Androgen-dependent condition * Aromatase deficiency * Complete androgen insensitivity syndrome * Mild androgen insensitivity syndrome * Hypergonadotropic hypogonadism * Hypogonadotropic hypogonadism * Fertile eunuch syndrome * Estrogen-dependent condition * Premature thelarche * Gonadotropin insensitivity * Hypergonadotropic hypergonadism [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection	Hypogonadism	c0271623	5,094	wikipedia	https://en.wikipedia.org/wiki/Hypogonadism	2021-01-18T19:06:51	{"mesh": ["D007006"], "umls": ["C0020619", "C0271623", "C0948896", "C3489396"], "icd-9": ["257.2"], "icd-10": ["E23.0", "E28.3", "E29.1"], "wikidata": ["Q938107"]}
An extremely rare type of arthrogryposis multiplex congenita characterized by the combination of multiple joint contractures with movement limitation, microstomia with a whistling appearance of the mouth that may cause feeding, swallowing, and speech difficulties, a distinctive expressionless facies, severe developmental delay, central and autonomous nervous system dysfunction (excessive salivation, temperature instability, myoclonic epileptic fits, bradycardia), occasionally Pierre-Robin sequence, and lethality generally occurring during the first months of life. Arthrogryposis multiplex congenita-whistling face syndrome has been suggested to be a fetal akinesia deformation sequence. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection	Arthrogryposis multiplex congenita-whistling face syndrome	c1859711	5,095	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1150	2021-01-23T18:03:40	{"gard": ["792"], "mesh": ["C538401"], "omim": ["208155"], "umls": ["C1859711"], "icd-10": ["Q87.8"], "synonyms": ["Illum syndrome"]}
Loss of hair from the head or body "Bald" redirects here. For other uses, see Bald (disambiguation). "Balding" redirects here. For the surname, see Balding (surname). "Alopecia" redirects here. For other uses, see Alopecia (disambiguation). Hair loss Other namesAlopecia, baldness A bald spot on a man Pronunciation * Alopecia: /ˌæloʊˈpiːʃə/ SpecialtyDermatology SymptomsLoss of hair from part of the head or body.[1] ComplicationsPsychological distress[2] TypesMale-pattern hair loss, female-pattern hair loss, alopecia areata, telogen effluvium[3] TreatmentAccepting the condition, medications, surgery[3] MedicationPattern hair loss: minoxidil, finasteride[4] Alopecia areata: steroid injections[3] Frequency50% of males, 25% of females (pattern hair loss by age 50)[3][5] Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body.[1] Typically at least the head is involved.[3] The severity of hair loss can vary from a small area to the entire body.[6] Inflammation or scarring is not usually present.[3] Hair loss in some people causes psychological distress.[2] Common types include male-pattern hair loss, female-pattern hair loss, alopecia areata, and a thinning of hair known as telogen effluvium.[3] The cause of male-pattern hair loss is a combination of genetics and male hormones; the cause of female pattern hair loss is unclear; the cause of alopecia areata is autoimmune; and the cause of telogen effluvium is typically a physically or psychologically stressful event.[3] Telogen effluvium is very common following pregnancy.[3] Less common causes of hair loss without inflammation or scarring include the pulling out of hair, certain medications including chemotherapy, HIV/AIDS, hypothyroidism, and malnutrition including iron deficiency.[2][3] Causes of hair loss that occurs with scarring or inflammation include fungal infection, lupus erythematosus, radiation therapy, and sarcoidosis.[2][3] Diagnosis of hair loss is partly based on the areas affected.[3] Treatment of pattern hair loss may simply involve accepting the condition, which can also include shaving one's head.[3] Interventions that can be tried include the medications minoxidil (or finasteride) and hair transplant surgery.[4][5] Alopecia areata may be treated by steroid injections in the affected area, but these need to be frequently repeated to be effective.[3] Hair loss is a common problem.[3] Pattern hair loss by age 50 affects about half of men and a quarter of women.[3] About 2% of people develop alopecia areata at some point in time.[3] ## Contents * 1 Terminology * 1.1 Hypotrichosis * 2 Signs and symptoms * 2.1 Skin conditions * 2.2 Psychological * 3 Causes * 3.1 Pattern hair loss * 3.2 Infection * 3.3 Drugs * 3.4 Trauma * 3.5 Pregnancy * 3.6 Other causes * 3.7 Genetics * 4 Pathophysiology * 5 Diagnosis * 6 Management * 6.1 Hiding hair loss * 6.1.1 Head * 6.1.2 Eyebrows * 6.2 Medications * 6.3 Surgery * 6.4 Chemotherapy * 6.5 Embracing baldness * 6.6 Alternative medicine * 7 Research * 7.1 Hair follicle aging * 8 Etymology * 9 See also * 10 References * 11 External links ## Terminology Baldness is the partial or complete lack of hair growth, and part of the wider topic of "hair thinning". The degree and pattern of baldness varies, but its most common cause is androgenic hair loss, alopecia androgenetica, or alopecia seborrheica, with the last term primarily used in Europe.[citation needed] ### Hypotrichosis Hypotrichosis is a condition of abnormal hair patterns, predominantly loss or reduction. It occurs, most frequently, by the growth of vellus hair in areas of the body that normally produce terminal hair. Typically, the individual's hair growth is normal after birth, but shortly thereafter the hair is shed and replaced with sparse, abnormal hair growth. The new hair is typically fine, short and brittle, and may lack pigmentation. Baldness may be present by the time the subject is 25 years old.[7] ## Signs and symptoms A case of mid-frontal baldness: Andre Agassi Symptoms of hair loss include hair loss in patches usually in circular patterns, dandruff, skin lesions, and scarring. Alopecia areata (mild – medium level) usually shows in unusual hair loss areas, e.g., eyebrows, backside of the head or above the ears, areas the male pattern baldness usually does not affect. In male-pattern hair loss, loss and thinning begin at the temples and the crown and hair either thins out or falls out. Female-pattern hair loss occurs at the frontal and parietal. People have between 100,000 and 150,000 hairs on their head. The number of strands normally lost in a day varies but on average is 100.[8] In order to maintain a normal volume, hair must be replaced at the same rate at which it is lost. The first signs of hair thinning that people will often notice are more hairs than usual left in the hairbrush after brushing or in the basin after shampooing. Styling can also reveal areas of thinning, such as a wider parting or a thinning crown.[citation needed] Throughout his political career, Urho Kekkonen, the President of Finland, was well known for his baldness. He was last known to have had hair in about the 1920s.[9] This photo is of Kekkonen in 1959. ### Skin conditions A substantially blemished face, back and limbs could point to cystic acne. The most severe form of the condition, cystic acne, arises from the same hormonal imbalances that cause hair loss and is associated with dihydrotestosterone production.[10] Seborrheic dermatitis, a condition in which an excessive amount of sebum is produced and builds up on the scalp (looking like an adult cradle cap), is also a symptom of hormonal imbalances, as is an excessively oily or dry scalp. Both can cause hair thinning.[citation needed] ### Psychological Hair thinning and baldness cause psychological stress due to their effect on appearance. Although societal interest in appearance has a long history, this particular branch of psychology came into its own during the 1960s and has gained momentum as messages associating physical attractiveness with success and happiness grow more prevalent.[11] The psychology of hair thinning is a complex issue. Hair is considered an essential part of overall identity: especially for women, for whom it often represents femininity and attractiveness. Men typically associate a full head of hair with youth and vigor. Although they may be aware of pattern baldness in their family, many are uncomfortable talking about the issue. Hair thinning is therefore a sensitive issue for both sexes. For sufferers, it can represent a loss of control and feelings of isolation. People experiencing hair thinning often find themselves in a situation where their physical appearance is at odds with their own self-image and commonly worry that they appear older than they are or less attractive to others. Psychological problems due to baldness, if present, are typically most severe at the onset of symptoms.[12] Hair loss induced by cancer chemotherapy has been reported to cause changes in self-concept and body image. Body image does not return to the previous state after regrowth of hair for a majority of patients. In such cases, patients have difficulties expressing their feelings (alexithymia) and may be more prone to avoiding family conflicts. Family therapy can help families to cope with these psychological problems if they arise.[13] ## Causes Although not completely understood,[citation needed] hair loss can have many causes: ### Pattern hair loss Main article: Pattern hair loss Male pattern hair loss is believed to be due to a combination of genetics and the male hormone dihydrotestosterone.[3] The cause in female pattern hair loss remains unclear.[3] ### Infection * Dissecting cellulitis * Fungal infections (such as tinea capitis) * Folliculitis * Secondary syphilis[14] * Demodex folliculorum, a microscopic mite that feeds on the sebum produced by the sebaceous glands, denies hair essential nutrients and can cause thinning. Demodex folliculorum is not present on every scalp and is more likely to live in an excessively oily scalp environment. ### Drugs * Temporary or permanent hair loss can be caused by several medications, including those for blood pressure problems, diabetes, heart disease and cholesterol.[15] Any that affect the body's hormone balance can have a pronounced effect: these include the contraceptive pill, hormone replacement therapy, steroids and acne medications.[16] * Some treatments used to cure mycotic infections can cause massive hair loss.[17] * Medications (side effects from drugs, including chemotherapy, anabolic steroids, and birth control pills[18][15]) ### Trauma * Traction alopecia is most commonly found in people with ponytails or cornrows who pull on their hair with excessive force. In addition, rigorous brushing and heat styling, rough scalp massage can damage the cuticle, the hard outer casing of the hair. This causes individual strands to become weak and break off, reducing overall hair volume. * Frictional alopecia is hair loss caused by rubbing of the hair or follicles, most infamously around the ankles of men from socks, where even if socks are no longer worn, the hair often will not grow back. * Trichotillomania is the loss of hair caused by compulsive pulling and bending of the hairs. Onset of this disorder tends to begin around the onset of puberty and usually continues through adulthood. Due to the constant extraction of the hair roots, permanent hair loss can occur. * Traumas such as childbirth, major surgery, poisoning, and severe stress may cause a hair loss condition known as telogen effluvium,[19] in which a large number of hairs enter the resting phase at the same time, causing shedding and subsequent thinning. The condition also presents as a side effect of chemotherapy – while targeting dividing cancer cells, this treatment also affects hair's growth phase with the result that almost 90% of hairs fall out soon after chemotherapy starts.[20] * Radiation to the scalp, as when radiotherapy is applied to the head for the treatment of certain cancers there, can cause baldness of the irradiated areas. ### Pregnancy Hair loss often follows childbirth in the postpartum period without causing baldness. In this situation, the hair is actually thicker during pregnancy owing to increased circulating oestrogens. Approximately three months after giving birth (typically between 2 and 5 months), oestrogen levels drop and hair loss occurs, often particularly noticeably around the hairline and temple area. Hair typically grows back normally and treatment is not indicated.[21][22] A similar situation occurs in women taking the fertility-stimulating drug clomiphene. ### Other causes * Alopecia areata is an autoimmune disorder also known as "spot baldness" that can result in hair loss ranging from just one location (Alopecia areata monolocularis) to every hair on the entire body (Alopecia areata universalis). Although thought to be caused by hair follicles becoming dormant, what triggers alopecia areata is not known. In most cases the condition corrects itself, but it can also spread to the entire scalp (alopecia totalis) or to the entire body (alopecia universalis). * Localized or diffuse hair loss may also occur in cicatricial alopecia (lupus erythematosus, lichen plano pilaris, folliculitis decalvans, central centrifugal cicatricial alopecia, postmenopausal frontal fibrosing alopecia, etc.). Tumours and skin outgrowths also induce localized baldness (sebaceous nevus, basal cell carcinoma, squamous cell carcinoma). * Hypothyroidism (an under-active thyroid) and the side effects of its related medications can cause hair loss, typically frontal, which is particularly associated with thinning of the outer third of the eyebrows (also seen with syphilis). Hyperthyroidism (an over-active thyroid) can also cause hair loss, which is parietal rather than frontal.[23][unreliable medical source?] * Temporary loss of hair can occur in areas where sebaceous cysts are present for considerable duration (normally one to several weeks). * Congenital triangular alopecia – It is a triangular, or oval in some cases, shaped patch of hair loss in the temple area of the scalp that occurs mostly in young children. The affected area mainly contains vellus hair follicles or no hair follicles at all, but it does not expand. Its causes are unknown, and although it is a permanent condition, it does not have any other effect on the affected individuals.[24] * Gradual thinning of hair with age is a natural condition known as involutional alopecia. This is caused by an increasing number of hair follicles switching from the growth, or anagen, phase into a resting phase, or telogen phase, so that remaining hairs become shorter and fewer in number. * An unhealthy scalp environment can play a significant role in hair thinning by contributing to miniaturization or causing damage.[citation needed] Air and water pollutants[citation needed], environmental toxins,[citation needed] conventional styling products and excessive amounts of sebum have the potential to build up on the scalp.[citation needed]. This debris can block hair follicles and cause their deterioration and consequent miniaturization of hair.[citation needed]. It can also physically restrict hair growth or damage the hair cuticle[citation needed], leading to hair that is weakened and easily broken off before its natural lifecycle has ended.[citation needed] Other causes of hair loss include: * Alopecia mucinosa * Biotinidase deficiency * Chronic inflammation * Diabetes[25] * Lupus erythematosus * Pseudopelade of Brocq * Telogen effluvium * Tufted folliculitis ### Genetics Genetic forms of localized autosomal recessive hypotrichosis include: Type OMIM Gene Locus LAH1 607903 DSG4 18q12 LAH2 604379 LIPH 3q27 LAH3 611452 P2RY5 13q14.12-q14.2 ## Pathophysiology Hair follicle growth occurs in cycles. Each cycle consists of a long growing phase (anagen), a short transitional phase (catagen) and a short resting phase (telogen). At the end of the resting phase, the hair falls out (exogen) and a new hair starts growing in the follicle beginning the cycle again. Normally, about 40 (0–78 in men) hairs reach the end of their resting phase each day and fall out.[26] When more than 100 hairs fall out per day, clinical hair loss (telogen effluvium) may occur.[citation needed] A disruption of the growing phase causes abnormal loss of anagen hairs (anagen effluvium). ## Diagnosis Because they are not usually associated with an increased loss rate, male-pattern and female-pattern hair loss do not generally require testing. If hair loss occurs in a young man with no family history, drug use could be the cause. * The pull test helps to evaluate diffuse scalp hair loss. Gentle traction is exerted on a group of hairs (about 40–60) on three different areas of the scalp. The number of extracted hairs is counted and examined under a microscope. Normally, fewer than three hairs per area should come out with each pull. If more than ten hairs are obtained, the pull test is considered positive.[27] * The pluck test is conducted by pulling hair out "by the roots". The root of the plucked hair is examined under a microscope to determine the phase of growth, and is used to diagnose a defect of telogen, anagen, or systemic disease. Telogen hairs have tiny bulbs without sheaths at their roots. Telogen effluvium shows an increased percentage of hairs upon examination. Anagen hairs have sheaths attached to their roots. Anagen effluvium shows a decrease in telogen-phase hairs and an increased number of broken hairs.[citation needed] * Scalp biopsy is used when the diagnosis is unsure; a biopsy allows for differing between scarring and nonscarring forms. Hair samples are taken from areas of inflammation, usually around the border of the bald patch.[citation needed] * Daily hair counts are normally done when the pull test is negative. It is done by counting the number of hairs lost. The hair from the first morning combing or during washing should be counted. The hair is collected in a clear plastic bag for 14 days. The strands are recorded. If the hair count is >100/day, it is considered abnormal except after shampooing, where hair counts will be up to 250 and be normal.[citation needed] * Trichoscopy is a noninvasive method of examining hair and scalp. The test may be performed with the use of a handheld dermoscope or a video dermoscope. It allows differential diagnosis of hair loss in most cases.[28] There are two types of identification tests for female pattern baldness: the Ludwig Scale and the Savin Scale. Both track the progress of diffused thinning, which typically begins on the crown of the head behind the hairline, and becomes gradually more pronounced. For male pattern baldness, the Hamilton–Norwood scale tracks the progress of a receding hairline and/or a thinning crown, through to a horseshoe-shaped ring of hair around the head and on to total baldness.[citation needed] In almost all cases of thinning, and especially in cases of severe hair loss, it is recommended to seek advice from a doctor or dermatologist. Many types of thinning have an underlying genetic or health-related cause, which a qualified professional will be able to diagnose.[citation needed] ## Management See also: Management of hair loss ### Hiding hair loss General Douglas MacArthur with a comb over #### Head One method of hiding hair loss is the comb over, which involves restyling the remaining hair to cover the balding area. It is usually a temporary solution, useful only while the area of hair loss is small. As the hair loss increases, a comb over becomes less effective. Another method is to wear a hat or a hairpiece such as a wig or toupee. The wig is a layer of artificial or natural hair made to resemble a typical hair style. In most cases the hair is artificial. Wigs vary widely in quality and cost. In the United States, the best wigs—those that look like real hair—cost up to tens of thousands of dollars. Organizations also collect individuals' donations of their own natural hair to be made into wigs for young cancer patients who have lost their hair due to chemotherapy or other cancer treatment in addition to any type of hair loss. #### Eyebrows Though not as common as the loss of hair on the head, chemotherapy, hormone imbalance, forms of hair loss, and other factors can also cause loss of hair in the eyebrows. Loss of growth in the outer one third of the eyebrow is often associated with hypothyroidism. Artificial eyebrows are available to replace missing eyebrows or to cover patchy eyebrows. Eyebrow embroidery is another option which involves the use of a blade to add pigment to the eyebrows. This gives a natural 3D look for those who are worried about an artificial look and it lasts for two years. Micropigmentation (permanent makeup tattooing) is also available for those who want the look to be permanent. ### Medications Treatments for the various forms of hair loss have limited success. Three medications have evidence to support their use in male pattern hair loss: minoxidil, finasteride, and dutasteride.[29][30] They typically work better to prevent further hair loss, than to regrow lost hair.[29] * Minoxidil (Rogaine) is a nonprescription medication approved for male pattern baldness and alopecia areata. In a liquid or foam, it is rubbed into the scalp twice a day. Some people have an allergic reaction to the propylene glycol in the minoxidil solution and a minoxidil foam was developed without propylene glycol. Not all users will regrow hair. The longer the hair has stopped growing, the less likely minoxidil will regrow hair. Minoxidil is not effective for other causes of hair loss. Hair regrowth can take 1 to 6 months to begin. Treatment must be continued indefinitely. If the treatment is stopped, hair loss resumes. Any regrown hair and any hair susceptible to being lost, while Minoxidil was used, will be lost. Most frequent side effects are mild scalp irritation, allergic contact dermatitis, and unwanted hair in other parts of the body.[30] * Finasteride (Propecia) is used in male-pattern hair loss in a pill form, taken 1 milligram per day. It is not indicated for women and is not recommended in pregnant women. Treatment is effective starting within 6 weeks of treatment. Finasteride causes an increase in hair retention, the weight of hair, and some increase in regrowth. Side effects in about 2% of males, include decreased sex drive, erectile dysfunction, and ejaculatory dysfunction. Treatment should be continued as long as positive results occur. Once treatment is stopped, hair loss resumes.[30] * Corticosteroids injections into the scalp can be used to treat alopecia areata. This type of treatment is repeated on a monthly basis. Oral pills for extensive hair loss may be used for alopecia areata. Results may take up to a month to be seen.[citation needed] * Immunosuppressants applied to the scalp have been shown to temporarily reverse alopecia areata, though the side effects of some of these drugs make such therapy questionable.[31] * There is some tentative evidence that anthralin may be useful for treating alopecia areata.[32] * Hormonal modulators (oral contraceptives or antiandrogens such as spironolactone and flutamide) can be used for female-pattern hair loss associated with hyperandrogenemia.[citation needed] ### Surgery Hair transplantation is usually carried out under local anaesthetic. A surgeon will move healthy hair from the back and sides of the head to areas of thinning. The procedure can take between four and eight hours, and additional sessions can be carried out to make hair even thicker. Transplanted hair falls out within a few weeks, but regrows permanently within months. Hair transplants, takes tiny plugs of skin, each which contains a few hairs, and implants the plugs into bald sections. The plugs are generally taken from the back or sides of the scalp. Several transplant sessions may be necessary.[33] * Surgical options, such as follicle transplants, scalp flaps, and hair loss reduction, are available. These procedures are generally chosen by those who are self-conscious about their hair loss, but they are expensive and painful, with a risk of infection and scarring. Once surgery has occurred, six to eight months are needed before the quality of new hair can be assessed. * Scalp reduction is the process is the decreasing of the area of bald skin on the head. In time, the skin on the head becomes flexible and stretched enough that some of it can be surgically removed. After the hairless scalp is removed, the space is closed with hair-covered scalp. Scalp reduction is generally done in combination with hair transplantation to provide a natural-looking hairline, especially those with extensive hair loss. * Hairline lowering can sometimes be used to lower a high hairline secondary to hair loss, although there may be a visible scar after further hair loss. * Wigs are an alternative to medical and surgical treatment; some patients wear a wig or hairpiece. They can be used permanently or temporarily to cover the hair loss. High-quality, natural-looking wigs and hairpieces are available. ### Chemotherapy Hypothermia caps may be useful to prevent hair loss during some kinds of chemotherapy, specifically when tazanes or anthracyclines are used.[34] It should not be used when cancer is present in the skin of the scalp or for lymphoma or leukemia.[35] There are generally only minor side effects from treatment.[36] ### Embracing baldness Instead of attempting to conceal their hair loss, some people embrace it by either doing nothing about it or sporting a shaved head.[37][38] The general public became more accepting of men with shaved heads in the early 1950s, when Russian-American actor Yul Brynner began sporting the look; the resulting phenomenon inspired many of his male fans to shave their heads.[39] Male celebrities then continued to bring mainstream popularity to shaved heads,[40][41][42] including athletes such as Michael Jordan[43] and Zinedine Zidane[44] and actors such as Dwayne Johnson,[45] Ben Kingsley,[46] and Jason Statham.[47] Baldness in females, however, is still viewed as less "normal" in various parts of the world.[48][49] ### Alternative medicine Dietary supplements are not typically recommended.[30] There is only one small trial of saw palmetto which shows tentative benefit in those with mild to moderate androgenetic alopecia.[30] There is no evidence for biotin.[30] Evidence for most other produces is also insufficient.[50] There was no good evidence for ginkgo, aloe vera, ginseng, bergamot, hibiscus, or sorphora as of 2011.[50] Many people use unproven treatments.[29] Egg oil, in Indian,[51] Japanese, Unani (Roghan Baiza Murgh)[52] and Chinese[53] traditional medicine, was traditionally used as a treatment for hair loss.[medical citation needed] ## Research Research is looking into connections between hair loss and other health issues. While there has been speculation about a connection between early-onset male pattern hair loss and heart disease, a review of articles from 1954 to 1999 found no conclusive connection between baldness and coronary artery disease. The dermatologists who conducted the review suggested further study was needed.[54] Environmental factors are under review. A 2007 study indicated that smoking may be a factor associated with age-related hair loss among Asian men. The study controlled for age and family history, and found statistically significant positive associations between moderate or severe male pattern hairloss and smoking status.[55] Vertex baldness is associated with an increased risk of coronary heart disease (CHD) and the relationship depends upon the severity of baldness, while frontal baldness is not. Thus, vertex baldness might be a marker of CHD and is more closely associated with atherosclerosis than frontal baldness.[26] ### Hair follicle aging A key aspect of hair loss with age is the aging of the hair follicle.[56] Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be primed by a sustained cellular response to the DNA damage that accumulates in renewing stem cells during aging.[57] This damage response involves the proteolysis of type XVII collagen by neutrophil elastase in response to the DNA damage in the hair follicle stem cells. Proteolysis of collagen leads to elimination of the damaged cells and then to terminal hair follicle miniaturization. ## Etymology The term alopecia (/ˌæləˈpiːʃiə/) is from the Classical Greek ἀλώπηξ, alōpēx, meaning "fox". The origin of this usage is because this animal sheds its coat twice a year, or because in ancient Greece foxes often lost hair because of mange. The term bald likely derives from the English word balde, which means "white, pale" or Celtic ball, which means "white patch or blaze", such as on a horse's head.[58] ## See also * Alopecia in animals * Lichen planopilaris * List of conditions caused by problems with junctional proteins ## References 1. ^ a b "Hair loss". NHS Choices. Archived from the original on 27 September 2013. Retrieved 22 September 2013. 2. ^ a b c d Nalluri, R; Harries, M (February 2016). "Alopecia in general medicine". Clinical Medicine. 16 (1): 74–8. doi:10.7861/clinmedicine.16-1-74. PMC 4954340. PMID 26833522. 3. ^ a b c d e f g h i j k l m n o p q r s Vary JC, Jr (November 2015). "Selected Disorders of Skin Appendages--Acne, Alopecia, Hyperhidrosis". The Medical Clinics of North America. 99 (6): 1195–211. doi:10.1016/j.mcna.2015.07.003. PMID 26476248. 4. ^ a b McElwee, Kevin J.; Shapiro, Jerry (June 2012). "Promising therapies for treating and/or preventing androgenic alopecia". Skin Therapy Letter. 17 (6): 1–4. PMID 22735503. 5. ^ a b Leavitt, M. (2008). "Understanding and Management of Female Pattern Alopecia". Facial Plastic Surgery. 24 (4): 414–427. doi:10.1055/s-0028-1102905. PMID 19034818. 6. ^ "Hair loss". DermNet. Archived from the original on 2016. Retrieved 2016-08-03. 7. ^ Dawber, Rodney P. R.; Van Neste, Dominique (2004). Hair and scalp disorders: common presenting signs, differential diagnosis and treatment (2nd ed.). Informa Health Care. pp. 53–54. ISBN 978-1-84184-193-9. 8. ^ Hair growth at eMedicine 9. ^ Kuvat: Kekkonen ei ollut aina kalju – tältä tuleva presidentti näytti teini-ikäisenä (in Finnish) 10. ^ Bergler-Czop, Beata; Brzezińska-Wcisło, Ligia (May 2004). "Czynniki hormonalne w etiologii tradziku pospolitego" [Hormonal factors in etiology of common acne]. Polski Merkuriusz Lekarski (in Polish). 16 (95): 490–2. PMID 15518435. 11. ^ Rumsey, Nichola (September 2008). "The psychology of appearance: Why health psychologists should 'do looks'". European Health Psychologist. 10 (3): 46–50. 12. ^ Passchier, Jan; Erdman, Jeroen; Hammiche, Fatima; Erdman, Ruud A. M. (September 2016). "Androgenetic Alopecia: Stress of Discovery". Psychological Reports. 98 (1): 226–228. doi:10.2466/PR0.98.1.226-228. 13. ^ Poot, F (September 2004). "Le retentissement psychologique des pathologies chroniques du cheveu" [Psychological consequences of chronic hair diseases]. Revue Médicale de Bruxelles (in French). 25 (4): A286-8. PMID 15516058. 14. ^ "Infectious hair disease – syphilis". Keratin.com. Retrieved 2011-11-17. 15. ^ a b "Drug-Induced Hair Loss". WebMD. 16. ^ "Drug Induced Hair Loss". American Hair Loss Association. 17. ^ Pappas, Peter G.; Kauffman, CA; Perfect, J; Johnson, PC; McKinsey, DS; Bamberger, DM; Hamill, R; Sharkey, PK; Chapman, SW; Sobel, JD (1 September 1995). "Alopecia Associated with Fluconazole Therapy". Annals of Internal Medicine. 123 (5): 354. doi:10.7326/0003-4819-123-5-199509010-00006. PMID 7625624. 18. ^ "Alopecia". Healthgrades. 26 June 2014. 19. ^ Nnoruka, Nkechi Edith (October 2005). "Hair loss: is there a relationship with hair care practices in Nigeria?". International Journal of Dermatology. 44 (s1): 13–17. doi:10.1111/j.1365-4632.2005.02801.x. PMID 16187950. 20. ^ "Causes of Hair Loss". American Hair Loss Association. 21. ^ Schiff, Bencel L.; Kern, A B (1 May 1963). "Study of Postpartum Alopecia". Archives of Dermatology. 87 (5): 609. doi:10.1001/archderm.1963.01590170067011. PMID 13991677. 22. ^ Eastham, John H (February 2001). "Postpartum Alopecia". The Annals of Pharmacotherapy. 35: 255–258. doi:10.1345/1542-6270(2001)035<0255:pa>2.0.co;2. 23. ^ Alopecia Areata Archived 2008-10-13 at the Wayback Machine, by Maria G. Essig, MS, ELS, Yahoo! Health 24. ^ "Congenital triangular alopecia". Retrieved 2010-06-29. 25. ^ "What is Alopecia: What Causes Alopecia?". MedicalBug. 6 February 2012. Archived from the original on 22 January 2013. Retrieved 28 March 2012. 26. ^ a b Yamada, T; Hara, K; Umematsu, H; Kadowaki, T (2013). "Male pattern baldness and its association with coronary heart disease: A meta-analysis". BMJ Open. 3 (4): e002537. doi:10.1136/bmjopen-2012-002537. PMC 3641488. PMID 23554099. 27. ^ "The hair pull test". Keratin.com. Retrieved 28 March 2012.[self-published source?] 28. ^ Rudnicka L, Olszewska M, Rakowska A, Kowalska-Oledzka E, Slowinska M (2008). "Trichoscopy: a new method for diagnosing hair loss". J Drugs Dermatol. 7 (7): 651–654. PMID 18664157. 29. ^ a b c Banka, N; Bunagan, MJ; Shapiro, J (January 2013). "Pattern hair loss in men: diagnosis and medical treatment". Dermatologic Clinics. 31 (1): 129–40. doi:10.1016/j.det.2012.08.003. PMID 23159182. 30. ^ a b c d e f Rogers, Nicole E.; Avram, Marc R. (October 2008). "Medical treatments for male and female pattern hair loss". Journal of the American Academy of Dermatology. 59 (4): 547–566. doi:10.1016/j.jaad.2008.07.001. PMID 18793935. 31. ^ Joly, Pascal (October 2006). "The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis". Journal of the American Academy of Dermatology. 55 (4): 632–636. doi:10.1016/j.jaad.2005.09.010. PMID 17010743. 32. ^ Shapiro, Jerry (December 2013). "Current Treatment of Alopecia Areata". Journal of Investigative Dermatology Symposium Proceedings. 16 (1): S42–S44. doi:10.1038/jidsymp.2013.14. PMID 24326551. 33. ^ ‘Hair Transplants’, WebMD: "Hair Transplant Procedures: Average Cost, What to Expect, and More". Archived from the original on 2013-09-21. Retrieved 2013-09-21. 34. ^ Grevelman, E.G.; Breed, W.P.M. (March 2005). "Prevention of chemotherapy-induced hair loss by scalp cooling". Annals of Oncology. 16 (3): 352–358. doi:10.1093/annonc/mdi088. PMID 15642703. 35. ^ Breed, Wim P. M. (1 January 2004). "What is wrong with the 30-year-old practice of scalp cooling for the prevention of chemotherapy-induced hair loss?". Supportive Care in Cancer. 12 (1): 3–5. doi:10.1007/s00520-003-0551-8. PMID 14615930. 36. ^ Komen, Manon M.C.; Smorenburg, Carolien H.; van den Hurk, Corina J.G.; Nortier, J.W.R. (Hans) (2011). "Hoofdhuidkoeling tegen alopecia door chemotherapie" [Scalp cooling for chemotherapy-induced alopecia] (PDF). Nederlands tijdschrift voor geneeskunde (in Dutch). 155 (45): A3768. PMID 22085565. 37. ^ Benedictus, Leo (February 2, 2013). "The 10 rules for bald men". The Guardian. ISSN 0261-3077. Retrieved December 1, 2018. 38. ^ Rockwell, Taylor (October 16, 2015). "The 20 Greatest Bald Heads in the History of Soccer". pastemagazine.com. Retrieved December 1, 2018. 39. ^ Brynner, Rock (2006). Empire & odyssey: the Brynners in Far East Russia and beyond. Steerforth Press. 40. ^ Crouse, Richard (2005). Reel Winners: Movie Award Trivia. Dundurn. p. 171. 41. ^ Doyle, Hubert (2008). Ventures with the World of Celebrities, Movies & TV. 42. ^ Douty, Linda (2011). How Did I Get to Be 70 When I'm 35 Inside?: Spiritual Surprises of Later Life. 43. ^ Gaines, Cork (17 April 2020). "Michael Jordan once turned down a huge endorsement deal because he didn't like the product's name and another one because he was going bald". Business Insider. 44. ^ Will (5 March 2020). "The Bald Icons: Who is Zinedine Zidane?". The Bald Brothers. Retrieved 9 June 2020.[self-published source?] 45. ^ Bryant, Kenzie (3 April 2017). "Dwayne 'The Rock' Johnson Explains Why He's Bald". Vanity Fair. 46. ^ Steele, Francesca (19 April 2014). "Ferdinand Kingsley interview: 'Yeah, but mum's dad was totally bald too!'". Spectator. Retrieved 8 June 2020. 47. ^ Huynh, Mike (24 July 2019). "Jason Statham Is Showing Bald Men How To Look Stylishly Masculine". DMARGE. Retrieved 9 June 2020. 48. ^ "Cultural Perceptions of Hair & Baldness". The Trichological Society.[self-published source?] 49. ^ Ramos, Paulo Müller; Miot, Hélio Amante (2015). "Female Pattern Hair Loss: a clinical and pathophysiological review". Anais Brasileiros de Dermatologia. 90 (4): 529–543. doi:10.1590/abd1806-4841.20153370. PMC 4560543. 50. ^ a b Blumeyer, A; Tosti, A; Messenger, A; Reygagne, P; Del Marmol, V; Spuls, PI; Trakatelli, M; Finner, A; Kiesewetter, F; Trüeb, R; Rzany, B; Blume-Peytavi, U; European Dermatology Forum, (EDF) (October 2011). "Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men". Journal of the German Society of Dermatology. 9 Suppl 6: S1–57. doi:10.1111/j.1610-0379.2011.07802.x. PMID 21980982. 51. ^ Panda, H. (2004). Handbook On Ayurvedic Medicines With Formulae, Processes And Their Uses. NIIR Project Consultancy Services. p. 146. ISBN 978-81-86623-63-3. 52. ^ Babu, S. Suresh (2005). Home Made Herbal Cosmetics. Pustak Mahal. p. 103. ISBN 978-81-223-0775-7. 53. ^ Zhou, Zhongying; Jin, Hui De (1997). Clinical Manual of Chinese Herbal Medicine and Acupuncture. Churchill Livingstone. p. 222. ISBN 978-0-443-05128-9. 54. ^ Rebora, Alfredo (1 July 2001). "Baldness and Coronary Artery Disease: The Dermatologic Point of View of a Controversial Issue". Archives of Dermatology. 137 (7): 943–947. PMID 11453815. 55. ^ Su, Lin-Hui; Chen, Tony Hsiu-Hsi (1 November 2007). "Association of Androgenetic Alopecia With Smoking and Its Prevalence Among Asian Men". Archives of Dermatology. 143 (11). doi:10.1001/archderm.143.11.1401. PMID 18025364. Lay summary. 56. ^ Lei M, Chuong CM (2016). "STEM CELLS. Aging, alopecia, and stem cells". Science. 351 (6273): 559–60. Bibcode:2016Sci...351..559L. doi:10.1126/science.aaf1635. PMID 26912687. 57. ^ Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, Nishimura EK (2016). "Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis". Science. 351 (6273): aad4395. doi:10.1126/science.aad4395. PMID 26912707. 58. ^ Harper, Douglas. "Entry for "bald"". Online Etymology Dictionary. Archived from the original on 2006-05-09. Retrieved 2006-12-07. ## External links * Hair loss at Curlie * Media related to Alopecia at Wikimedia Commons * The dictionary definition of hair loss at Wiktionary Classification D * ICD-10: L65.9 * ICD-9-CM: 704.09 * MeSH: D000505 * DiseasesDB: 14765 External resources * MedlinePlus: 003246 * Patient UK: Hair loss * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia * v * t * e Human hair Classification by type * Lanugo * Androgenic * Terminal * Vellus by location * Body * Ear * Nose * Eyebrow * unibrow * Eyelash * Underarm * Chest * Abdominal * Pubic * Leg Head hairstyles (list) * Afro * Afro puffs * Asymmetric cut * Bald * Bangs * Beehive * Big hair * Blowout * Bob cut * Bouffant * Bowl cut * Braid * Brush cut * Bun (odango) * Bunches * Burr * Businessman cut * Butch cut * Buzz cut * Caesar cut * Chignon * Chonmage * Chupryna * Comb over * Conk * Cornrows * Crew cut * Crochet braids * Croydon facelift * Curly hair * Curtained hair * Devilock * Dido flip * Digital perm * Dreadlocks * Duck's ass * Eton crop * Extensions * Feathered hair * Finger wave * Flattop * Fontange * French braid * French twist * Fringe * Frosted tips * Hair crimping * Harvard clip * High and tight * Hime cut * Historical Christian hairstyles * Hi-top fade * Induction cut * Ivy League * Jewfro * Jheri curl * Kiss curl * Layered hair * Liberty spikes * Long hair * Lob cut * Marcelling * Mod cut * Mohawk * Mullet * 1950s * 1980s * Pageboy * Part * Payot * Pigtail * Pixie cut * Polish halfshaven head * Pompadour * Ponytail * Punch perm * Princeton * Professional cut * Queue * Quiff * Rattail * Razor cut * Regular haircut * Ringlets * Shag * Shape-Up * Shimada * Short back and sides * Short brush cut * Short hair * Spiky hair * Straight hair * Standard haircut * Surfer hair * Taper cut * Temple Fade * Tonsure * Updo * Undercut * Waves * Widow's peak * Wings Facial hair (list) * Beard * Chinstrap * Goatee * Shenandoah * Soul patch * Van Dyke * Moustache * Fu Manchu * handlebar * horseshoe * pencil * toothbrush * walrus * Designer stubble * Sideburns Hair loss cosmetic * Removal * waxing * threading * plucking * chemical * electric * laser * IPL * Shaving * head * leg * cream * brush * soap * Razor * electric * safety * straight other * Alopecia * areata * totalis * universalis * Frictional alopecia * Male-pattern hair loss * Hypertrichosis * Management * Trichophilia * Trichotillomania * Pogonophobia Haircare products * Brush * Clay * Clipper * Comb * Conditioner * Dryer * Gel * Hot comb * Iron * Mousse * Pomade * Relaxer * Rollers * Shampoo * Spray * Wax Haircare techniques * Backcombing * Crimping * Curly Girl Method * Hair cutting * Perm * Shampoo and set * Straightening Related topics * Afro-textured hair (kinky hair) * Beard and haircut laws by country * Bearded lady * Barber (pole) * Eponymous hairstyle * Frizz * Good hair * Hairdresser * Hair fetishism (pubic) * Hair follicle * Hair growth * Hypertrichosis * Trichotillomania [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection	Hair loss	c0002170	5,096	wikipedia	https://en.wikipedia.org/wiki/Hair_loss	2021-01-18T18:32:57	{"mesh": ["D000505"], "icd-9": ["704.09"], "icd-10": ["L65.9"], "wikidata": ["Q2697787"]}
Helminthiasis Sparganosis SpecialtyInfectious disease Sparganosis is a parasitic infection caused by the plerocercoid larvae of the genus Spirometra including S. mansoni, S. ranarum, S. mansonoides and S. erinacei.[1][2] It was first described by Patrick Manson from China in 1882,[3] and the first human case was reported by Charles Wardell Stiles from Florida in 1908.[4] The infection is transmitted by ingestion of contaminated water, ingestion of a second intermediate host such as a frog or snake, or contact between a second intermediate host and an open wound or mucous membrane.[5][6] Humans are the accidental hosts in the life cycle, while dogs, cats, and other mammals are definitive hosts. Copepods (freshwater crustaceans) are the first intermediate hosts, and various amphibians and reptiles are second intermediate hosts.[7] Once a human becomes infected, the plerocercoid larvae migrate to a subcutaneous location, where they typically develop into a painful nodule.[8] Migration to the brain results in cerebral sparganosis, while migration to the eyes results in ocular sparganosis.[1][9] Sparganosis is most prevalent in Eastern Asia, although cases have been described in countries throughout the world. In total, approximately 300 cases have been described in the literature up to 2003.[8][10] Diagnosis is typically not made until the sparganum larva has been surgically removed.[8] Praziquantel is the drug of choice, although its efficacy is unknown and surgical removal of the sparganum is generally the best treatment. Public health interventions should focus on water and dietary sanitation, as well as education about the disease in rural areas and discouragement of the use of poultices. ## Contents * 1 Symptoms * 2 Transmission * 3 Hosts, reservoirs, and vectors * 4 Incubation period * 5 Morphology * 6 Life cycle * 7 Diagnosis * 8 Prevention * 9 Management * 10 Epidemiology * 11 History of discovery * 12 References * 13 External links ## Symptoms[edit] Clinical presentation of sparganosis most often occurs after the larvae have migrated to a subcutaneous location. The destination of the larvae is often a tissue or muscle in the chest, abdominal wall, extremities, or scrotum, although other sites include the eyes, brain, urinary tract, pleura, pericardium, and spinal canal. The early stages of disease in humans are often asymptomatic, but the spargana typically cause a painful inflammatory reaction in the tissues surrounding the subcutaneous site as they grow. Discrete subcutaneous nodules develop that may appear and disappear over a period of time. The nodules usually itch, swell, turn red, and migrate, and are often accompanied by painful edema.[7][8] Seizures, hemiparesis, and headaches are also common symptoms of sparganosis, especially cerebral sparganosis, and eosinophilia is a common sign.[1][8] Clinical symptoms also vary according to the location of the sparganum; possible symptoms include elephantiasis from location in the lymph channels, peritonitis from location in the intestinal perforation, and brain abscesses from location in the brain.[7] In genital sparganosis, subcutaneous nodules are present in the groin, labia, or scrotum and may appear tumor-like.[8] Ocular sparganosis a particularly well-described type of sparganosis. Early signs of the ocular form include eye pain, epiphora (excessive watering of the eye), and/or ptosis (drooping of the upper eyelid). Other signs include periorbital edema and/or edematous swelling that resembles Romana’s sign in Chagas disease, lacrimation, orbital cellulitis, exophthalmos (protrusion of the eyeball), and/or an exposed cornea ulcer.[7][9] The most common sign at presentation is a mass lesion in the eye. If untreated, ocular sparganosis can lead to blindness.[11] In one case of brain infestation by Spirometra erinaceieuropaei, a man sought treatment on suffering headaches, seizures, memory flashbacks and strange smells. Magnetic resonance imaging (MRI) scans showed a cluster of rings, initially in the right medial temporal lobe, but moving over time to the other side of the brain. The cause was not determined for four years; ultimately a biopsy was performed and a 1 cm-long tapeworm was found and removed. The patient continued to suffer symptoms.[12] ## Transmission[edit] The parasite is transmitted to humans in three different ways. First, humans may acquire the infection by drinking water that is contaminated with copepods housing Spirometra larvae.[5] Second, humans may acquire the infection by consuming the raw flesh of one of the second intermediate hosts, such as frogs or snakes.[7] For example, humans consume raw snakes or tadpoles for medicinal purposes in some Asian cultures; if the snakes or tadpoles are infected, the larvae may be transmitted to humans. Third, humans may acquire the infection by placing raw poultices of the second intermediate hosts on open wounds, lesions, or the eyes for medicinal or ritualistic reasons. If the poultice is infected with plerocercoid larvae, the human may become infected.[1][9] According to Zunt et al., human infection most often occurs following ingestion of infected raw snake, frog, or pig, although contact with infected flesh of an intermediate host can also cause infection. The high prevalence in Korea may be explained by the ingestion of dog meat. In the Western hemisphere, the most common cause of infection is drinking contaminated water.[9] ## Hosts, reservoirs, and vectors[edit] Definitive hosts of Spirometra include dogs, cats, birds, and wild carnivores, while humans are accidental hosts.[1][5][9] First intermediate hosts include copepods and other fresh-water crustaceans, while second intermediate hosts include birds, reptiles, and amphibians. The intermediate hosts are also the reservoirs of Spirometra. There are no vectors of Spirometra.[8] ## Incubation period[edit] The incubation period of Spirometra is 20 days to 3 years.[8] ## Morphology[edit] The sparganum larvae are white, wrinkled, and ribbon-shaped. They range from a few millimeters in length to several centimeters. The anterior end can invaginate and bears suggestions of the sucking grooves that are present in the scolex of the mature worm.[1] The absence of a scolex or protoscolex in Spirometra is a key difference in differentiating between Taenia solium and Spirometra.[13] The worm’s body is also characterized by a stromal network of smooth muscle. In general, plerocercoids in the East (S. mansoni) are described as larger and more delicate than those in the West.[14] The eggs of S. mansonoides provide an example of the general morphological characteristics of Spirometra eggs. S. mansonoides eggs resemble the eggs of D. latum, with some specific differences. S. mansonoides eggs measure 57-66 µm by 33-37 µm, which is smaller than the eggs of D. latum. The eggs of S. mansonoides are also ellipsoidal and have a conical, prominent operculum.[15] ## Life cycle[edit] The adult Spirometra live in the small intestine of the definitive host—a dog, cat, raccoon, or other mammal—for up to 9 years, where they produce many eggs.[7][8][14] When the host defecates, the unembryonated eggs leave the body in the feces and hatch when they reach fresh water. The eggs are eaten by copepods (crustaceans of the genus Cyclops), which are the first intermediate hosts.[8] In the copepods, the eggs develop into procercoid larvae that live in the body cavity.[7] The second intermediate hosts include fish, reptiles, or amphibians that consume the copepods. The larvae penetrate the intestinal tract of the second intermediate host, where they become plerocercoid larvae and proliferate to the subcutaneous tissues and muscles. The second intermediate host is eventually eaten by a definitive host predator, such as a dog, and the cycle begins again.[9][16] Humans are accidental hosts in the cycle, becoming infected with the plerocercoid larvae by contact with or ingestion of the first or second intermediate hosts.[7] The larvae migrate to the subcutaneous tissues in humans; however, no development takes place and the human is not capable of transmitting the disease. In S. proliferum, many larvae, rather than just a few, proliferate throughout the subcutaneous tissues of humans.[8] ## Diagnosis[edit] Sparganosis is typically diagnosed following surgical removal of the worms, although the infection may also be diagnosed by identification of eosinophilia or identification of the parasite in a tissue specimen. If such biopsy and excision procedures are not feasible, the antisparganum ELISA test may be used.[9] In theory, a pre-operative diagnosis could be made by identification of exposure history and a painful, migratory, subcutaneous nodule. Sparganosis usually presents as a single nodule, while other cestode infections such as cysticercosis typically present as multiple nodules. Preoperative diagnosis, however, is rare.[1][13] CT and MRI scans are especially useful for diagnosis of cerebral sparganosis, as they reveal lesions in the brain. Through a retrospective analysis of 25 cases of cerebral sparganosis from 2000 to 2006, Song et al. found a number of characteristic signs that could be used in the future to diagnose cerebral sparganosis without performing an excision or tissue biopsy. The most characteristic finding was the "tunnel sign" on MRI images, showing the migrating track of the worm,[17] while the most common finding was multiple conglomerated ring-shaped enhancements, seen as bead-shaped, usually with 3 to 6 rings. These findings led Song et al. to suggest that clinical history, ELISA, and either MRI or CT scans could be sufficient to make a sparganosis diagnosis. These lesions, however, are sometimes mistaken for tuberculosis lesions.[18] In one case cerebral sparganosis was not diagnosed for four years, during which scans showed a cluster of rings moving from the right to the left side of the brain; ultimately the worm was found on biopsy.[12] ## Prevention[edit] Because sparganosis is a rare infection, public health strategies have not made its prevention a priority. Public health strategies focusing on providing basic access to clean water may help to reduce future sparganosis infections. In their retrospective study of 25 cases of cerebral sparganosis, Song et al. found that 12 patients (48%) had eaten raw or uncooked frog or snake that was infected with sparganum, 5 patients (20%) had applied an animal's flesh as a poultice to an open wound, 4 patients had drunk contaminated water, and the cause of infection was not known for 4 patients. As a result of these findings, Song et al. conclude that health education about sparganosis and the importance of food sanitation should be implemented in all rural endemic areas.[18] It has been recommended that water consumed in endemic areas should be boiled or treated to prevent ingestion of Cyclops or Spirometra larvae. Especially in areas where ponds or ditches provide potential habitats for infected copepods, public health strategies should include education campaigns about how to identify drinking water that could potentially be infected. Strategies should warn people against ingesting the raw flesh of the intermediate hosts, such as snakes and frogs, and against using them as poultices.[1] ## Management[edit] One treatment for sparganosis is praziquantel, administered at a dose of 120 to 150 mg/kg body weight over 2 days; however, praziquantel has had limited success. In general, infestation by one or a few sparganum larvae is often best treated by surgical removal.[1][9] DNA analysis of rare worms removed surgically can provide genome information to identify and characterise each parasite; treatments for the more common tapeworms can be cross-checked to see whether they are also likely to be effective against the species in question.[12] ## Epidemiology[edit] Sparganosis is endemic or potentially endemic in 48 countries, and although rare, cases have been described in Asia, Africa, Australia, South America, and the United States.[1][8][9] The majority of cases occur in Southeast Asia and Eastern Africa.[8] Ocular sparganosis is especially prevalent in China and Vietnam.[1] The highest numbers of cases occur in Korea and Japan.[9] As of 2003, only seven cases of sparganosis had ever been described in Europe.[10] ## History of discovery[edit] Diesing first named the Sparganum genus of cestodes in 1854. Patrick Manson first reported sparganosis and the species Sparganum mansoni in China in 1882, while making the post-mortem examination of a man in Amoy, China.[6][19] The first case of sparganosis in the United States was reported by Stiles in 1908; this was a case of infection by Spirometra proliferum. Mueller first described Spirometra mansonoides in the United States in 1935.[14] ## References[edit] 1. ^ a b c d e f g h i j k John, D.T. and Petri, W.A. Markell and Voge’s Medical Parasitology. 9th edition. St. Louis: Saunders Elsevier, 2006. 2. ^ https://www.cdc.gov/dpdx/sparganosis/ 3. ^ Lescano, Andres G; Zunt, Joseph (2013). "Other cestodes: sparganosis, coenurosis and Taenia crassiceps cysticercosis". Handbook of Clinical Neurology. 114: 335–345. doi:10.1016/B978-0-444-53490-3.00027-3. ISBN 9780444534903. PMC 4080899. PMID 23829923. Cite journal requires `\|journal=` (help) 4. ^ Read, Clark P. (1952). "Human sparganosis in South Texas". The Journal of Parasitology. 38 (1): 29–31. doi:10.2307/3274168. JSTOR 3274168. PMID 14928149.(registration required) 5. ^ a b c Hughes A.J., Biggs B.A. (2001). "Parasitic worms of the central nervous system: an Australian perspective". Internal Medicine Journal. 32 (11): 541–543. doi:10.1046/j.1445-5994.2002.00265.x. 6. ^ a b Manson, P., Manson-Bahr, P., and Wilcocks, C. Manson’s Tropical Diseases: A Manual of the Diseases. New York: William Wood and Company, 1921. 7. ^ a b c d e f g h Garcia, L., and Bruckner, D.A. Diagnostic Medical Parasitology. Herndon, VA: ASM Press, 2007. 8. ^ a b c d e f g h i j k l m GIDEON, "Sparganosis." Date viewed February 26, 2009 9. ^ a b c d e f g h i j Walker M.D., Zunt (2005). "Neuroparasitic Infections: Cestodes, Trematodes, and Protozoans". Seminars in Neurology. 25 (3): 262–277. doi:10.1055/s-2005-917663. PMC 2683840. PMID 16170739. 10. ^ a b Pampliglione S.; Fioravanti M.L.; Rivasi F. (2003). "Human sparganosis in Italy. Case report and review of the European cases". APMIS. 111 (2): 349–54. doi:10.1034/j.1600-0463.2003.1110208.x. PMID 12716392. 11. ^ Yang J.W.; Lee J.H.; Kang M.S. (2007). "A Case of Ocular Sparganosis". Korean Journal of Ophthalmology. 21 (1): 48–50. doi:10.3341/kjo.2007.21.1.48. PMC 2629689. PMID 17460433. 12. ^ a b c The Guardian newspaper: Man’s headaches due to tapeworm living in his brain for four years, 21 November 2014 13. ^ a b Iwatani K.; Kubota I.; Hirotsu Y.; et al. (2006). "Sparganum mansoni parasitic infection in the lung showing a nodule". Pathology International. 56 (11): 674–7. doi:10.1111/j.1440-1827.2006.02028.x. PMID 17040290. 14. ^ a b c Mueller J.F.; Coulston F. "Experimental human infection with the sparganum larva of Spirometra mansonoides". The American Journal of Tropical Medicine and Hygiene. 21 (3): 399. 15. ^ Ash, L.R. and Orihel, T.C.. Atlas of Human Parasitology. Chicago: ASCP Press, 1990. 16. ^ CDC: Sparganosis, Date viewed February 25, 2009 17. ^ Rengarajan, S; Nanjegowda, N; Bhat, D; Mahadevan, A; Sampath, S; Krishna, S (2008). "Cerebral sparganosis: a diagnostic challenge". British Journal of Neurosurgery. 22 (6): 784–786. doi:10.1080/02688690802088073. PMID 18661311. 18. ^ a b Song, T; Wang, WS; Zhou, BR; Mai, WW; Lifirst5=ZZ; Guo, HC; Zhou, F (October 2008). "CT and MR Characteristics of Cerebral Sparganosis". Am J Neuroradiol. 28 (9): 1700–1705. doi:10.3174/ajnr.a0659. PMID 17885230. 19. ^ Fantahm, H.B., and Stephens, J.W.W., and Theobald, F.V. The Animal Parasites of Man. New York: William Wood and Company, 1916. ## External links[edit] Classification D * ICD-10: B70.1 * ICD-9-CM: 123.5 * MeSH: D013031 * DiseasesDB: 32210 * 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 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection	Sparganosis	c0037753	5,097	wikipedia	https://en.wikipedia.org/wiki/Sparganosis	2021-01-18T19:00:41	{"mesh": ["D013031"], "umls": ["C0037753"], "wikidata": ["Q842169"]}
A rare acrofacial dysostosis that is characterized by mandibular and malar hypoplasia, small and cup-shaped ears, lower lid ectropion, and symmetrical postaxial limb deficiencies with absence of the fifth digital rays and ulnar hypoplasia. ## Epidemiology Less than 30 cases of Postaxial acrofacial dysostosis (POADS) have been described in the literature. ## Clinical description Clinical features further include cholestasis, bilateral inguinal hernia and cleft palate. The patients can develop myopic astigmatism and speech delay can be present. Facial features include sparse eyebrows, almond shaped eyes with up-slanting palpebral fissures, malar hypoplasia, long philtrum, small mouth, and low-set, malformed ears. ## Etiology The disease arises from biallelic gene mutations for the enzyme dihydroorotate dehydrogenase (DHODH, 16q22.2), involved in pyrimidine biosynthesis. Nonetheless, despite demonstrated loss of enzyme activity, dihydroorotate (DHO) has not been shown to accumulate. ## Diagnostic methods DHODH mutations can be determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot test can be performed using liquid chromatography-tandem mass spectrometry. ## Differential diagnosis The clinical phenotype of Miller syndrome overlaps with mandibulofacial and other acrofacial dysostosis syndromes including Treacher Collins, Guion-Almeida (mandibulofacial dysostosis with microcephaly) and Nager syndromes. ## Antenatal diagnosis Due to postaxial oligodactyly of fingers and toes, the diagnosis can be established prenatally on clinical grounds and confirmed by molecular testing. ## Genetic counseling Inheritance appears to be autosomal recessive. For parents of an affected individual, there is a 25% risk of having and affected child at each pregnancy. Recurrence risk for children of an affected individual is low if there is no consanguinity. ## Management and treatment The patients do not usually need surgical treatment, but sometimes need hearing aids. Logopedic treatment might be helpful. ## Prognosis There is usually no reduced life expectancy, but intrauterine death has been described. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection	Postaxial acrofacial dysostosis	c0265257	5,098	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=246	2021-01-23T18:45:57	{"gard": ["8410"], "mesh": ["C537680"], "omim": ["263750"], "umls": ["C0265257"], "icd-10": ["Q75.4"], "synonyms": ["Acrofacial dysostosis, Genee-Wiedemann type", "Mandibulofacial dysostosis with postaxial limb anomalies", "Miller syndrome", "POADS", "Postaxial acrodysostosis"]}
Pathological demand avoidance (PDA) is a proposed sub-type of autism spectrum disorder.[1] Characteristics ascribed to the condition include greater refusal to do what is asked of the person, even to activities the person would normally like.[1] It is not recognized by either the DSM-5[2] or the ICD-10[3] and is unlikely to be separated out now that the umbrella diagnosis of ASD has been adopted. In 2011, it was suggested that these symptoms could represent the condition oppositional defiant disorder (ODD).[4] Elizabeth O'Nions and others, argue that unlike ASD, “children with PDA are said to use socially manipulative avoidance strategies”; and unlike ODD, they “resort to extreme, embarrassing or age-inappropriate behaviour”.[5] The term was proposed in 1980 by the UK child psychologist Elizabeth Ann Newson.[6][7] ## Contents * 1 Recognition * 2 Proposed diagnostic criteria * 3 History * 4 Bibliography * 5 References ## Recognition[edit] Pathological demand avoidance is not recognized by the DSM-5 or ICD-10, the two main classification systems for mental disorders.[4] To be recognized a sufficient amount of consensus and clinical history needs to be present, and as a newly proposed condition, PDA had not met the standard of evidence required at the time of recent revisions. However, DSM-5 also moved from sub-type classification to the use of ‘Autistic Spectrum Disorder’ which allows for the behavioural traits of different profiles to be described. In 2011 the National Institute for Health and Care Excellence commented on the fact that PDA has been proposed as part of the autism spectrum but did not include further discussion within the guideline.[1] NICE guidance also expects an ‘ASD’ diagnosis be accompanied by a diagnostic assessment providing a profile of key strengths and difficulties. Demand Avoidance is listed as a ‘sign or symptom of ASD’ (Appendix 3).[1] In response to the recent research Christopher Gillberg wrote a commentary article which stated “Experienced clinicians throughout child psychiatry, child neurology and paediatrics testify to its existence and the very major problems encountered when it comes to intervention and treatment.”[8] ## Proposed diagnostic criteria[edit] As of 2014 there are no recognized diagnostic criteria.[4] Proposed criteria by Newson include: 1. Passive early history in the first year, avoiding ordinary demands and missing milestones 2. Continuing to avoid demands, panic attacks if demands are escalated 3. Surface sociability, but apparent lack of sense of social identity 4. Lability of mood and impulsive 5. Comfortable in role play and pretending 6. Language delay, seemingly the result of passivity, often caught up quickly 7. Obsessive behavior 8. Neurological signs (awkwardness, similar to autism spectrum disorders[9]) The underlying cause for this avoidance is said to be a high level of anxiety, usually from expectations of demands being placed on children, which can lead to a feeling of not being in control of a situation.[10] Children with PDA feel threatened when they are not in control of their environment and their actions, which triggers the fight, flight or freeze response.[11] ## History[edit] Newson first began to look at PDA as a specific syndrome in the 1980s when certain children referred to the Child Development Clinic at the University of Nottingham appeared to display and share many of the same characteristics. These children had often been referred because they seemed to show many autistic traits but were not typical in their presentation like those with classical autism or Asperger's syndrome. They had often been labelled as 'atypical autism' or Persistent Development Disorder- Not Otherwise Specified (PDD-NOS). Both of these terms were felt by parents to be unhelpful. When Newson was made professor of developmental psychology at the University of Nottingham in 1994, she dedicated her inaugural lecture to talking about pathological demand avoidance syndrome.[12] In 1997, the PDA Society was established in the UK by parents of children with a PDA profile of autism. It became a registered charity in January 2016.[13] In July 2003, Newson published in Archives of Disease in Childhood for PDA to be recognized as a separate syndrome within the pervasive developmental disorders.[6] ## Bibliography[edit] * Fidler, Ruth; Christie, Phil (2019). Collaborative Approaches to Learning for Pupils with PDA: Strategies for Education Professionals. Jessica Kingsley Publishers. ISBN 9781784502614. ## References[edit] 1. ^ a b c d National Collaborating Centre for Women’s and Children’s Health (September 2011). "Autism: recognition, referral and diagnosis of children and young people on the autism spectrum": 235, 286. PMID 22624178. Cite journal requires `\|journal=` (help) 2. ^ American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 3. ^ "ICD-10 Version:2016". apps.who.int. Retrieved 22 January 2018. 4. ^ a b c Westminster, Department of the Official Report (Hansard), House of Commons. "House of Commons Hansard Written Answers for 28 Apr 2014 (pt 0002)". 5. ^ Elizabeth N, Phil C, Judith G, Essi V, Francesca H (July 2014). "Development of the 'Extreme Demand Avoidance Questionnaire' (EDA-Q): preliminary observations on a trait measure for Pathological Demand Avoidance". Journal of Child Psychology and Psychiatry. 55 (7): 758–768. doi:10.1111/jcpp.12149. 6. ^ a b Newson E, Le Maréchal K, David C (July 2003). "Pathological demand avoidance syndrome: a necessary distinction within the pervasive developmental disorders". Archives of Disease in Childhood. Royal College of Paediatrics and Child Health. 88 (7): 595–600. doi:10.1136/adc.88.7.595. PMC 1763174. PMID 12818906. 7. ^ Feinstein, Adam (2010). A History of Autism: Conversations with the Pioneers. Wiley-Blackwell. p. 181. ISBN 978-1-4051-8654-4. 8. ^ Gillberg, Christopher (2014-07-01). "Commentary: PDA – public display of affection or pathological demand avoidance? – reflections on O'Nions et al. (2014)". Journal of Child Psychology and Psychiatry. 55 (7): 769–770. doi:10.1111/jcpp.12275. ISSN 1469-7610. PMID 24890260. 9. ^ "PDA Society • Part of the Autism Spectrum". 10. ^ Longo, Sharon (November 19, 2019). "Pathological Demand Avoidance and Autism". Autism Parenting Magazine. Retrieved December 13, 2020. 11. ^ Dundon, Raelene. The Parents’ Guide to Managing Anxiety in Children with Autism. Jessica Kingsley Publishers. p. 114. ISBN 9781785926570. 12. ^ Christie, Phil (February 20, 2014). "Elizabeth Newson obituary". The Guardian. Retrieved December 13, 2020. 13. ^ "About the PDA Society". PDA Society. Retrieved December 13, 2020. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection	Pathological demand avoidance	c4076623	5,099	wikipedia	https://en.wikipedia.org/wiki/Pathological_demand_avoidance	2021-01-18T19:00:10	{"umls": ["C4076623"], "wikidata": ["Q7144824"]}

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