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A rare disorder characterized by slowly progressive spasticity, extrapyramidal movement disorders (dystonia, choreoathetosis and rigidity), cerebellar ataxia, moderate to severe cognitive deficit, and anarthria/dysarthria. ## Epidemiology So far, around 20 cases have been reported in the literature. The syndrome affects both males and females and onset occurs in infancy or early childhood. ## Etiology The etiology is unknown. ## Diagnostic methods H-ABC is diagnosed on the basis of the distinctive MRI findings of diffuse but partial hypomyelination of the cerebral hemispheres, mild to severe cerebellar atrophy and atrophy of the basal ganglia. ## Genetic counseling All of the reported cases were sporadic and the mode of inheritance remains unclear. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hypomyelination with atrophy of basal ganglia and cerebellum	c2676244	5,500	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139441	2021-01-23T18:38:15	{"gard": ["10917"], "mesh": ["C567314"], "omim": ["612438", "617899"], "icd-10": ["E75.2"], "synonyms": ["H-ABC"]}
Hepatoblastoma is a rare malignant (cancerous) tumor of the liver that usually occurs in the first 3 years of life. In early stages of the condition, there may be no concerning signs or symptoms. As the tumor gets larger, affected children may experience a painful, abdominal lump; swelling of the abdomen; unexplained weight loss; loss of appetite; and/or nausea and vomiting. The exact underlying cause of hepatoblastoma is poorly understood. Risk factors for the tumor include prematurity with a very low birth weight, early exposure to hepatitis B infection, biliary atresia, and several different genetic conditions (i.e. Beckwith-Wiedemann syndrome, familial adenomatous polyposis, Aicardi syndrome, Glycogen storage disease, and Simpson-Golabi-Behmel syndrome). Treatment varies based on the severity of the condition but may include a combination of surgery, watchful waiting, chemotherapy, and/or radiation therapy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hepatoblastoma	c0206624	5,501	gard	https://rarediseases.info.nih.gov/diseases/2657/hepatoblastoma	2021-01-18T18:00:05	{"mesh": ["D018197"], "omim": ["114550"], "umls": ["C0206624"], "orphanet": ["449"], "synonyms": []}
There are 2 branched-chain amino acid transferases, BCT1 (113520) and BCT2 (113530). There is evidence, furthermore, that the transamination of valine may be separate from the transamination of leucine and isoleucine (see 277100). The only description of a leucine-isoleucine abnormality was provided by Jeune et al. (1970) in a French family. A brother and sister presented at ages 2 to 3 months with seizures, failure to thrive, and mental retardation. The girl had retinal degeneration and sensorineural hearing loss as well. Blood analysis showed elevated concentrations of leucine, isoleucine, and proline with normal levels of valine. Aminotransferase activity in the leukocytes of these 2 patients showed decreased transfer from leucine and isoleucine but normal activity with valine. Treatment with diets low in leucine and isoleucine did not improve the clinical phenotype and the boy died in his third year. HEENT \- Retinal degeneration \- Sensorineural hearing loss Growth \- Failure to thrive Neuro \- Seizures \- Mental retardation Lab \- Elevated blood leucine, isoleucine, and proline \- Normal blood valine \- Decreased leucine and isoleucine aminotransferase \- Normal valine aminotransferase Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HYPERLEUCINE-ISOLEUCINEMIA	c0268574	5,502	omim	https://www.omim.org/entry/238340	2019-09-22T16:26:52	{"mesh": ["C562674"], "omim": ["238340"], "icd-10": ["E71.19"]}
A group of rare, genetic, progressive muscular dystrophies, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and a symptomatic form in female carriers. The diseases represent a spectrum of severity ranging from progressive skeletal and cardiac muscle wasting and weakness (DMD, BMD) to less severe muscle weakness or isolated cardiomyopathy affecting carrier females. ## Epidemiology The prevalence of DMD ranges between 1/3,500-1/ 9,300 male births. The prevalence of BMD varies from 1/16,700 to 1/18,500 male births. The prevalence of symptomatic female carriers is unknown. ## Clinical description Dystrophinopathies present with a spectrum of severity whereby BMD is at the mildest end and DMD the most severe, there is an intermediate phenotype in between. At the mildest end of the spectrum exercise-induced muscle cramps and myoglobinuria may be the only feature while at the severe end, there may be complete loss of muscle function, cardiomyopathy and respiratory failure. DMD presents in early childhood, motor milestones are delayed. Brain involvement leads to cognitive impairment (affecting about a third of patients) and/or pervasive behavioral disorders such as ADHD (attention deficit hyperactivity disorder), autism, anxiety and obsessive compulsive disorder. Muscle hypertrophy is evident, especially in the calf muscles. Progression is rapid, such that by the age of 5 there is likely to be a waddling gait and positive Gowers' sign. In untreated boys, walking is lost by 13 years of age (mean 9.5 years). Following loss of ambulation, scoliosis, respiratory failure and cardiomyopathy develop. BMD presents a broad spectrum of clinical severity, with onset of symptoms occurring from early childhood to as late as the sixth decade. Manifesting carriers of DMD and BMD may present with varying degrees of cardiomyopathy and muscle weakness. X-linked dilated cardiomyopathy (XLDCM), which may be caused by mutations in the dystrophin gene, presents with very severe, rapidly progressive, dilated cardiomyopathy. ## Etiology Dystrophinopathies are allelic conditions caused by deletions, duplications and mutations in the DMD gene, located on the X chromosome (Xp21.2). DMD genetic variants are frame-shift, while BMD variants are in-frame. ## Diagnostic methods The clinical diagnosis can be confirmed by several methods. Creatine Kinase (CK) is very raised. Molecular genetic analysis by MLPA (multiplex ligation-dependent probe amplification) will show a deletion in 60%; full gene sequencing is necessary to identify small deletions, duplications and nonsense mutations. Muscle biopsy for dystrophin analysis which is absent in DMD and reduced in BMD. ## Differential diagnosis The differential diagnosis includes LGMD and, in adults, other muscle disorders presenting with a raised CK. ## Antenatal diagnosis Prenatal diagnosis requires the most precise molecular diagnosis possible in the index case. ## Genetic counseling The pattern of inheritance is X-linked recessive. Genetic counselling of affected families is recommended and screening of women carriers in the family is important. ## Management and treatment There is no known cure for this group of dystrophinopathies. In DMD, treatment with corticosteroids stabilizes motor function and delays loss of ambulation and respiratory failure by several years. Physiotherapy and orthotics delay the onset of joint contractures. Non-invasive ventilation (NIV) to treat respiratory failure prolongs life expectancy. Regular cardiac monitoring from diagnosis with early treatment using ACE (angiotensin-converting enzyme) inhibitors and beta blockers stabilizes cardiomyopathy. For XLDCM, cardiac transplantation is the treatment of choice. ## Prognosis Life expectancy is shortened by cardiac and respiratory involvement, but can be substantially improved with regular monitoring and pro-active management. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Duchenne and Becker muscular dystrophy	c0917713	5,503	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=262	2021-01-23T17:49:38	{"mesh": ["D020388"], "umls": ["C0917713", "C3542021"], "icd-10": ["G71.0"], "synonyms": ["Severe dystrophinopathy, Duchenne and Becker type"]}
Intellectual disability-obesity-prognathism-eye and skin anomalies syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by mild to profound intellectual disability, delayed speech, obesity, ocular anomalies (blepharophimosis, blepharoptosis, hyperopic astigmatism, decreased visual acuity, strabismus, abducens nerve palsy, and/or accommodative esotropia), and dermal manifestations, such as chronic atopic dermatitis. Associated craniofacial dysmorphism includes macrocephaly, maxillary hypoplasia, mandibular prognathism, and crowding of teeth. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Intellectual disability-obesity-prognathism-eye and skin anomalies syndrome	c1847522	5,504	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=397973	2021-01-23T17:37:37	{"mesh": ["C564660"], "omim": ["606772"], "umls": ["C1847522"], "icd-10": ["Q87.8"], "synonyms": ["MOMES syndrome"]}
A multiple congenital anomalies/dysmorphic syndrome-intellectual disability that is characterized by facial dysmorphism, short stature with delayed bone age, and expressive language delay. ## Epidemiology Floating-Harbor syndrome prevalence and incidence are unknown. Around 100 cases have been reported in the literature to date. ## Clinical description Facial features include a triangular-shaped face, a prominent bulbous nose with a broad nasal bridge, a wide columella, deep-set eyes with long eyelashes, a wide mouth with a thin upper lip, low-set ears and sometimes broad thumbs and big toes. The speech defect is marked by impairment of expressive language and is often associated with a peculiar hypernasal voice. Stature is usually reported to be below the third percentile and between 2 and 4 SD below the mean. Bone age is always delayed. Other variable manifestations include celiac disease, pseudoarthrosis of the clavicle, intellectual disability, dental anomalies (malocclusion, microdontia, supernumerary upper teeth), a short neck, brachydactyly, and clinodactyly of the 5th finger. Associated genitourinary and cardiac anomalies have been reported in a few cases. ## Etiology The syndrome is associated with heterozygous mutations in exon 33 or mostly in exon 34 of the SRCAP gene (16p11.2), with two recurrent mutations (Arg2444* and Arg2435). SRCAP encodes an ATPase which is involved in chromatin remodeling and is the cofactor of CREBBP, the gene responsible for Rubinstein-Taybi syndrome. ## Diagnostic methods Diagnosis is based on clinical examination and can be confirmed by genetic testing. ## Differential diagnosis The differential diagnosis should include other dysmorphic syndromes, in particular Rubinstein-Taybi syndrome. ## Antenatal diagnosis Prenatal diagnosis can be considered for families in which the disease-causing mutation has been identified. ## Genetic counseling The majority of reported cases are sporadic, but a few familial cases with autosomal dominant inheritance have been reported. ## Management and treatment Management is only symptomatic. Patients may benefit from developmental and educational programs and should receive regular orthodontic care. Growth hormone therapy may be of benefit in some patients. ## Prognosis Despite the presence of short stature and learning difficulties, in general patients appear to remain in good health and have a good quality of life. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors *[GHB]: γ-hydroxybutyric acid	Floating-Harbor syndrome	c0729582	5,505	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2044	2021-01-23T18:16:35	{"gard": ["3221", "6455"], "mesh": ["C537062"], "omim": ["136140"], "umls": ["C0729582"], "icd-10": ["Q87.8"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs attention from an expert in medicine. Please add a reason or a talk parameter to this template to explain the issue with the article. WikiProject Medicine may be able to help recruit an expert. (July 2011) This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Roemheld syndrome" – news · newspapers · books · scholar · JSTOR (July 2011) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Roemheld syndrome Other namesRoemheld-Techlenburg-Ceconi-Syndrome or Gastric-cardia SpecialtyGastroenterology/cardiology Roemheld syndrome (RS), or gastrocardiac syndrome,[1][2][3][4] or gastric cardiac syndrome[5] or Roemheld-Techlenburg-Ceconi-Syndrome[6] or gastric-cardia,[6] was a medical syndrome first coined by Ludwig von Roemheld (1871–1938) describing a cluster of cardiovascular symptoms stimulated by gastrointestinal changes. Although it is currently considered an obsolete medical diagnosis, recent studies have described similar clinical presentations and highlighted potential underlying mechanisms.[3][7][8] ## Contents * 1 Symptoms * 1.1 Mechanical * 1.2 Neurological * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Etiology * 6 History * 7 See also * 8 References ## Symptoms[edit] Symptoms can be as follows.[9][10] They are periodic, and occur only during an "episode", usually after eating. * Sinus bradycardia * Difficulty inhaling * Angina pectoris * Left ventricular discomfort * Fatigue * Anxiety * Uncomfortable breathing * Poor perfusion * Muscle pain (crampiness) * Burst or sustained vertigo or dizziness * Sleep disturbance (particularly when sleeping within a few hours of eating, or lying on the left side) * Extrasystoles * Hot flashes * Tachycardia ### Mechanical[edit] Mechanically induced RS is characterized by pressure in the epigastric and left hypochondriac region. Often the pressure is in the fundus of the stomach, esophagus or distention of the bowel. It is believed this leads to elevation of the diaphragm, and secondary displacement of the heart. This reduces the heart's ability to fill and increases the contractility of the heart to maintain homeostasis. ### Neurological[edit] The cranium dysfunction mechanical changes in the gut can compress the vagus nerve at any number of locations along the vagus, slowing the heart. As the heart slows, autonomic reflexes are triggered to increase blood pressure and heart rate. This is complemented by gastro-coronary reflexes whereby the coronary arteries constrict with "functional cardiovascular symptoms" similar to chest-pain on the left side and radiation to the left shoulder, dyspnea, sweating, up to angina pectoris -like attacks with extrasystoles, drop of blood pressure, and tachycardia (high heart beat) or sinus bradycardia (heart beat below 60). Typically, there are no changes / abnormalities related in the EKG detected. This can actually trigger a heart attack for persons with cardiac structural abnormalities i.e. coronary bridge, missing coronary, and atherosclerosis. If the heart rate drops too low for too long, catecholamines are released to counteract any lowering of blood pressure. Catecholamines bind to alpha receptors and beta receptors, decreasing vasodilation and increasing contractility of the heart. Sustaining this state causes heart fatigue which results in fatigue and chest pain. ## Causes[edit] * Gastroesophageal reflux disease[11] * Excessive gas in the transverse colon caused by: * Lactose intolerance * Abnormal gall bladder function and/or blood flow * Gall stones * Sphincter of Oddi dysfunction * Hiatal hernia * Cardiac bridge (Coronary occluding reflexes triggered by coronary reflexes) * Enteric disease * Aneructonia, the loss of the ability to belch (continuous or intermittent)[citation needed] * Bowel obstruction (Less common, this usually leads to intense pain in short time) * Acute pancreatic necrosis[12] ## Diagnosis[edit] 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. (July 2011) (Learn how and when to remove this template message) There is significant scope of misdiagnosis of RS. Diagnosis of RS usually starts with a cardiac workup, as the gastric symptoms may go unnoticed, the cardiac symptoms are scary and can be quite severe. After an EKG, Holter monitor, tilt test, cardiac MRI, cardiac CT, heart catheterization, EP study, echo-cardiogram, and extensive blood work, and possibly a sleep study, a cardiologist may rule out a heart condition. Often a psych workup may ensue as a conversion disorder may be suspected in the absence of heart disease, or structural heart abnormalities. Diagnosis is often made based on symptoms in the absence of heart abnormalities. A gastroenterologist will perform a colonoscopy, endoscopy, and ultrasound to locate or eliminate problems in the abdomen. Determining the cause of Roemheld syndrome is still not an exact science. If you have an ultrasound or sleep study, ensure that you know how to reproduce the symptoms, as it is difficult to detect any abnormalities when symptoms have subsided. ## Treatment[edit] Treatment of the primary gastroenterological distress is the first concern, mitigation of gastric symptoms will also alleviate cardiac distress. * Anticholinergics, magnesium, or sodium (to raise blood pressure) supplements * Anticonvulsants have eliminated all symptoms in some RS sufferers; Lorazepam, Oxcarbazepine increase GI motility, reduce vagus "noise" (sodium channel blocking believed to contribute to positive effects) * Alpha blockers may increase gi motility if that is an issue, also 5 mg to 10 mg amitriptyline if motility is an issue that can't be solved by other methods * Antigas - simethicone, beano, omnimax reduces epigastric pressure * Antacids \- calcium carbonate, famotidine, omeprazole, etc. reduces acid reflux in the case of hiatal hernia or other esophageal type RS. * Vagotomy * Beta blockers \- reduces contractility and automaticity of the heart which reduces irregular rhythms but also lowers blood pressure when symptoms occur, and further reduces perfusion ex: Carvedilol, this will control abnormal heart rhythms, but can precipitate Prinzmetal angina and heart block. ## Etiology[edit] Roemheld syndrome is characterized strictly by abdominal maladies triggering reflexes in the heart. There are a number of pathways through which cardiac reflexes can occur: hormones, mechanical, neurological and immunological.[citation needed] ## History[edit] Ludwig Roemheld characterized this particular syndrome shortly before his death; one of his research topics around this time was the effects of calorie intake on the heart. In Elsevier, there is no current research or publishing under the name Roemheld syndrome, and as a result many cases go undiagnosed. German publishing on the subject remains untranslated as of 2009. ## See also[edit] * Swallowing syncope ## References[edit] 1. ^ Pelner, Louis (1944). The Diet Therapy of Disease: A Handbook of Practical Nutrition. Personal diet service. "ROEMHELD, L.; Treatment of Gastrocardiac Syndrome" 2. ^ Hempen, Carl-Hermann; Fischer (MD.), Toni (2009-01-01). A Materia Medica for Chinese Medicine: Plants, Minerals, and Animal Products. Elsevier Health Sciences. ISBN 9780443100949. 3. ^ a b Saeed, Mohammad; Bhandohal, Janpreet Singh; Visco, Ferdinand; Pekler, Gerald; Mushiyev, Savi (2018-05-09). "Gastrocardiac syndrome: A forgotten entity". The American Journal of Emergency Medicine. 36 (8): 1525.e5–1525.e7. doi:10.1016/j.ajem.2018.05.002. ISSN 0735-6757. PMID 29764738. S2CID 21725954. 4. ^ "Current Medical Literature volume 97 number 12" (PDF). "p882 This complex of symptoms, for which the term "gastrocardiac syndrome" (gastric cardiopathy" 5. ^ "Clinical experience of treating 82 cases of gastric cardiac syndrome with traditional Chinese medicine". 6. ^ a b Modestus, Jamey Franciscus (October 2011). Roemheld Syndrome. Strupress. ISBN 9786137960998. 7. ^ Linz, Dominik; Hohl, Mathias; Vollmar, J; Ukena, C; Mahfoud, F; Böhm, M (January 2017). "Atrial fibrillation and gastroesophageal reflux disease: the cardiogastric interaction". EP Europace. 19 (1): 16–20. doi:10.1093/europace/euw092. PMID 27247004. S2CID 24306731. 8. ^ Ehlers, A; Mayou, RA; Sprigings, DC; Birkhead, J (1999). "Psychological and perceptual factors associated with arrhythmias and benign palpitations". Psychosomatic Medicine. 62 (5): 693–702. doi:10.1097/00006842-200009000-00014. PMID 11020100. S2CID 23760133. 9. ^ Lok, NS; Lau, CP (June 1996). "Prevalence of palpitations, cardiac arrhythmias and their associated risk factors in ambulant elderly". International Journal of Cardiology. 54 (3): 231–6. doi:10.1016/0167-5273(96)02601-0. PMID 8818746. 10. ^ Sharma, Shekhar. "Roemheld Syndrome - Gastric Cardia". roemheld-syndrome.com. Retrieved 28 March 2017. 11. ^ Roman, C; Bruley des Varannes, S; Muresan, L; Picos, A; Dumitrascu, DL (28 July 2014). "Atrial fibrillation in patients with gastroesophageal reflux disease: a comprehensive review". World Journal of Gastroenterology. 20 (28): 9592–9. doi:10.3748/wjg.v20.i28.9592. PMC 4110594. PMID 25071357. 12. ^ Dittler, Edgar Leon; McGavack, Thomas H. (September 1938). "Pancreatic necrosis associated with auricular fibrillation and flutter". American Heart Journal. 16 (3): 354–362. doi:10.1016/S0002-8703(38)90615-5. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Roemheld syndrome	c0877059	5,506	wikipedia	https://en.wikipedia.org/wiki/Roemheld_syndrome	2021-01-18T19:09:27	{"umls": ["C0877059"], "wikidata": ["Q1638006"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-68 (DFNB68) is caused by homozygous mutation in the S1PR2 gene (605111) on chromosome 19p13. Clinical Features Santos et al. (2006) reported 2 consanguineous Pakistani families with autosomal recessive nonsyndromic congenital sensorineural hearing loss. In a follow-up of one of these families (DEM4154), reported by Santos et al. (2006) to be negative for limb deformities or any other syndromic features, Santos-Cortez et al. (2016) found that 6 of the 7 affected individuals had severe asymmetric lower limb anomalies, including short and/or bent tibiae, bent or absent fibulae, and absent knee joint. Various foot defects included overlapping or missing digits and syndactyly with soft tissue fusion. One patient had only a mild foot deformity with prominence of the midfoot and interdigital crease, and clubbed toes; x-rays of his knees and feet revealed loss of the medial joint space of the right knee, a lytic lesion of the upper end of the right fibula, and a missing right navicular bone that appeared to be fused to the talus. In addition, the hands of all affected individuals showed long fingers and fifth finger camptodactyly, but radiographs were not available. The authors stated that overall, the asymmetric lower limb deformities resembled tibial hemimelia with split-foot malformation. In a second consanguineous Pakistani family (PKDF1400) reported by Santos-Cortez et al. (2016), affected individuals had profound hearing loss across all frequencies, but exhibited no skeletal, immunologic, cardiovascular, or endocrine features. Mapping Santos et al. (2006) reported 2 consanguineous Pakistani families with autosomal recessive nonsyndromic sensorineural hearing loss. Genomewide linkage analysis followed by fine mapping identified a locus, termed DFNB68, on chromosome 19p13.2 (maximum multipoint lod scores of 4.8 and 4.6 at markers D19S581 and D19S432-D19S714-D19S252 in the 2 families, respectively). Haplotype analysis identified a 1.4-Mb (1.9-cM) overlapping interval flanked by markers D19S586 and D19S584. The DFNB68 locus is located within the chromosome 19p13.3-p13.2 region, and DFNB15 (601869) and DFNB81 (614129) are mapped to the same region of chromosome 19. Sequence analysis excluded pathogenic mutations in the KEAP1 (606016), CTL2 (606106), and CDKN2D (600927) genes. In a consanguineous Pakistani family (DEM4154) with congenital profound deafness and lower limb malformations mapping to chromosome 19, previously studied by Santos et al. (2006), Santos-Cortez et al. (2016) obtained a maximum 2-point lod score of 6.4 (theta = 0) for the R108P variant (605111.0001) in the S1PR2 gene on chromosome 19p13. In another consanguineous Pakistani family (PKDF1400) with isolated hearing impairment, they obtained a maximum multipoint lod score of 3.3 on chromosome 19p13.2-p13.12. Molecular Genetics In a consanguineous Pakistani family (DEM4154) with congenital profound deafness and severe asymmetric lower limb malformations mapping to chromosome 19, previously studied by Santos et al. (2006), Santos-Cortez et al. (2016) performed exome sequencing and identified a homozygous missense mutation in the S1PR2 gene (R108P; 605111.0001) that segregated with disease in the family and was not found in 720 Pakistani control chromosomes or in the dbSNP or ExAC databases. In another consanguineous Pakistani family (PKDF1400) with isolated hearing impairment mapping to chromosome 19p13, the authors performed whole-exome sequencing and identified a different missense mutation in S1PR2 (Y140C; 605111.0002) that segregated with disease and was not found in Pakistani controls or public databases. Noting that gross limb deformities were not observed in family PKDF1400 or in S1pr2-null mice, Santos-Cortez et al. (2016) suggested that the limb deformities in family DEM4154 were not due to the mutation in S1PR2 but rather to a variant in another gene. ### Exclusion Studies By sequencing the S1PR2 gene in the other Pakistani family (DEM4100) with congenital deafness studied by Santos et al. (2006), Santos-Cortez et al. (2016) did not detect any mutations; however, they identified a putatively pathogenic variant in the ESSRB gene (602167; see DFNB35, 608565). INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Deafness, sensorineural, profound \- Prelingual onset MISCELLANEOUS \- Based on report of 2 consanguineous Pakistani families (last curated March 2016) \- Affected individuals in 1 family also exhibited severe asymmetric lower limb anomalies, which were believed to be due to mutation in another gene MOLECULAR BASIS \- Caused by mutation in the sphingosine-1-phosphate receptor-2 gene (S1PR2, 605111.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	DEAFNESS, AUTOSOMAL RECESSIVE 68	c1835854	5,507	omim	https://www.omim.org/entry/610419	2019-09-22T16:04:37	{"doid": ["0110519"], "mesh": ["C563669"], "omim": ["610419"], "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"]}
Mowat-Wilson syndrome (MWS) is a rare genetic disorder that affects many systems of the body. Some of the main features include intellectual disability, distinctive facial features, delayed development, and Hirschsprung disease. Other features may include microcephaly, structural brain abnormalities, epilepsy, short stature, and defects of the heart, urinary tract, or genitalia. MWS is caused by a mutation in the ZEB2 gene. It typically occurs for the first time in a person with MWS and is not inherited from a parent. Vary rarely, more than one child in a family will have MWS. Treatment depends on the symptoms present and focuses on the specific needs of 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Mowat-Wilson syndrome	c1856113	5,508	gard	https://rarediseases.info.nih.gov/diseases/9673/mowat-wilson-syndrome	2021-01-18T17:58:58	{"mesh": ["C536990"], "omim": ["235730"], "umls": ["C1856113"], "orphanet": ["2152"], "synonyms": ["Intellectual disability, microcephaly, and distinct facial features with or without Hirschsprung disease", "Hirschsprung disease intellectual disability syndrome"]}
Alcohol use disorder is a diagnosis made when an individual has severe problems related to drinking alcohol. Alcohol use disorder can cause major health, social, and economic problems, and can endanger affected individuals and others through behaviors prompted by impaired decision-making and lowered inhibitions, such as aggression, unprotected sex, or driving while intoxicated. Alcohol use disorder is a broad diagnosis that encompasses several commonly used terms describing problems with drinking. It includes alcoholism, also called alcohol addiction, which is a long-lasting (chronic) condition characterized by a powerful, compulsive urge to drink alcohol and the inability to stop drinking after starting. In addition to alcoholism, alcohol use disorder includes alcohol abuse, which involves problem drinking without addiction. Habitual excessive use of alcohol changes the chemistry of the brain and leads to tolerance, which means that over time the amount of alcohol ingested needs to be increased to achieve the same effect. Long-term excessive use of alcohol may also produce dependence, which means that when people stop drinking, they have physical and psychological symptoms of withdrawal, such as sleep problems, irritability, jumpiness, shakiness, restlessness, headache, nausea, sweating, anxiety, and depression. In severe cases, agitation, fever, seizures, and hallucinations can occur; this pattern of severe withdrawal symptoms is called delirium tremens. The heavy drinking that often occurs in alcohol use disorder, and can also occur in short-term episodes called binge drinking, can lead to a life-threatening overdose known as alcohol poisoning. Alcohol poisoning occurs when a large quantity of alcohol consumed over a short time causes problems with breathing, heart rate, body temperature, and the gag reflex. Signs and symptoms can include vomiting, choking, confusion, slow or irregular breathing, pale or blue-tinged skin, seizures, a low body temperature, a toxic buildup of substances called ketones in the blood (alcoholic ketoacidosis), and passing out (unconsciousness). Coma, brain damage, and death can occur if alcohol poisoning is not treated immediately. Chronic heavy alcohol use can also cause long-term problems affecting many organs and systems of the body. These health problems include irreversible liver disease (cirrhosis), inflammation of the pancreas (pancreatitis), brain dysfunction (encephalopathy), nerve damage (neuropathy), high blood pressure (hypertension), stroke, weakening of the heart muscle (cardiomyopathy), irregular heartbeats (arrhythmia), and immune system problems. Long-term overuse of alcohol also increases the risk of certain cancers, including cancers of the mouth, throat, esophagus, liver, and breast. Alcohol use in pregnant women can cause birth defects and fetal alcohol syndrome, which can lead to lifelong physical and behavioral problems in the affected child. ## Frequency Alcohol use disorder is a very common condition. According to the 2015 National Survey on Drug Use and Health, about 16 million Americans have alcohol use disorder, which affects about 8 percent of adult men, 4 percent of adult women, and 2.5 percent of adolescents ages 12 to 17. In total, approximately 38 million people in the United States are considered by public health experts to drink too much alcohol, which includes high weekly use (15 or more drinks per average week for men, and 8 for women), binge drinking, and any drinking by pregnant women or individuals under age 21. Heavy drinking, either with or without a diagnosis of alcohol use disorder, accounts for approximately 88,000 preventable deaths in the United States every year, including almost a third of driving fatalities, and is the third leading cause of preventable deaths in the United States after tobacco use and poor diet coupled with physical inactivity. ## Causes The causes of alcohol use disorder are complex. This condition results from a combination of genetic, environmental, and lifestyle factors, some of which have not been identified. Variations in genes that affect the metabolism (breakdown) of alcohol in the body have been studied as factors that can increase or decrease the risk of alcohol use disorder. Gene variations that result in skin flushing, nausea, headaches, and rapid heartbeat when drinking alcohol discourage its consumption and reduce the risk of alcohol use disorder. Populations that have a higher prevalence of such gene variations, such as people of Asian or Jewish descent, tend to have a lower risk of alcohol use disorder than other populations. The risk of alcohol use disorder is also related to variations in genes involved in nervous system function. Some of these genes play roles in various neurotransmitter pathways, in which chemicals in the nervous system called neurotransmitters and their receptors relay signals from one nerve cell (neuron) to another. Although variations in several of these genes have been associated with alcohol use disorder, it is unclear how these genetic changes influence the way in which the nervous system responds to alcohol. Nongenetic factors also play a critical role in alcohol use disorder. Factors that increase the risk of this condition include depression or other psychiatric disorders and certain psychological traits, including impulsivity and low self-esteem. Stress, associating with others who abuse alcohol, and having easy access to alcohol also contribute to a person's risk. ### Learn more about the genes associated with Alcohol use disorder * COMT * OPRM1 * SLC6A3 Additional Information from NCBI Gene: * ADH1B * ADH1C * ADH4 * ALDH2 * CHRM2 * DRD2 * DRD3 * GABRA2 * GABRG3 * HTR2A * SLC6A4 * TAS2R16 ## Inheritance Pattern Alcohol use disorder does not have a clear pattern of inheritance, although many affected individuals have a family history of problems with alcohol or other substances. Children of people with alcohol use disorder are two to six times more likely than the general public to develop alcohol problems. This increased risk is likely due in part to shared genetic factors, but it may also be related to environment, lifestyle, and other nongenetic influences that are shared by members of a 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Alcohol use disorder	c0001973	5,509	medlineplus	https://medlineplus.gov/genetics/condition/alcohol-use-disorder/	2021-01-27T08:24:37	{"mesh": ["D000437"], "omim": ["103780"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that juvenile myelomonocytic leukemia (JMML) can be caused by germline heterozygous mutation in the CBL gene (165360) on chromosome 11q23. One such family has been reported. Description Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). ### Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML. ### Genetic Heterogeneity of Chronic Myelomonocytic Leukemia Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML. Clinical Features Pathak et al. (2015) reported a family in which 4 patients developed leukemia in the first few years of life. One patient died at age 16 months, whereas the other 3 patients were followed for 35 years. Retrospective diagnosis was consistent with JMML. Two of the patients had some persistent hematologic abnormalities into adulthood, and the third had continued splenomegaly. None had clinical features consistent with Noonan syndrome (see 613563), although 1 of the patients had dysmorphic facial features at age 18 months, including slanted palpebral fissures, small mouth, long grooved philtrum, short upturned nose, and facial hypotonia. Several other family members had acute myelomonocytic leukemia, splenomegaly, polyclonal gammopathy, and monocytosis. Cytogenetics In a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the HIP1 gene (601767) to the platelet-derived growth factor-beta receptor gene (PDGFRB; 173410). They identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFRB gene. The reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein product was a 180-kD protein when expressed in a murine hematopoietic cell line and was constitutively tyrosine phosphorylated. Furthermore, the fusion gene transformed the same mouse hematopoietic cell line to interleukin-3-independent growth. In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner fused in-frame to the 5-prime portion of the PDGFBR gene. The fusion protein included more than 85% of the native rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRB. Rabaptin-5 is an essential and rate-limiting component of early endosomal fusion. The new fusion protein links 2 important pathways of growth regulation. Molecular Genetics ### Mutations Associated with Noonan Syndrome and JMML Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I; 176876.0011), and that somatic mutations in PTPN11 are associated with isolated JMML. Jongmans et al. (2005) described a patient with Noonan syndrome and mild JMML who carried a mutation in the PTPN11 gene (176876.0011). Schubbert et al. (2006) described a 3-month-old female with Noonan syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented with a JMML-like myeloproliferative disorder. The patient was heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This mutation was also present in her buccal cells, but was absent in parental DNA. De Filippi et al. (2009) reported a boy who presented in infancy with JMML but was later noted to have dysmorphic features suggestive of, but not diagnostic of, Noonan syndrome (NS6; 613224). Features included short stature, relative macrocephaly, high forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac studies were normal. Genetic analysis revealed a de novo germline heterozygous mutation in the NRAS gene (G13D; 164790.0003). In 3 unrelated patients with a Noonan syndrome-like disorder (613563) who developed JMML, Perez et al. (2010) identified a heterozygous germline mutation in the CBL gene (Y371H; 165360.0005). The mutation occurred de novo in 2 patients and was inherited from an unaffected father in 1 patient. Leukemia cells of all patients showed somatic loss of heterozygosity at chromosome 11q23, including the CBL gene. The findings indicated that germline heterozygous mutations in the CBL gene are associated with predisposition for the development of JMML. In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009) identified 25 homozygous and 2 heterozygous mutations in the CBL gene. The mutations were located throughout the linker and RING finger domains, and Y371H was the most common mutation. Leukemic cells from 3 patients examined in detail had acquired isodisomy of chromosome 11q including the CBL gene. Each of these 3 patients had a heterozygous germline CBL mutation, whereas their tumor cells had homozygous mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high levels of STAT5 (601511) in response to GM-CSF. These findings indicated that reduplication of an inherited CBL mutation in a pluripotent hematopoietic stem cell confers a selective advantage for the homozygous state. Loh et al. (2009) estimated the frequency of CBL mutations to be 10 to 15% of JMML patients overall. They did not find CBL mutations in JMML patients with known PTPN11/RAS mutation, indicating that CBL and PTPN11/RAS mutations are mutually exclusive. The finding that heterozygous germline mutations may predispose to development of JMML suggested that CBL acts as a tumor suppressor gene. ### Isolated Juvenile or Chronic Myelomonocytic Leukemia In 3 affected members of a family with JMML, Pathak et al. (2015) identified a germline heterozygous missense mutation in the CBL gene (Y371C; 165360.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in 4 family members without JMML, consistent with incomplete penetrance. Structural modeling predicted that the mutation would abrogate the ability of the mutant protein to adopt a conformation that would permit protein ubiquitination. Functional studies of the variant were not performed. In white blood cells derived from 11 patients with juvenile myelomonocytic leukemia, Matsuda et al. (2007) identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, 190070.0003; G12D, 190070.0005; and G12S, 190070.0007) and 5 different somatic mutations in the NRAS gene (see, e.g., G12D, 164790.0007 and G13D, 164790.0003). Each patient carried a single somatic mutation. The patients were ascertained from a cohort of 80 children with JMML. Jankowska et al. (2009) identified recurrent areas of somatic copy number-neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in patients with MDS/MPD. Subsequent analysis identified somatic mutations in the TET2 gene (612839) in 6 of 17 cases of chronic myelomonocytic leukemia. Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene in 29 (42%) of 69 CMML. Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene (612990) may act as a tumor suppressor in myeloid malignancies. They identified somatic ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic leukemia samples. Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from patients with CMML, which shares features with JMML. Muramatsu et al. (2010) identified uniparental disomy of 11q23 in leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the CBL gene identified somatic mutations in 5 (10%) of 49 patients. Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively. None of the patients had mutations in the TET2 gene (612839), which had previously been shown to be present in a significant proportion of patients with MDS/MPD, including CMML (see Jankowska et al., 2009). Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al. (2010) did not have any of the known pathogenic defects. Klinakis et al. (2011) identified novel somatic-inactivating Notch (see 190198) pathway mutations in a fraction of patients with CMML. Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1 (139605). Klinakis et al. (2011) concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue. Sakaguchi et al. (2013) performed whole-exome sequencing for paired tumor-normal DNA from 13 individuals with JMML (cases), followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 nonsilent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 (611060) and JAK3 (600173) mutations were among common targets for secondary mutations. Mutations in JAK3 were often subclonal, and Sakaguchi et al. (2013) hypothesized that they may be involved in the progression rather than the initiation of leukemia; these mutations associated with poor clinical outcomes. ### Exclusion Studies Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a cause of JMML in 16 specimens obtained from patients with the disorder who did not have mutations in the KRAS, NRAS, or PTPN11 genes. Genotype/Phenotype Correlations Matsuda et al. (2007) reported 3 with patients with an NRAS or KRAS gly12-to-ser (G12S) mutation who showed spontaneous improvement of hematologic abnormalities lasting for 2 to 4 years with neither intensive therapy nor HSCT. They suggested that the mild course correlated with the G12S RAS mutation and recommended that patients found to have this mutation receive close follow-up but no chemotherapy. Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007) as premature. They reviewed 50 patients with JMML who were not given HSCT within the first 3 years after diagnosis; of these, 17 survived without treatment from 4 to 21 years. Six of 7 carried a RAS mutation different from R12S. INHERITANCE \- Autosomal dominant \- Somatic mutation HEMATOLOGY \- Juvenile myelomonocytic leukemia MISCELLANEOUS \- One family has been reported with germline CBL mutation (last curated May 2016) MOLECULAR BASIS \- Caused by mutation in the CBL gene (CBL, 165360.0009 ) \- Caused by mutation in the NF1 gene (NF1, 613113.0019 ) \- Caused by somatic mutation in the RHO GTPase-activating protein 26 gene (ARHGAP26, 605370.0001}) \- Caused by somatic mutation in the protein tyrosine phosphatase, nonreceptor-type, 11 gene (PTPN11, 176876.0014}) \- Caused by somatic mutation in the neuroblastoma Ras viral oncogene (NRAS, 164790.0003}) \- Caused by somatic mutation in the Kirsten rat sarcoma-2 viral (v-Ki-ras2) oncogene homolog gene (KRAS, 190070.0003 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	JUVENILE MYELOMONOCYTIC LEUKEMIA	c0349639	5,510	omim	https://www.omim.org/entry/607785	2019-09-22T16:08:44	{"doid": ["0050458"], "mesh": ["D054429"], "omim": ["607785"], "icd-10": ["C93.30", "C93.3", "C93.1", "C93.10"], "orphanet": ["86834"], "synonyms": ["Alternative titles", "LEUKEMIA, JUVENILE MYELOMONOCYTIC"]}
Contact stomatitis Other namesContact lichenoid reaction,[1] lichenoid amalgam reaction,[1] oral mucosal cinnamon reaction[1] Contact stomatitis is characterized by cutaneous lesions that may be located where the offending agent contacts the mucosa for a prolonged time.[1] ## See also[edit] * Contact urticaria * List of cutaneous conditions ## References[edit] 1. ^ a b c d Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Contact stomatitis	c1290773	5,511	wikipedia	https://en.wikipedia.org/wiki/Contact_stomatitis	2021-01-18T18:30:41	{"umls": ["C1290773"], "wikidata": ["Q5164851"]}
An autosomal form of visceral heterotaxy, designated HTX3, has been mapped to chromosome 6q21. Description Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955). Clinical Features Peeters et al. (2001) reported a patient in whom routine ultrasound examination at gestational age 28 weeks had shown atrioventricular septal defect and abdominal situs inversus. Postnatally, the patient was found to have mesocardia, atrioventricular septal defect with monoatrium (large atrial septal defect type I), and left atrial isomerism. The abdominal aorta was on the right side. The inferior vena cava was on the left side. The liver was on the left, the stomach and spleen on the right, and intestinal malrotation was present. Cytogenetics Kato et al. (1996, 1997) described heterotaxy in association with a de novo balanced translocation involving 6q21 and 18q21.3 (or q22). In a patient with heterotaxy, Peeters et al. (2001) described a de novo, apparently balanced reciprocal translocation with breakpoints at 6q21 and 20p13. The breakpoints on 6q21 in both patients were located in the same chromosomal region spanning maximally 2 Mb. Peeters et al. (2001) speculated that the 2 breakpoints led to disruption of the function of a single gene, either directly or through long distance effects. Molecular Genetics ### Associations Pending Confirmation In the patient with heterotaxia and a de novo reciprocal translocation, t(6;18)(q21;q21), reported by Kato et al. (1996), Peeters et al. (2003) found that the PA26 gene (SESN1; 606103) was disrupted by the 6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26 gene in an Epstein-Barr virus-transformed cell line from this patient. Mutation analysis of the PA26 gene in 40 unrelated individuals with unexplained heterotaxia failed to identify mutations, indicating that PA26 mutations are not a frequent cause of heterotaxia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HETEROTAXY, VISCERAL, 3, AUTOSOMAL	c3178805	5,512	omim	https://www.omim.org/entry/606325	2019-09-22T16:10:29	{"doid": ["0050545"], "mesh": ["D059446"], "omim": ["606325"], "orphanet": ["450"]}
A number sign (#) is used with this entry because the form of hydrolethalus syndrome belonging to the Finnish disease heritage, hydrolethalus-1 (HLS1), is caused by homozygous mutation in the HYLS1 gene (610693) on chromosome 11q24. See also HLS2 (614120), caused by mutation in the KIF7 gene (611254) on chromosome 15q26. Clinical Features This lethal syndrome was discovered in Finland in the course of studying the Meckel syndrome (see 249000), which is frequent there (Salonen et al., 1981). Like the Meckel syndrome, this disorder is characterized by polydactyly and central nervous system malformation, but unlike that syndrome, it does not show cystic kidney and liver and the CNS derangement is hydrocephalus not encephalocele. The pregnancy is characterized by hydramnios, which is often massive, and by preterm delivery. The ventricles are open to the subarachnoid space so that the hydrocephalus is external. The foramen magnum is keyhole-shaped. The polydactyly is postaxial in the hands and preaxial in the feet. A highly characteristic hallux duplex is seen in almost no other situation. The feet are clubbed. The mandible is always small and the nose poorly formed; the eyes are hypoplastic. About half the affected have a large atrioventricular communis defect of the heart. Stenosis of the airway and abnormal lobation of the lungs are also found. Prenatal diagnosis by ultrasonography is possible. The grandparents of affected persons come from a thinly populated area of eastern Finland. Salonen et al. (1981) described the syndrome in 28 newborns in 18 Finnish families. Polyhydramnios and stillbirth or neonatal death were the rule. Anyane-Yeboa et al. (1987) described 2 infant brothers with this syndrome. Both showed severe CNS abnormalities, cleft lip/palate, polydactyly, and lung hypoplasia. The parents were related as double first cousins once removed. Aughton and Cassidy (1987) presented a case still living at more than 5 months of age; previously, the longest survival reported had been 2 days. Comparisons with 50 previously reported cases were presented. Macrocephaly with frontal and occipital protuberances, postaxial hexadactyly, and duplicated hallux were illustrated. Bachman et al. (1990) described 2 fetuses with features of holoprosencephaly, hydrocephalus, and postaxial polydactyly, who were born to a consanguineous Mexican-American couple. The features were considered consistent with the hydrolethalus syndrome, although holoprosencephaly had not previously been seen in that condition. Bachman et al. (1990) suggested that cases of 'pseudotrisomy 13,' i.e., trisomy 13 phenotype with normal chromosomes, may be instances of the hydrolethalus syndrome; see 264480. Pryde et al. (1993) described the hydrolethalus syndrome in 2 successive pregnancies in a nonconsanguineous black couple, and discussed the problems in prenatal differential diagnosis. The second fetus showed what they referred to as crossed polydactyly: upper postaxial and lower preaxial (bifid hallux) polydactyly. The fetus had bilateral cleft lip and palate, as well as short, distorted lower limbs and omphalocele. Morava et al. (1996) described a Hungarian infant with macrocephaly, Dandy-Walker malformation (including absence of cerebellar vermis), keyhole foramen magnum with occipitoschisis, and postaxial polydactyly of the left hand and both feet. No visceral abnormalities were found. The authors considered this case to be a variant of hydrolethalus syndrome, although absence of hydrocephaly and preaxial polydactyly of the feet may suggest other diagnoses, e.g., Joubert syndrome (213300). De Ravel et al. (1999) reported a non-Finnish (Portuguese/German/South African) family with hydrolethalus syndrome. The first affected child presented with a milder form of the disorder and survived to 7 months; there were 2 subsequent pregnancies with typical features detected early by ultrasound evaluation. De Ravel et al. (1999) proposed that the 'milder' cases are indeed true cases of the hydrolethalus syndrome and that allelic variability may be responsible for these 'non-typically Finnish' findings. They also demonstrated that, especially in families where there has been a previously affected fetus, echographic diagnosis can be made in the first trimester, as early as the eleventh week of gestation. Shotelersuk et al. (2001) described the first Asian case of hydrolethalus syndrome. The patient lived to 44 days of age, making her the fourth reported case to survive the neonatal period. Population Genetics Salonen and Herva (1990) referred to a total of about 56 cases of the hydrolethalus syndrome in Finland, giving an incidence of at least 1 in 20,000. They found 5 reports of cases from other parts of the world. After identifying the mutation responsible for hydrolethalus syndrome in the Finnish population, Mee et al. (2005) genotyped 908 Finnish control chromosomes and 98 chromosomes of mixed European descent to determine the population frequency of this variant. They found that among chromosomes originating from the late settlement central and eastern Finland, 2.5% (14/556) carried this change, whereas 1.1% (4/352) chromosomes collected from early settlement western Finland carried the change. No carriers were identified in the European sample. Mapping Visapaa et al. (1999) assigned the hydrolethalus syndrome locus to 11q23-q25 in Finnish families. The initial genome scan was performed using DNA samples from only 15 affected individuals. In the next step, the locus was assigned to an 8.5-cM interval between markers D11S4144 and D11S1351 by linkage analysis in 8 families. Finally, the critical locus could be restricted by linkage disequilibrium and haplotype analyses to a 0.5- to 1-cM region between markers D11S933 and D11S934. Genealogic studies performed in 40 families affected by hydrolethalus revealed no regional clustering, suggesting a relatively early introduction of the disease mutation into the Finnish population and the spreading of the mutation with the inhabitation of the late-settlement area. Molecular Genetics Mee et al. (2005) identified the gene carrying the mutation responsible for hydrolethalus syndrome in the Finnish population, HYLS1 (610693). They determined that a D211G mutation (610693.0001) is the common mutation carried in the Finnish population. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation HEAD & NECK Face \- Micrognathia Ears \- Malformed ears \- Low-set ears Eyes \- Microphthalmia Nose \- Bifid nose Mouth \- Cleft palate \- Lateral or midline cleft lip \- Lower lip cleft Neck \- Broad neck CARDIOVASCULAR Heart \- Atrioventricular canal \- Ventricular septal defect RESPIRATORY Larynx \- Hypoplastic larynx Airways \- Tracheal stenosis \- Bronchial stenosis Lung \- Defective lobation \- Pulmonary agenesis CHEST Diaphragm \- Agenesis of diaphragm ABDOMEN External Features \- Omphalocele Spleen \- Accessory spleen Gastrointestinal \- Incomplete bowel rotation GENITOURINARY External Genitalia (Male) \- Hypospadias Internal Genitalia (Female) \- Duplicated uterus \- Vaginal malformation Kidneys \- Hydronephrosis SKELETAL Skull \- Cleft in skull base \- 'Key hole-shaped' deformity of base of skull (occipitoschisis) Limbs \- Short arms \- Proximal tibial hypopolasia Hands \- Postaxial polydactyly Feet \- Preaxial polydactyly \- Club feet \- Hallux duplication NEUROLOGIC Central Nervous System \- Severe prenatal onset hydrocephalus \- Absent corpus callosum \- Absent septum pellucidum \- Absent pituitary \- Arhinencephaly \- Anencephaly \- Cerebral gyral anomalies \- Cerebellar heterotopias \- Dandy-Walker anomaly ENDOCRINE FEATURES \- Dysplastic adrenal glands MISCELLANEOUS \- Polyhydramnios \- Seventy percent of cases are stillborn \- Live born infants die within few hours of birth \- Increased frequency in Finland (prevalence of 1 in 20,000) MOLECULAR BASIS \- Caused by mutation in the HYLS1 gene (HYLS1, 610693.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HYDROLETHALUS SYNDROME 1	c2931104	5,513	omim	https://www.omim.org/entry/236680	2019-09-22T16:27:01	{"doid": ["0111355"], "mesh": ["C536079"], "omim": ["236680"], "orphanet": ["2189"]}
In the families reported by Van Bogaert and Moreau (1939-41), Charcot-Marie-Tooth disease and Friedreich ataxia occurred in the same individuals in a pattern of sex-linked recessive inheritance. Possibly this is a mutation distinct from that responsible for the 2 disorders separately. If the genes for peroneal muscular atrophy and Friedreich ataxia are closely situated on the X chromosome, deletion is another possible explanation for the finding in this family, namely, a 'contiguous gene syndrome' (Schmickel, 1986). In the kindred reported by Biemond (1928), some individuals had Charcot-Marie-Tooth disease (in a pedigree pattern consistent with X-linked inheritance), whereas 2 females of 1 sibship had Friedreich ataxia. In addition, many members of the kindred had congenital deafness (in a pattern consistent with autosomal recessive inheritance). Thus, 3 seemingly independent hereditary traits were observed in the same family. Van Bogaert's family is probably the only one in which the 2 neurologic diseases always occurred together in an X-linked pattern. Skel \- Pes cavus \- Scoliosis \- Hammer toe Limbs \- Foot drop \- Steppage gait \- Pes cavus Neuro \- Neuropathy \- Areflexia \- Ulnar nerve enlargement \- Mild to moderate distal limb sensory loss \- Cerebellar ataxia \- Dysarthria \- Nystagmus \- Incoordined limb movements \- Diminished or absent tendon reflexes \- Babinski sign \- Impaired position sense \- Impaired vibratory sense \- Hypoactive knee and ankle jerks Inheritance \- X-linked \- ? contiguous gene syndrome Metabolic \- Diabetes mellitus \- Diabetic ketosis Cardiac \- Symmetric, concentric, hypertrophic cardiomyopathy \- Congestive heart failure \- Muscular subaortic stenosis Muscle \- Tibialis weakness and atrophy \- Anterior peroneal weakness and atrophy \- Intrinsic hand muscles weakness and atrophy Misc \- Onset before adolescence Lab \- Abnormal motor and sensory nerve conduction \- Abnormal spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum and medulla \- Abnormal EKG \- Abnormal echocardiogram \- Low pyruvate carboxylase activity in liver and cultured fibroblasts \- Mitochondrial malic enzyme reduced ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CHARCOT-MARIE-TOOTH PERONEAL MUSCULAR ATROPHY AND FRIEDREICH ATAXIA, COMBINED	c1844863	5,514	omim	https://www.omim.org/entry/302900	2019-09-22T16:18:34	{"mesh": ["C564446"], "omim": ["302900"]}
A number sign (#) is used with this entry because serum uric acid concentration and susceptibility to gout-4 can be conferred by variation in the SLC17A3 gene (611034) on chromosome 6p21. For a phenotypic description of gout and a discussion of genetic heterogeneity of serum uric acid concentration quantitative trait loci, see UAQTL1 (138900). Mapping By genomewide linkage analysis of 7,699 participants in the Framingham cohort, Dehghan et al. (2008) found a significant association between serum uric acid concentration and rs1165205 in intron 1 of the SLC17A3 gene (611034) on chromosome 6p21 (p 5.6 x 10(-10)). The locus showed linkage disequilibrium extending downstream to include the SLC17A1 (182308) and SLC17A4 (604216) genes. The findings were replicated in 11,024 white individuals in the ARIC cohort, yielding a p value of 8.4 x 10(-11). For white individuals from the Framingham, ARIC, and Rotterdam cohorts, the combined p value was 3.8 x 10(-29), and further analysis showed that the SNP was also associated with the development of gout in white participants (odds ratio of 0.85; p = 2.0 x 10(-3)). SNP rs1165205 did not show significant association with serum uric acid concentration or gout in 3,843 black individuals from the ARIC cohort or 4,148 participants in the Rotterdam cohort. Molecular Genetics In 2 unrelated Japanese men in their sixties with hyperuricemia and gout, respectively, Jutabha et al. (2010) identified 2 different heterozygous missense mutations in the SLC17A3 gene (611034.0001 and 611034.0002). Each mutation caused reduced urate efflux compared to wildtype when expressed in Xenopus oocytes. INHERITANCE \- Autosomal dominant SKELETAL \- Gout LABORATORY ABNORMALITIES \- Hyperuricemia MOLECULAR BASIS \- Caused by mutation in the solute carrier family 17 (sodium phosphate cotransporter), member 3 gene (SLC17A3, 611034.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 4	c2675207	5,515	omim	https://www.omim.org/entry/612671	2019-09-22T16:00:56	{"omim": ["612671"], "synonyms": ["Alternative titles", "GOUT SUSCEPTIBILITY 4"]}
A very rare form of congenital adrenal hyperplasia (CAH) encompassing salt-wasting and non-salt wasting forms with a wide variety of symptoms, including glucocorticoid deficiency and male undervirilization manifesting as a micropenis to severe perineoscrotal hypospadias. ## Epidemiology The prevalence is unknown as it is extremely rare. ## Clinical description Boys present at birth with variable levels of undervirilization. In both sexes, salt wasting forms of CAH lead to symptoms of dehydration and hypotension in the first few weeks of life and can be life threatening. ## Etiology The disease is caused by a mutation in the HSD3B2 gene located on chromosome 1p13.1. ## Genetic counseling The disease follows an autosomal recessive pattern of inheritance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency	c0342471	5,516	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90791	2021-01-23T19:01:02	{"gard": ["9152"], "mesh": ["C579862"], "omim": ["201810"], "icd-10": ["E25.0"], "synonyms": ["CAH due to 3-beta-hydroxysteroid dehydrogenase deficiency"]}
A number sign (#) is used with this entry because of evidence that Meester-Loeys syndrome (MRLS) is caused by mutation in the BGN gene (301870) on chromosome Xq28. Clinical Features Meester et al. (2017) studied 5 families in which affected males had early-onset aortic aneurysm and dissection, with the earliest occurrences at age 1 year and 15 years, respectively. The aneurysms involved the aortic root or more distal ascending aorta in all families. There was mild mitral or aortic insufficiency in some families. Cardiovascular phenotypes of carrier females ranged from unaffected to fatal aortic dissection. Affected individuals exhibited facial dysmorphism, including hypertelorism, proptosis, downslanting palpebral fissures, frontal bossing, and malar hypoplasia. Nonspecific connective tissue features included pectus deformities, joint hypermobility or contractures, and skin striae, as well as features of Loeys-Dietz syndrome (LDS; see 609192) such as bifid uvula and cervical spine instability. Other unusual features not typically seen in LDS or in Marfan syndrome (MFS; 154700) that were inconsistently observed in these patients included ventricular dilation on brain imaging, relative macrocephaly, hypertrichosis, and gingival hypertrophy, as well as evidence of skeletal dysplasia, including hip dislocation, platyspondyly, phalangeal dysplasia, and dysplastic epiphyses of the long bones. Meester et al. (2017) noted that histologic staining of aortic wall tissue from 2 of the probands showed low to normal collagen content and normal-appearing elastin fibers, in contrast to the increase in collagen content and fragmentation of elastic fibers that is typically observed in MFS and LDS. Molecular Genetics Meester et al. (2017) analyzed 368 extracellular matrix-related and TGFB (190180)-related genes in a cohort of 11 probands with molecularly unexplained MFS and identified 2 probands with mutations in the BGN gene (301870.0003 and 301870.0004). By sequencing BGN in 715 probands with thoracic aneurysm (see AAT1, 607086) who were negative for mutation in known AAT-associated genes, they identified 3 more probands with BGN mutations (see, e.g., 301870.0005 and 301870.0006). All of the mutations caused partial or total loss of function and segregated with disease in the 3 families for which DNA of other family members was available. Meester et al. (2017) concluded that BGN gene defects in humans cause a syndromic form of severe thoracic aortic aneurysm and dissection, the clinical features of which overlap with those of LDS and MFS patients. INHERITANCE \- X-linked HEAD & NECK Head \- Relative macrocephaly (in some patients) Face \- Frontal bossing \- Malar hypoplasia Eyes \- Hypertelorism \- Downslanting palpebral fissures \- Proptosis Mouth \- Bifid uvula (in 1 patient) CARDIOVASCULAR Heart \- Mitral valve insufficiency, mild \- Aortic valve insufficiency, mild Vascular \- Aneurysm of aortic root \- Aneurysm of ascending aorta (in some patients) \- Aortic dissection (in some patients) \- Pulmonary artery aneurysm (rare) \- Cerebral aneurysm (rare) CHEST Ribs Sternum Clavicles & Scapulae \- Pectus deformities (in some patients) SKELETAL Skull \- Relative macrocephaly (in some patients) Spine \- Cervical spine instability (rare) Limbs \- Joint hypermobility \- Joint dislocation (in some patients) \- Joint contracture (in some patients) Hands \- Joint hypermobility \- Short spatulate fingers \- Camptodactyly (in some patients) Feet \- Flat feet (in some patients) \- Camptodactyly (in some patients) SKIN, NAILS, & HAIR Skin \- Skin striae (in some patients) NEUROLOGIC Central Nervous System \- Dilated cerebral ventricles (in some patients) MISCELLANEOUS \- Phenotype of carrier females ranges from unaffected to fatal aortic dissection MOLECULAR BASIS \- Caused by mutation in the biglycan gene (BGN, 301870.0003 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MEESTER-LOEYS SYNDROME	c4310811	5,517	omim	https://www.omim.org/entry/300989	2019-09-22T16:19:01	{"omim": ["300989"], "genereviews": ["NBK1120"]}
Hyperparathyroidism Thyroid and parathyroid SpecialtyEndocrinology SymptomsNone, kidney stones, weakness, depression, bone pains, confusion, increased urination[1][2][3] ComplicationsOsteoporosis[2][3] Usual onset50 to 60[2] TypesPrimary, secondary CausesPrimary: parathyroid adenoma, multiple benign tumors, parathyroid cancer[1][2] Secondary: vitamin D deficiency, chronic kidney disease, low blood calcium[1] Diagnostic methodHigh blood calcium and high PTH levels[2] TreatmentMonitoring, surgery, intravenous normal saline, cinacalcet[1][2] Frequency~2 per 1,000[3] Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood.[1][4] This occurs from a disorder either within the parathyroid glands (primary hyperparathyroidism) or outside the parathyroid glands (secondary hyperparathyroidism).[1] Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium leaving the bones and flowing into the blood stream in response to increased production of parathyroid hormone.[1] In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones.[1] Other symptoms may include bone pain, weakness, depression, confusion, and increased urination.[1][2] Both primary and secondary may result in osteoporosis (weakening of the bones).[2][3] In 80% of cases, primary hyperparathyroidism is due to a single benign tumor known as a parathyroid adenoma.[1][2] Most of the remainder are due to several of these adenomas.[1][2] Very rarely it may be due to parathyroid cancer.[2] Secondary hyperparathyroidism typically occurs due to vitamin D deficiency, chronic kidney disease, or other causes of low blood calcium.[1] The diagnosis of primary hyperparathyroidism is made by finding elevated calcium and PTH in the blood.[2] Primary hyperparathyroidism may only be cured by removing the adenoma or overactive parathyroid glands.[5][1][2] In those without symptoms, mildly increased blood calcium levels, normal kidneys, and normal bone density monitoring may be all that is required.[2] The medication cinacalcet may also be used to decrease PTH levels in those unable to have surgery although it is not a cure.[2] In those with very high blood calcium levels, treatment may include large amounts of intravenous normal saline.[1] Low vitamin D should be corrected in those with secondary hyperparathyroidism but low Vitamin D pre-surgery is controversial for those with primary hyperparathyroidism.[6] Low vitamin D levels should be corrected post-parathyroidectomy.[2] Primary hyperparathyroidism is the most common type.[1] In the developed world, between one and four per thousand people are affected.[3] It occurs three times more often in women than men and is often diagnosed between the ages of 50 and 60 but is not uncommon before then.[2] The disease was first described in the 1700s.[7] In the late 1800s, it was determined to be related to the parathyroid.[7] Surgery as a treatment was first carried out in 1925.[7] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Mechanism * 4 Diagnosis * 4.1 Differential diagnosis * 4.2 Blood tests * 4.2.1 Intact PTH * 4.2.2 Calcium levels * 4.2.3 Serum phosphate * 4.2.4 Alkaline phosphatase * 4.3 Nuclear medicine * 4.4 Classification * 4.4.1 Primary * 4.4.2 Secondary * 4.4.3 Tertiary * 5 Treatment * 5.1 Primary * 5.2 Secondary * 5.3 Calcimimetics * 6 History * 7 Notes * 8 References * 9 External links ## Signs and symptoms[edit] In primary hyperparathyroidism, about 75% of people are 'asymptomatic'.[1] While most primary patients are asymptomatic at the time of diagnosis, 'asymptomatic' is poorly defined and represents only those without "obvious clinical sequalae" such as kidney stones, bone disease, or hypercalcemic crisis.[5] These 'asymptomatic' patients may have other symptoms such as depression, anxiety, gastrointestinal distress, and neuromuscular problems that are not counted as symptoms.[5] The problem is often picked up incidentally during blood work for other reasons, and the test results show a higher amount of calcium in the blood than normal.[3] Many other people only have non-specific symptoms. Common manifestations of hypercalcemia include weakness and fatigue, depression, bone pain, muscle soreness (myalgias), decreased appetite, feelings of nausea and vomiting, constipation, pancreatitis, polyuria, polydipsia, cognitive impairment, kidney stones ([nb 1]) and osteopenia or osteoporosis.[10] A history of acquired racquet nails (brachyonychia) may be indicative of bone resorption.[11] Parathyroid adenomas are very rarely detectable on clinical examination. Surgical removal of a parathyroid tumor eliminates the symptoms in most patients. In secondary hyperparathyroidism due to lack of Vitamin D absorption, the parathyroid gland is behaving normally; clinical problems are due to bone resorption and manifest as bone syndromes such as rickets, osteomalacia, and renal osteodystrophy.[12] ## Causes[edit] Radiation exposure increases the risk of primary hyperparathyroidism.[1] A number of genetic conditions including multiple endocrine neoplasia syndromes also increase the risk.[1] ## Mechanism[edit] Normal parathyroid glands measure the ionized calcium (Ca2+) concentration in the blood and secrete parathyroid hormone accordingly; if the ionized calcium rises above normal, the secretion of PTH is decreased, whereas when the Ca2+ level falls, parathyroid hormone secretion is increased.[8] Secondary hyperparathyroidism occurs if the calcium level is abnormally low. The normal glands respond by secreting parathyroid hormone at a persistently high rate. This typically occurs when the 1,25 dihydroxyvitamin D3 levels in the blood are low and hypocalcemia is present. A lack of 1,25 dihydroxyvitamin D3 can result from a deficient dietary intake of vitamin D, or from a lack of exposure of the skin to sunlight, so the body cannot make its own vitamin D from cholesterol.[13] The resulting hypovitaminosis D is usually due to a partial combination of both factors. Vitamin D3 (or cholecalciferol) is converted to 25-hydroxyvitamin D (or calcidiol) by the liver, from where it is transported via the circulation to the kidneys, and it is converted into the active hormone, 1,25 dihydroxyvitamin D3.[8][13] Thus, a third cause of secondary hyperparathyroidism is chronic kidney disease. Here the ability to manufacture 1,25 dihydroxyvitamin D3 is compromised, resulting in hypocalcemia.[citation needed] ## Diagnosis[edit] Calcification in the brain due to hyperparathyroidism Pepper & Salt, classical X-Ray appearance of hyperparathyroidisim The gold standard of diagnosis is the PTH immunoassay. Once an elevated PTH has been confirmed, the goal of diagnosis is to determine whether the hyperparathyroidism is primary or secondary in origin by obtaining a serum calcium level: Serum calcium Phosphate ALP PTH Likely type ↑ ↓ ↑ ↑ Primary hyperparathyroidism[14] ↓ ↑ ↑ ↑ Secondary hyperparathyroidism[14] Tertiary hyperparathyroidism has a high PTH and a high serum calcium. It is differentiated from primary hyperparathyroidism by a history of chronic kidney failure and secondary hyperparathyroidism.[citation needed] Hyperparathyroidism can cause hyperchloremia and increase renal bicarbonate loss, which may result in a normal anion gap metabolic acidosis.[7] ### Differential diagnosis[edit] Familial benign hypocalciuric hypercalcaemia can present with similar lab changes.[1] In this condition, the calcium creatinine clearance ratio, however, is typically under 0.01.[1] ### Blood tests[edit] #### Intact PTH[edit] In primary hyperparathyroidism, parathyroid hormone (PTH) levels are either elevated or "inappropriately normal" in the presence of elevated calcium. Typically, PTH levels vary greatly over time in the affected patient and (as with Ca and Ca++ levels) must be retested several times to see the pattern. The currently accepted test for PTH is intact PTH, which detects only relatively intact and biologically active PTH molecules. Older tests often detected other, inactive fragments. Even intact PTH may be inaccurate in patients with kidney dysfunction.[citation needed] Intact pth blood tests may be falsely low if biotin has been ingested in the previous few days prior to the blood test.[15] #### Calcium levels[edit] In cases of primary hyperparathyroidism or tertiary hyperparathyroidism, heightened PTH leads to increased serum calcium (hypercalcemia) due to: 1. increased bone resorption, allowing flow of calcium from bone to blood 2. reduced kidney clearance of calcium 3. increased intestinal calcium absorption #### Serum phosphate[edit] In primary hyperparathyroidism, serum phosphate levels are abnormally low as a result of decreased reabsorption of phosphate in the kidney tubules. However, this is only present in about 50% of cases. This contrasts with secondary hyperparathyroidism, in which serum phosphate levels are generally elevated because of kidney disease.[citation needed] #### Alkaline phosphatase[edit] Alkaline phosphatase levels are usually elevated in hyperparathyroidism. In primary hyperparathyroidism, levels may remain within the normal range, but this is inappropriately normal given the increased levels of plasma calcium.[citation needed] ### Nuclear medicine[edit] Main article: Sestamibi parathyroid scintigraphy A technetium sestamibi scan is a procedure in nuclear medicine that identifies hyperparathyroidism (or parathyroid adenoma).[16] It is used by surgeons to locate ectopic parathyroid adenomas, most commonly found in the anterior mediastinum.[citation needed] ### Classification[edit] #### Primary[edit] Parathyroid adenoma. Primary hyperparathyroidism results from a hyperfunction of the parathyroid glands themselves. The oversecretion of PTH is due to a parathyroid adenoma, parathyroid hyperplasia, or rarely, a parathyroid carcinoma. This disease is often characterized by the quartet stones, bones, groans, and psychiatric overtones referring to the presence of kidney stones, hypercalcemia, constipation, and peptic ulcers, as well as depression, respectively.[17][18] In a minority of cases, this occurs as part of a multiple endocrine neoplasia (MEN) syndrome, either type 1 (caused by a mutation in the gene MEN1) or type 2a (caused by a mutation in the gene RET), which is also associated with the adrenal tumor pheochromcytoma. Other mutations that have been linked to parathyroid neoplasia include mutations in the genes HRPT2 and CASR.[19][20] Patients with bipolar disorder who are receiving long-term lithium treatment are at increased risk for hyperparathyroidism.[21] Elevated calcium levels are found in 15% to 20% of patients who have been taking lithium long-term. However, only a few of these patients have significantly elevated levels of parathyroid hormone and clinical symptoms of hyperparathyroidism. Lithium-associated hyperparathyroidism is usually caused by a single parathyroid adenoma.[21] #### Secondary[edit] Secondary hyperparathyroidism is due to physiological (i.e. appropriate) secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels). The most common causes are vitamin D deficiency[22] (caused by lack of sunlight, diet or malabsorption) and chronic kidney failure. Lack of vitamin D leads to reduced calcium absorption by the intestine leading to hypocalcemia and increased parathyroid hormone secretion. This increases bone resorption. In chronic kidney failure the problem is more specifically failure to convert vitamin D to its active form in the kidney. The bone disease in secondary hyperparathyroidism caused by kidney failure is termed renal osteodystrophy.[citation needed] #### Tertiary[edit] Tertiary hyperparathyroidism is seen in those with long-term secondary hyperparathyroidism, which eventually leads to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. This disorder is most often seen in patients with end-stage kidney disease and is an autonomous activity.[citation needed] ## Treatment[edit] Treatment depends on the type of hyperparathyroidism encountered. ### Primary[edit] People with primary hyperparathyroidism who are symptomatic benefit from parathyroidectomy—surgery to remove the parathyroid tumor (parathyroid adenoma). Indications for surgery are:[23] * Symptomatic hyperparathyroidism * Asymptomatic hyperparathyroidism with any of the following: * 24-hour urinary calcium > 400 mg (see footnote, below) * serum calcium > 1 mg/dl above upper limit of normal * Creatinine clearance > 30% below normal for patient's age * Bone density > 2.5 standard deviations below peak (i.e., T-score of -2.5) * People age < 50 Surgery can rarely result in hypoparathyroidism. ### Secondary[edit] In people with secondary hyperparathyroidism, the high PTH levels are an appropriate response to low calcium and treatment must be directed at the underlying cause of this (usually vitamin D deficiency or chronic kidney failure). If this is successful, PTH levels return to normal levels, unless PTH secretion has become autonomous (tertiary hyperparathyroidism).[citation needed] ### Calcimimetics[edit] A calcimimetic (such as cinacalcet) is a potential therapy for some people with severe hypercalcemia and primary hyperparathyroidism who are unable to undergo parathyroidectomy, and for secondary hyperparathyroidism on dialysis.[24][25]Treatment of secondary hyperparathyroidism with a calcimimetic in those on dialysis for CKD does not alter the risk of early death; however, it does decrease the likelihood of needing a parathyroidectomy.[26] Treatment carries the risk of low blood calcium levels and vomiting.[26] ## History[edit] The oldest known case was found in a cadaver from an Early Neolithic cemetery in southwest Germany.[27] ## Notes[edit] 1. ^ Although parathyroid hormone (PTH) promotes the reabsorption of calcium from the kidneys' tubular fluid, thus decreasing the rate of urinary calcium excretion, its effect is only noticeable at any given plasma ionized calcium concentration. The primary determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration. Thus, in primary hyperparathyroidism, the quantity of calcium excreted in the urine per day is increased despite the high levels of PTH in the blood, because hyperparathyroidism results in hypercalcemia, which increases the urinary calcium concentration (hypercalcuria). Kidney stones are, therefore, often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together, the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid “stones”.[8][9] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t Fraser WD (July 2009). "Hyperparathyroidism". Lancet. 374 (9684): 145–58. doi:10.1016/S0140-6736(09)60507-9. PMID 19595349. S2CID 208793932. 2. ^ a b c d e f g h i j k l m n o p q "Primary Hyperparathyroidism". NIDDK. August 2012. Archived from the original on 4 October 2016. Retrieved 27 September 2016. 3. ^ a b c d e f Michels TC, Kelly KM (August 2013). "Parathyroid disorders". American Family Physician. 88 (4): 249–57. PMID 23944728. 4. ^ Allerheiligen DA, Schoeber J, Houston RE, Mohl VK, Wildman KM (April 1998). "Hyperparathyroidism". American Family Physician. 57 (8): 1795–802, 1807–8. PMID 9575320. 5. ^ a b c McDow AD, Sippel RS (2018-01-01). "Should Symptoms Be Considered an Indication for Parathyroidectomy in Primary Hyperparathyroidism?". Clinical Medicine Insights. Endocrinology and Diabetes. 11: 1179551418785135. doi:10.1177/1179551418785135. PMC 6043916. PMID 30013413. 6. ^ Randle RW, Balentine CJ, Wendt E, Schneider DF, Chen H, Sippel RS (July 2016). "Should vitamin D deficiency be corrected before parathyroidectomy?". The Journal of Surgical Research. 204 (1): 94–100. doi:10.1016/j.jss.2016.04.022. PMID 27451873. 7. ^ a b c d Gasparri G, Camandona M, Palestini N (2015). Primary, Secondary and Tertiary Hyperparathyroidism: Diagnostic and Therapeutic Updates. Springer. ISBN 9788847057586. Archived from the original on 2017-09-08. 8. ^ a b c Blaine J, Chonchol M, Levi M (July 2015). "Renal control of calcium, phosphate, and magnesium homeostasis". Clinical Journal of the American Society of Nephrology. 10 (7): 1257–72. doi:10.2215/CJN.09750913. PMC 4491294. PMID 25287933. 9. ^ Harrison TR, Adams RD, Bennett Jr IL, Resnick WH, Thorn GW, Wintrobe MM (1958). "Metabolic and Endocrine Disorders.". Principles of Internal Medicine (Third ed.). New York: McGraw-Hill Book Company. pp. 575–578. 10. ^ Hyperparathyroidism Archived 2011-05-24 at the Wayback Machine. National Endocrine and Metabolic Diseases Information Service. May 2006. 11. ^ Baran R, Turkmani MG, Mubki T (February 2014). "Acquired racquet nails: a useful sign of hyperparathyroidism". Journal of the European Academy of Dermatology and Venereology. 28 (2): 257–9. doi:10.1111/jdv.12187. PMID 23682576. 12. ^ "Secondary Hyperparathyroidism: What is Secondary Hyperparathyroidism? Secondary Hyperparathyroidism Symptoms, Treatment, Diagnosis - UCLA". www.uclahealth.org. Retrieved 2021-01-18. 13. ^ a b Stryer L (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. p. 707. ISBN 0-7167-2009-4. 14. ^ a b Le T, Bhushan V, Sochat M, Kallianos K, Chavda Y, Zureick AH, Kalani M (2017). First aid for the USMLE step 1 2017. New York: Mcgraw-Hill Education. ISBN 978-1259837630. 15. ^ Waghray A, Milas M, Nyalakonda K, Siperstein AE (2013). "Falsely low parathyroid hormone secondary to biotin interference: a case series". Endocrine Practice. 19 (3): 451–5. doi:10.4158/EP12158.OR. PMID 23337137. 16. ^ Neish AS, Nagel JS, Holman BL. "Parathyroid Adenoma". BrighamRAD Teaching Case Database. Archived from the original on 2011-07-16. 17. ^ Carroll MF, Schade DS (May 2003). "A practical approach to hypercalcemia". American Family Physician. 67 (9): 1959–66. PMID 12751658. Archived from the original on 21 August 2014. "his constellation of symptoms has led to the mnemonic “Stones, bones, abdominal moans, and psychic groans,” which is used to recall the signs and symptoms of hypercalcemia, particularly as a result of primary hyperparathyroidism." 18. ^ McConnell, Thomas H. (2007). The Nature of Disease: Pathology for the Health Professions. Lippincott Williams & Wilkins. p. 466. ISBN 9780781753173. ""Stones" refers to kidney stones, "bones" to associated destructive bone changes, "groans" to the pain of stomach and peptic ulcers that occur in some cases, and "moans" to the depression that frequently accompanies the disease and is often its first and most prominent manifestation." 19. ^ Marx SJ (2011). "Hyperparathyroid genes: sequences reveal answers and questions". Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 17 Suppl 3: 18–27. doi:10.4158/EP11067.RA. PMC 3484688. PMID 21454225. 20. ^ Sulaiman L, Nilsson IL, Juhlin CC, Haglund F, Höög A, Larsson C, Hashemi J (June 2012). "Genetic characterization of large parathyroid adenomas". Endocrine-Related Cancer. 19 (3): 389–407. doi:10.1530/ERC-11-0140. PMC 3359501. PMID 22454399. 21. ^ a b Pomerantz JM (2010). "Hyperparathyroidism Resulting From Lithium Treatment Remains Underrecognized". Drug Benefit Trends. 22: 62–63. Archived from the original on 2010-07-01. 22. ^ Lips P (August 2001). "Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications". Endocrine Reviews. 22 (4): 477–501. doi:10.1210/er.22.4.477. PMID 11493580. 23. ^ Bilezikian JP, Silverberg SJ (April 2004). "Clinical practice. Asymptomatic primary hyperparathyroidism". The New England Journal of Medicine. 350 (17): 1746–51. doi:10.1056/NEJMcp032200. PMID 15103001. 24. ^ "Archived copy" (PDF). Archived (PDF) from the original on 2014-10-05. Retrieved 2014-10-29.CS1 maint: archived copy as title (link) 25. ^ Ott SM (April 1998). "Calcimimetics--new drugs with the potential to control hyperparathyroidism". The Journal of Clinical Endocrinology and Metabolism. 83 (4): 1080–2. doi:10.1210/jc.83.4.1080. PMID 9543121. 26. ^ a b Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GF (9 December 2014). "Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients". The Cochrane Database of Systematic Reviews. 12 (12): CD006254. doi:10.1002/14651858.CD006254.pub2. PMID 25490118. 27. ^ Zink AR, Panzer S, Fesq-Martin M, Burger-Heinrich E, Wahl J, Nerlich AG (January 2005). "Evidence for a 7000-year-old case of primary hyperparathyroidism". Jama. 293 (1): 40–2. doi:10.1001/jama.293.1.40-c. PMID 15632333. ## External links[edit] * Hyperparathyroidism at Curlie * Overview at Endocrine and Metabolic Diseases Information Service * Insogna KL (September 2018). "Primary Hyperparathyroidism". The New England Journal of Medicine (Review). 379 (11): 1050–1059. CiteSeerX 10.1.1.322.5883. doi:10.1056/NEJMcp1714213. PMID 30207907. S2CID 205069527. Classification D * ICD-10: E21 * ICD-9-CM: 252.0 * MeSH: D006961 * DiseasesDB: 20710 External resources * MedlinePlus: 001215 * eMedicine: emerg/265 med/3200 * Patient UK: Hyperparathyroidism * v * t * e Parathyroid disease Hypoparathyroidism * Pseudohypoparathyroidism * Pseudopseudohypoparathyroidism Hyperparathyroidism * Primary * Secondary * Tertiary * Osteitis fibrosa cystica Other * Parathyroiditis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hyperparathyroidism	c0020502	5,518	wikipedia	https://en.wikipedia.org/wiki/Hyperparathyroidism	2021-01-18T18:32:24	{"mesh": ["D006961"], "umls": ["C0020502"], "orphanet": ["99879", "181408"], "wikidata": ["Q1344835"]}
An X-linked syndromic intellectual disability characterised by severe intellectual disability, microcephaly and short stature in male patients. Strabismus and spastic diplegia have also 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	X-linked intellectual disability, Shrimpton type	c2678039	5,519	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85324	2021-01-23T17:06:15	{"mesh": ["C567474"], "omim": ["300709"], "icd-10": ["Q87.8"], "synonyms": ["MRXS9"]}
This article is about degeneration of the endometrium in horses. For degeneration of the endometrium in humans, see endometriosis. Endometrosis is a chronic degenerative syndrome of the lining of the uterus (the endometrium) in mares.[1] The cause is unknown, but the severity of endometrosis increases in parallel with the age and number of pregnancies of the mare.[2] Endometrosis is confirmed by histological examination of an endometrial biopsy, which shows degeneration of blood vessels in the endometrium, and fibrosis of the tissue, along with the development of endometrial cysts.[2] These changes cause subfertility;[1] in pregnant mares, the changes in the endometrium can cause the placenta to fail, leading to miscarriage of the foal.[2] Foals which are delivered at full term may be underdeveloped (dysmature).[3] No effective treatment is known.[3] The etymology of endometrosis is from the Greek endos (inside), metra (womb) and -osis (disease).[1] This term was adopted in 1992;[4] prior to that, endometrosis was variously known as chronic degenerative endometritis, endometrial fibrosis, or chronic endometrial disease.[4] ## References[edit] 1. ^ a b c Hanada, M; Maeda, Y; Oikawa, MA (2014). "Histopathological characteristics of endometrosis in thoroughbred mares in Japan: results from 50 necropsy cases". Journal of Equine Science. 25 (2): 45–52. doi:10.1294/jes.25.45. PMC 4090358. PMID 25013358. 2. ^ a b c Sprayberry, Kim A (2009). "Chapter 20: Fetal monitoring in broodmares". In Samper, JC (ed.). Equine breeding management and artificial insemination (2nd ed.). St. Louis, Missouri: Saunders/Elsevier. pp. 241–248. ISBN 9781416052340. 3. ^ a b Munroe, G; Campbell, M; Munroe, Z; Hanks, M (2011). "Chapter 2.1: Female reproductive tract. Chronic degenerative endometrosis". In Munroe, GA; Weese, J. Scott (eds.). Equine clinical medicine, surgery, and reproduction. London: Manson Publishing/The Veterinary Press. p. 318. ISBN 9781840766080. 4. ^ a b Flores, JM; Rodríguez, A; Sánchez, J; Gómez-Cuétara, C; Ramiro, F (April 1995). "Endometrosis in Mares: Incidence of Histopathological Alterations". Reproduction in Domestic Animals. 30 (2): 61–65. doi:10.1111/j.1439-0531.1995.tb00606.x. This veterinary medicine–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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Endometrosis	None	5,520	wikipedia	https://en.wikipedia.org/wiki/Endometrosis	2021-01-18T18:55:59	{"wikidata": ["Q1340734"]}
Hypoalphalipoproteinemia Hypoalphalipoproteinemia has an autosomal dominant pattern of inheritance. SpecialtyEndocrinology Hypoalphalipoproteinemia is a high-density lipoprotein deficiency, inherited in an autosomal dominant manner.[1] It can be associated with LDL receptor.[2] Associated regions and genes include: Name OMIM Locus Candidates HDLCQ1 606613 9p ABCA1 (Tangier disease)[3] HDLCQ2 607053 8q23 HDLCQ3 607687 16q24.1 Lecithin cholesterol acyltransferase deficiency (LCAT) HDLCQ4 610239 4q32 HDLD3 605201 11q23.3 APOA1 Niacin is sometimes prescribed to raise HDL levels. ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 604091 2. ^ Pisciotta L, Calabresi L, Lupattelli G, et al. (September 2005). "Combined monogenic hypercholesterolemia and hypoalphalipoproteinemia caused by mutations in LDL-R and LCAT genes". Atherosclerosis. 182 (1): 153–9. doi:10.1016/j.atherosclerosis.2005.01.048. PMID 16115486. 3. ^ Soro-Paavonen A, Naukkarinen J, Lee-Rueckert M, et al. (June 2007). "Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL". J. Lipid Res. 48 (6): 1409–16. doi:10.1194/jlr.P600012-JLR200. PMID 17372331. ## External links[edit] Classification D * ICD-10: E78.6 * ICD-9-CM: 272.5 * OMIM: 604091 * MeSH: D052456 External resources * eMedicine: med/3368 * v * t * e Inborn error of lipid metabolism: dyslipidemia Hyperlipidemia * Hypercholesterolemia/Hypertriglyceridemia * Lipoprotein lipase deficiency/Type Ia * Familial apoprotein CII deficiency/Type Ib * Familial hypercholesterolemia/Type IIa * Combined hyperlipidemia/Type IIb * Familial dysbetalipoproteinemia/Type III * Familial hypertriglyceridemia/Type IV * Xanthoma/Xanthomatosis Hypolipoproteinemia Hypoalphalipoproteinemia/HDL * Lecithin cholesterol acyltransferase deficiency * Tangier disease Hypobetalipoproteinemia/LDL * Abetalipoproteinemia * Apolipoprotein B deficiency * Chylomicron retention disease Lipodystrophy * Barraquer–Simons syndrome Other * Lipomatosis * Adiposis dolorosa * Lipoid proteinosis * APOA1 familial renal amyloidosis This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hypoalphalipoproteinemia	c0473527	5,521	wikipedia	https://en.wikipedia.org/wiki/Hypoalphalipoproteinemia	2021-01-18T18:30:54	{"mesh": ["D052456"], "umls": ["C0473527"], "icd-9": ["272.5"], "icd-10": ["E78.6"], "orphanet": ["31153"], "wikidata": ["Q5959167"]}
Brown et al. (1963) described a hemorrhagic diathesis apparently due to the presence of an antithrombin as the primary defect. The disorder occurred in a Mohawk Indian kindred. Recessive inheritance is not completely certain. See 107300 for a discussion of antithrombin III deficiency. Inheritance \- ? Autosomal recessive.(See 107300) Heme \- Antithrombin \- Hemorrhage ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ANTITHROMBIN, FAMILIAL HEMORRHAGIC DIATHESIS DUE TO	c1859761	5,522	omim	https://www.omim.org/entry/207300	2019-09-22T16:30:56	{"mesh": ["C565947"], "omim": ["207300"]}
A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency mitochondrial type 1 (MC1DM1) is caused by mutation in the MTND3 gene (516002). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010. Clinical Features Taylor et al. (2001) reported a 42-year-old man who had onset of migraine symptoms associated with flashing lights in his vision and right arm weakness at age 24 years. He subsequently developed myoclonus, seizures, cognitive decline, ataxia, peripheral neuropathy, eye movement abnormalities, and optic atrophy. Muscle biopsy showed a deficit (40% of controls) in complex I activity, but no ragged-red fibers. McFarland et al. (2004) reported a patient with infantile encephalopathy and complex I deficiency. From birth, he was lethargic with hypotonia, areflexia, and muscle atrophy. Micrognathia and talipes equinovarus were noted. Molecular Genetics In a patient with mitochondrial complex I deficiency, Taylor et al. (2001) identified a heteroplasmic 10191T-C transition in the MTND3 gene (516002.0001) in skeletal muscle (77%) and blood (14%), as well as in his mother (3% in blood) and 2 unaffected sibs (barely detectable in blood). McFarland et al. (2004) identified a mutation in the MTND3 gene (516002.0001) in a patient with infantile encephalopathy and complex I deficiency. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 1	None	5,523	omim	https://www.omim.org/entry/500014	2019-09-22T16:16:58	{"omim": ["500014"]}
A number sign (#) is used with this entry because Northern epilepsy, also known as progressive epilepsy with mental retardation (EPMR), is caused by a Finnish founder mutation in the CLN8 gene (607837.0001). Northern epilepsy is a form of neuronal ceroid lipofuscinosis (NCL, CLN) and is a variant of CLN8 (600143). Description The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN8 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles (Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). Clinical Features Hirvasniemi et al. (1994) presented genealogic and phenotypic features of a recessively inherited form of childhood epilepsy occurring in the population of northern Finland, referred to as 'Northern epilepsy.' With 1 exception, both parents of all 11 sibships with affected individuals descended from 1 or 2 founding couples. The patients were normal at birth and developed normally until school age. Age at onset ranged from 5 to 10 years (mean, 6.7 years) with generalized tonic-clonic seizures. The seizures increased in frequency reaching a maximum of approximately 1 or 2 seizures per week by puberty. After puberty, the frequency of seizures began to decline unrelated to changes in medication. In early adulthood, seizure frequency was between 6 and 25 attacks per year, and after 35 years of age many patients were virtually seizure-free. EEG showed focal and nonfocal paroxysmal seizures. Mental development, which was originally normal, began to deteriorate 2 to 5 years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. Haltia et al. (1999) and Herva et al. (2000) recognized Northern epilepsy as a subtype of neuronal ceroid lipofuscinosis. Herva et al. (2000) reported neuropathologic findings of 3 patients with Northern epilepsy. There was intraneuronal accumulation of cytoplasmic autofluorescent granules that were immunoreactive to subunit C of mitochondrial ATP synthase. Membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. The findings confirmed Northern epilepsy as a form of CLN with an exceptionally protracted course. Ranta et al. (2004) noted that although Northern epilepsy is allelic to CLN8, the clinical phenotype is distinct. Northern epilepsy presents between 5 and 10 years of age with frequent tonic-clonic seizures followed by progressive mental retardation. Visual loss is not a prominent feature of Northern epilepsy, there is no myoclonus, and the clinical progression is slower. Mapping Tahvanainen et al. (1994) assigned the locus for Northern epilepsy to the telomeric region of 8p by linkage. Analyses of recombinations placed the locus in a 7-cM interval between 2 markers. Haplotypes comprising alleles at 5 loci in this interval supported the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who had a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. One of the markers that was closely linked to EPMR was the most distal Genethon marker on 8p known at that time. In general, the linked markers were known to be in the 8pter-p22 region. Ranta et al. (1996) reported that a recombination detected with a new microsatellite marker narrowed the EPMR critical region to 4 cM. They constructed a YAC contig containing 22 YACs across the disease gene region. They characterized the YAC contig by a collection of 19 YAC-end sequence-tagged sites together with 7 microsatellite markers. The entire YAC contig spanned a minimum of 3 Mb. Molecular Genetics In 22 Finnish patients with Northern epilepsy, Ranta et al. (1999) identified homozygosity for an arg24-to-gly mutation in the CLN8 gene (R24G; 607837.0001). The carrier frequency was 1 in 135, compatible with a founder effect. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Seizures, onset age 5 to 10 years \- Generalized tonic-clonic seizures \- Complex partial seizures \- EEG abnormalities \- Mental deterioration beginning 2 to 5 years after onset of seizures \- Mental retardation by age 30 years \- Clumsiness \- Difficulties with equilibrium \- Cerebral atrophy, progressive \- Cerebellar atrophy, progressive \- Autofluorescent lipopigment in neurons Behavioral Psychiatric Manifestations \- Irritability beginning at puberty \- Inattentiveness \- Restlessness LABORATORY ABNORMALITIES \- Intracellular curvilinear profiles on ultrastructural analysis \- Intracellular granular material on ultrastructural analysis MISCELLANEOUS \- Onset age 5 to 10 years \- Decrease in seizure frequency in middle age \- Slowly progressive \- Protracted disease course \- Allelic disorder to CLN8 ( 600143 ) \- All known cases are caused by a Finnish founder mutation in the CLN8 gene ( 607837.0001 ) MOLECULAR BASIS \- Caused by mutation in the CLN8 gene (CLN8, 607837.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CEROID LIPOFUSCINOSIS, NEURONAL, 8, NORTHERN EPILEPSY VARIANT	c1864923	5,524	omim	https://www.omim.org/entry/610003	2019-09-22T16:05:16	{"doid": ["0110724"], "mesh": ["C537952"], "omim": ["610003"], "orphanet": ["1947"], "synonyms": ["Alternative titles", "NORTHERN EPILEPSY", "EPILEPSY, PROGRESSIVE, WITH MENTAL RETARDATION"]}
Congenital analbuminemia (CAA) is characterized by the absence or dramatic reduction of circulating human serum albumin (HSA). ## Epidemiology Prevalence has been estimated at approximately 1 case per million population, with less than 50 cases being reported in the literature so far. The disorder occurs with no geographic, sex or ethnic predilection. ## Clinical description In the majority of cases, CAA is diagnosed in adulthood. Although albumin is the most abundant plasma protein and has many functions, patients with CAA present with only a few mild clinical signs and biochemical abnormalities: fatigue, low blood pressure, edema, increased concentration of several plasma proteins and a prolonged albumin half-life. HSA is either absent or present at very low levels (<1 g/L) but liver function is normal and there is an absence of conditions leading to significant protein loss. The mildness of the clinical manifestations is attributed to the compensatory increase in hepatic biosynthesis of other plasma proteins, notably a compensatory increase in serum globulin concentrations. However, CAA patients may develop lipodystrophy and hypercholesterolemia, possibly leading to premature atherosclerosis and cardiovascular events. Rarely, CAA may be complicated by hypercoagulability, osteoporosis and respiratory tract infections. The disorder appears to be more severe in the fetus or during early infancy, as intrauterine growth retardation and intrauterine death have been reported. ## Etiology The disorder is caused by homozygous or compound heterozygous mutations in the gene coding for HSA (ALB; 4q13.3). More than ten different causative mutations have been identified to date. The Kayseri mutation (a homozygous AT deletion at nucleotides c.228-229, the 91st and 92nd bases of exon 3) appears to be the most common cause of analbuminemia in humans. ## Diagnostic methods Diagnosis is based on laboratory analysis of blood specimens (albumin immunoassays and serum protein electrophoresis). DNA analysis is required for identification of the mutation involved. ## Differential diagnosis The differential diagnosis should include a wide number of pathological conditions that present with reduction of HSA (glomerulonephritis, nephrosis, ascites, systemic lupus erythematosus, intestinal lymphangiectasia, and protein-losing enteropathies; see these terms). ## Genetic counseling CAA is transmitted as an autosomal recessive trait and consanguinity has been shown in all reported cases with available genealogic data. ## Management and treatment CAA is a relatively benign and tolerable condition. Management aims at prophylaxis and treatment of the possible cardiovascular complications related to hypercholesterolemia and atherosclerosis. Drugs that bind to the albumin plasma protein fraction should be used with caution in patients with CAA. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Congenital analbuminemia	c0878666	5,525	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86816	2021-01-23T17:11:20	{"omim": ["616000"], "icd-10": ["R77.0"]}
Intrauterine hypoxia Micrograph of a placental infarct (left of image), a cause of intrauterine hypoxia. H&E stain. SpecialtyPediatrics Intrauterine hypoxia (also known as fetal hypoxia) occurs when the fetus is deprived of an adequate supply of oxygen. It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord, placental infarction and maternal smoking. Intrauterine growth restriction may cause or be the result of hypoxia. Intrauterine hypoxia can cause cellular damage that occurs within the central nervous system (the brain and spinal cord). This results in an increased mortality rate, including an increased risk of sudden infant death syndrome (SIDS). Oxygen deprivation in the fetus and neonate have been implicated as either a primary or as a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy, attention deficit hyperactivity disorder, eating disorders and cerebral palsy.[1][2][3][4][5][6] ## Contents * 1 Cause * 2 Maternal Consequences * 3 Treatment * 4 Prevention * 5 Epidemiology * 6 Society * 6.1 Medicolegal * 7 References * 8 External links ## Cause[edit] Intrauterine hypoxia can be attributed to maternal, placental, or fetal conditions.[7] Kingdom and Kaufmann classifies three categories for the origin of fetal hypoxia: 1) pre-placental (both mother and fetus are hypoxic), 2) utero-placental (mother is normal but placenta and fetus is hypoxic), 3) post-placental (only fetus is hypoxic).[8] Pre-placental hypoxia is most commonly caused by external hypoxic environments (such as high altitude). It can also be caused by maternal respiratory conditions (such as asthma), cardiovascular conditions (such as heart failure, pulmonary hypertension, and cyanotic heart disease), and hematological conditions (such as anemia).[9] Conditions such as obesity, nutritional deficiencies, infections, chronic inflammations, and stress can also affect the maternal oxygen supply and fetal uptake.[7] The most preventable cause is maternal smoking. Cigarette smoking by expectant mothers has been shown to have a wide variety of deleterious effects on the developing fetus.[10] Among the negative effects are carbon monoxide induced tissue hypoxia and placental insufficiency which causes a reduction in blood flow from the uterus to the placenta thereby reducing the availability of oxygenated blood to the fetus. Placental insufficiency as a result of smoking has been shown to have a causal effect in the development of pre-eclampsia. While some previous studies have suggested that carbon monoxide from cigarette smoke may have a protective effect against preeclampsia, a recent study conducted by the Genetics of Pre-Eclampsia Consortium in the United Kingdom found that smokers were five times more likely to develop pre-eclampsia.[11] Nicotine alone has been shown to be a teratogen which affects the autonomic nervous system, leading to increased susceptibility to hypoxia-induced brain damage.[11][12][13][14][15][16] Maternal anemia in which smoking has also been implicated is another factor associated with IH/BA.[clarification needed] Smoking by expectant mothers causes a decrease in maternal nucleated red blood cells, thereby reducing the amount of red blood cells available for oxygen transport.[17][18][19] Utero-placental hypoxia is associated with abnormal placental implantation, impaired vascular remodeling and vascular diseases.[9] It is also associated with pregnancies complicated by gestational hypertension, intrauterine growth restriction, and pre-eclampsia.[citation needed] Post-placental hypoxia is associated with mechanical obstructions of the umbilical cords, reduced uterine artery flow, progressive fetal cardiac failure, and genetic anomalies.[7][9] The perinatal brain injury occurring as a result of birth asphyxia, manifesting within 48 hours of birth, is a form of hypoxic ischemic encephalopathy.[citation needed] ## Maternal Consequences[edit] Complications arising from intrauterine hypoxia are some of the leading causes of preeclampsia. [20] Preeclampsia is a hypertensive disorder that occurs during the second trimester (after the 20th week of pregnancy) resulting from a poorly perfused placenta.[21] Studies from the World Health Organization show that globally, about 14% (50,000- 750000 women) of maternal deaths annually are caused by preeclampsia and eclampsia.[22] During pregnancy, women with preeclampsia faces serious risk of damage to vital organs such as the kidneys, liver, brain, and the blood system. This hypertensive disorder may also cause damage to the placenta leading to issues such as premature births, miscarriages, placental abruption, or even stillbirths. In some cases, preeclampsia can eventually lead to stroke and organ failure. Untreated, preeclampsia can progress and turn into eclampsia which is much more severe with the addition of seizures. Eclampsia seizures could lead to uncontrollable twitching and a loss of consciousness, which could potentially lead to the death of the mother and or the baby.[23] ## Treatment[edit] Treatment of infants suffering birth asphyxia by lowering the core body temperature is now known to be an effective therapy to reduce mortality and improve neurological outcome in survivors, and hypothermia therapy for neonatal encephalopathy begun within 6 hours of birth significantly increases the chance of normal survival in affected infants.[citation needed] There has long been a debate over whether newborn infants with birth asphyxia should be resuscitated with 100% oxygen or normal air.[24] It has been demonstrated that high concentrations of oxygen lead to generation of oxygen free radicals, which have a role in reperfusion injury after asphyxia.[25] Research by Ola Didrik Saugstad and others led to new international guidelines on newborn resuscitation in 2010, recommending the use of normal air instead of 100% oxygen.[26][27] Increasing the oxygen concentration to the mother has shown little effect on the fetus as hyperoxygenated blood does not perfuse the placental exchange site well.[28] Underlying etiology of intrauterine hypoxia serves as a potential therapeutic target. If maternal preeclampsia[29] is the underlying cause of fetal growth restriction (FGR) antihypertensive therapy and magnesium sulfate are potential therapies.[7] Antihypertensive treatment is used to reduce blood pressure and prevent pulmonary edema and cerebral hemorrhages. An effective course of antihypertensive treatments should reduce blood pressure to below 160/110 mmHg. Magnesium sulfate acts as a vasodilator, reducing vascular resistance and protect the blood-brain barrier (BBB). The goal of these treatments is to prolong pregnancy and increase fetal survival. Each day gained by treatment in utero increases fetal survival and intact survival by 1%–2% up to 28 weeks gestation.[30] ## Prevention[edit] Medical testing and care can be performed in order to prevent intrauterine hypoxia, though can be difficult. These tests don't directly detect hypoxia, but instead detects the general well-being of the baby and ensures that the baby is healthy since hypoxia causes a wide range of responses. These tests can include prenatal testing, such as fetal movement and amniotic fluid levels, Doppler examination, or fetal heart rate.[31] Another risk factor is premature birth in which medical intervention, such as premature birth prevention or C-section delivery, can be used as prevention for intrauterine hypoxia.[32] Studies have shown a connection between tetrahydrobiopterin (BH4) deficiency and hypoxia-ischemia brain injury, though further studies need to be done.[33] Measuring fetal BH4 levels can be another way to look out for intrauterine hypoxia.[citation needed] During birth, birth asphyxia can occur in which cardiotocograph can be used to monitor the baby's health during labor.[34] ## Epidemiology[edit] In the United States, intrauterine hypoxia and birth asphyxia were listed together as the tenth leading cause of neonatal death.[35] ## Society[edit] IH/BA is also a causative factor in cardiac and circulatory birth defects the sixth most expensive condition, as well as premature birth and low birth weight the second most expensive and it is one of the contributing factors to infant respiratory distress syndrome (RDS) also known as hyaline membrane disease, the most expensive medical condition to treat and the number one cause of infant mortality.[36][37][38] Most expensive medical condition treated in U.S. hospitals. 4 out of 10 linked to intrauterine hypoxia/birth asphxia Cost Hospital Charge 1\. Infant respiratory distress syndrome $45,542 $138,224 2\. Premature birth and low birth weight $44,490 $119,389 6\. Cardiac and circulatory birth defects $35,960 $101,412 9\. Intrauterine hypoxia or birth asphyxia $27,962 $74,942 ### Medicolegal[edit] In the United States the National Practitioner Data Bank 2006 Annual Report obstetrics-related cases accounted for 8.7 percent of all 2006 physician Malpractice Payment Reports and had the highest median payment amounts ($333,334).[39] ## References[edit] 1. ^ Maslova MV, Maklakova AS, Sokolova NA, Ashmarin IP, Goncharenko EN, Krushinskaya YV (July 2003). "The effects of ante- and postnatal hypoxia on the central nervous system and their correction with peptide hormones". Neuroscience and Behavioral Physiology. 33 (6): 607–11. doi:10.1023/A:1023938905744. PMID 14552554. S2CID 1170955. 2. ^ Habek D, Habek JC, Jugović D, Salihagić A (2002). "[Intrauterine hypoxia and sudden infant death syndrome]". Acta Medica Croatica. 56 (3): 109–18. PMID 12630342. 3. ^ Bulterys MG, Greenland S, Kraus JF (October 1990). "Chronic fetal hypoxia and sudden infant death syndrome: interaction between maternal smoking and low hematocrit during pregnancy". Pediatrics. 86 (4): 535–40. PMID 2216618. 4. ^ Peleg D, Kennedy CM, Hunter SK (August 1998). "Intrauterine growth restriction: identification and management". American Family Physician. 58 (2): 453–60, 466–7. PMID 9713399. 5. ^ Rosenberg A (June 2008). "The IUGR newborn". Seminars in Perinatology. 32 (3): 219–24. doi:10.1053/j.semperi.2007.11.003. PMID 18482625. 6. ^ Gonzalez FF, Miller SP (November 2006). "Does perinatal asphyxia impair cognitive function without cerebral palsy?". Archives of Disease in Childhood. Fetal and Neonatal Edition. 91 (6): F454-9. doi:10.1136/adc.2005.092445. PMC 2672766. PMID 17056843. 7. ^ a b c d Fajersztajn L, Veras MM (October 2017). "Hypoxia: From Placental Development to Fetal Programming". Birth Defects Research. 109 (17): 1377–1385. doi:10.1002/bdr2.1142. PMID 29105382. 8. ^ Kingdom JC, Kaufmann P (November 1997). "Oxygen and placental villous development: origins of fetal hypoxia". Placenta. 18 (8): 613–21, discussion 623-6. doi:10.1016/s0143-4004(97)90000-x. PMID 9364596. 9. ^ a b c Hutter D, Kingdom J, Jaeggi E (2010). "Causes and mechanisms of intrauterine hypoxia and its impact on the fetal cardiovascular system: a review". International Journal of Pediatrics. 2010: 401323. doi:10.1155/2010/401323. PMC 2963133. PMID 20981293. 10. ^ Mund M, Louwen F, Klingelhoefer D, Gerber A (November 2013). "Smoking and pregnancy--a review on the first major environmental risk factor of the unborn". International Journal of Environmental Research and Public Health. 10 (12): 6485–99. doi:10.3390/ijerph10126485. PMC 3881126. PMID 24351784. 11. ^ a b Pipkin FB (April 2008). "Smoking in moderate/severe preeclampsia worsens pregnancy outcome, but smoking cessation limits the damage". Hypertension. 51 (4): 1042–6. doi:10.1161/HYPERTENSIONAHA.107.106559. PMID 18259022. 12. ^ Slotkin TA (June 1998). "Fetal nicotine or cocaine exposure: which one is worse?". The Journal of Pharmacology and Experimental Therapeutics. 285 (3): 931–45. PMID 9618392. 13. ^ Bouhours-Nouet N, May-Panloup P, Coutant R, de Casson FB, Descamps P, Douay O, et al. (January 2005). "Maternal smoking is associated with mitochondrial DNA depletion and respiratory chain complex III deficiency in placenta". American Journal of Physiology. Endocrinology and Metabolism. 288 (1): E171-7. doi:10.1152/ajpendo.00260.2003. PMID 15585597. S2CID 16661101. 14. ^ Gogiia TE (November 2005). "[Risk of iugr syndrome development during preeclampsia of the pregnant]". Georgian Medical News (128): 15–7. PMID 16369054. 15. ^ Salafia CM, Minior VK, Pezzullo JC, Popek EJ, Rosenkrantz TS, Vintzileos AM (October 1995). "Intrauterine growth restriction in infants of less than thirty-two weeks' gestation: associated placental pathologic features". American Journal of Obstetrics and Gynecology. 173 (4): 1049–57. doi:10.1016/0002-9378(95)91325-4. PMID 7485292. 16. ^ Kingdom JC, Kaufmann P (November 1997). "Oxygen and placental villous development: origins of fetal hypoxia". Placenta. 18 (8): 613–21, discussion 623-6. doi:10.1016/S0143-4004(97)90000-X. PMID 9364596. 17. ^ Chełchowska M, Laskowska-Klita T (2002). "Effect of maternal smoking on some markers of iron status in umbilical cord blood". Roczniki Akademii Medycznej W Bialymstoku. 47: 235–40. PMID 12533965. 18. ^ Habek D, Habek JC, Ivanisević M, Djelmis J (2002). "Fetal tobacco syndrome and perinatal outcome". Fetal Diagnosis and Therapy. 17 (6): 367–71. doi:10.1159/000065387. PMID 12393968. S2CID 46837857. 19. ^ Benirschke K, Kaufmann P (March 2000). Pathology of the human placenta (4th ed.). Springer. p. 453. ISBN 978-0-387-98894-8. 20. ^ Thompson LP, Crimmins S, Telugu BP, Turan S (September 2015). "Intrauterine hypoxia: clinical consequences and therapeutic perspectives". Research and Reports in Neonatology. 5: 79–89. doi:10.2147/RRN.S57990. 21. ^ Publishing, Harvard Health. "Preeclampsia And Eclampsia". Harvard Health. Retrieved 2020-07-28. 22. ^ Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Alkema L (June 2014). "Global causes of maternal death: a WHO analysis". The Lancet Global Health. 2 (6): e323–33. doi:10.1016/S2214-109X(14)70227-X. PMID 25103301. 23. ^ Peres GM, Mariana M, Cairrão E (January 2018). "Pre-Eclampsia and Eclampsia: An Update on the Pharmacological Treatment Applied in Portugal". Journal of Cardiovascular Development and Disease. 5 (1): 3. doi:10.3390/jcdd5010003. PMC 5872351. PMID 29367581. 24. ^ Davis PG, Tan A, O'Donnell CP, Schulze A (2004). "Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis". Lancet. 364 (9442): 1329–33. doi:10.1016/S0140-6736(04)17189-4. PMID 15474135. S2CID 24825982. 25. ^ Kutzsche S, Ilves P, Kirkeby OJ, Saugstad OD (June 2001). "Hydrogen peroxide production in leukocytes during cerebral hypoxia and reoxygenation with 100% or 21% oxygen in newborn piglets". Pediatric Research. 49 (6): 834–42. doi:10.1203/00006450-200106000-00020. PMID 11385146. 26. ^ ILCOR Neonatal Resuscitation Guidelines 2010 27. ^ "Norwegian paediatrician honoured by University of Athens". Norway.gr. 28. ^ Seeds AE, Escarcena L (September 1974). "Prevention and correction of fetal acidosis and hypoxia". Clinical Obstetrics and Gynecology. 17 (3): 115–34. doi:10.1097/00003081-197409000-00008. PMID 4606933. 29. ^ "Maternal preeclampsia". Mayo Clinic. 30. ^ Baschat AA, Cosmi E, Bilardo CM, Wolf H, Berg C, Rigano S, et al. (February 2007). "Predictors of neonatal outcome in early-onset placental dysfunction". Obstetrics and Gynecology. 109 (2 Pt 1): 253–61. doi:10.1097/01.AOG.0000253215.79121.75. PMID 17267821. S2CID 25449681. 31. ^ Salihagić-Kadić A, Medić M, Jugović D, Kos M, Latin V, Kusan Jukić M, Arbeille P (July 2006). "Fetal cerebrovascular response to chronic hypoxia--implications for the prevention of brain damage" (PDF). The Journal of Maternal-Fetal & Neonatal Medicine. 19 (7): 387–96. doi:10.1080/14767050600637861. PMID 16923693. S2CID 8301182. 32. ^ "Preventing Hypoxic-Ischemic Encephalopathy (HIE)". HIE Help Center. Retrieved 2020-07-28. 33. ^ Vásquez-Vivar J, Whitsett J, Derrick M, Ji X, Yu L, Tan S (September 2009). "Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain". Annals of Neurology. 66 (3): 323–31. doi:10.1002/ana.21738. PMC 2785106. PMID 19798726. 34. ^ Chandraharan E, Arulkumaran S (August 2007). "Prevention of birth asphyxia: responding appropriately to cardiotocograph (CTG) traces". Best Practice & Research. Clinical Obstetrics & Gynaecology. Risk Management in Obstetrics and Gynaecology. 21 (4): 609–24. doi:10.1016/j.bpobgyn.2007.02.008. PMID 17400026. 35. ^ "Deaths: Preliminary Data for 2004". National Center for Health Statistics. 36. ^ Rueda-Clausen CF, Morton JS, Davidge ST (March 2009). "Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood". Cardiovascular Research. 81 (4): 713–22. doi:10.1093/cvr/cvn341. PMID 19088083. 37. ^ Sly PD, Drew JH (March 1981). "Massive pulmonary haemorrhage: a cause of sudden unexpected deaths in severely growth retarded infants". Australian Paediatric Journal. 17 (1): 32–4. doi:10.1111/j.1440-1754.1981.tb00010.x. PMID 7247876. 38. ^ "Hyaline Membrane Disease". eMedicine. 39. ^ "National Practitioner Data Bank 2006 Annual Report" (PDF). ## External links[edit] * Zanelli SA. "Hypoxic-Ischemic Brain Injury in the Newborn". Medscape. WebMD LLC. * Zanelli SA. "Hypoxic-Ischemic Encephalopathy". Medscape. WebMD LLC. * Johnson K. "Clear Criteria for Defining Birth Asphyxia". Medscape. WebMD LLC. Classification D * ICD-10: P20 * ICD-9-CM: 768 * MeSH: D005311 * v * t * e Conditions originating in the perinatal period / fetal disease Maternal factors complicating pregnancy, labour or delivery placenta * Placenta praevia * Placental insufficiency * Twin-to-twin transfusion syndrome chorion/amnion * Chorioamnionitis umbilical cord * Umbilical cord prolapse * Nuchal cord * Single umbilical artery presentation * Breech birth * Asynclitism * Shoulder presentation Growth * Small for gestational age / Large for gestational age * Preterm birth / Postterm pregnancy * Intrauterine growth restriction Birth trauma * scalp * Cephalohematoma * Chignon * Caput succedaneum * Subgaleal hemorrhage * Brachial plexus injury * Erb's palsy * Klumpke paralysis Affected systems Respiratory * Intrauterine hypoxia * Infant respiratory distress syndrome * Transient tachypnea of the newborn * Meconium aspiration syndrome * Pleural disease * Pneumothorax * Pneumomediastinum * Wilson–Mikity syndrome * Bronchopulmonary dysplasia Cardiovascular * Pneumopericardium * Persistent fetal circulation Bleeding and hematologic disease * Vitamin K deficiency bleeding * HDN * ABO * Anti-Kell * Rh c * Rh D * Rh E * Hydrops fetalis * Hyperbilirubinemia * Kernicterus * Neonatal jaundice * Velamentous cord insertion * Intraventricular hemorrhage * Germinal matrix hemorrhage * Anemia of prematurity Gastrointestinal * Ileus * Necrotizing enterocolitis * Meconium peritonitis Integument and thermoregulation * Erythema toxicum * Sclerema neonatorum Nervous system * Perinatal asphyxia * Periventricular leukomalacia Musculoskeletal * Gray baby syndrome * muscle tone * Congenital hypertonia * Congenital hypotonia Infections * Vertically transmitted infection * Neonatal infection * rubella * herpes simplex * mycoplasma hominis * ureaplasma urealyticum * Omphalitis * Neonatal sepsis * Group B streptococcal infection * Neonatal conjunctivitis Other * Miscarriage * Perinatal mortality * Stillbirth * Infant mortality * Neonatal withdrawal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Intrauterine hypoxia	c0015924	5,526	wikipedia	https://en.wikipedia.org/wiki/Intrauterine_hypoxia	2021-01-18T18:51:52	{"mesh": ["D005311"], "icd-9": ["768"], "icd-10": ["P21", "P20"], "wikidata": ["Q4113828"]}
## Clinical Features Le Merrer et al. (1991) described 4 patients from the same family with a characteristic localization of chondromatosis: clavicle, upper end of humerus, and lower end of femur (hence, 'geno-' for knee). The patients were a mother and her daughter and 2 sons. The condition showed a benign course and was clearly different from metachondromatosis (156250), generalized enchondromatosis (166000), and spondyloenchondrodysplasia (607944). ### Clinical Variability Kozlowski and Jarrett (1992) described a family with similar yet distinctive findings to those described by Le Merrer et al. (1991). They reported an autosomal dominant disorder with symmetric chondromata localized to the metaphyses of all the tubular long bones, but without involvement of the clavicles. The radius and ulna showed abnormal shape and there was coxa vara. The vertebral bodies were square-shaped. Kozlowski and Jarrett (1992) proposed the name genochondromatosis II for the disorder affecting their patients to distinguish it from the disorder described by Le Merrer et al. (1991). Isidor et al. (2007) reported a 12-year-old boy who had radiographic metaphyseal changes consistent with chondromas in the lower femoral and radial metaphyses as well as in the phalanges, metacarpals, and metatarsals. The changes formed irregular bands parallel to the longitudinal axis of the bone with lucencies and increased densities. The clavicles, skull, and spine were unaffected. Radiographic examination of the parents was normal, suggesting a de novo mutation. Isidor et al. (2007) stated that the skeletal findings in this patient were similar to those of the proband with 'genochondromatosis type II' described by Kozlowski and Jarrett (1992) and also to the 'expansile bone lesions' (603439) in the 3-generation family described by Dinulos et al. (1999); Isidor et al. (2007) suggested that the latter family might represent a variable form of the same disorder. Skel \- Chondromatosis of clavicle, upper humerus, and lower femur 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	GENOCHONDROMATOSIS	c1300229	5,527	omim	https://www.omim.org/entry/137360	2019-09-22T16:40:50	{"mesh": ["C563215"], "omim": ["137360"], "orphanet": ["93398", "85197"], "synonyms": []}
Benign prostatic hyperplasia Other namesBenign enlargement of the prostate (BEP, BPE), adenofibromyomatous hyperplasia, benign prostatic hypertrophy,[1] benign prostatic obstruction[1] Diagram of a normal prostate (left) and benign prostatic hyperplasia (right) SpecialtyUrology SymptomsFrequent urination, trouble starting to urinate, weak stream, inability to urinate, loss of bladder control[1] ComplicationsUrinary tract infections, bladder stones, kidney failure[2] Usual onsetAge over 40[1] CausesUnclear[1] Risk factorsFamily history, obesity, type 2 diabetes, not enough exercise, erectile dysfunction[1] Diagnostic methodBased on symptoms and examination after ruling out other possible causes[2] Differential diagnosisHeart failure, diabetes, prostate cancer[2] TreatmentLifestyle changes, medications, a number of procedures, surgery[1][2] MedicationAlpha blockers such as terazosin, 5α-reductase inhibitors such as finasteride[1] Frequency105 million affected globally (2015)[3] Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland.[1] Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control.[1] Complications can include urinary tract infections, bladder stones, and chronic kidney problems.[2] The cause is unclear.[1] Risk factors include a family history, obesity, type 2 diabetes, not enough exercise, and erectile dysfunction.[1] Medications like pseudoephedrine, anticholinergics, and calcium channel blockers may worsen symptoms.[2] The underlying mechanism involves the prostate pressing on the urethra thereby making it difficult to pass urine out of the bladder.[1] Diagnosis is typically based on symptoms and examination after ruling out other possible causes.[2] Treatment options include lifestyle changes, medications, a number of procedures, and surgery.[1][2] In those with mild symptoms weight loss, exercise, and decreasing caffeine intake is recommended.[2][4] In those with more significant symptoms, medications may include alpha blockers such as terazosin or 5α-reductase inhibitors such as finasteride.[1] Surgical removal of part of the prostate may be carried out in those who do not improve with other measures.[2] Phytotherapies that have been studied, such as saw palmetto, have not been shown to help.[2] About 105 million men are affected globally.[3] BPH typically begins after the age of 40.[1] Half of males age 50 and over are affected.[2] After the age of 80 about 90% of males are affected.[1] Although prostate specific antigen levels may be elevated in males with BPH, the condition does not increase the risk of prostate cancer.[5] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Hormones * 2.2 Diet * 2.3 Degeneration * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 4.1.1 Medical conditions * 4.1.2 Medications * 5 Management * 5.1 Lifestyle * 5.1.1 Voiding position * 5.2 Medications * 5.2.1 Alpha blockers * 5.2.2 5α-Reductase inhibitors * 5.2.3 Phosphodiesterase-5 inhibitors * 5.2.4 Others * 5.3 Self-catheterization * 5.4 Surgery * 5.5 Endovascular * 5.6 Transurethral microwave thermotherapy * 5.7 Alternative medicine * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] BPH is the most common cause of lower urinary tract symptoms (LUTS), which are divided into storage, voiding, and symptoms which occur after urination.[6] Storage symptoms include the need to urinate frequently, waking at night to urinate, urgency (compelling need to void that cannot be deferred), involuntary urination, including involuntary urination at night, or urge incontinence (urine leak following a strong sudden need to urinate).[7] Voiding symptoms include urinary hesitancy (a delay between trying to urinate and the flow actually beginning), intermittency (not continuous),[8] involuntary interruption of voiding, weak urinary stream, straining to void, a sensation of incomplete emptying, and uncontrollable leaking after the end of urination.[9][10][11] These symptoms may be accompanied by bladder pain or pain while urinating, called dysuria.[12] Bladder outlet obstruction (BOO) can be caused by BPH.[13] Symptoms are abdominal pain, a continuous feeling of a full bladder, frequent urination, acute urinary retention (inability to urinate), pain during urination (dysuria), problems starting urination (urinary hesitancy), slow urine flow, starting and stopping (urinary intermittency), and nocturia. BPH can be a progressive disease, especially if left untreated. Incomplete voiding results in residual urine or urinary stasis, which can lead to an increased risk of urinary tract infection.[14] ## Causes[edit] ### Hormones[edit] Most experts consider androgens (testosterone and related hormones) to play a permissive role in the development of BPH. This means that androgens must be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by evidence suggesting that castrated boys do not develop BPH when they age. In an unusual study of 26 eunuchs from the palace of the Qing dynasty still living in Beijing in 1960, the prostate could not be felt in 81% of the studied eunuchs.[15] The average time since castration was 54 years (range, 41–65 years). On the other hand, some studies suggest that administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms, so the role of testosterone in prostate cancer and BPH is still unclear. Further randomized controlled trials with more participants are needed to quantify any risk of giving exogenous testosterone.[16] Dihydrotestosterone (DHT), a metabolite of testosterone, is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. DHT is ten times more potent than testosterone because it dissociates from the androgen receptor more slowly. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase such as finasteride is given to men with this condition. Therapy with a 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and BPH symptoms.[17][18] Testosterone promotes prostate cell proliferation,[19] but relatively low levels of serum testosterone are found in patients with BPH.[20][21] One small study has shown that medical castration lowers the serum and prostate hormone levels unevenly, having less effect on testosterone and dihydrotestosterone levels in the prostate.[22] While there is some evidence that estrogen may play a role in the cause of BPH, this effect appears to be mediated mainly through local conversion of androgens to estrogen in the prostate tissue rather than a direct effect of estrogen itself.[23] In canine in vivo studies castration, which significantly reduced androgen levels but left estrogen levels unchanged, caused significant atrophy of the prostate.[24] Studies looking for a correlation between prostatic hyperplasia and serum estrogen levels in humans have generally shown none.[21][25] In 2008, Gat et al. published evidence that BPH is caused by failure in the spermatic venous drainage system resulting in increased hydrostatic pressure and local testosterone levels elevated more than 100 fold above serum levels.[26] If confirmed, this mechanism explains why serum androgen levels do not seem to correlate with BPH and why giving exogenous testosterone would not make much difference. ### Diet[edit] Studies indicate that dietary patterns may affect development of BPH, but further research is needed to clarify any important relationship.[27] Studies from China suggest that greater protein intake may be a factor in development of BPH. Men older than 60 in rural areas had very low rates of clinical BPH, while men living in cities and consuming more animal protein had a higher incidence.[28][29] On the other hand, a study in Japanese-American men in Hawaii found a strong negative association with alcohol intake, but a weak positive association with beef intake.[30] In a large prospective cohort study in the US (the Health Professionals Follow-up Study), investigators reported modest associations between BPH (men with strong symptoms of BPH or surgically confirmed BPH) and total energy and protein, but not fat intake.[31] There is also epidemiological evidence linking BPH with metabolic syndrome (concurrent obesity, impaired glucose metabolism and diabetes, high triglyceride levels, high levels of low-density cholesterol, and hypertension).[32] ### Degeneration[edit] Benign prostatic hyperplasia is an age-related disease. Misrepair-accumulation aging theory[33][34] suggests that development of benign prostatic hyperplasia is a consequence of fibrosis and weakening of the muscular tissue in the prostate.[35] The muscular tissue is important in the functionality of the prostate, and provides the force for excreting the fluid produced by prostatic glands. However, repeated contractions and dilations of myofibers will unavoidably cause injuries and broken myofibers. Myofibers have a low potential for regeneration; therefore, collagen fibers need to be used to replace the broken myofibers. Such misrepairs make the muscular tissue weak in functioning, and the fluid secreted by glands cannot be excreted completely. Then, the accumulation of fluid in glands increases the resistance of muscular tissue during the movements of contractions and dilations, and more and more myofibers will be broken and replaced by collagen fibers. ## Pathophysiology[edit] Benign prostate hyperplasia As men age, the enzymes aromatase and 5-alpha reductase increase in activity. These enzymes are responsible for converting androgen hormones into estrogen and dihydrotestosterone, respectively. This metabolism of androgen hormones leads to a decrease in testosterone but increased levels of DHT and estrogen. Both the glandular epithelial cells and the stromal cells (including muscular fibers) undergo hyperplasia in BPH.[2] Most sources agree that of the two tissues, stromal hyperplasia predominates, but the exact ratio of the two is unclear.[36]:694 Anatomically the median and lateral lobes are usually enlarged, due to their highly glandular composition. The anterior lobe has little in the way of glandular tissue and is seldom enlarged. (Carcinoma of the prostate typically occurs in the posterior lobe – hence the ability to discern an irregular outline per rectal examination). The earliest microscopic signs of BPH usually begin between the age of 30 and 50 years old in the PUG, which is posterior to the proximal urethra.[36]:694 In BPH, the majority of growth occurs in the transition zone (TZ) of the prostate.[36]:694 In addition to these two classic areas, the peripheral zone (PZ) is also involved to a lesser extent.[36]:695 Prostatic cancer typically occurs in the PZ. However, BPH nodules, usually from the TZ are often biopsied anyway to rule out cancer in the TZ.[36]:695 BPH can be a progressive growth that in rare instances leads to exceptional enlargement.[37] In some males, the prostate enlargement exceeds 200 to 500 grams.[37] This condition has been defined as giant prostatic hyperplasia (GPH).[37] ## Diagnosis[edit] The clinical diagnosis of BPH is based on a history of LUTS (lower urinary tract symptoms), a digital rectal exam, and exclusion of other causes of similar signs and symptoms. The degree of LUTS does not necessarily correspond to the size of the prostate. An enlarged prostate gland on rectal examination that is symmetric and smooth supports a diagnosis of BPH.[2] However, if the prostate gland feels asymmetrical, firm, or nodular, this raises concern for prostate cancer.[2] Urinalysis is typically performed when LUTS are present and BPH is suspected to evaluate for signs of a urinary tract infection, glucose in the urine (suggestive of diabetes), or protein in the urine (suggestive of kidney disease).[2] Bloodwork including kidney function tests and prostate specific antigen (PSA) are often ordered to evaluate for kidney damage and prostate cancer, respectively.[2] However, checking blood PSA levels for prostate cancer screening is controversial and not necessarily indicated in every evaluation for BPH.[2] Benign prostatic hyperplasia and prostate cancer are both capable of increasing blood PSA levels and PSA elevation is unable to differentiate these two conditions well.[2] If PSA levels are checked and are high, then further investigation is warranted. Measures including PSA density, free PSA, rectal examination, and transrectal ultrasonography may be helpful in determining whether a PSA increase is due to BPH or prostate cancer.[2] Ultrasound examination of the testes, prostate, and kidneys is often performed, again to rule out cancer and hydronephrosis. Validated questionnaires such as the American Urological Association Symptom Index (AUA-SI), the International Prostate Symptom Score (I-PSS), and more recently the UWIN score (urgency, weak stream, incomplete emptying, and nocturia) are useful aids to making the diagnosis of BPH and quantifying the severity of symptoms.[2][38][39] ### Differential diagnosis[edit] #### Medical conditions[edit] The differential diagnosis for LUTS is broad and includes various medical conditions, neurologic disorders, and other diseases of the bladder, urethra, and prostate such as bladder cancer, urinary tract infection, urethral stricture, urethral calculi (stones), chronic prostatitis, and prostate cancer.[2] Neurogenic bladder can cause urinary retention and cause symptoms similar to those of BPH. This may occur as a result of uncoordinated contraction of the bladder muscle or impairment in the timing of bladder muscle contraction and urethral sphincter relaxation.[2] Notable causes of neurogenic bladder include disorders of the central nervous system such as Parkinson's disease, multiple sclerosis, and spinal cord injuries as well as disorders of the peripheral nervous system such as diabetes mellitus, vitamin B12 deficiency, and alcohol-induced nerve damage.[2] Individuals affected by heart failure often experience nighttime awakenings to urinate due to redistribution of fluid accumulated in swollen legs.[2] #### Medications[edit] Certain medications can increase urination difficulties by increasing bladder outlet resistance due to increased smooth muscle tone at the prostate or bladder neck and contribute to LUTS.[2] Alpha-adrenergic agonist medications, such as decongestants with pseudoephedrine can increase bladder outlet resistance.[2] In contrast, calcium channel blockers and anticholinergic medications can worsen urinary retention by promoting bladder muscle relaxation.[2] Diuretic medications such as loop diuretics (e.g., furosemide) or thiazides (e.g., chlorthalidone) can cause or worsen urinary frequency and nighttime awakenings to urinate.[2] * Micrograph showing nodular hyperplasia (left off center) of the prostate from a transurethral resection of the prostate (TURP). H&E stain. * Microscopic examination of different types of prostate tissues (stained with immunohistochemical techniques): A. Normal (non-neoplastic) prostatic tissue (NNT). B. Benign prostatic hyperplasia. C. High-grade prostatic intraepithelial neoplasia. D. Prostatic adenocarcinoma (PCA). ## Management[edit] When treating and managing benign prostatic hyperplasia, the aim is to prevent complications related to the disease and improve or relieve symptoms.[40] Approaches used include lifestyle modifications, medications, and surgery. ### Lifestyle[edit] Lifestyle alterations to address the symptoms of BPH include physical activity,[41] decreasing fluid intake before bedtime, moderating the consumption of alcohol and caffeine-containing products and following a timed voiding schedule. Patients can also attempt to avoid products and medications with anticholinergic properties that may exacerbate urinary retention symptoms of BPH, including antihistamines, decongestants, opioids, and tricyclic antidepressants; however, changes in medications should be done with input from a medical professional.[42] #### Voiding position[edit] Voiding position when urinating may influence urodynamic parameters (urinary flow rate, voiding time, and post-void residual volume).[43] A meta-analysis found no differences between the standing and sitting positions for healthy males, but that, for elderly males with lower urinary tract symptoms, voiding in the sitting position:[44] * decreased the post void residual volume * increased the maximum urinary flow, comparable with pharmacological intervention * decreased the voiding time This urodynamic profile is associated with a lower risk of urologic complications, such as cystitis and bladder stones. ### Medications[edit] The two main medication classes for BPH management are alpha blockers and 5α-reductase inhibitors.[45] #### Alpha blockers[edit] Selective α1-blockers are the most common choice for initial therapy.[46][47][48] They include alfuzosin,[49][50] doxazosin,[51] silodosin, tamsulosin, terazosin, and naftopidil.[40] They have a small to moderate benefit at improving symptoms.[52][40][53] Selective alpha-1 blockers are similar in effectiveness but have slightly different side effect profiles.[52][40][53] Alpha blockers relax smooth muscle in the prostate and the bladder neck, thus decreasing the blockage of urine flow. Common side effects of alpha blockers include orthostatic hypotension (a head rush or dizzy spell when standing up or stretching), ejaculation changes, erectile dysfunction,[54] headaches, nasal congestion, and weakness. Naftopidil and tamsulosin may have similar levels of unwanted sexual side effects and silodosin may have more unwanted side effects.[40] Tamsulosin and silodosin are selective α1 receptor blockers that preferentially bind to the α1A receptor in the prostate instead of the α1B receptor in the blood vessels. Less-selective α1 receptor blockers such as terazosin and doxazosin may lower blood pressure. The older, less selective α1-adrenergic blocker prazosin is not a first line choice for either high blood pressure or prostatic hyperplasia; it is a choice for patients who present with both problems at the same time. The older, broadly non-selective alpha blocker medications such as phenoxybenzamine are not recommended for control of BPH.[55] Non-selective alpha blockers such as terazosin and doxazosin may also require slow dose adjustments as they can lower blood pressure and cause syncope (fainting) if the response to the medication is too strong. #### 5α-Reductase inhibitors[edit] The 5α-reductase inhibitors finasteride and dutasteride may also be used in men with BPH.[56] These medications inhibit the 5α-reductase enzyme, which, in turn, inhibits production of DHT, a hormone responsible for enlarging the prostate. Effects may take longer to appear than alpha blockers, but they persist for many years.[57] When used together with alpha blockers, no benefit was reported in short-term trials, but in a longer-term study (3–4 years) there was a greater reduction in BPH progression to acute urinary retention and surgery than with either agent alone, especially in people with more severe symptoms and larger prostates.[58][59][60] Other trials have confirmed reductions in symptoms, within 6 months in one trial, an effect that was maintained after withdrawal of the alpha blocker.[59][61] Side effects include decreased libido and ejaculatory or erectile dysfunction.[62][63] The 5α-reductase inhibitors are contraindicated in pregnant women because of their teratogenicity due to interference with fetal testosterone metabolism, and as a precaution, pregnant women should not handle crushed or broken tablets.[64] #### Phosphodiesterase-5 inhibitors[edit] A meta‐analysis found that tadalafil 5 mg once daily is an effective treatment for lower urinary tract symptoms and that such treatment had a low rate of adverse effects. Other phosphodiesterase-5 inhibitors are also effective, but may require multiple doses daily to maintain adequate urine flow,[65][66] suggesting a possible common cause with erectile dysfunction. Tadalafil was considered then rejected by NICE in the UK for the treatment of symptoms associated with BPH.[67] In 2011, the U.S. Food and Drug Administration approved tadalafil to treat the signs and symptoms of benign prostatic hyperplasia, and for the treatment of BPH and erectile dysfunction (ED), when the conditions occur simultaneously.[68] #### Others[edit] Antimuscarinics such as tolterodine may also be used, especially in combination with alpha blockers.[69] They act by decreasing acetylcholine effects on the smooth muscle of the bladder, thus helping control symptoms of an overactive bladder.[70] ### Self-catheterization[edit] Intermittent urinary catheterization is used to relieve the bladder in people with urinary retention. Self-catheterization is an option in BPH when it is difficult or impossible to completely empty the bladder.[71] Urinary tract infection is the most common complication of intermittent catheterization.[72] Several techniques and types of catheter are available, including sterile (single-use) and clean (multiple use) catheters, but, based on current information, none is superior to others in reducing the incidence of urinary tract infection.[73] ### Surgery[edit] Main article: Surgery for benign prostatic hyperplasia Transurethral resection of the prostate (TURP) If medical treatment is not effective, surgery may be performed. Surgical techniques used include the following: * Transurethral resection of the prostate (TURP): the gold standard.[74] TURP is thought to be the most effective approach for improving urinary symptoms and urinary flow, however, this surgical procedure may be associated with complications in up to 20% of men.[74] Surgery carries some risk of complications, such as retrograde ejaculation (most commonly), erectile dysfunction, urinary incontinence, urethral strictures.[75] * Open prostatectomy: not usually performed nowadays, even if results are very good. * Transurethral incision of the prostate (TUIP): rarely performed; the technique is similar to TURP but less definitive. * Photoselective (laser) vaporization of the prostate (PVP): common treatment. * Water vapor thermal therapy (marketed as Rezum): a newer office procedure for removing prostate tissue using steam, while preserving sexual function. * Prostatic urethral lift (marketed as UroLift), a minimally invasive device to open the urethra. May preserve sexual function. [76] ### Endovascular[edit] Main article: Prostatic artery embolization As of 2017, the latest alternative to surgical treatment was arterial embolization, an endovascular procedure performed in interventional radiology.[77] Through catheters, embolic agents are released in the main branches of the prostatic artery, in order to induce a decrease in the size of the prostate gland, thus reducing the urinary symptoms.[78] ### Transurethral microwave thermotherapy[edit] Transurethral microwave thermotherapy (TUMT) is an outpatient procedure that is less invasive compared to surgery and involves using microwaves (heat) to shrink prostate tissue that is enlarged.[74] TUMT may be effective at safely improving symptoms, however, TUMT does not appear to be as effective as a surgical approaches such as TURP.[74] ### Alternative medicine[edit] While herbal remedies are commonly used, a 2016 review found the herbs studied to be no better than placebo.[79] Saw palmetto extract from Serenoa repens, while one of the most commonly used, is no better than placebo in both symptom relief and decreasing prostate size.[80][81][82] Other ineffective herbal medicines include beta-sitosterol[83] from Hypoxis rooperi (African star grass), pygeum (extracted from the bark of Prunus africana),[84] pumpkin seeds (Cucurbita pepo) and stinging nettle (Urtica dioica) root.[85] A systematic review of Chinese herbal medicines found that Chinese herbal medicine, either as monotherapy or an adjuvant therapy with Western medicine, was similar to either placebo or Western medicine in the treatment of BPH. Chinese herbal medicine was found to be superior to Western medicine in improving quality of life and reducing prostate volume.[86] ## Epidemiology[edit] Disability-adjusted life year for benign prostatic hyperplasia per 100,000 inhabitants in 2004[87] no data less than 20 20–28 28–36 36–44 44–52 52–60 60–68 68–76 76–84 84–92 92–100 more than 100 Globally, benign prostatic hyperplasia affects about 210 million males as of 2010 (6% of the population).[88] The prostate gets larger in most men as they get older. For a symptom-free man of 46 years, the risk of developing BPH over the next 30 years is 45%. Incidence rates increase from 3 cases per 1000 man-years at age 45–49 years, to 38 cases per 1000 man-years by the age of 75–79 years. While the prevalence rate is 2.7% for men aged 45–49, it increases to 24% by the age of 80 years.[89] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q "Prostate Enlargement (Benign Prostatic Hyperplasia)". NIDDK. September 2014. 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PMID 1383816. 63. ^ Gacci, M; Ficarra, V; Sebastianelli, A; Corona, G; Serni, S; Shariat, SF; Maggi, M; Zattoni, F; Carini, M; Novara, G (June 2014). "Impact of medical treatments for male lower urinary tract symptoms due to benign prostatic hyperplasia on ejaculatory function: a systematic review and meta-analysis". The Journal of Sexual Medicine. 11 (6): 1554–66. doi:10.1111/jsm.12525. PMID 24708055. 64. ^ Deters, Levi. "Benign Prostatic Hypertrophy Treatment & Management". Medscape. Archived from the original on 30 October 2015. Retrieved 14 November 2015. 65. ^ Wang Y, Bao Y, Liu J, Duan L, Cui Y (January 2018). "Tadalafil 5 mg Once Daily Improves Lower Urinary Tract Symptoms and Erectile Dysfunction: A Systematic Review and Meta-analysis". Low Urin Tract Symptoms. 10 (1): 84–92. doi:10.1111/luts.12144. PMID 29341503. S2CID 23929021. 66. ^ Pattanaik, Smita; Mavuduru, Ravimohan S.; Panda, Arabind; Mathew, Joseph L.; Agarwal, Mayank M.; Hwang, Eu Chang; Lyon, Jennifer A.; Singh, Shrawan K.; Mandal, Arup K. (16 November 2018). "Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia". The Cochrane Database of Systematic Reviews. 11: CD010060. doi:10.1002/14651858.CD010060.pub2. ISSN 1469-493X. PMC 6517182. PMID 30480763. 67. ^ "Hyperplasia (benign prostatic) – tadalafil (terminated appraisal) (TA273)". National Institute for Health and Clinical Excellence (NICE). Archived from the original on 24 February 2013. Retrieved 27 January 2013. 68. ^ "FDA approves Cialis to treat benign prostatic hyperplasia". U.S. Food and Drug Administration (FDA). Archived from the original on 11 May 2013. Retrieved 7 May 2013. 69. ^ Kaplan, S. A.; Roehrborn, C. G.; Rovner, E. S.; Carlsson, M.; Bavendam, T.; Guan, Z. (2006). "Tolterodine and Tamsulosin for Treatment of Men With Lower Urinary Tract Symptoms and Overactive Bladder: A Randomized Controlled Trial". JAMA: The Journal of the American Medical Association. 296 (19): 2319–28. doi:10.1001/jama.296.19.2319. PMID 17105794. 70. ^ Abrams, P; Andersson, KE (November 2007). "Muscarinic receptor antagonists for overactive bladder". BJU International. 100 (5): 987–1006. doi:10.1111/j.1464-410x.2007.07205.x. PMID 17922784. S2CID 30983780. 71. ^ "Prostate enlargement (benign prostatic hyperplasia)". Harvard Health Content. Harvard Health Publications. Archived from the original on 3 April 2015. Retrieved 2 February 2015. 72. ^ Wyndaele, JJ (2002). "Complications of intermittent catheterization: their prevention and treatment". Spinal Cord. 40 (10): 536–41. doi:10.1038/sj.sc.3101348. PMID 12235537. 73. ^ Prieto, J; Murphy, CL; Moore, KN; Fader, M (10 September 2014). "Intermittent catheterisation for long-term bladder management". 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PMID 12361895. ## External links[edit] * Medicine portal Wikimedia Commons has media related to Benign prostatic hyperplasia. * Extrinsic Compression by Prostate Classification D * ICD-10: N40 * ICD-9-CM: 600 * OMIM: 600082 * MeSH: D011470 * DiseasesDB: 10797 External resources * MedlinePlus: 000381 * eMedicine: med/1919 * Patient UK: Benign prostatic hyperplasia * v * t * e Male diseases of the pelvis and genitals Internal Testicular * Orchitis * Hydrocele testis * Testicular cancer * Testicular torsion * Male infertility * Aspermia * Asthenozoospermia * Azoospermia * Hyperspermia * Hypospermia * Oligospermia * Necrospermia * Teratospermia Epididymis * Epididymitis * Spermatocele * Hematocele Prostate * Prostatitis * Acute prostatitis * Chronic bacterial prostatitis * Chronic prostatitis/chronic pelvic pain syndrome * Asymptomatic inflammatory prostatitis * Benign prostatic hyperplasia * Prostate cancer Seminal vesicle * Seminal vesiculitis External Penis * Balanoposthitis / Balanitis * Balanitis plasmacellularis * Pseudoepitheliomatous keratotic and micaceous balanitis * Phimosis * Paraphimosis * Priapism * Sexual dysfunction * Erectile dysfunction * Peyronie's disease * Penile cancer * Penile fracture * Balanitis xerotica obliterans Other * Hematospermia * Retrograde ejaculation * Postorgasmic illness syndrome Authority control * GND: 4137018-1 * NDL: 00967993 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Benign prostatic hyperplasia	c1704272	5,528	wikipedia	https://en.wikipedia.org/wiki/Benign_prostatic_hyperplasia	2021-01-18T18:44:46	{"mesh": ["D011470"], "umls": ["C1704272"], "icd-9": ["600"], "icd-10": ["N40"], "wikidata": ["Q506659"]}
Precocious puberty is when a person's sexual and physical traits develop and mature earlier than normal. Normal puberty typically begins between ages 10 and 14 for girls, and ages 12 and 16 for boys. The start of puberty depends on various factors such as family history, nutrition and gender. The cause of precocious puberty is not always known. Some cases of precocious puberty are due to conditions that cause changes in the body's release of hormones. Treatment involves medications that can stop the release of sexual hormones. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Precocious puberty	c3805879	5,529	gard	https://rarediseases.info.nih.gov/diseases/7446/precocious-puberty	2021-01-18T17:58:12	{"omim": ["176400"], "synonyms": ["Sexual precocity", "Idiopathic sexual precocity", "Familial precocious puberty"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive hypophosphatemic rickets-2 (ARHR2) is caused by homozygous mutation in the ENPP1 gene (173335) on chromosome 6q. Mutation in ENPP1 also causes generalized arterial calcification of infancy (GACI; 208000). For a general phenotypic description and a discussion of genetic heterogeneity of hypophosphatemic rickets, see 193100. Mapping Lorenz-Depiereux et al. (2010) performed genomewide linkage analysis in 2 families segregating autosomal recessive hypophosphatemic rickets (ARHR) and then analyzed the data by homozygosity mapping, which revealed a 4.1-Mb candidate region on chromosome 6q23 between rs9388766 and rs6569926, an interval containing approximately 35 genes. In a Bedouin family with ARHR, Levy-Litan et al. (2010) performed homozygosity mapping and identified linkage to chromosome 6q23, obtaining a lod score of 3.45 for D6S262 under an assumption of recessive inheritance with 99% penetrance and an incidence of 0.01 or 0.001 of the disease allele in the population. Multipoint analysis yielded a lod score of 4.27 for a 7.39-Mb linkage interval containing 70 genes. Molecular Genetics In a cohort of 60 probands with autosomal recessive hypophosphatemic rickets, who were negative for mutation in known hypophosphatemia genes, Lorenz-Depiereux et al. (2010) sequenced the candidate gene ENPP1 (173335) and identified homozygosity for a deletion, missense, or frameshift mutation in 4 families (173335.0010-173335.0012) that were not found in 355 controls. In 1 family, previously studied by Rutsch et al. (2003) ('family 4'), a father and son who were both homozygous for a missense mutation (G266V; 173335.0011) had different phenotypes: the father had hypophosphatemic rickets, whereas his son had severe generalized arterial calcification of infancy (GACI; 208000) and hypophosphatemia. Ultrasound examination of large blood vessels in the father and the other 4 mutation-positive patients showed normal carotid and renal arteries and a normal thoracic and abdominal aorta. Lorenz-Depiereux et al. (2010) found inappropriately elevated plasma FGF23 (605380) levels in all 6 patients with ENPP1 mutations and concluded that this is the fourth gene (in addition to PHEX (300550), DMP1 (600980), and FGF23 itself) that, if mutated, causes hypophosphatemic rickets due to elevated FGF23 levels. In a Bedouin family with ARHR mapping to chromosome 6q23, Levy-Litan et al. (2010) sequenced the candidate gene ENPP1 and identified homozygosity for a missense mutation (Y901S; 173335.0013) that segregated with disease and was not found in 236 Bedouin controls from the same geographic region. X-rays of the chest, abdomen, and lower limbs of the 3 affected individuals showed no evidence of vascular or periarticular calcifications. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Teeth \- Hypoplastic teeth (in 1 patient) \- Dental caries (rare) CARDIOVASCULAR Heart \- Thickening of aortic valves (in 1 patient) Vascular \- Aortic root dissection (in 1 patient) \- Pulmonary stenosis, mild (in 1 patient) GENITOURINARY Kidneys \- Medullary nephrocalcinosis (in 1 patient) SKELETAL \- Delayed bone age Pelvis \- Coxa valga (in 1 patient) Limbs \- Slight widening of the wrist \- Widening of growth pate of radius \- Widening of growth plate of ulna \- Cupping of growth plate of radius \- Cupping of growth plate of ulna \- Bowing of femur \- Genu valgum \- Genu varum \- Bowing of tibia LABORATORY ABNORMALITIES \- Hypophosphatemia \- Hyperphosphaturia \- Elevated plasma alkaline phosphatase \- Normal calcium level \- Normal calcium excretion \- Normal PTH \- Normal vitamin D metabolites MISCELLANEOUS \- Normal renal function \- No vascular or periarticular calcifications MOLECULAR BASIS \- Caused by mutation in the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene (ENPP1, 173335.0010 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2	c2750078	5,530	omim	https://www.omim.org/entry/613312	2019-09-22T15:59:02	{"doid": ["0050949"], "mesh": ["C567647"], "omim": ["613312"], "orphanet": ["289176"], "synonyms": ["ARHR"]}
A rare neurological disorder comprising fluctuating trunk and limb stiffness, painful muscle spasms, task-specific phobia, an exaggerated startle response, and ankylosing deformities such as fixed lumbar hyperlordosis. ## Epidemiology The prevalence is estimated at about 1/1,000,000. Approximately 2/3 of patients are female. ## Clinical description Age of onset peaks around 45 and symptoms develop over months or years. Progressive muscle stiffness renders the trunk and hips immobile, and the gait becomes stiff and awkward. Superimposed painful spontaneous or reflex-induced muscle spasms may cause serious falls. A specific fear of crossing open spaces (pseudo-agoraphobia) may induce freezing of gait, sudden spasms, and falls. Focal neurological signs are absent. Clinical variants of SMS include the stiff limb syndrome (SLS) where symptoms affect only one limb, and progressive encephalomyelitis with rigidity and myoclonus (PERM) where stiffness and myoclonic spasms are associated with focal neurological signs. Many patients with SMS, SLS, or PERM have insulin-dependent diabetes mellitus (30%), autoimmune thyroiditis (10%), atrophic gastritis with pernicious anaemia (5%), and some have tumours of the breast, lung, or colon. ## Etiology The presence of antibodies against glutamic acid decarboxylase (GAD-Abs) in more than 70% of cases suggests an autoimmune pathogenesis. GAD-Abs may block synthesis of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) thereby attenuating inhibition of spinal motoneurones. ## Diagnostic methods Diagnosis essentially relies on clinical observation, and is substantiated by detection of GAD-Abs in the serum and by characteristic electromyographic abnormalities. Scans of the spinal cord can help to exclude mechanical causes such as a cyst or disc compression of the spinal cord. Cerebrospinal fluid (CSF) examination is necessary to detect GAD-Abs in CSF and exclude active inflammation. ## Differential diagnosis Differential diagnosis includes an atypical manifestation of a spinal cord disease (e.g. multiple sclerosis; tumours), axial dystonia, neuromyotonia, acquired hyperekplexia (startle disease), and psychogenic movement disorders (see these terms). ## Management and treatment Benzodiazepines and baclofen are standard drugs for symptomatic treatment. Immunomodulating therapies (corticosteroids, intravenous immunoglobulin, and plasmapheresis) have been proposed with variable results. Treatments help to control symptoms in the majority of patients affected by SMS and SLS. PERM is slightly harder to control and may have 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Stiff person spectrum disorder	c0085292	5,531	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3198	2021-01-23T17:14:26	{"gard": ["5023"], "mesh": ["D016750"], "omim": ["184850"], "umls": ["C0085292"], "icd-10": ["G25.8"], "synonyms": ["Moersch-Woltman syndrome", "SMS", "SPS", "Stiff man syndrome"]}
Tailor's bunion Other namesBunionette or Digitus quintus varus Radiograph showing a tailor's bunion SpecialtyPodiatry Tailor's bunion is a condition caused as a result of inflammation of the fifth metatarsal bone at the base of the little toe.[1] It is usually characterized by inflammation, pain and redness of the little toe. Often a tailor's bunion is caused by a faulty mechanical structure of the foot. The fifth metatarsal bone starts to protrude outward, while the little toe moves inward. This change in alignment creates an enlargement on the outside of the foot. It is mostly similar to a bunion (the same type of ailment affecting the big toe). It is called Tailor's Bunion because in past centuries, tailors sat cross-legged,[2] and this was thought to cause this protrusion on the outside aspect of the foot. ## Contents * 1 Treatment * 2 Diagnosis * 3 See also * 4 References ## Treatment[edit] Non-surgical therapies include:[1] * Shoe modifications: wearing shoes that have a wide toe box, and avoiding those with pointed toes or high heels. * Oral nonsteroidal anti-inflammatory drugs may help in relieving the pain and inflammation. * Injections of corticosteroid are commonly used to treat the inflammation. * Bunionette pads placed over the affected area may help reduce pain. * An ice pack may be applied to reduce pain and inflammation. Surgery is often considered when pain continues for a long period with no improvement in these non-surgical therapies. ## Diagnosis[edit] Tailor's bunion is easily diagnosed because the protrusion is visually apparent. X-rays may be ordered to help the surgeon find out the severity of the deformity. ## See also[edit] Look up tailor-fashion in Wiktionary, the free dictionary. * Tailor's muscle ## References[edit] 1. ^ a b "Tailor's Bunion". footphysicians.com. Retrieved December 31, 2009. 2. ^ "A Patient's Guide to Bunionette (Tailor's Bunion)". Medical Multimedia Group. July 22, 2002. Retrieved May 3, 2015. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Tailor's bunion	c0263957	5,532	wikipedia	https://en.wikipedia.org/wiki/Tailor%27s_bunion	2021-01-18T18:59:58	{"mesh": ["D050489"], "wikidata": ["Q2928210"]}
Congenital hemolytic anemia characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood Congenital dyserythropoietic anemia Other namesCDA[1] CDA causes decrease in red blood cells SpecialtyHematology SymptomsWeakness[2] TypesCDA Type I, CDA Type II, CDA Type III, and CDA Type IV[1] Diagnostic methodGenetic testing[3] TreatmentBlood transfusions(also depends on which type)[4] Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood.[2] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 3.1 Types * 4 Treatment * 4.1 Gene therapy * 5 See also * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] The symptoms and signs of congenital dyserythropoietic anemia are consistent with:[2] * Tiredness (fatigue) * Weakness * Pale skin ## Genetics[edit] CDA may be transmitted by both parents autosomal recessively or dominantly and has four different subtypes, CDA Type I, CDA Type II, CDA Type III, and CDA Type IV . CDA type II (CDA II) is the most frequent type of congenital dyserythropoietic anemias. More than 300 cases have been described, but with the exception of a report by the International CDA II Registry, these reports include only small numbers of cases and no data on the lifetime evolution of the disease.[2][citation needed] Chromosome 15(KIF23) Type OMIM Gene Locus CDAN1 224120 CDAN1 (gene) 15q15 CDAN2 224100 SEC23B 20p11.2 CDAN3 105600 KIF23 15q21 CDAN4 613673 KLF1 19p13.13-p13.12 ## Diagnosis[edit] The diagnosis of congenital dyserythropoietic anemia can be done via sequence analysis of the entire coding region, types I,[5] II,[6] III[7] and IV ( is a relatively new form of CDA that had been found, just 4 cases have been reported[8]) according to the genetic testing registry.[citation needed] ### Types[edit] * Congenital dyserythropoietic anemia type I-is defined by moderate to severe macrocytic anemia (commonly in neonates as intrauterine growth retardation).[9] * Congenital dyserythropoietic anemia type II-is defined by moderate anemia, splenomegaly, and hepatomegaly.[10] * Congenital dyserythropoietic anemia type III\- is defined by mild anemia and retinal degeneration.[10] * Congenital dyserythropoietic anemia type IV\- is defined by having severe anemia at birth (type V and VI are recognized).[11][8] ## Treatment[edit] Deferasirox Treatment of individuals with CDA usually consist of frequent blood transfusions, but this can vary depending on the type that the individual has.[4] Patients report going every 2–3 weeks for blood transfusions.[citation needed] In addition, they must undertake chelation therapy to survive;[12] either deferoxamine, deferasirox, or deferiprone to eliminate the excess iron that accumulates.[13] Removal of the spleen[14] and gallbladder[15] are common. Hemoglobin levels can run anywhere between 8.0 g/dl and 11.0 g/dl in untransfused patients, the amount of blood received by the patient is not as important as their baseline pre-transfusion hemoglobin level.[16] This is true for ferritin levels and iron levels in the organs as well, it is important for patients to go regularly for transfusions in order to maximize good health, normal ferritin levels run anywhere between 24 and 336 ng/ml,[17] hematologists generally do not begin chelation therapy until ferritin levels reach at least 1000 ng/ml.[18] It is more important to check iron levels in the organs through MRI scans, however, than to simply get regular blood tests to check ferritin levels, which only show a trend, and do not reflect actual organ iron content.[13] ### Gene therapy[edit] Gene therapy, as well as, bone marrow transplant are also possible treatments for the disorder, but each have their own risks at this point in time. Bone marrow transplantation is the more used method between the two, whereas researchers are still trying to definitively establish the results of gene therapy treatment. It generally requires a 10/10 HLA matched donor, however, who is usually a sibling. As most patients do not have this, they must rely on gene therapy research to potentially provide them with an alternative.[medical citation needed] CDA at both clinical and genetic aspects are part of a heterogeneous group of genetic conditions. Gene therapy is still experimental and has largely only been tested in animal models until now. This type of therapy has promise, however, as it allows for the autologous transplantation of the patient's own healthy stem cells rather than requiring an outside donor, thereby bypassing any potential for graft vs. host disease (GVHD).[15][19] In the United States, the FDA approved clinical trials on Beta thalassemia patients in 2012. The first study, which took place in July 2012, recruited human subjects with thalassemia major,[20] ## See also[edit] * Thalassemia * Hemoglobinopathy * List of hematologic conditions ## References[edit] 1. ^ a b RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Congenital dyserythropoietic anemia". www.orpha.net. Retrieved 2 January 2018. 2. ^ a b c d "CDA". Genetics Home Reference. 2016-01-25. Retrieved 2016-01-29. 3. ^ "Congenital dyserythropoietic anemia - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2 January 2018. 4. ^ a b Greer, John P.; Arber, Daniel A.; Glader, Bertil; List, Alan F.; Means, Robert T.; Paraskevas, Frixos; Rodgers, George M. (2013-08-29). Wintrobe's Clinical Hematology. Lippincott Williams & Wilkins. p. 994. ISBN 9781469846224. 5. ^ "Congenital dyserythropoietic anemia, type I - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-01-29. 6. ^ "Congenital dyserythropoietic anemia, type II - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-01-29. 7. ^ "Congenital dyserythropoietic anemia, type III - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-01-29. 8. ^ a b RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Congenital dyserythropoietic anemia type IV". www.orpha.net. Retrieved 2016-01-29. 9. ^ Tamary, Hannah; Dgany, Orly (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Congenital Dyserythropoietic Anemia Type I. Seattle (WA): University of Washington, Seattle. PMID 20301759. 10. ^ a b Delaunay, Jean (2003). "Congenital dyserythropoietic anemia" (PDF). Orpha.net. Orphanet. Retrieved 29 January 2016. 11. ^ Lanzkowsky, Philip (2005-06-06). Manual of Pediatric Hematology and Oncology. Academic Press. p. 159. ISBN 9780123751553. 12. ^ "Congenital dyserythropoietic anemia type 2 \| Disease \| Treatment \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2016-01-29. 13. ^ a b "Iron Overload. Medical information about Iron Overload \| Patient". Patient. Retrieved 2016-01-29. 14. ^ Heimpel, Hermann; Anselstetter, Volker; Chrobak, Ladislav; Denecke, Jonas; Einsiedler, Beate; Gallmeier, Kerstin; Griesshammer, Antje; Marquardt, Thorsten; Janka-Schaub, Gritta (2003-12-15). "Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation". Blood. 102 (13): 4576–4581. doi:10.1182/blood-2003-02-0613. ISSN 0006-4971. PMID 12933587. 15. ^ a b Iolascon, A.; Esposito, M. R.; Russo, R. (2012-12-01). "Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach". Haematologica. 97 (12): 1786–1794. doi:10.3324/haematol.2012.072207. PMC 3590084. PMID 23065504. 16. ^ Denecke, Jonas; Marquardt, Thorsten (2009-09-01). "Congenital dyserythropoietic anemia type II (CDAII/HEMPAS): Where are we now?" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. Genetic Glycosylation Diseases. 1792 (9): 915–920. doi:10.1016/j.bbadis.2008.12.005. PMID 19150496. 17. ^ "Ferritin: Reference Range, Interpretation, Collection and Panels". 2018-07-05. Cite journal requires `\|journal=` (help) 18. ^ "Monitoring Treatment \| Treatment and Management \| Training & Education \| Hemochromatosis (Iron Storage Disease) \| NCBDDD \| CDC". www.cdc.gov. Retrieved 2016-01-29. 19. ^ "Gene Therapy is 'Becoming a Clinical Reality'". 20. ^ "Launch of Stem Cell Therapy Trial Offers Hope for Patients with Inherited Blood Disorder". ## Further reading[edit] * Greer, John P.; Arber, Daniel A.; Glader, Bertil; List, Alan F.; Means, Robert T.; Paraskevas, Frixos; Rodgers, George M. (2013-08-29). Wintrobe's Clinical Hematology. Lippincott Williams & Wilkins. ISBN 9781469846224. * Iolascon, Achille; Delaunay, Jean; Wickramasinghe, Sunitha N.; Perrotta, Silverio; Gigante, Maddalena; Camaschella, Clara (2001-08-15). "Natural history of congenital dyserythropoietic anemia type II". Blood. 98 (4): 1258–1260. doi:10.1182/blood.V98.4.1258. ISSN 0006-4971. PMID 11493480. ## External links[edit] Classification D * ICD-10: D64.4 * ICD-9-CM: 285.8 * MeSH: D000742 External resources * Orphanet: 85 Scholia has a topic profile for Congenital dyserythropoietic anemia. * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology 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Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline * v * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Congenital dyserythropoietic anemia	c0002876	5,533	wikipedia	https://en.wikipedia.org/wiki/Congenital_dyserythropoietic_anemia	2021-01-18T18:57:49	{"gard": ["1999"], "mesh": ["D000742"], "umls": ["C0002876"], "icd-9": ["285.8"], "orphanet": ["85"], "wikidata": ["Q5160422"]}
Cleft palate-large ears-small head syndrome is a rare, genetic syndrome characterized by cleft palate, large protruding ears, microcephaly and short stature (prenatal onset). Other skeletal abnormalities (delayed bone age, distally tapering fingers, hypoplastic distal phalanges, proximally placed thumbs, fifth finger clinodactyly), Pierre Robin sequence, cystic renal dysplasia, proximal renal tubular acidosis, hypospadias, cerebral anomalies on imaging (enlargement of lateral ventricles, mild cortical atrophy), seizures, hypotonia and developmental delay are also observed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Cleft palate-large ears-small head syndrome	c1867023	5,534	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2013	2021-01-23T17:33:09	{"gard": ["162"], "mesh": ["C536621"], "omim": ["181180"], "umls": ["C1867023"], "icd-10": ["Q87.8"], "synonyms": ["Say-Barber-Hobbs syndrome"]}
A rare genetic disease characterized by congenital cataract, neonatal hepatic failure and cholestatic jaundice, and global developmental delay. Neonatal death due to progressive liver failure has been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome	None	5,535	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=521432	2021-01-23T17:09:24	{}
An inherited lethal mitochondrial disorder characterized by fetal growth restriction (GR), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E). ## Epidemiology The typical GRACILE syndrome is prevalent in Finland, where it has an incidence of about 1/50,000 births. It has also rarely been found in Sweden and the U.K. ## Clinical description Fetal growth restriction appears early during the pregnancy without signs of chronic hypoxia. Because of small fetal size, the pregnancies are usually interrupted a few weeks before the estimated due date (median 38 gestational weeks). The newborn infant is small for gestational age (birth weight approximately 1,700 g) and develops fulminant lactic acidosis (median pH 7.02, lactate 12.8 mmol/l) during the first day of life. In metabolic screening, marked aminoaciduria is found due to renal proximal tubulopathy of Fanconi type. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. Further signs of hepatopathy are cholestasis with steatosis, fibrosis and cirrhosis. No dysmorphic features are noted. No distinct cerebral abnormalities have so far been found, however in some infants, EEG has been abnormal, maybe as a result of severe metabolic acidosis. The hearing response assessed with BAEP has been abnormal. ## Etiology GRACILE syndrome is caused by a mutation in BCS1L, located on chromosome 2q35, encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain. In Finnish patients, the disease is caused by one homozygous mutation (c.232A>G) leading to an amino acid change (Serine on position 78 to Glycine) in the BCS1L protein. Several recently discovered mutations in the gene can cause variable phenotypes ranging from neonatal GRACILE-like hepatopathy and tubulopathy to those presenting during infancy or childhood with encephalopathy and psychiatric disorders. ## Diagnostic methods GRACILE syndrome is suspected if an infant is severely small for gestational age, develops hypoglycemia and lactic acidosis, has tubulopathy and increased ferritin levels and shows signs of liver dysfunction. Iron overload is illustrated by increased plasma ferritin and decreased transferrin concentrations and accumulation of iron in the liver. In patients of Finnish descent, the diagnosis is confirmed by assessing the single-nucleotide polymorphism (accredited method in HUS-LAB, Helsinki). In other patients, the entire BCS1L gene should be sequenced. Respirometry should be performed in a mitochondrial laboratory. ## Differential diagnosis Other mitochondrial hepatopathies such as Pearson syndrome should be excluded. Disorders of mitochondrial fatty acid oxidation and Krebs cycle disorders may also mimic GRACILE syndrome. ## Antenatal diagnosis In families with a previous case of GRACILE syndrome or renal tubulopathy, encephalopathy, liver failure, the causative BCS1L mutation can be investigated antenatally. ## Genetic counseling GRACILE syndrome is inherited autosomal recessively so genetic counseling should be offered to affected families. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring. ## Management and treatment There is no cure for the disease and treatments are purely symptomatic. Infants require intensive care, including alkali therapy and supplementation of urinary losses. Lactic acidosis responds only slightly to treatment. ## Prognosis The prognosis is life threatening with half of infants decease during the first days of life and the other half not living past 4 months of age, mainly because of energy depletion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	GRACILE syndrome	c1864002	5,536	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=53693	2021-01-23T18:32:26	{"gard": ["1"], "mesh": ["C537934"], "omim": ["603358"], "umls": ["C1864002"], "icd-10": ["E88.8"], "synonyms": ["Fellman disease", "Growth restriction-aminoaciduria-cholestasis-iron overload-lactic acidosis-early death syndrome"]}
Pituitary stalk interruption syndrome (PSIS) is a congenital abnormality of the pituitary gland characterized by the triad of a very thin or interrupted pituitary stalk, a misplaced (ectopic) or absent posterior pituitary and a small or absent anterior pituitary, with permanent growth hormone (GH) deficit. Signs and symptoms in newborns include low blood sugar levels (hypoglycemia), jaundice, congenital abnormalities and small penis (micropenis) and/or testis that are not in the scrotal sac (cryptorchidism). Later in childhood, signs may include short stature, seizures, low arterial pressure (hypotension) and/or intellectual delay. Some people can also have vision problems (septooptic dysplasia) and Fanconi anemia. The cause of this condition is unknown. Rare mutations in the HESX1, LHX4, OTX2, SOX3, and PROKR2 genes can be the cause in familial cases. The diagnosis is confirmed through MRI showing the characteristic findings. Treatment is based on replacement of deficient hormones, particularly GH, and should be started at birth to avoid hormone deficiencies and intellectual delay. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pituitary stalk interruption syndrome	c4053775	5,537	gard	https://rarediseases.info.nih.gov/diseases/13209/pituitary-stalk-interruption-syndrome	2021-01-18T17:58:18	{"orphanet": ["95496"], "synonyms": ["PSIS", "Ectopic neurohypophysis"]}
Bietti crystalline dystrophy is a disorder in which numerous small, yellow or white crystal-like deposits of fatty (lipid) compounds accumulate in the light-sensitive tissue that lines the back of the eye (the retina). The deposits damage the retina, resulting in progressive vision loss. People with Bietti crystalline dystrophy typically begin noticing vision problems in their teens or twenties. They experience a loss of sharp vision (reduction in visual acuity) and difficulty seeing in dim light (night blindness). They usually lose areas of vision (visual field loss), most often side (peripheral) vision. Color vision may also be impaired. The vision problems may worsen at different rates in each eye, and the severity and progression of symptoms varies widely among affected individuals, even within the same family. However, most people with this condition become legally blind by their forties or fifties. Most affected individuals retain some degree of vision, usually in the center of the visual field, although it is typically blurry and cannot be corrected by glasses or contact lenses. Vision impairment that cannot be improved with corrective lenses is called low vision. ## Frequency Bietti crystalline dystrophy has been estimated to occur in 1 in 67,000 people. It is more common in people of East Asian descent, especially those of Chinese and Japanese background. Researchers suggest that Bietti crystalline dystrophy may be underdiagnosed because its symptoms are similar to those of other eye disorders that progressively damage the retina. ## Causes Bietti crystalline dystrophy is caused by mutations in the CYP4V2 gene. This gene provides instructions for making a member of the cytochrome P450 family of enzymes. These enzymes are involved in the formation and breakdown of various molecules and chemicals within cells. The CYP4V2 enzyme is involved in a multi-step process called fatty acid oxidation in which lipids are broken down and converted into energy, but the enzyme's specific function is not well understood. CYP4V2 gene mutations that cause Bietti crystalline dystrophy impair or eliminate the function of this enzyme and are believed to affect lipid breakdown. However, it is unknown how they lead to the specific signs and symptoms of Bietti crystalline dystrophy. For unknown reasons, the severity of the signs and symptoms differs significantly among individuals with the same CYP4V2 gene mutation. ### Learn more about the gene associated with Bietti crystalline dystrophy * CYP4V2 ## 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Bietti crystalline dystrophy	c1859486	5,538	medlineplus	https://medlineplus.gov/genetics/condition/bietti-crystalline-dystrophy/	2021-01-27T08:25:43	{"gard": ["10050"], "mesh": ["C535440"], "omim": ["210370"], "synonyms": []}
Denial of pregnancy (also called pregnancy denial) is a form of denial exhibited by women to either the fact or the implications of their own pregnancy. One study found that women who denied their pregnancy represented 0.26% of all deliveries.[1] A later study cited that at 20 weeks gestation approximately 1 in 475 pregnant women denied their pregnancy, and said the proportion of cases persisting even until delivery is about 1 in 2500 refusing to acknowledge that they are pregnant.[2] ## Contents * 1 Psychotic denial * 2 See also * 3 References * 4 Further reading ## Psychotic denial[edit] This is a form of denial that is so extreme as to fall under the category of delusion. While physical symptoms of pregnancy do usually occur, they are sometimes misinterpreted by the woman. Some women interpret the sensation of something growing inside them as cancer, or a blood clot. Some women might believe fetal movements are their organs coming loose inside their body.[3] During the psychotic denial pregnancy, women tend to hide their pregnancy from everyone and put their fetus at a high risk.[4] ## See also[edit] * Cryptic pregnancy * False pregnancy ## References[edit] 1. ^ Friedman, Susan Hatters; Heneghan, Amy; Rosenthal, Miriam (2007). "Characteristics of Women Who Deny or Conceal Pregnancy". Psychosomatics. 48 (2): 117–22. doi:10.1176/appi.psy.48.2.117. PMID 17329604. 2. ^ Jenkins A, Millar S, Robins J (July 2011). "Denial of pregnancy: a literature review and discussion of ethical and legal issues". Journal of the Royal Society of Medicine. 104 (7): 286–91. doi:10.1258/jrsm.2011.100376. PMC 3128877. PMID 21725094. 3. ^ Miller, Laura J. (2008). "Denial of Pregnancy". In Spinelli, Margaret G. (ed.). Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. American Psychiatric. pp. 81–104. ISBN 978-1-58562-754-7. 4. ^ Miller, Laura J. (1990). "Psychotic Denial of Pregnancy: Phenomenology and Clinical Management". Psychiatric Services. 41 (11): 1233–7. doi:10.1176/ps.41.11.1233. PMID 2249803. ## Further reading[edit] * Wessel, Jens; Gauruder-Burmester, Annett; Gerlinger, Christoph (2007). "Denial of pregnancy – characteristics of women at risk". Acta Obstetricia et Gynecologica Scandinavica. 86 (5): 542–6. doi:10.1080/00016340601159199. PMID 17464581. * Beier, Klaus M.; Wille, Reinhard; Wessel, Jens (2006). "Denial of pregnancy as a reproductive dysfunction: A proposal for international classification systems". Journal of Psychosomatic Research. 61 (5): 723–30. doi:10.1016/j.jpsychores.2005.11.002. PMID 17084153. * Kaplan, Robert; Grotowski, Therese (1996). "Denied pregnancy". Australian and New Zealand Journal of Psychiatry. 30 (6): 861–3. doi:10.3109/00048679609065056. PMID 9034478. * Spielvogel, Anna M.; Hohener, Heidi C. (1995). "Denial of Pregnancy: A Review and Case Reports". Birth. 22 (4): 220–6. doi:10.1111/j.1523-536X.1995.tb00262.x. PMID 8573237. * Brezinka, C.; Brezinka, C.; Biebl, W.; Kinzl, J. (1994). "Denial of pregnancy: obstetrical aspects". Journal of Psychosomatic Obstetrics & Gynecology. 15 (1): 1–8. doi:10.3109/01674829409025623. 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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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Denial of pregnancy	None	5,539	wikipedia	https://en.wikipedia.org/wiki/Denial_of_pregnancy	2021-01-18T18:51:18	{"wikidata": ["Q3044521"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (February 2013) Injection fibrosis is a complication of intramuscular injection, occurring especially often in infants and children. Injections are often delivered to the quadriceps, triceps, and gluteal muscles, and thus the complication often manifests itself in those muscles. Patients are unable to fully flex the affected muscle. The condition is painless but progressively worsens over time. Orthopedic surgery is the typical treatment.[1] ## See also[edit] * Fibrosis ## References[edit] 1. ^ Mukherjee PK, Das AK (1980). "Injection fibrosis in the quadriceps femoris muscle in children". J Bone Joint Surg Am. 62 (3): 453–6. doi:10.2106/00004623-198062030-00016. PMID 7364817. This article about a disease of musculoskeletal and connective tissue 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Injection fibrosis	c0151649	5,540	wikipedia	https://en.wikipedia.org/wiki/Injection_fibrosis	2021-01-18T18:47:22	{"umls": ["C0151649"], "wikidata": ["Q6034286"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-20 (SCAR20) is caused by homozygous mutation in the SNX14 gene (616105) on chromosome 6q14. Description Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by Thomas et al., 2014). Clinical Features Sousa et al. (2014) reported 22- and 19-year-old Portuguese sisters, born of consanguineous parents, with severely delayed psychomotor development and intellectual disability, hypotonia, ataxia, and absent speech. The disorder became apparent in early infancy. Additional neurologic features included hyporeflexia, apraxia, spasticity, and extensor plantar responses. Both patients also had relative macrocephaly, high palate with dental crowding, and coarse facies manifest as short palpebral fissures, broad nasal base, long and broad philtrum, and thick lips. Clinodactyly, camptodactyly, and talipes equinovarus were noted. Brain imaging showed cerebellar hypoplasia and thickening of the cranial vault in both patients; nonspecific white matter abnormalities were found in 1 patient. Thomas et al. (2014) reported 5 children from 2 unrelated consanguineous families who had developmental delay, severe intellectual disability, and cerebellar ataxia. The patients also had progressive coarsening of facial features, relative macrocephaly, and progressive cerebellar atrophy on brain imaging. Some had sensorineural hearing loss; seizures were not present. Akizu et al. (2015) reported 12 consanguineous families, all of Arab descent, in which multiple children presented in the first months or years of life with severely delayed psychomotor development, coarse facial features, absent or delayed speech, hypotonia, decreased deep tendon reflexes, and a wide-based, staggering gait or inability to walk. The children were noted to have coarse facial features, including prominent forehead, epicanthal folds, long philtrum, and full lips. More variable features included nystagmus, seizures, hearing loss, kyphoscoliosis, hepatosplenomegaly, macroglossia, hypertrichosis, and autistic features. All patients had cerebellar and cerebral atrophy on brain imaging. Five patients had altered urine oligosaccharides or glycosaminoglycans, but most had normal urinary studies. Neuropathologic examination of 1 child showed almost complete absence of Purkinje cells in the cerebellum and neuronal loss in the cortex. Inheritance The transmission pattern of SCAR20 in the families reported by Sousa et al. (2014), Thomas et al. (2014), and Akizu et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of 3 unrelated consanguineous families with autosomal recessive SCAR20, including the family reported by Sousa et al. (2014), Thomas et al. (2014) identified 3 different homozygous mutations in the SNX14 gene (616105.0001-616105.0003). Two of the mutations were truncating, and 1 was an intragenic deletion. The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the families. The findings were consistent with a loss of function. Patient fibroblasts showed cytoplasmic vacuolation with electron-dense material, some reminiscent of lamellar bodies, suggesting a defect in the autophagy pathway. Sequencing of the SNX14 gene in 36 additional patients with pontocerebellar hypoplasia and 168 with idiopathic cerebellar ataxia did not identify any mutations. Thomas et al. (2014) postulated a role for SNX14 in the breakdown and recycling of cellular components in human cerebellar development and maintenance. In affected members of 12 consanguineous families of Arab descent with SCAR20, Akizu et al. (2015) identified homozygous truncating mutations in the SNX14 gene (see, e.g., 616105.0004-616105.0007). The mutations in 2 families were found by whole-exome sequencing, and mutations in the remaining families were identified by focusing on the SNX14 gene. Overall, SNX14 mutations accounted for 9.9% of the larger cohort of families with cerebellar ataxia who underwent exome sequencing. Patient-derived neuronal cells showed absence of the SNX14 protein, increased lysosomal size, and impaired autophagosome clearance. Akizu et al. (2015) postulated a role for SNX14 in mediating the fusion of lysosomes to autophagosomes. Animal Model Akizu et al. (2015) found that morpholino knockdown of the snx14 ortholog in zebrafish resulted in loss of neural tissue volume, reduced cellular area, activation of apoptosis, and impaired autophagic degradation. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Macrocephaly, relative Face \- Prominent forehead \- Coarse facial features \- Broad face \- Long philtrum \- Broad philtrum Ears \- Sensorineural hearing loss (in some patients) Eyes \- Short palpebral fissures \- Fullness of the upper eyelid \- Epicanthal folds \- Nystagmus (in some patients) Nose \- Broad nasal base \- Underdevelopment of the nasal alae \- Upturned nares Mouth \- High-arched palate \- Thick lips \- Macroglossia (in some patients) Teeth \- Delayed tooth eruption \- Dental crowding SKELETAL Spine \- Scoliosis (in some patients) Hands \- Clinodactyly \- Camptodactyly \- Brachydactyly Feet \- Talipes equinovarus \- Brachydactyly SKIN, NAILS, & HAIR Hair \- Hypertrichosis (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Poor or absent speech \- Ataxia \- Inability to walk \- Apraxia \- Spasticity \- Extensor plantar responses \- Seizures (in some patients) \- Cerebellar hypoplasia \- Cerebellar atrophy, progressive \- Cortical atrophy \- Decreased Purkinje cells in the cerebellum Peripheral Nervous System \- Hyporeflexia Behavioral Psychiatric Manifestations \- Autistic behavior MISCELLANEOUS \- Onset in infancy MOLECULAR BASIS \- Caused by mutation in the sorting nexin 14 gene (SNX14, 616105.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 20	c4225355	5,541	omim	https://www.omim.org/entry/616354	2019-09-22T15:49:10	{"doid": ["0080066"], "omim": ["616354"], "orphanet": ["397709"], "synonyms": ["Autosomal recessive spinocerebellar ataxia type 20", "Intellectual disability-coarse face-macrocephaly-cerebellar hypoplasia syndrome", "SCAR20"]}
Alcoholic liver disease Other namesAlcohol-related liver disease Microscopy of liver showing fatty change, cell necrosis, Mallory bodies SpecialtyGastroenterology Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis.[1] It is the major cause of liver disease in Western countries. Although steatosis (fatty liver disease) will develop in any individual who consumes a large quantity of alcoholic beverages over a long period of time, this process is transient and reversible.[1] More than 90% of all heavy drinkers develop fatty liver whilst about 25% develop the more severe alcoholic hepatitis, and 15% cirrhosis.[2] ## Contents * 1 Risk factors * 2 Pathophysiology * 2.1 Fatty change * 2.2 Alcoholic hepatitis * 2.3 Cirrhosis * 3 Diagnosis * 3.1 Laboratory findings * 4 Treatment * 4.1 Medications * 4.2 Transplantation * 5 Prognosis * 6 References * 7 Further reading * 8 External links ## Risk factors[edit] The risk factors presently (2010) known are: * Quantity of alcohol taken: Consumption of 60–80g per day (14g is considered one standard drink in the US, i.e., 1.5 fl oz hard liquor, 5 fl oz wine, 12 fl oz beer; drinking a six-pack of 5% ABV beer daily would be 84g and just over the upper limit) for 20 years or more in men, or 20g/day for women significantly increases the risk of hepatitis and fibrosis by 7% to 47%,[1][3] * Pattern of drinking: Drinking outside of meal times increases up to 3 times the risk of alcoholic liver disease.[4] * Sex: Women are twice as susceptible to alcohol-related liver disease, and may develop alcoholic liver disease with shorter durations and doses of chronic consumption. The lesser amount of alcohol dehydrogenase secreted in the gut, higher proportion of body fat in women, and changes in fat absorption due to the menstrual cycle may explain this phenomenon.[4] * Hepatitis C infection: A concomitant hepatitis C infection significantly accelerates the process of liver injury.[4] * Genetic factors: Genetic factors predispose both to alcoholism and to alcoholic liver disease. Both monozygotic twins are more likely to be alcoholics and to develop liver cirrhosis than both dizygotic twins. Polymorphisms in the enzymes involved in the metabolism of alcohol, such as ADH, ALDH, CYP4502E1, mitochondrial dysfunction, and cytokine polymorphism may partly explain this genetic component. However, no specific polymorphisms have currently been firmly linked to alcoholic liver disease. * Iron overload (hemochromatosis) * Diet: Malnutrition, particularly vitamin A and E deficiencies, can worsen alcohol-induced liver damage by preventing regeneration of hepatocytes. This is particularly a concern as alcoholics are usually malnourished because of a poor diet, anorexia, and encephalopathy.[4] ## Pathophysiology[edit] Pathogenesis of alcohol induced liver injury The mechanism of ALD is not completely understood. 80% of alcohol passes through the liver to be detoxified. Chronic consumption of alcohol results in the secretion of pro-inflammatory cytokines (TNF-alpha, Interleukin 6 [IL6] and Interleukin 8 [IL8]), oxidative stress, lipid peroxidation, and acetaldehyde toxicity. These factors cause inflammation, apoptosis and eventually fibrosis of liver cells. Why this occurs in only a few individuals is still unclear. Additionally, the liver has tremendous capacity to regenerate and even when 75% of hepatocytes are dead, it continues to function as normal.[5] ### Fatty change[edit] Main article: Fatty liver Fatty change, or steatosis, is the accumulation of fatty acids in liver cells. These can be seen as fatty globules under the microscope. Alcoholism causes development of large fatty globules (macro-vesicular steatosis) throughout the liver and can begin to occur after a few days of heavy drinking.[6] Alcohol is metabolized by alcohol dehydrogenase (ADH) into acetaldehyde, then further metabolized by aldehyde dehydrogenase (ALDH) into acetic acid, which is finally oxidized into carbon dioxide (CO 2) and water (H 2O).[7] This process generates NADH, and increases the NADH/NAD+ ratio. A higher NADH concentration induces fatty acid synthesis while a decreased NAD level results in decreased fatty acid oxidation. Subsequently, the higher levels of fatty acids signal the liver cells to compound it to glycerol to form triglycerides. These triglycerides accumulate, resulting in fatty liver. ### Alcoholic hepatitis[edit] Main article: Alcoholic hepatitis Alcoholic hepatitis is characterized by the inflammation of hepatocytes. Between 10% and 35% of heavy drinkers develop alcoholic hepatitis (NIAAA, 1993). While development of hepatitis is not directly related to the dose of alcohol, some people seem more prone to this reaction than others. This is called alcoholic steato-necrosis and the inflammation appears to predispose to liver fibrosis. Inflammatory cytokines (TNF-alpha, IL6 and IL8) are thought to be essential in the initiation and perpetuation of liver injury by inducing apoptosis and necrosis. One possible mechanism for the increased activity of TNF-α is the increased intestinal permeability due to liver disease. This facilitates the absorption of the gut-produced endotoxin into the portal circulation. The Kupffer cells of the liver then phagocytose endotoxin, stimulating the release of TNF-α. TNF-α then triggers apoptotic pathways through the activation of caspases, resulting in cell death.[4] ### Cirrhosis[edit] Main article: Cirrhosis Cirrhosis is a late stage of serious liver disease marked by inflammation (swelling), fibrosis (cellular hardening) and damaged membranes preventing detoxification of chemicals in the body, ending in scarring and necrosis (cell death).[8] Between 10% to 20% of heavy drinkers will develop cirrhosis of the liver (NIAAA, 1993). Acetaldehyde may be responsible for alcohol-induced fibrosis by stimulating collagen deposition by hepatic stellate cells.[4] The production of oxidants derived from NADPH oxi- dase and/or cytochrome P-450 2E1 and the formation of acetaldehyde-protein adducts damage the cell membrane.[4] Symptoms include jaundice (yellowing), liver enlargement, and pain and tenderness from the structural changes in damaged liver architecture. Without total abstinence from alcohol use, cirrhosis will eventually lead to liver failure. Late complications of cirrhosis or liver failure include portal hypertension (high blood pressure in the portal vein due to the increased flow resistance through the damaged liver), coagulation disorders (due to impaired production of coagulation factors), ascites (heavy abdominal swelling due to buildup of fluids in the tissues) and other complications, including hepatic encephalopathy and the hepatorenal syndrome. Cirrhosis can also result from other causes than alcohol abuse, such as viral hepatitis and heavy exposure to toxins other than alcohol. The late stages of cirrhosis may look similar medically, regardless of cause. This phenomenon is termed the "final common pathway" for the disease. Fatty change and alcoholic hepatitis with abstinence can be reversible. The later stages of fibrosis and cirrhosis tend to be irreversible, but can usually be contained with abstinence for long periods of time. ## Diagnosis[edit] In the early stages, patients with ALD exhibit subtle and often no abnormal physical findings. It is usually not until development of advanced liver disease that stigmata of chronic liver disease become apparent. Early ALD is usually discovered during routine health examinations when liver enzyme levels are found to be elevated. These usually reflect alcoholic hepatic steatosis. Microvesicular and macrovesicular steatosis with inflammation are seen in liver biopsy specimens. These histologic features of ALD are indistinguishable from those of nonalcoholic fatty liver disease. Steatosis usually resolves after discontinuation of alcohol use. Continuation of alcohol use will result in a higher risk of progression of liver disease and cirrhosis. In patients with acute alcoholic hepatitis, clinical manifestations include fever, jaundice, hepatomegaly, and possible hepatic decompensation with hepatic encephalopathy, variceal bleeding, and ascites accumulation. Tender hepatomegaly may be present, but abdominal pain is unusual. Occasionally, the patient may be asymptomatic.[9] ### Laboratory findings[edit] In people with alcoholic hepatitis, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is greater than 2:1. AST and ALT levels are almost always less than 500. The elevated AST to ALT ratio is due to deficiency of pyridoxal phosphate, which is required in the ALT enzyme synthetic pathway. Furthermore, alcohol metabolite–induced injury of hepatic mitochondria results in AST isoenzyme release. Other laboratory findings include red blood cell macrocytosis (mean corpuscular volume > 100) and elevations of serum gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels. Folate level is reduced in alcoholic patients due to decreased intestinal absorption, increased bone marrow requirement for folate in the presence of alcohol, and increased urinary loss. The magnitude of leukocytosis (white blood cell depletion) reflects severity of liver injury. Histologic features include Mallory bodies, giant mitochondria, hepatocyte necrosis, and neutrophil infiltration in the area around the veins. Mallory bodies, which are also present in other liver diseases, are condensations of cytokeratin components in the hepatocyte cytoplasm and do not contribute to liver injury. Up to 70% of patients with moderate to severe alcoholic hepatitis already have cirrhosis identifiable on biopsy examination at the time of diagnosis.[10] ## Treatment[edit] Not drinking further alcohol is the most important part of treatment.[11] People with chronic HCV infection should abstain from any alcohol intake, due to the risk for rapid acceleration of liver disease.[10] ### Medications[edit] A 2006 Cochrane review did not find evidence sufficient for the use of androgenic anabolic steroids.[12] Corticosteroids are sometimes used; however, this is recommended only when severe liver inflammation is present.[11] Silymarin has been investigated as a possible treatment, with ambiguous results.[13][14][15] One review claimed benefit for S-adenosyl methionine in disease models.[16][17] The effects of anti-tumor necrosis factor medications such as infliximab and etanercept are unclear and possibly harmful.[18] Evidence is unclear for pentoxifylline.[11][19] Propylthiouracil may result in harm.[20] Evidence does not support supplemental nutrition in liver disease.[21] ### Transplantation[edit] Although in rare cases liver cirrhosis is reversible, the disease process remains mostly irreversible. Liver transplantation remains the only definitive therapy. Today, survival after liver transplantation is similar for people with ALD and non-ALD. The requirements for transplant listing are the same as those for other types of liver disease, except for a 6-month sobriety prerequisite along with psychiatric evaluation and rehabilitation assistance.[22][clarification needed] Specific requirements vary among the transplant centers. Relapse to alcohol use after transplant listing results in delisting. Re-listing is possible in many institutions, but only after 3–6 months of sobriety. There are limited data on transplant survival in patients transplanted for acute alcoholic hepatitis, but it is believed to be similar to that in nonacute ALD, non-ALD, and alcoholic hepatitis with MDF less than 32.[23] ## Prognosis[edit] The prognosis for people with ALD depends on the liver histology as well as cofactors, such as concomitant chronic viral hepatitis. Among patients with alcoholic hepatitis, progression to liver cirrhosis occurs at 10–20% per year, and 70% will eventually develop cirrhosis. Despite cessation of alcohol use, only 10% will have normalization of histology and serum liver enzyme levels.[24] As previously noted, the MDF has been used to predict short-term mortality (i.e., MDF ≥ 32 associated with spontaneous survival of 50–65% without corticosteroid therapy, and MDF < 32 associated with spontaneous survival of 90%). The Model for End-Stage Liver Disease (MELD) score has also been found to have similar predictive accuracy in 30-day (MELD > 11) and 90-day (MELD > 21) mortality. Liver cirrhosis develops in 6–14% of those who consume more than 60–80 g of alcohol daily for men and more than 20 g daily for women. Even in those who drink more than 120 g daily, only 13.5% will suffer serious alcohol-related liver injury. Nevertheless, alcohol-related mortality was the third leading cause of death in 2003 in the United States. Worldwide mortality is estimated to be 150,000 per year.[25] ## References[edit] 1. ^ a b c O'Shea RS, Dasarathy S, McCullough AJ (January 2010). "Alcoholic liver disease: AASLD Practice Guidelines" (PDF). Hepatology. 51 (1): 307–28. doi:10.1002/hep.23258. PMID 20034030. Archived from the original (PDF) on 21 October 2014. Retrieved 18 October 2011. 2. ^ Basra, Sarpreet (2011). "Definition, epidemiology and magnitude of alcoholic hepatitis". World Journal of Hepatology. 3 (5): 108–113. doi:10.4254/wjh.v3.i5.108. PMC 3124876. PMID 21731902. 3. ^ Mandayam S, Jamal MM, Morgan TR (August 2004). "Epidemiology of alcoholic liver disease". Semin. Liver Dis. 24 (3): 217–32. CiteSeerX 10.1.1.594.1256. doi:10.1055/s-2004-832936. PMID 15349801. 4. ^ a b c d e f g Menon KV, Gores GJ, Shah VH (October 2001). "Pathogenesis, diagnosis, and treatment of alcoholic liver disease" (PDF). Mayo Clin. Proc. 76 (10): 1021–9. doi:10.4065/76.10.1021. PMID 11605686. 5. ^ Longstreth, George F.; Zieve, David, eds. (18 October 2009). "Alcoholic Liver Disease". MedLinePlus: Trusted Health Information for You. Bethesda, MD: US National Library of Medicine & National Institutes of Health. Archived from the original on 22 January 2010. Retrieved 27 January 2010. 6. ^ Inaba, Darryl; Cohen, William B. (2004). Uppers, downers, all arounders: physical and mental effects of psychoactive drugs (5th ed.). Ashland, Or: CNS Publications. ISBN 978-0-926544-27-7. 7. ^ Inaba & Cohen 2004, p. 185 8. ^ Loyd, Dr. Stephen (15 February 2020). "What are the early signs of liver damage?". journeypure.com. Retrieved 11 June 2020. 9. ^ McCullough, AJ; O'Connor, JF (November 1998). "Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology". The American Journal of Gastroenterology. 93 (11): 2022–36. PMID 9820369. 10. ^ a b Niemelä, O (February 2007). "Biomarkers in alcoholism". Clinica Chimica Acta. 377 (1–2): 39–49. doi:10.1016/j.cca.2006.08.035. PMID 17045579. 11. ^ a b c Suk, KT; Kim, MY; Baik, SK (28 September 2014). "Alcoholic liver disease: treatment". World Journal of Gastroenterology. 20 (36): 12934–44. doi:10.3748/wjg.v20.i36.12934. PMC 4177474. PMID 25278689. 12. ^ Rambaldi, A; Gluud, C (18 October 2006). "Anabolic-androgenic steroids for alcoholic liver disease". The Cochrane Database of Systematic Reviews (4): CD003045. doi:10.1002/14651858.CD003045.pub2. PMID 17054157. 13. ^ Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, et al. (1989). "Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver". J Hepatol. 9 (1): 105–113. doi:10.1016/0168-8278(89)90083-4. PMID 2671116. 14. ^ Rambaldi A, Jacobs BP, Iaquinto G, Gluud C (November 2005). "Milk thistle for alcoholic and/or hepatitis B or C liver diseases—a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials". Am. J. Gastroenterol. 100 (11): 2583–91. PMID 16279916. 15. ^ Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C (2011). Bjelakovic G (ed.). "Antioxidant supplements for liver diseases". Cochrane Database Syst Rev (3): CD007749. doi:10.1002/14651858.CD007749.pub2. PMID 21412909. 16. ^ Cederbaum AI, Department of Pharmacology and Systems Therapeutics, Box 1603, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029, United States (March 2010). "Hepatoprotective effects of S -adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury". World J Gastroenterol. 16 (11): 1366–1376. doi:10.3748/wjg.v16.i11.1366. PMC 2842529. PMID 20238404. 17. ^ Rambaldi, A; Gluud, C (19 April 2006). Rambaldi, Andrea (ed.). "S-adenosyl-L-methionine for alcoholic liver diseases". The Cochrane Database of Systematic Reviews (2): CD002235. doi:10.1002/14651858.CD002235.pub2. PMID 16625556. (Retracted, see doi:10.1002/14651858.cd002235.pub3. If this is an intentional citation to a retracted paper, please replace `{{Retracted}}` with `{{Retracted\|intentional=yes}}`.) 18. ^ Tilg, H; Day, CP (January 2007). "Management strategies in alcoholic liver disease". Nature Clinical Practice Gastroenterology & Hepatology. 4 (1): 24–34. doi:10.1038/ncpgasthep0683. PMID 17203086. S2CID 22443776. 19. ^ Whitfield, K; Rambaldi, A; Wetterslev, J; Gluud, C (7 October 2009). "Pentoxifylline for alcoholic hepatitis". The Cochrane Database of Systematic Reviews (4): CD007339. doi:10.1002/14651858.CD007339.pub2. PMC 6769169. PMID 19821406. 20. ^ Fede, G; Germani, G; Gluud, C; Gurusamy, KS; Burroughs, AK (15 June 2011). "Propylthiouracil for alcoholic liver disease". The Cochrane Database of Systematic Reviews (6): CD002800. doi:10.1002/14651858.CD002800.pub3. PMC 7098215. PMID 21678335. 21. ^ Koretz, RL; Avenell, A; Lipman, TO (16 May 2012). "Nutritional support for liver disease". The Cochrane Database of Systematic Reviews. 5 (5): CD008344. doi:10.1002/14651858.CD008344.pub2. PMC 6823271. PMID 22592729. 22. ^ Stravitz, R. Todd (2006). "Management of the Cirrhotic Patient Before Liver Transplantation: The Role of the Referring Gastroenterologist". Gastroenterology & Hepatology. 2 (5): 346–354. ISSN 1554-7914. PMC 5338188. PMID 28289338. 23. ^ Neuberger, J; Schulz, KH; Day, C; Fleig, W; Berlakovich, GA; Berenguer, M; Pageaux, GP; Lucey, M; Horsmans, Y; Burroughs, A; Hockerstedt, K (January 2002). "Transplantation for alcoholic liver disease". Journal of Hepatology. 36 (1): 130–7. doi:10.1016/s0168-8278(01)00278-1. PMC 1837536. PMID 11804676. 24. ^ Dunn, W; Jamil, LH; Brown, LS; Wiesner, RH; Kim, WR; Menon, KV; Malinchoc, M; Kamath, PS; Shah, V (February 2005). "MELD accurately predicts mortality in patients with alcoholic hepatitis". Hepatology. 41 (2): 353–8. doi:10.1002/hep.20503. PMID 15660383. 25. ^ Sheth, M; Riggs, M; Patel, T (2002). "Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis". BMC Gastroenterology. 2 (1): 2. doi:10.1186/1471-230X-2-2. PMC 65516. PMID 11835693. ## Further reading[edit] * "Alcoholic liver disease (per capita) (most recent) by country". NationMaster. Archived from the original on 21 June 2009. Retrieved 29 July 2009. ## External links[edit] Classification D * ICD-10: K70 * ICD-9-CM: 571.1 * MeSH: D008108 External resources * MedlinePlus: 000281 * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous system diseases * Alcohol-related dementia (ARD) * Alcohol intoxication * Hangover Neurological disorders * Alcoholic hallucinosis * Alcoholic polyneuropathy * Alcohol-related brain damage * Alcohol withdrawal syndrome (AWS): * Alcoholic hallucinosis * Delirium tremens (DTs) * Fetal alcohol spectrum disorder (FASD) * Fetal alcohol syndrome (FAS) * Korsakoff syndrome * Positional alcohol nystagmus (PAN) * Wernicke–Korsakoff syndrome (WKS, Korsakoff psychosis) * Wernicke encephalopathy (WE) Respiratory tract diseases * Alcohol-induced respiratory reactions * Alcoholic lung disease SUD * Alcoholism (alcohol use disorder (AUD)) * Binge drinking Caffeine * SID * Caffeine-induced anxiety disorder * Caffeine-induced sleep disorder * Caffeinism * SUD * Caffeine dependence Cannabis * SID * Cannabis arteritis * Cannabinoid hyperemesis syndrome (CHS) * SUD * Amotivational syndrome * Cannabis use disorder (CUD) * Synthetic cannabinoid use disorder Cocaine * SID * Cocaine intoxication * Prenatal cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum Authority control * NDL: 01169255 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Alcoholic liver disease	c0023896	5,542	wikipedia	https://en.wikipedia.org/wiki/Alcoholic_liver_disease	2021-01-18T18:38:47	{"mesh": ["D008108"], "icd-9": ["571.1"], "icd-10": ["K70"], "wikidata": ["Q558404"]}
Ring chromosome 15 is a chromosome abnormality that affects growth, learning, and speech. People with ring chromosome 15 often have growth delays before and after birth, resulting in short stature; varying degrees of intellectual disability; low muscle tone (hypotonia); craniofacial malformations; and limb abnormalities. Other symptoms might include congenital heart defects, kidney problems, congenital dislocation of the hips, and cafe-au-lait spots. Ring chromosome 15 is caused by an abnormal chromosome known as a ring chromosome 15 or r(15). A ring chromosome is a circular structure that occurs when a chromosome breaks in two places and the broken ends fuse together. The features of ring chromosome 15 appear to result from the loss (deletion) of genetic material from the long (q) arm of chromosome 15. Ring chromosome 15 is usually caused by spontaneous (de novo) errors very early in embryonic development. In rare cases, it is passed through families, either from a parent who also has a ring chromosome 15, or from a parent who has a balanced translocation. Treatment for ring chromosome 15 is focused on addressing the symptoms present in each individual and may require a team of medical specialists. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Ring chromosome 15	c2931703	5,543	gard	https://rarediseases.info.nih.gov/diseases/1328/ring-chromosome-15	2021-01-18T17:57:53	{"mesh": ["C538035"], "umls": ["C2931703"], "orphanet": ["96177"], "synonyms": ["Chromosome 15 ring", "Ring 15", "R15"]}
Nodding disease Other namesNodding syndrome Map of counties of South Sudan affected by nodding disease. Several of these are in the Central Equatoria state, in the south of the country near the border with Uganda; Juba on the White Nile is the nation's capital. The red district was already affected in 2001, in yellow districts the disease was prevalent as of 2011 and in green districts there are only sporadic reports.[1] SpecialtyInfectious disease Nodding disease is a disease which emerged in Sudan in the 1960s.[2] It is a mentally and physically disabling disease that only affects children, typically between the ages of 5 and 15. It is currently restricted to small regions in South Sudan, Tanzania, and northern Uganda.[3][4] Prior to the South Sudan outbreaks and subsequent limited spread, the disease was first described in 1962 existing in secluded mountainous regions of Tanzania,[5] although the connection between that disease and nodding syndrome was only made recently.[4] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Management * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Children affected by nodding disease experience a complete and permanent stunting of growth. The growth of the brain is also stunted, leading to mental handicap. The disease is named for the characteristic, pathological nodding seizure, which often begins when the children begin to eat, or sometimes when they feel cold.[6] These seizures are brief and halt after the children stop eating or when they feel warm again. Seizures in nodding disease span a wide range of severity. Neurotoxicologist Peter Spencer, who has investigated the disease, has stated that upon presentation with food, "one or two [children] will start nodding very rapidly in a continuous, pendulous nod. A nearby child may suddenly go into a tonic–clonic seizure, while others will freeze."[7] Severe seizures can cause the child to collapse, leading to further injury.[8] Sub-clinical seizures have been identified in electroencephalograms, and MRI scans have shown brain atrophy and damage to the hippocampus and glia cells.[5] It has been found that no seizures occur when victims are given an unfamiliar or non-traditional food, such as chocolate.[9] ## Causes[edit] It is currently not known what causes the disease, but it is believed to be connected to infestations of the parasitic worm Onchocerca volvulus, which is prevalent in all outbreak areas,[10] and a possible explanation involves the formation of antibodies against parasite antigen that are cross-reactive to leiomodin-1 in the hippocampus.[11] O. volvulus, a nematode, is carried by the black fly and causes river blindness. In 2004, most children suffering from nodding disease lived close to the Yei River, a hotbed for river blindness, and 93.7% of nodding disease sufferers were found to harbour the parasite — a far higher percentage than in children without the disease.[12] A link between river blindness and normal cases of epilepsy,[13] as well as retarded growth,[14] had been proposed previously, although the evidence for this link is inconclusive.[15] Of the connection between the worm and the disease, Scott Dowell, the lead investigator into the syndrome for the US Centers for Disease Control and Prevention (CDC), stated: "We know that [Onchocerca volvulus] is involved in some way, but it is a little puzzling because [the worm] is fairly common in areas that do not have nodding disease".[10] Andrea Winkler, the first author of a 2008 Tanzanian study, has said of the connection: "We could not establish any hint that Onchocerca volvulus is actually going into the brain, but what we cannot exclude is that there is an autoimmune mechanism going on."[5] In the most severely affected region of Uganda, infection with microfilariae in epileptic or nodding children ranged from 70% to 100%.[16] The CDC is investigating a possible connection with wartime chemical exposure. The team is also investigating whether a deficiency in vitamin B6 (pyridoxine) could be a cause, noting the seizures of pyridoxine-dependent epilepsy and this common deficiency in disease sufferers.[5] Older theories include a 2002 toxicology report that postulated a connection with tainted monkey meat, as well as the eating of agricultural seeds provided by relief agencies that were covered in toxic chemicals.[6] ## Diagnosis[edit] Diagnosis is not very advanced and is based on the telltale nodding seizures of the victims. When stunted growth and mental disability are also present, probability of nodding syndrome is high. In the future, neurological scans may also be used in diagnosis.[17] ## Management[edit] As there is no known cure for the disease, treatment has been directed at symptoms, and has included the use of anticonvulsants such as sodium valproate[10] and phenobarbitol. Anti-malaria drugs have also been administered, to unknown effect.[7] Nutritional deficiencies may also be present. ## Prognosis[edit] Nodding syndrome is debilitating both physically and mentally. In 2004, Peter Spencer stated: "It is, by all reports, a progressive disorder and a fatal disorder, perhaps with a duration of about three years or more."[7] While a few children are said to have recovered from it, many have died from the illness.[6] Seizures can also cause children to collapse, potentially causing injury or death.[citation needed] ## Epidemiology[edit] While the majority of occurrences of the disease known as "nodding syndrome" have been relatively recent, it appears that the condition was first documented in 1962 in southern Tanzania.[5] More recently, nodding syndrome had become most prevalent in South Sudan, where in 2003 approximately 300 cases were found in Mundri alone. By 2009, it had spread across the border to Uganda's Kitgum district,[3] and the Ugandan ministry of health declared that more than 2000 children had the disease.[5] As of the end of 2011, outbreaks were concentrated in Kitgum, Pader and Gulu. More than 1000 cases were diagnosed in the last half of that year.[10] There were further outbreaks in early 2012, in South Sudan, Uganda, and Tanzania.[18] The spread and manifestation of outbreaks may further be exacerbated due to the poor availability of health care in the region.[7] ## See also[edit] * List of mystery diseases ## References[edit] 1. ^ Meredith Wadman (13 July 2011). "Box: A growing threat". Nature. Retrieved 11 July 2011. 2. ^ Lacey M (2003). "Nodding disease: mystery of southern Sudan". Lancet Neurology. 2 (12): 714. doi:10.1016/S1474-4422(03)00599-4. PMID 14649236. S2CID 12387559. 3. ^ a b UGANDA: Nodding disease or "river epilepsy"? IRIN Africa. Accessed 19 October 2010 4. ^ a b "Nodding disease in East Africa". CNN. Retrieved 6 June 2011. 5. ^ a b c d e f Wadman, Meredith (13 July 2011). "African outbreak stumps experts". Nature. Retrieved 25 December 2011. 6. ^ a b c 'Nodding disease' hits Sudan Andrew Harding BBC News 23 September 2003, Accessed 19 October 2007 7. ^ a b c d Ross, Emma (3 February 2004). "Sudan A Hotbed Of Exotic Diseases". CBS News. Rumbek, Sudan. Archived from the original on February 18, 2004. Retrieved 25 December 2011. 8. ^ Bizarre Illness Terrifies Sudanese - 'Nodding Disease' Victims Suffer Seizures, Retardation, Death Emma Ross, CBS News, Jan. 28, 2004. Accessed 19 October 2007 9. ^ "WHO document describing disease with unusual observation re: unfamiliar food". World Health Organisation. WHO. Retrieved 25 December 2011. 10. ^ a b c d Abraham, Curtis (23 December 2011). "Mysterious nodding syndrome spreading through Uganda". New Scientist. Retrieved 25 December 2011. 11. ^ Johnson, Tory P.; Tyagi, Richa; Lee, Paul R.; Lee, Myoung-Hwa; Johnson, Kory R.; Kowalak, Jeffrey; Elkahloun, Abdel; Medynets, Marie; Hategan, Alina (2017-02-15). "Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus". Science Translational Medicine. 9 (377): eaaf6953. doi:10.1126/scitranslmed.aaf6953. ISSN 1946-6234. PMC 5434766. PMID 28202777. 12. ^ When Nodding Means Dying: A baffling new epidemic is sweeping Sudan. Lekshmi Santhosh The Yale Journal of Public Health Vol. 1, No. 1, 2004. Accessed 25 December 2011 13. ^ Druet-Cabanac M, Boussinesq M, Dongmo L, Farnarier G, Bouteille B, Preux PM (2004). "Review of epidemiological studies searching for a relationship between onchocerciasis and epilepsy". Neuroepidemiology. 23 (3): 144–9. doi:10.1159/000075958. PMID 15084784. S2CID 10903855. 14. ^ Ovuga E, Kipp W, Mungherera M, Kasoro S (1992). "Epilepsy and retarded growth in a hyperendemic focus of onchocerciasis in rural western Uganda". East African Medical Journal. 69 (10): 554–6. PMID 1473507. 15. ^ Marin B, Boussinesq M, Druet-Cabanac M, Kamgno J, Bouteille B, Preux PM (2006). "Onchocerciasis-related epilepsy? Prospects at a time of uncertainty". Trends Parasitol. 22 (1): 17–20. doi:10.1016/j.pt.2005.11.006. PMID 16307906. 16. ^ Dan Michael Komakech (2011-11-07). "Nodding disease community dialogue meeting held in Pader district". Acholi Times. 17. ^ "CDC - Global Health - Nodding Syndrome". www.cdc.gov. Retrieved 2017-03-29. 18. ^ "East African Mystery Disease: Nodding Syndrome". Daily Kos. March 14, 2012. Retrieved March 14, 2012. ## External links[edit] Classification D * MeSH: D064128 * McKenzie, David (19 March 2012). "Mysterious disease devastating families" (2 min 44 sec video report). CNN. Retrieved 20 March 2012. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Nodding disease	c3658353	5,544	wikipedia	https://en.wikipedia.org/wiki/Nodding_disease	2021-01-18T18:33:56	{"gard": ["12133"], "mesh": ["D064128"], "wikidata": ["Q895930"]}
Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) is a condition that affects the brain and spinal cord (central nervous system). In particular, the condition affects nerves in specific regions (called tracts) within the spinal cord and the brainstem, which is the part of the brain that connects to the spinal cord. HBSL is a form of leukodystrophy, which is a group of conditions that involve abnormalities of the nervous system's white matter. The white matter consists of nerve fibers covered by a fatty substance, called myelin, that insulates the fibers and promotes the rapid transmission of nerve impulses. In HBSL, the nervous system has a reduced ability to form myelin (hypomyelination). In HBSL, early development of motor skills (such as rolling over and sitting) may be normal, but movement problems typically begin within the infant's first year. However, in some individuals, these problems do not appear until adolescence. The characteristic feature of HBSL is muscle stiffness (spasticity) in the legs that worsens over time. Most people with HBSL are unable to walk independently. Other neurological problems in affected individuals can include abnormal side-to-side movements of the eyes (nystagmus), weak muscle tone (hypotonia) in the torso, and mild intellectual disability. Distinct changes in the brains of people with HBSL can be seen using magnetic resonance imaging (MRI). These characteristic abnormalities typically involve specific regions (called tracts) within the brainstem and spinal cord, especially the pyramidal tract, lateral corticospinal tract, and the dorsal column. ## Frequency HBSL is a rare condition. Its prevalence is unknown. ## Causes HBSL is caused by mutations in a gene called DARS1, which provides instructions for making an enzyme called aspartyl-tRNA synthetase. This enzyme is important in the production (synthesis) of proteins. During protein synthesis, building blocks (amino acids) are connected together in a specific order, creating a chain of amino acids that forms the protein. Aspartyl-tRNA synthetase plays a role in adding the amino acid aspartate at the proper place in proteins. Mutations in the DARS1 gene result in decreased aspartyl-tRNA synthetase enzyme activity, which hinders the addition of aspartate to proteins. It is unclear how the DARS1 gene mutations lead to the signs and symptoms of HBSL. Researchers do not understand why reduced activity of aspartyl-tRNA synthetase affects myelination or why specific parts of the brainstem and spinal cord are involved. ### Learn more about the gene associated with Hypomyelination with brainstem and spinal cord involvement and leg spasticity * DARS1 ## 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Hypomyelination with brainstem and spinal cord involvement and leg spasticity	c3809008	5,545	medlineplus	https://medlineplus.gov/genetics/condition/hypomyelination-with-brainstem-and-spinal-cord-involvement-and-leg-spasticity/	2021-01-27T08:25:25	{"omim": ["615281"], "synonyms": []}
Lowry–MacLean syndrome SpecialtyDermatology Lowry–MacLean syndrome is a congenital condition that may be characterized by an ear pit.[1] ## See also[edit] * Limb–mammary syndrome * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Lowry–MacLean syndrome	c0796020	5,546	wikipedia	https://en.wikipedia.org/wiki/Lowry%E2%80%93MacLean_syndrome	2021-01-18T19:01:00	{"gard": ["3300"], "mesh": ["C537037"], "umls": ["C0796020"], "orphanet": ["2409"], "wikidata": ["Q6694174"]}
A number sign (#) is used with this entry because of evidence that hypertrophic cardiomyopathy-17 can be caused by heterozygous mutation in the junctophilin gene (JPH2; 605267) on chromosome 20q12. For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600). Clinical Features Matsushita et al. (2007) studied 4 Japanese probands with hypertrophic cardiomyopathy (CMH). The first proband was diagnosed at 14 years of age and had anterolateral hypertrophy of the free left ventricular wall. His mother, who was diagnosed at 40 years of age, had left ventricular hypertrophy (LVH) on electrocardiogram (ECG) and a sigmoid septum with hyperdynamic LV motion on echocardiography. A younger sister had died suddenly at 3 years of age. The second proband was diagnosed with CMH at 33 years of age, and had a family history of CMH involving her grandfather, father, and the father's sibs, who were unavailable for study. The third proband was diagnosed with CMH at 7 months of age and had hypertrophy of the interventricular septum and posterior wall of the left ventricle (both 15 mm to 16 mm in thickness) and left ventricular outflow tract obstruction. The fourth proband was diagnosed at 35 years of age, and had negative T wave, abnormal Q wave, and nonsustained ventricular tachycardia on ECG. Echocardiography showed interventricular septal hypertrophy of the left ventricle and paradoxical flow; MRI revealed an aneurysm of the left ventricular apex. Myocardial biopsy showed myocyte hypertrophy and disarray and myocardial fibrosis, consistent with a diagnosis of hypertrophic cardiomyopathy. Molecular Genetics In 223 unrelated patients with hypertrophic cardiomyopathy (CMH), who were negative for mutation in 8 myofilament-associated genes and 5 Z disc-associated genes, Landstrom et al. (2007) analyzed the candidate gene JPH2 and identified heterozygosity for 3 different missense mutations in 3 probands (605267.0001-605267.0003, respectively). Matsushita et al. (2007) analyzed the candidate gene JPH2 in 148 Japanese probands with CMH and 48 affected family members, as well as 32 patients with dilated cardiomyopathy (CMD; see 115200) and 8 patients with restrictive cardiomyopathy (RCM; see 115210) and identified the same missense mutation (605267.0004) in 4 CMH probands that was not found in CMD or RCM patients or in 236 Japanese controls. Subsequent analysis of 15 known CMH genes in the probands revealed that 1 patient also carried 2 mutations in the MYH7 gene (see, e.g., 160760.0016). INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Left ventricular hypertrophy \- Palpitations \- Interventricular septal hypertrophy (in some patients) \- Left ventricular outflow obstruction (in some patients) \- Ventricular tachycardia (in some patients) \- Myocyte hypertrophy \- Disarray and myocardial fibrosis on histologic analysis of myocardial biopsy RESPIRATORY Lung \- Dyspnea MOLECULAR BASIS \- Caused by mutation in the junctophilin-2 gene (JPH2, 605267.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 17	c3151264	5,547	omim	https://www.omim.org/entry/613873	2019-09-22T15:57:14	{"omim": ["613873"]}
Pediculosis corporis Other namesPediculosis vestimenti" and Vagabond's disease This 2006 photograph depicted a dorsal view of a male body louse, Pediculus humanus var. corporis. Some of the external morphologic features displayed by members of the genus Pediculus include an elongated abdominal region without any processes, and three pairs of legs, all equal in length and width. The distal tip of the male’s abdomen is rounded, whereas, the female’s (PHIL# 9202) is concave. Body lice are parasitic insects that live on the body, and in the clothing or bedding of infested humans. Infestation is common, found worldwide, and affects people of all races. Body lice infestations spread rapidly under crowded conditions where hygiene is poor, and there is frequent contact among people. Note the sensorial setae, or hairs that cover the louse’s body, which pick up, and transmit information to the insect about changes in its environment such as temperature, and chemical cues. The dark mass inside the abdomen is a previously ingested blood meal. SpecialtyDermatology Risk factorsothers around you having it. Treatmentimproving hygiene, Pediculicide. Pediculosis corporis is a cutaneous condition caused by body lice (specifically Pediculus corporis) that lay their eggs in the seams of clothing.[1]:447 ## Contents * 1 Signs and symptoms * 2 Risk factors * 3 Pathophysiology * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Body lice are a nuisance in themselves and cause intense itching. They are also vectors (transmitters) of other diseases and can spread epidemic typhus, trench fever, and louse-borne relapsing fever.[citation needed] ## Risk factors[edit] Body lice are spread through prolonged direct physical contact with a person who has them or through contact with articles such as clothing, beds, bed linens, or towels that have been in contact with an infested person. In the United States, body lice infestations are rare, typically found mainly in homeless transient populations who do not have access to bathing and regular changes of clean clothes. Infestation is unlikely to persist on anyone who bathes regularly and who has at least weekly access to freshly laundered clothing and bedding.[2] Although louse-borne (epidemic) typhus is no longer widespread, outbreaks of this disease still occur during times of war, civil unrest, natural or man-made disasters, and in prisons where people live together in unsanitary conditions. Louse-borne typhus still exists in places where climate, chronic poverty, and social customs or war and social upheaval prevent regular changes and laundering of clothing.[citation needed] ## Pathophysiology[edit] Body lice frequently lay their eggs on or near the seams of clothing. They must feed on blood and usually only move to the skin to feed. They exist worldwide and infest people of all races and can therefore spread rapidly under crowded living conditions where hygiene is poor (homeless, refugees, victims of war or natural disasters).[citation needed] ## Treatment[edit] A body lice infestation is treated by improving the personal hygiene of the infested person, including assuring a regular (at least weekly) change of clean clothes. Clothing, bedding, and towels used by the infested person should be laundered using hot water (at least 130 °F or 54 °C) and machine dried using the hot cycle.[citation needed] Sometimes the infested person also is treated with a pediculicide (a medicine that can kill lice); however, a pediculicide generally is not necessary if hygiene is maintained and items are laundered appropriately at least once a week. A pediculicide should be applied exactly as directed on the bottle or by a physician.[citation needed] Delousing can also be practically achieved by boiling all clothes and bedding, or washing them at a high temperature.[3] A temperature of 130 °F or 54 °C for 5 minutes will kill most of the adults and prevent eggs from hatching.[4] Leaving the clothes unwashed, but unworn for a full week, also results in the death of lice and eggs.[3] Where this is not practical or possible, powder dusting with 10% DDT, 1% malathion or 1% permethrin is also effective.[3] Oral ivermectin at a dose of 12 mg on days 0, 7 and 14 has been used in a small trial of 33 people in Marseilles, but did not result in complete eradication, although there was a significant fall in the number of parasites and proportion of people infected.[5] At the moment, ivermectin cannot be routinely recommended for the treatment of body lice. Medication, insecticide or burning of clothing and bedding is usually not necessary, as the problem normally goes away with daily bathing, weekly (or more frequent) laundering and drying of clothing, bedding, towels, etc. in a hot clothes drier.[4] ## See also[edit] * Pediculosis * Skin lesion * Vagabond's leukomelanoderma * List of cutaneous conditions ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ Global Health - Division of Parasitic Diseases and Malaria (24 September 2013). "CDC - Lice - Body Lice - Frequently Asked Questions (FAQs)". Retrieved 4 March 2014. 3. ^ a b c Raoult D, Roux V (1999). "The body louse as a vector of reemerging human diseases". Clinical Infectious Diseases. 29 (4): 888–911. doi:10.1086/520454. PMID 10589908. 4. ^ a b Page on website of CIGNA 5. ^ Foucault C, Ranque S, Badiaga S (2006). "Oral ivermectin in the treatment of body lice". Journal of Infectious Diseases. 193 (3): 474–476. doi:10.1086/499279. PMID 16388498. ## External links[edit] Classification D * ICD-10: B85.1 * ICD-9-CM: 132.1 * MeSH: D010373 * DiseasesDB: 29587 External resources * MedlinePlus: 000838 * eMedicine: med/1769 * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pediculosis corporis	c0030758	5,548	wikipedia	https://en.wikipedia.org/wiki/Pediculosis_corporis	2021-01-18T19:10:08	{"umls": ["C0030758"], "wikidata": ["Q4364722"]}
## Description Berg and Bearn (1966, 1966) discovered an X-linked serum protein type by means of heteroantiserum made specific by absorption. Since the group-specific antigen appears to be located in the alpha-2-macroglobulin of serum, the name Xm was assigned to the system. The distribution of phenotypes in families and in populations was consistent with X-linkage. Mapping Berg et al. (1968) concluded that the Hunter syndrome locus (309900) and the Xm locus are within measurable distance of each other, the best estimate of the recombination fraction being 0.09. The strongest evidence of linkage was between Xm and deutan colorblindness (303800) where Berg (1969) found a lod score of 2.5 at recombination fraction of 0.05 and 0.10. Lab \- Blood group XM Inheritance \- X-linked ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	XM SYSTEM	c1839088	5,549	omim	https://www.omim.org/entry/314900	2019-09-22T16:17:02	{"omim": ["314900"]}
A rare genetic hematologic disease characterized by decreased or undetectable serum L-ferritin with otherwise normal laboratory parameters. Clinical signs and symptoms include generalized seizures, atypical restless leg syndrome, mild neuropsychologic impairment, and progressive hair loss. Asymptomatic cases have also been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	L-ferritin deficiency	c3810090	5,550	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=440731	2021-01-23T17:53:42	{"omim": ["615604"]}
A number sign (#) is used with this entry because of evidence that glycosylphosphatidylinositol biosynthesis defect-15 (GPIBD15) is caused by homozygous or compound heterozygous mutation in the GPAA1 gene (603048) on chromosome 8q24. Description GPIBD15 is an autosomal recessive disorder characterized by delayed psychomotor development, variable intellectual disability, hypotonia, early-onset seizures in most patients, and cerebellar atrophy, resulting in cerebellar signs including gait ataxia and dysarthria. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Nguyen et al., 2017). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). Clinical Features Nguyen et al. (2017) reported 10 patients from 5 unrelated families with GPIBD15. The families were ascertained from several research studies and were of various origins, including Caucasian, Hispanic, Egyptian, Pakistani, and Finnish. The patients ranged in age from 3.8 to 30 years. All patients showed global developmental delay with mild to moderate intellectual disability, hypotonia, delayed sitting, severely delayed speech, and cerebellar atrophy. The patients had very poor speech with dysarthria and all except 2 were unable to walk or could only walk with support due to ataxic gait and gait instability; the 2 who could walk achieved the skill around age 3 years. Two older sibs in their thirties were wheelchair-bound. Three patients from a Pakistani family were noted to have frank spasticity, whereas others had brisk reflexes. Cerebellar signs included dysarthria, dysmetria, uncoordinated eye movements with ocular ataxia and apraxia, nystagmus, and tremor. Intellectual disability varied; a few patients had moderate cognitive impairment (e.g., IQ of 50 in 1 patient) and could only say a few words, whereas some patients were able to play on a computer and understand most conversation. Three children from a Pakistani family (family 4) could attend normal school with help; these children did not have seizures. The older sibs in their thirties (family 5, Finnish) lived in a sheltered housing with daily assistance, although they were able to eat and dress independently. One patient had cortical visual impairment, 3 had myopia, and 1 had optic atrophy. Seven patients from 4 families had onset of generalized seizures within the first 2 years of life that were only partially or not well controlled by medication and associated with generalized polyspike discharges on EEG. One patient had a history of status epilepticus. Brain imaging showed cerebellar atrophy or hypoplasia, which was progressive in some patients. Common dysmorphic features, seen in one-third to one-half of the patients, included bitemporal narrowing, prominent forehead, widely spaced eyes, broad nasal root, and anteverted nares. Eight patients had osteopenia or osteoporosis, and a ninth had hip dysplasia; however, plasma alkaline phosphatase was normal. Inheritance The transmission pattern of GPIBD15 in the family reported by Nguyen et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 10 patients from 5 unrelated families with GPIBD15, Nguyen et al. (2017) identified homozygous or compound heterozygous mutations in the GPAA1 gene (see, e.g., 603048.0001-603048.0007). The mutations, which were found by exome sequencing, segregated with the disorder in all families. There were 6 missense mutations, 2 frameshift mutations, and 1 splicing mutation, but none of the patients carried 2 frameshift or spicing mutations. Cells derived from several of the patients showed variably decreased amounts of GPI-anchored proteins at the cell surface, including CD16 (FCGR3A; 146740), CD24 (600074), CD109 (608859), and CD73 (129190). These defects could be partially rescued by expression of wildtype GPAA1. Transfection of plasmids containing the mutations into GPAA1-deficient HEK293 cells showed that some of the missense variants had decreased activity, whereas others had residual activity. The findings indicated that the mutations caused a defect in the biosynthesis of GPI-anchored proteins, and highlighted the role of this transamidase complex in the development and function of the cerebellum and the skeletal system. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Dysmorphic facial features, mild (in some patients) \- Bitemporal narrowing \- Prominent forehead Eyes \- Myopia \- Ocular apraxia \- Nystagmus \- Optic atrophy (rare) \- Visual impairment (rare) Nose \- Broad nasal root \- Anteverted nares SKELETAL \- Osteopenia \- Osteoporosis MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability, mild to moderate \- Delayed speech \- Poor speech \- Dysarthria \- Delayed sitting \- Inability to walk independently \- Gait ataxia \- Tremor \- Dysmetria \- Spasticity \- Hyperreflexia \- Seizures (in most patients) \- EEG abnormalities (in most patients) \- Cerebellar atrophy \- Cerebellar hypoplasia LABORATORY ABNORMALITIES \- Normal alkaline phosphatase MISCELLANEOUS \- Onset in infancy \- Onset of seizures in first years of life \- Seizures are only partially responsive to medication \- Variable severity \- Some patients may be able to attend school with help MOLECULAR BASIS \- Caused by mutation in the glycosylphosphatidylinositol anchor attachment protein 1 gene (GPAA1, 603048.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 15	c4540520	5,551	omim	https://www.omim.org/entry/617810	2019-09-22T15:44:42	{"omim": ["617810"], "orphanet": ["529665"], "synonyms": ["GPAA1-related biosynthesis defect", "Alternative titles", "DEVELOPMENTAL DELAY, EPILEPSY, CEREBELLAR ATROPHY, AND OSTEOPENIA"]}
Autoimmune blistering diseases It has been suggested that this article be split into multiple articles. (Discuss) (January 2019) Pemphigoid Vesicles and bullae shown on the lower leg, some ruptured leaving a crusted area in bullous pemphigoid SpecialtyDermatology Pemphigoid is a group of rare autoimmune blistering diseases of the skin, and mucous membranes. As its name indicates, pemphigoid is similar in general appearance to pemphigus,[1] but, unlike pemphigus, pemphigoid does not feature acantholysis, a loss of connections between skin cells.[2] Pemphigoid is more common than pemphigus, and is slightly more common in women than in men. It is also more common in people aged over 70 years than it is in younger people.[3] ## Contents * 1 Classification * 1.1 IgG * 1.2 IgA * 2 Bullous pemphigoid * 2.1 Presentation * 2.1.1 Non-bullous pemphigoid * 2.1.2 Bullous phase * 2.2 Cause * 2.3 Pathophysiology * 2.4 Diagnosis * 2.4.1 Clinical assessment * 2.4.2 Histopathology * 2.4.3 Direct immunofluorescence * 2.4.4 Indirect immunofluorescence * 2.4.5 Enzyme-linked immunosorbent assay (ELISA) * 2.5 Treatment * 2.5.1 Corticosteroids * 2.5.1.1 Topical Corticosteroids * 2.5.1.2 Systemic corticosteroids * 2.5.2 Glucocorticoid sparing drugs * 2.5.2.1 Immunosuppressant drug * 2.5.2.2 Anti-inflammatory drugs * 2.5.2.3 Biologic therapy * 2.6 Epidemiology * 3 Mucous membrane pemphigoid * 3.1 Presentation * 3.1.1 Oral disease * 3.1.2 Ocular disease * 3.1.3 Other mucous membranes * 3.1.4 Skin disease * 3.1.5 Mucous membrane pemphigoid is also associated with malignancy * 3.2 Cause * 3.3 Pathophysiology * 3.4 Diagnosis * 3.4.1 Clinical assessment * 3.4.2 Histopathology * 3.4.3 Direct immunofluorescence studies * 3.4.4 Indirect immunofluorescence * 3.4.5 Antigen-specific serologic testing * 3.5 Treatment * 3.6 Epidemiology * 4 See also * 5 References * 6 Further reading * 7 External links ## Classification[edit] ### IgG[edit] The forms of pemphigoid are considered to be connective tissue autoimmune skin diseases. There are several types: * Gestational pemphigoid (PG) (formerly called Herpes gestationis) * Bullous pemphigoid (BP) Rarely affects the mouth * Mucous membrane pemphigoid (MMP) or (cicatricial pemphigoid), (No skin involvement) Bullous and mucous membrane pemphigoid usually affect persons who are over age 60.[4][5] Gestational pemphigoid occurs during pregnancy,[6] typically in the second or third trimester, or immediately following pregnancy. ### IgA[edit] Pemphigoid is usually considered to be mediated by IgG, but IgA-mediated forms have also been described.[7] IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab.[8] ## Bullous pemphigoid[edit] Main article: Bullous pemphigoid Bullous pemphigoid is a rare and chronic autoimmune disorder characterised by large sub-epidermal blisters called bullae, that predominantly involves the skin and less commonly the mucous membranes. It is the most common type of the pemphigoid group, representing 80% of sub-epidermal immunobullous cases.[9] It is more commonly known as cutaneous pemphigoid. ### Presentation[edit] Primary lesions of small and large blisters, known as vesicles and bullae, are found on the skin and sometimes on the mucous membranes. [10] #### Non-bullous pemphigoid[edit] In some patients, pemphigoid starts off with cutaneous manifestations of BP without bullae, as the only sign of the disease. Pruritic eczematous, papular, or urticaria-like skin lesions may also persist for weeks to months.[11] #### Bullous phase[edit] The bullous stage of BP shows vesicles and bulla, appearing on apparently normal or erythematous skin, predominantly at the flexural aspects of the extremities and the lower trunk.[11] Mucosal lesions, which typically are erosions of the oral mucosa, are present in 10 to 30 percent of patients.[12] Occasionally, the blister fluid becomes blood-tinged. The blisters are tense, about 1–4 cm in diameter, leaving eroded and crusted areas, together with urticarial and infiltrated papules and plaques in an annular or figurate pattern.[11][12] Homology between bullous pemphigoid antigens in the skin and neuronal antigens in the central nervous system has been proposed as a cause for the observed link between bullous pemphigoid and neurologic disease, along with a genetic predisposition. Patients with bullous pemphigoid usually present with two or more other chronic diseases such as neurological disorders(dementia, Parkinson's disease, or stroke). However, further studies are necessary to explore the relationship between these disorders.[12] ### Cause[edit] The pathogenetic mechanism of blister formation is known, the trigger to the formation of the antibodies to the hemidesmosome antigens is still unknown.[13] Most of the bullous pemphigoid cases are due to autoantibodies (mostly IgG) directed at antigens (BP180 and BP230) arranged at the dermal-epidermal junction.[14] However, most commonly, drug can be one of the cause of bullous pemphigoid, such as thiazide diuretics, antibiotics (e.g., penicillins, vancomycin), nonsteroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril) and possibly angiotensin receptor blockers (ARBs, e.g., valsartan).[10] The implicated drugs include penicillin derivatives, sulfasalazine, ibuprofen, phenacetin, enalapril, captopril, lisinopril, gabapentin, novoscabin, levobunolol ophthalmic solution, tetracoq, influenza, tetanus, and other vaccinations, a homeopathy regimen, nifedipine, 5-aminosalicylic acid, doxazosin, serratiopeptidase, losartan, cephalexin, bumetanide, fluoxetine, chloroquine, antipsychotic drugs, enoxaparin, ciprofloxacin, furosemide (frusemide), neuroleptics, penicillamine, gliptin plus metformin, intravenous iodine, etanercept, levofloxacin, and topical fluorouracil. Influenza vaccination does not appear to be an important trigger for bullous pemphigoid. Trauma, burns, lymphedema, phototherapy, and radiation have been implicated in a very small number of cases.[13] The blisters are tense, about 1–4 cm in diameter, leaving eroded and crusted areas ### Pathophysiology[edit] The pathophysiology of bullous pemphigoid consists of two major components, which are immunologic and inflammatory. In the immunologic component, autoantibodies act against the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP 180(BPAg2 or type XVII collagen) which are located at the lamina lucida of the basement membrane zone. These antigens play an important role in the adhesion complexes that promote epithelial-stromal adhesion.[9] The predominant subclass of antibodies that acts against the antigens is IgG4. IgG1 and IgG2 antibodies are less frequently detected compared to IgG4 antibodies, while IgG3 antibodies are usually absent.[14] When the autoantibodies bind specifically to the target antigens, the complement system and mast cells are activated, thereby representing the inflammatory component. Inflammatory cells such as neutrophils and eosinophils are then attracted to the affected area. They are postulated to release proteolytic enzymes which degrade the hemidesmosomal proteins, resulting in blister formation.[9] Other potential contributory factors including genetic factors, environmental exposures to infections and drugs as well as the phenomenon of epitope spreading are also known to cause bullous pemphigoid.[14] ### Diagnosis[edit] Diagnosis of bullous pemphigoid includes clinical assessment, skin biopsy for histopathology and direct immunofluorescence, indirect immunofluorescence and ELISA test. Among all, direct immunofluorescence is the gold standard for diagnosis of bullous pemphigoid. #### Clinical assessment[edit] For patients greater than 70 years old [15][16] * Blistering skin disease characterized by the presence of tense blisters and erosions that occur without another identifiable cause and rarely on mucosa. * Unexplained pruritus, pruritic eczematous eruptions, or urticarial plaques #### Histopathology[edit] Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E)staining. Typical histopathologic findings include:[17][13] * Sub-epidermal split with numerous eosinophils within the cleft. * A superficial dermal inflammatory cell infiltrate of variable intensity with lymphocytes, eosinophils, and neutrophils. * Eosinophlic spongiosis (Specifically in early lesion or may be seen in clinically erythematous skin surrounding the blister) #### Direct immunofluorescence[edit] Direct immunofluorescence (DIF) studies involves directly detecting tissue bound antibodies. Biopsy specimens for DIF should be taken from perilesional skin instead of lesional skin for H&E histopathologic evaluation. DIF of bullous pemphigoid will show the presence of fine, continuous and linear deposits of IgG and/or C3 along the epidermal basement membrane. Other classes of immunoglobulins such as IgM and IgA are present in approximately 20% of cases and usually are less intense. In some cases with the deposits of IgA, patient may have oral lesion. At early stages of the disease, only C3 may be present.[13] #### Indirect immunofluorescence[edit] Indirect immunofluorescence is used to detect circulating antibodies targeting the antigens at the basement membrane zone in patients with pemphigoid. In this procedure, patient's serum is collected and overlaid on salt-split normal human skin and incubated. Following this, the specimen will be stained for fluorescent detection of antibodies. In bullous pemphigoid, circulating IgG targeting the basement membrane, mainly BP180 and BP230 hemidesmosomal proteins are detectable in 60-80% of patients. IgA and IgE classes can also be detected, but less frequently.[13] #### Enzyme-linked immunosorbent assay (ELISA)[edit] ELISA for bullous pemphigoid are commercially available to test for circulating Ig against NC16A domain of BP180 and BP230, known as bullous pemphigoid antigen 2 [BPAg2] and bullous pemphigoid antigen 1 [BPAg1] respectively. Antibodies to BP180NC16A domain is useful for the diagnosis of bullous pemphigoid as it has a sensitivity of 89% and specificity of 98%.[18] Detection of BP180 and/or BP230 antibodies in serum does not give a confirmative diagnosis of bullous pemphigoid. A study has reported that 7% were tested positive for one or both autoantibodies in one series of 337 people without bullous pemphigoid.[19] ELISA findings should be correlated with DIF to reduce the risk of misdiagnosis. ### Treatment[edit] The treatment for bullous pemphigoid include: 1\. Corticosteroids i. Topical Corticosteroids ii. Systemic corticosteroids 2\. Glucocorticoid-sparing drugs i. Immunosuppressive drugs ii. Anti-inflammatory drugs 3\. Biologic therapy i. Intravenous immunoglobulin ii. Rituximab Among all, topical or systemic corticosteroids are considered as the first line therapy in controlling bullous pemphigoid. Other drugs and immunomodulatory therapies are often used as adjunct to minimize the adverse effect of long term use of corticosteroids and improve the healing of the disease. There are several factors that have to be taken into account when choosing the therapies given to the patient: (a) patient's age (b) underlying disease such as hypertension, diabetes mellitus and other cardiovascular disease (c) side effect with the use of drugs (d) patient's ability to compliant to the therapy (d) severity and extent of disease (e) cost of drugs. #### Corticosteroids[edit] High potency topical corticosteroid is preferred as the first line treatment due to its efficacy and fewer systemic adverse effects when compared to systemic corticosteroids. Studies have shown that patients with extensive bullous pemphigoid (defined as >10 new bullae per day) treated with topical corticosteroids (Topical Clobetasol Propionate 0.05% cream) had better clinical outcomes than patients with extensive bullae pemphigoid who were treated with systemic glucocorticoid therapy (Prednisone).[20] Systemic glucocorticoids can be used for patients when there are factors that make the use of topical corticosteroids not feasible, such as elderly patient inability to apply the cream on their own, cost or patient's own preference. ##### Topical Corticosteroids[edit] Topical Clobetasol Propionate 0.05% cream is usually used and applied twice daily. A study by Joly et al. demonstrated that the use of 10 to 20g of Clobetasol Propionate per day for moderate disease and 20 to 30g per day for extensive disease until 15 days after disease control, then tapered to discontinuation over four months was as effective as the standard regime (40g per day tapered slowly over 12 months).[21] ##### Systemic corticosteroids[edit] Prednisone is usually used to treat bullous pemphigoid. The dose varies between 0.2 and 0.5 mg/kg/day and will continue until active inflammation, new blister formation, pruritus has stopped for at least 2 weeks. The dose is then slowly tapered over the months. Initially, prednisolone can be reduced by relative large amounts (approximately 10 mg) and smaller amount (2.5–5 mg) subsequently. Should the patient develop flare up of the lesion, the dose should be increased to the previous level or higher and maintained longer before further, slower tapering.[22] #### Glucocorticoid sparing drugs[edit] For patients who require high dose of corticosteroids for clearing or maintenance, glucocorticoid sparing agents such as immunosuppressive drugs and anti-inflammatory drugs can be used as an adjunct therapy to reduce the systemic side effects of corticosteroids. Patients who have comorbidities and contraindications for corticosteroids may also consider these glucocorticoid sparing agents. ##### Immunosuppressant drug[edit] Immunosuppressant drugs include azathioprine (1–3 mg/kg/day in two equally divided doses), mycophenolate mofetil (1000–3000 mg/day or 40 mg/kg/day in two divided doses), and methotrexate (10–15 mg/week).[22] ##### Anti-inflammatory drugs[edit] Tetracycline antibiotics are often used in combination of nicotinamide to treat bullous pemphigoid.[23][24] For the administration of drugs, tetracycline is prescribed as 500 mg four times daily, doxycycline and minocycline as 100 mg twice daily and nicotinamide, 500 mg 4 times daily. Dapsone is also shown to be effective in treating bullous pemphigoid.[25] However, the efficacy of dapsone is limited. Dapsone is usually commenced at a low dose of 25 to 50 mg/day and increase by 25 mg every week until the condition improves. Maximum dose that can be prescribed is 250 mg/day.[22] ##### Biologic therapy[edit] For refractory disease, biologic therapies such as intravenous immunoglobulin and Rituximab should be considered. [1,19,20][9][26][27] ### Epidemiology[edit] Bullous pemphigoid is primarily a disease of older adults and it rarely occurs in children. The vast majority of cases involved individuals between the ages of 60 and 80 years. Two European studies have also suggested the increased risk of bullous pemphigoid with advancing age.[28][29] According to the results of several retrospective studies, there is an increasing incidence of bullous pemphigoid.[30][31][32] Bullous pemphigoid can be considered as the most common autoimmune blistering disease in Europe, while pemphigus may be more common in locations such as Thailand and Malaysia. It is reported that bullous pemphigoid has a slight female preponderance. However, the reasons for this are unknown.[14] ## Mucous membrane pemphigoid[edit] Main article: Mucous membrane pemphigoid Mucous membrane pemphigoid (MMP), or cicatricial pemphigoid, is a rare, chronic, autoimmune sub-epidermal blistering disorder which predominantly involves the mucosae and has a tendency towards scarring of the affected areas.[11] Any mucous membrane can be involved, but the most commonly involved site is the oral mucosa, followed by conjunctiva, skin, pharynx, external genitalia, nasal mucosa, larynx, anus, and esophagus.[33] As MMP may lead to serious complications such as blindness and airway compression, early and aggressive treatment initiation may be needed.[34] ### Presentation[edit] Scarring is a common consequence of MMP that distinguishes this variant from mucosal involvement in bullous pemphigoid, which typically does not scar. Reticulated, white striations representing mucosal fibrosis often are present at sites of healed lesions, and functional limitations secondary to scarring may occur. As examples, MMP involving the ocular mucosa can lead to symblepharon, ankyloblepharon, and eventual blindness, and progressive laryngeal and tracheal involvement can result in asphyxiation.[14] #### Oral disease[edit] Most commonly affecting the mouth, including the buccal mucosa, gingiva, tongue, vermillion lips, and palate. Desquamative gingivitis is the most frequent manifestation.[35][34] The gingiva is erythematous, in which patients usually complaint of bleeding upon brushing.[34] Rupturing of oral vesiculobullous lesions leave clean, noninflamed, painless erosions. The vermilion border of the lips is spared, which is typical in pemphigus. Hoarseness due to laryngeal involvement can be seen in 8% of cases. A subset of patients have only oral disease, which has a relatively benign course compared with patients with oral cavity and other mucosae and skin involvement.[34] #### Ocular disease[edit] The eye is involved in 65% of cases. Initially presented with unilateral conjunctivitis (such as burning or excessive tearing), then fibrosis beneath the conjunctival epithelium.[35][36] Shrinkage of the conjunctiva leads to obliteration of the conjunctival sac.[35] Symblepharons are fibrous strands connecting the conjunctiva of the lid to the globe.[34] Besides, reduced tearing with erosion and neovascularization of the cornea leads to corneal opacification and perforation.[35] Scarring of the lid results in entropion (inward turning of the lid) and trichiasis (in-turning of the eyelashes).[37] These conditions ultimately lead to blindness in approximately 20% of cases. It is crucial to go for follow-up because relapse occurs in 22% of those who were in remission and not undergoing therapy.[35] #### Other mucous membranes[edit] Less common sites that might get involved are nasopharynx, esophagus, and urethra.[35] Nasopharyngeal involvement can lead to ulcerations of the septum and airway obstruction which might require tracheostomy.[35] Esophageal disease may present with ulcerations, dysphagia, odynophagia, and stenosis. Stenosis at urethra, vaginal orifice and rectal have also resulted from chronic inflammation and scarring.[35] #### Skin disease[edit] About 25% of patients have cutaneous lesions, with tense vesicles or bullae, mainly on the face, neck, and scalp. Healing of erosion is either with or without atrophic scars.[35] Cutaneous lesions of mucous membrane pemphigoid presents in 2 subtypes: (1)presents as generalized eruption of tense bullae without scarring (2) presents as localised blisters on an erythematous base, resulting in atrophic scarring.[36] #### Mucous membrane pemphigoid is also associated with malignancy[edit] Malignancy — MMP with antibodies directed against laminin 332 (previously known as laminin 5 and epiligrin) has been associated with an increased risk for internal malignancy. In a cohort of 35 patients with this type of pemphigoid (diagnosed with immunoprecipitation), 10 (29 percent) developed solid organ malignancies, 7 of which were diagnosed within 14 months after a diagnosis of MMP.[14] Occurrences of non-Hodgkin lymphoma and cutaneous T cell lymphoma have also been reported in individual patients with anti-laminin 332 MMP. The pathophysiologic relationship of this subtype of MMP to cancer is unknown. However, expression of laminin 332 has been detected in malignant cells, and laminin 332 appears to be capable of promoting tumor cell growth, invasion, and metastasis.[14] The clinical manifestations of MMP in patients with laminin 332 antibodies are similar to the features of MMP with other antibody profiles.[14] Therefore, clinical examination cannot reliably distinguish anti-laminin 332 MMP from other forms of MMP. Additional studies are necessary to confirm the findings of a retrospective study of 154 patients with MPP that associated the detection of laminin 332 antibodies via a novel enzyme-linked immunosorbent assay (ELISA) with a greater likelihood for severe disease. Since diagnostic laboratory testing for laminin 332 antibodies is not commercially available, suspicion for laminin 332 primarily is based upon immunofluorescence microscopy findings.[14] Although not exclusive to laminin 332 MPP, the detection of antibodies bound to the dermal side of basement membrane zone-split (salt-split) skin suggests the possibility of this diagnosis. Until definitive testing for laminin 332 antibodies becomes available, we recommend that patients with MMP in whom serum indirect immunofluorescence (IIF) studies reveal antibodies bound to the dermal side of basement membrane zone-split skin undergo age and gender appropriate cancer screening.[14] Additional evaluation for malignancy should be performed as indicated based upon a review of symptoms, physical examination, and the results of age-appropriate screening. ### Cause[edit] Autoantibodies targeted to components of the basement membrane zone have been identified as pathogenic in mucous membrane pemphigoid. Antigens include 180-kD bullous pemphigoid antigen (BP180), laminin 332, beta-4-integrin, and other antigens that are not fully discovered are identified against the basement membrane.[34] Complication of D- penicillamine therapy may trigger and causes mucous membrane pemphigoid. It also occurs after acute severe ocular inflammation in patients with Stevens-Johnson syndrome.[38] ### Pathophysiology[edit] Autoantibodies target the basement membrane zone proteins which are responsible to promote adhesion within the basement membrane zone of the mucosa and the skin. The major basement membrane zone proteins identified include : * C-terminus of BP180 * BP230 * Laminin 332(also known as laminin 5 or epiligrin) * Alpha-6-beta-4 integrin Type VII collagen. In contrast to the target of the N-terminus of BP180 that is located in the hemidesmosomes and upper lamina lucida in bullous pemphigoid, the target antigen in MMP is the C-terminus of BP180 which is located in the lower lamina lucida and lamina densa. This results in a deeper separation that is more likely to scar as compared to a more superficial blister that is unlikely to scar in bullous pemphigoid. Antibodies to the beta-4 integrin subunit of alpha-6-beta-4 integrin is shown to be associated with ocular disease while oral involvement is suggested to be linked with antibody reaction towards the alpha-6 subunit. Besides, MMP with antibody reaction against laminin 332 has an association with an increased risk for internal malignancy. Similar to bullous pemphigoid, other factors such as genetic factors, environmental exposures and the phenomenon of epitope spreading potentially result in MMP. Multiple studies have also reported an association of HLA-DQB10301 with MPP.[14][39][40][41][42] ### Diagnosis[edit] Diagnosis of bullous pemphigoid includes clinical assessment, skin biopsy for histopathology and direct immunofluorescence, indirect immunofluorescence and ELISA test. Among all, direct immunofluorescence is the gold standard for diagnosis of mucous membrane pemphigoid. #### Clinical assessment[edit] Presence of tense blisters and erosions that occur on skin without another identifiable cause. * Desquamative gingivitis or mucositis involving oral, ocular, nasal, genital, anal, pharyngeal, laryngeal, and/or esophageal mucosae * Presence of pruritic eczematous eruptions, or urticarial plaques without identifiable cause. * Patient's age over 60 years old. #### Histopathology[edit] Lesional tissue, preferably of an intact vesicle or the edge of an intact bulla is obtained using punch biopsy for Haemotoxylin and Eosin (H&E) staining. The findings are sub-epidermal blister with dermal infiltrated with lymphocytes, neutrophils and eosinophils. Additional findings include sub-epidermal fibrosis which is consistent with the scarring nature of mucous membrane pemphigoid in older lesions and plasma cell infiltration.[37][36] #### Direct immunofluorescence studies[edit] Direct immunofluorescence (DIF) studies involves directly detecting tissue bound antibodies. Biopsy specimens for DIF should be taken from perilesional skin instead of lesional skin for H&E histopathologic evaluation. Linear band of IgG and C3 deposits are found along the basement membrane. Occasionally, linear deposition of IgA at the basement membrane zone can also be seen.[43][44] Multiple and repeated biopsies increase the sensitivity of DIF studies to diagnose MMP. #### Indirect immunofluorescence[edit] Indirect immunofluorescence is used to detect circulating antibodies targeting the antigens at the basement membrane zone in patients with pemphigoid. In early studies using routine techniques, only one third of patient with MPP were being tested positive. Circulating IgG and IgA antibodies are found in patient's serum. To increase the likelihood of detecting circulating antibodies, human basement membrane zone-split skin and/or concentrated serum should be used.[37][45][46] #### Antigen-specific serologic testing[edit] Autoantibodies directed against a variety of antigens, including BP180, BP230, laminin 332, and type VII collagen may be detected.[47][48][49] However, this test could not be used as the only diagnostic tool for testing as ELISA testing has limited sensitivity. ### Treatment[edit] The factors that determine the type of therapy used for mucous membrane pemphigoid are: [1] site(s) of involvement, [2] severity of disease, [3] rate of progression. Oral mucosa is the most common site being affected in mucous membrane pemphigoid. For the mild oral mucosa lesion, high potency topical steroids such as 0.05% Clobetasol propionate is used. Patients are instructed to apply the ointment or gel 2-3 times a day after drying the oral mucosa to enhance the adherence of mediation to oral mucosa. Patients are instructed to avoid drinking or eating for at least 30 minutes after application. Dental tray can also be fabricated to help in the application of topical steroids to lesional sites under occlusion for patients with gingival involvement. Furthermore, topical tacrolimus, a calcineurin inhibitor, has also shown to be effective to control the disease, including some patients who failed to respond well to topical corticosteroids. Topical tacrolimus 0.1% ointment is applied two to three times a day and tapered after improvement in healing of pemphigoid. Another method is to use intralesional corticosteroids (Triamcinolone acetonide, dilution of 5 to 10 mg/ml; repeated every 2–4 weeks). Intralesional therapy is used when the patient does not respond to local therapies. For moderate to severe disease (including the ones involving ocular, nasopharyngeal, or anogenital mucosa) and patient who did not respond to local therapy adequately, systemic agents should be used. Systemic corticosteroids and dapsone are used in such cases. The dose of dapsone ranges from 50 to 200 mg daily. Dapsone is shown to be effective in treating mucous membrane pemphigoid that does not respond to systemic corticosteroids.[37] Whereas for systemic corticosteroids, 0.25 to 0.5 mg/kg of prednisolone is prescribed per day (twice-daily dosage is used during the acute stage and change to a single daily morning dose after new blister formation stops). Thereafter, the dosage of prednisolone is slowly tapered over the months in combination with topical therapy or glucocorticoid-sparing agent (e.g., dapsone, azathioprine). Patients with severe mucous membrane pemphigoid that cannot be controlled by the intervention above and would need aggressive immunosuppressive regimens and biologic therapies to control the lesions.[37] Azathioprine or Cyclosphosphamide are the choices of immunosuppressive drugs that can be used. Sometimes, immunosuppressive agents and prednisolone can be combined if dapsone fails to improve the condition. Lastly, in patients who do not respond to the conventional therapy, rituximab may be an option.[35] There is insufficient evidence that cyclophosphamide combined with corticosteriods are effective in treating mucous membrane pemphigoid.[50] Other than that, oral hygiene instructions should be given to patients as oral care is a critical part in treating mucous membrane pemphigoid.[51] Before meals, patients are advised to rinse with hydrogen peroxide (diluted with water to a concentration of 1:4 or 1:6) and diphenhydramine to reduce the pain. Patient would then rinse with hydrogen peroxide to remove food particles and debris and later rinse with dexamethasone for anti-inflammatory effect. Hydrogen peroxide, elixir of dexamethasone and elixir of diphenhydramine are each diluted with water to a concentration of 1:4 or 1:6 and are instructed not to swallow in the end.[35] ### Epidemiology[edit] MMP mainly affect the elderly population of ages between 60 and 80 years and rarely children. Women are affected twice as frequently than in men.[52] There is no known racial or geographic predilection, but several studies have suggested that there is an association of specific immunogenetic haplotype HLA-DQB10301 with MMP.[11][39][40][41][42] ## See also[edit] List of cutaneous conditions * List of target antigens in pemphigoid ## References[edit] 1. ^ "pemphigoid" at Dorland's Medical Dictionary 2. ^ Pemphigoid at the US National Library of Medicine Medical Subject Headings (MeSH) 3. ^ "British Association of Dermatologists - Patient Information Leaflets (PILs)". www.bad.org.uk. Retrieved 11 June 2020. 4. ^ Cicatricial Pemphigoid at eMedicine 5. ^ Bullous Pemphigoid at eMedicine 6. ^ Pemphigoid Gestationis at eMedicine 7. ^ Provost TT, Flynn JA (2001). Cutaneous medicine: cutaneous manifestations of systemic disease. PMPH-USA. pp. 209–. ISBN 978-1-55009-100-7. Retrieved 25 June 2010. 8. ^ He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, et al. (June 2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatology. 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938. 9. ^ a b c d Baigrie D, Nookala V (2020). "Bullous Pemphigoid". StatPearls. StatPearls Publishing. PMID 30570995. Retrieved 2019-01-19. 10. ^ a b Mirowski GW, Leblanc J, Mark LA (2016). "Oral disease and oral-cutaneous manifestations of gastrointestinal and liver disease". In Feldman M (ed.). Sleisenger & Fordtran's Gastrointestinal and Liver Disease (10th ed.). Philadelphia, Pa: Saunders Elsevier. pp. 377–396. 11. ^ a b c d e Bernard P, Borradori L (2018). "Pemphigoid Group". In Bolognia JL (ed.). Dermatology (4th ed.). Philadelphia, Pa: Elsevier Limited. pp. 510–526. 12. ^ a b c Chow YW, Pietranico R, Mukerji A (October 1975). "Studies of oxygen binding energy to hemoglobin molecule". Biochemical and Biophysical Research Communications. 66 (4): 1424–31. doi:10.1016/0006-291X(75)90518-5. PMID 6. 13. ^ a b c d e Patterson JW, Hosler GA, Weedon D (2016). Weedon's Skin Pathology (4th ed.). London: Churchill Livingstone Elsevier. ISBN 978-0-7020-5183-8. 14. ^ a b c d e f g h i j k Leiferman KM. Zone JJ, Ofori AO (eds.). "Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid". UpToDate. Wolters Kluwer. Retrieved 2019-01-17. 15. ^ Vaillant L, Bernard P, Joly P, Prost C, Labeille B, Bedane C, et al. (September 1998). "Evaluation of clinical criteria for diagnosis of bullous pemphigoid. French Bullous Study Group". Archives of Dermatology. 134 (9): 1075–80. doi:10.1001/archderm.134.9.1075. PMID 9762017. 16. ^ Kershenovich R, Hodak E, Mimouni D (2014-04-01). "Diagnosis and classification of pemphigus and bullous pemphigoid". Autoimmunity Reviews. Diagnostic criteria in Autoimmune diseases. 13 (4–5): 477–81. doi:10.1016/j.autrev.2014.01.011. PMID 24424192. 17. ^ Schmidt E, della Torre R, Borradori L (July 2011). "Clinical features and practical diagnosis of bullous pemphigoid". Dermatologic Clinics. 29 (3): 427–38, viii–ix. doi:10.1016/j.det.2011.03.010. PMID 21605808. 18. ^ Samuel M, Pixley RA, Villanueva MA, Colman RW, Villanueva GB (September 1992). "Human factor XII (Hageman factor) autoactivation by dextran sulfate. Circular dichroism, fluorescence, and ultraviolet difference spectroscopic studies". The Journal of Biological Chemistry. 267 (27): 19691–7. PMID 1527088. 19. ^ Wieland CN, Comfere NI, Gibson LE, Weaver AL, Krause PK, Murray JA (January 2010). "Anti-bullous pemphigoid 180 and 230 antibodies in a sample of unaffected subjects". Archives of Dermatology. 146 (1): 21–5. doi:10.1001/archdermatol.2009.331. PMID 20083688. 20. ^ Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E, et al. (January 2002). "A comparison of oral and topical corticosteroids in patients with bullous pemphigoid". The New England Journal of Medicine. 346 (5): 321–7. doi:10.1056/NEJMoa011592. PMID 11821508. 21. ^ Joly P, Roujeau JC, Benichou J, Delaporte E, D'Incan M, Dreno B, et al. (July 2009). "A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study". The Journal of Investigative Dermatology. 129 (7): 1681–7. doi:10.1038/jid.2008.412. PMID 19177141. 22. ^ a b c Kellerman RD, Rakel D, eds. (2020). "Bulbous Disease: Method of Diya F. Mutasim". Conn's current therapy 2020 (20th ed.). Philadelphia: Elsevier. p. 228. ISBN 978-0-323-71184-5. 23. ^ Berk MA, Lorincz AL (June 1986). "The treatment of bullous pemphigoid with tetracycline and niacinamide. A preliminary report". Archives of Dermatology. 122 (6): 670–4. doi:10.1001/archderm.1986.01660180076019. PMID 2940979. 24. ^ Thomas I, Khorenian S, Arbesfeld DM (January 1993). "Treatment of generalized bullous pemphigoid with oral tetracycline". Journal of the American Academy of Dermatology. 28 (1): 74–7. doi:10.1016/0190-9622(93)70013-J. PMID 8425974. 25. ^ Bouscarat F, Chosidow O, Picard-Dahan C, Sakiz V, Crickx B, Prost C, et al. (April 1996). "Treatment of bullous pemphigoid with dapsone: retrospective study of thirty-six cases". Journal of the American Academy of Dermatology. 34 (4): 683–4. doi:10.1016/S0190-9622(96)80085-5. PMID 8601662. 26. ^ Czernik A, Toosi S, Bystryn JC, Grando SA (February 2012). "Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update". Autoimmunity. 45 (1): 111–8. doi:10.3109/08916934.2011.606452. PMID 21923613. S2CID 19942412. 27. ^ Kasperkiewicz M, Shimanovich I, Ludwig RJ, Rose C, Zillikens D, Schmidt E (September 2011). "Rituximab for treatment-refractory pemphigus and pemphigoid: a case series of 17 patients". Journal of the American Academy of Dermatology. 65 (3): 552–558. doi:10.1016/j.jaad.2010.07.032. PMID 21641080. 28. ^ Marazza G, Pham HC, Schärer L, Pedrazzetti PP, Hunziker T, Trüeb RM, et al. (October 2009). "Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study". The British Journal of Dermatology. 161 (4): 861–8. doi:10.1111/j.1365-2133.2009.09300.x. PMID 19566661. S2CID 30118554. 29. ^ Bertram F, Bröcker EB, Zillikens D, Schmidt E (May 2009). "Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany". Journal of the German Society of Dermatology. 7 (5): 434–40. doi:10.1111/j.1610-0387.2008.06976.x. PMID 19170813. S2CID 25769559. 30. ^ Joly P, Baricault S, Sparsa A, Bernard P, Bédane C, Duvert-Lehembre S, et al. (August 2012). "Incidence and mortality of bullous pemphigoid in France". The Journal of Investigative Dermatology. 132 (8): 1998–2004. doi:10.1038/jid.2012.35. PMID 22418872. 31. ^ Försti AK, Jokelainen J, Timonen M, Tasanen K (November 2014). "Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital". The British Journal of Dermatology. 171 (5): 1223–6. doi:10.1111/bjd.13189. PMID 24934834. S2CID 207071905. 32. ^ Brick KE, Weaver CH, Lohse CM, Pittelkow MR, Lehman JS, Camilleri MJ, et al. (July 2014). "Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009". Journal of the American Academy of Dermatology. 71 (1): 92–9. doi:10.1016/j.jaad.2014.02.030. PMC 4324601. PMID 24704091. 33. ^ Habif TP, Campbell JL, Chapman MS, Dinulos JG, Zug KA (2011), "Vesicular and bullous diseases", Skin Disease, Elsevier, pp. 366–377, doi:10.1016/b978-0-323-07700-2.00013-5, ISBN 9780323077002 34. ^ a b c d e f Tolaymat L, Hall MR (2020). "Cicatricial Pemphigoid". StatPearls. StatPearls Publishing. PMID 30252376. Retrieved 2019-01-19. 35. ^ a b c d e f g h i j k Mascaró JM (2010). "Other Vesiculobullous Diseases". Sleisenger & Fordtran's Gastrointestinal and Liver Disease (9th ed.). Philadelphia, Pa: Saunders Elsevier. 36. ^ a b c Domloge-Hultsch N, Gammon WR, Briggaman RA, Gil SG, Carter WG, Yancey KB (October 1992). "Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease". The Journal of Clinical Investigation. 90 (4): 1628–33. doi:10.1172/JCI116033. PMC 443212. PMID 1401088. 37. ^ a b c d e Fleming TE, Korman NJ (October 2000). "Cicatricial pemphigoid". Journal of the American Academy of Dermatology. 43 (4): 571–91, quiz 591–4. doi:10.1067/mjd.2000.107248. PMID 11004612. 38. ^ Hamodat M. "Cicatricial pemphigoid". www.pathologyoutlines.com. Retrieved 2019-01-17. 39. ^ a b Chan LS, Hammerberg C, Cooper KD (February 1997). "Significantly increased occurrence of HLA-DQB10301 allele in patients with ocular cicatricial pemphigoid". The Journal of Investigative Dermatology. 108 (2): 129–32. doi:10.1111/1523-1747.ep12332352. PMID 9008223. 40. ^ a b Delgado JC, Turbay D, Yunis EJ, Yunis JJ, Morton ED, Bhol K, et al. (August 1996). "A common major histocompatibility complex class II allele HLA-DQB1 0301 is present in clinical variants of pemphigoid". Proceedings of the National Academy of Sciences of the United States of America. 93 (16): 8569–71. Bibcode:1996PNAS...93.8569D. doi:10.1073/pnas.93.16.8569. PMC 38713. PMID 8710911. 41. ^ a b Setterfield J, Theron J, Vaughan RW, Welsh KI, Mallon E, Wojnarowska F, et al. (September 2001). "Mucous membrane pemphigoid: HLA-DQB10301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production". The British Journal of Dermatology. 145 (3): 406–14. doi:10.1046/j.1365-2133.2001.04380.x. PMID 11531829. 42. ^ a b Yunis JJ, Mobini N, Yunis EJ, Alper CA, Deulofeut R, Rodriguez A, et al. (August 1994). "Common major histocompatibility complex class II markers in clinical variants of cicatricial pemphigoid". Proceedings of the National Academy of Sciences of the United States of America. 91 (16): 7747–51. Bibcode:1994PNAS...91.7747Y. doi:10.1073/pnas.91.16.7747. PMC 44479. PMID 8052655. 43. ^ Bean SF, Waisman M, Michel B, Thomas CI, Knox JM, Levine M (August 1972). "Cicatricial pemphigoid. Immunofluorescent studies". Archives of Dermatology. 106 (2): 195–9. doi:10.1001/archderm.1972.01620110031007. PMID 4558699. 44. ^ Leonard JN, Wright P, Williams DM, Gilkes JJ, Haffenden GP, McMinn RM, Fry L (March 1984). "The relationship between linear IgA disease and benign mucous membrane pemphigoid". The British Journal of Dermatology. 110 (3): 307–14. doi:10.1111/j.1365-2133.1984.tb04636.x. PMID 6365149. S2CID 8889595. 45. ^ Kelly SE, Wojnarowska F (January 1988). "The use of chemically split tissue in the detection of circulating anti-basement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid". The British Journal of Dermatology. 118 (1): 31–40. doi:10.1111/j.1365-2133.1988.tb01747.x. PMID 3277659. S2CID 43832261. 46. ^ Setterfield J, Shirlaw PJ, Kerr-Muir M, Neill S, Bhogal BS, Morgan P, et al. (April 1998). "Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA signifies a more severe and persistent disease". The British Journal of Dermatology. 138 (4): 602–10. doi:10.1046/j.1365-2133.1998.02168.x. PMID 9640363. S2CID 20114355. 47. ^ Bernard P, Antonicelli F, Bedane C, Joly P, Le Roux-Villet C, Duvert-Lehembre S, et al. (May 2013). "Prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel enzyme-linked immunosorbent assay in mucous membrane pemphigoid". JAMA Dermatology. 149 (5): 533–40. doi:10.1001/jamadermatol.2013.1434. PMID 23426192. 48. ^ Yasukochi A, Teye K, Ishii N, Hashimoto T (August 2016). "Clinical and Immunological Studies of 332 Japanese Patients Tentatively Diagnosed as Anti-BP180-type Mucous Membrane Pemphigoid: A Novel BP180 C-terminal Domain Enzyme-linked Immunosorbent Assay". Acta Dermato-Venereologica. 96 (6): 762–7. doi:10.2340/00015555-2407. PMID 26984589. 49. ^ Sezin T, Egozi E, Hillou W, Avitan-Hersh E, Bergman R (July 2013). "Anti-laminin-332 mucous membrane pemphigoid developing after a diphtheria tetanus vaccination". JAMA Dermatology. 149 (7): 858–62. doi:10.1001/jamadermatol.2013.741. PMID 23700098. 50. ^ Kirtschig G, Murrell D, Wojnarowska F, Khumalo N, et al. (Cochrane Skin Group) (2003-01-20). "Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita". The Cochrane Database of Systematic Reviews (1): CD004056. doi:10.1002/14651858.CD004056. PMID 12535507. 51. ^ Knudson RM, Kalaaji AN, Bruce AJ (May 2010). "The management of mucous membrane pemphigoid and pemphigus". Dermatologic Therapy. 23 (3): 268–80. doi:10.1111/j.1529-8019.2010.01323.x. PMID 20597945. S2CID 205694155. 52. ^ Xu HH, Werth VP, Parisi E, Sollecito TP (October 2013). "Mucous membrane pemphigoid". Dental Clinics of North America. 57 (4): 611–30. doi:10.1016/j.cden.2013.07.003. PMC 3928007. PMID 24034069. ## Further reading[edit] Schmidt E, Zillikens D (January 2013). "Pemphigoid diseases". Lancet. London, England. 381 (9863): 320–32. doi:10.1016/S0140-6736(12)61140-4. PMID 23237497. S2CID 8746415. ## External links[edit] Classification D * ICD-10: L12 * ICD-9-CM: 694.5 * MeSH: D010391 * DiseasesDB: 9760 * v * t * e Vesiculobullous disease Acantholysis (epidermis) Pemphigus * Pemphigus vulgaris: Pemphigus vegetans * of Hallopeau * of Neumann * Pemphigus foliaceus: Pemphigus erythematosus * Endemic pemphigus * Paraneoplastic pemphigus * IgA pemphigus * Subcorneal pustular * Intraepidermal neutrophilic Other * Transient acantholytic dermatosis Pemphigoid (dermis) IgG: * Bullous pemphigoid * Cicatricial pemphigoid * Localised * Gestational pemphigoid * Pemphigoid nodularis * Epidermolysis bullosa acquisita IgA: * Linear IgA bullous dermatosis * Childhood * Adult Other bullous * Dermatitis herpetiformis In diseases classified elsewhere * Porphyria cutanea tarda * Bullous lupus erythematosus * PUVA-induced acrobullous dermatosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Pemphigoid	c0030805	5,552	wikipedia	https://en.wikipedia.org/wiki/Pemphigoid	2021-01-18T19:07:02	{"mesh": ["D010391"], "umls": ["CL449041"], "icd-9": ["694.5"], "icd-10": ["L12"], "wikidata": ["Q881811"]}
A number sign (#) is used with this entry because dilated cardiomyopathy-1Y (CMD1Y) and left ventricular noncompaction-9 (LVNC9) are caused by heterozygous mutation in the TPM1 gene (191010) on chromosome 15q22.1. For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200). Description Dilated cardiomyopathy-1Y (CMD1Y) is characterized by severe progressive cardiac failure, resulting in death in the third to sixth decades of life in some patients. Electron microscopy shows an abnormal sarcomere structure (Olson et al., 2001). In left ventricular noncompaction-9 (LVNC9), patients may present with cardiac failure or may be asymptomatic. Echocardiography shows noncompaction of the apex and midventricular wall of the left ventricle (Probst et al., 2011). Some patients also exhibit Ebstein anomaly of the tricuspid valve (Kelle et al., 2016) and some have mitral valve insufficiency (Nijak et al., 2018). Clinical Features Olson et al. (2001) described 2 probands with familial dilated cardiomyopathy. One was a 27-year-old man whose father and paternal uncle died from heart failure at age 27 and 49 years, respectively. Because of suspected familial CMD, screening echocardiogram was performed when the proband was 17 years old but was reportedly normal. At 26 years of age, the proband developed shortness of breath, edema, and nonsustained ventricular tachycardia. He had no echocardiographic features of hypertrophic cardiomyopathy, coronary arteries were normal by angiography, and cardiac biopsy findings were nonspecific and consistent with idiopathic CMD. Despite aggressive medical therapy and implantation of an automatic cardioverter defibrillator, he died at age 27 while on a cardiac transplant waiting list. The second proband presented at 3 months of age with congestive heart failure and was diagnosed with idiopathic CMD based on echocardiographic findings; her heart failure progressed while on medical therapy and she underwent cardiac transplantation at 10 years of age. Electron microscopy of her explanted heart tissue revealed an abnormal sarcomere structure in which the thin filaments of many sarcomeres appeared irregular and fragmented; the sarcomeres were also contracted with decreased distance between Z bands and the sarcolemma had a scalloped appearance. The girl's mother, who had developed heart palpitations during pregnancy that recurred 6 months after delivery, was diagnosed with idiopathic CMD at 33 years of age based on echocardiographic and cardiac biopsy findings and the absence of coronary artery disease on angiography. She remained stable on minimal medical therapy. Family history included a maternal grandfather who had died at 59 years of age from presumed myocardial infarction, and his father and several sibs reportedly died in their 50s from heart disease. ### Left Ventricular Noncompaction 9 Probst et al. (2011) described 2 white families of western European descent with left ventricular noncompaction (LVNC) due to mutations in the TPM1 gene (see MOLECULAR GENETICS). In the first family, the proband was a man who presented at 63 years of age with congestive heart failure and was found to have noncompacted segments of the apex and midventricular wall, with a left ventricular ejection fraction (LVEF) of 19% and left ventricular fractional shortening (LVFS) of 18%. He had 2 affected asymptomatic children, a 32-year-old daughter and a 34-year-old son, who were identified only by family screening and were found to have noncompacted apical segments by echocardiography, with an LVEF of 37% and 53% and an LVFS of 20% and 32%, respectively. In addition, a granddaughter had congestive heart failure and atrial fibrillation that was believed to be due to myocarditis, for which she underwent cardiac transplantation at age 5 years. She was diagnosed with dilated cardiomyopathy without signs of LVNC. A myocardial tissue sample from the explanted left ventricular apex revealed pronounced endomyocardial fibroelastosis and minimal interstitial fibrosis. In the second family, the 55-year-old male proband presented with chest pain and dyspnea, and echocardiography revealed pronounced LVNC of the apex and midventricular wall, with increased right ventricular trabeculations. Cardiac MRI showed normal left ventricular (LV) mass and extensive diffuse fibrosis of the LV, predominantly located on the epicardium and extending transmurally into the anterior and inferior LV wall. The hypertrophic interventricular septum was spared and showed no recesses or prominent trabeculations. Family history revealed that the proband's father had died from heart disease at age 60 and an uncle had a sudden cardiac death at age 40. Kelle et al. (2016) reported a 2-year-old girl who presented at birth with heart failure and was found to have severe Ebstein anomaly (EA) of the tricuspid valve as well as LVNC. At age 2 years, chest x-ray showed massive cardiomegaly, and echocardiography revealed apical displacement of the tricuspid valve annulus with tethering of the septal leaflet and a large coaptation gap, resulting in severe tricuspid regurgitation. Cardiac MRI confirmed LVNC and globally reduced ventricular systolic function, with ejection fractions of 33% on the right and 20% on the left. Due to severe left ventricular dysfunction and pulmonary hypertension, she was not a candidate for repair of EA; she died following a cardiac catheterization procedure, from presumed pulmonary hemorrhage. Autopsy findings were unavailable at the time of the report. Nijak et al. (2018) studied a family in which 2 sisters had LVNC and EA. The more severely affected sister developed progressive heart failure and died at age 3.5 years, while awaiting transplantation. Her younger sister, who also had mild mitral valve insufficiency, maintained normal left ventricular function on ACE (106180) inhibitors. Their father was evaluated after his daughters were diagnosed; MRI at age 33 showed LVNC and a mildly dilated left atrium, with normal left ventricular function. The father's male cousin had been diagnosed with LVNC and mitral insufficiency as a neonate, and the cousin had a son with LVNC, who also had progressive mitral insufficiency and pulmonary hypertension and underwent mitral valve replacement at age 3.5 years. Molecular Genetics In affected individuals from 2 unrelated families with idiopathic dilated cardiomyopathy, Olson et al. (2001) identified heterozygosity for missense mutations in the TPM1 gene: E54K (191010.0004) and E40K (191010.0005). ### Left Ventricular Noncompaction 9 In a cohort of 63 unrelated white patients of western European descent with left ventricular noncompaction, Probst et al. (2011) analyzed 8 sarcomere genes and identified 2 probands with heterozygous missense mutations in the TPM1 gene (191010.0006 and 191010.0007). In a 2-year-old girl with LVNC and Ebstein anomaly, Kelle et al. (2016) screened 38 CMD- or LVNC-associated genes and identified heterozygosity for a de novo missense mutation in the TPM1 gene (D159N; 191010.0008). The authors stated that the mutation had been previously identified in a patient with dilated cardiomyopathy, although it was not reported in the published literature. In a family with LVNC with or without Ebstein anomaly and/or mitral valve insufficiency, Nijak et al. (2018) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the TPM1 gene (L113V; 191010.0009) that segregated with disease and was not found in public variant databases. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Heart failure, progressive and sometimes fatal \- Ventricular tachycardia, nonsustained (in some patients) \- Decreased left ventricular ejection fraction \- Decreased left ventricular fractional shortening \- Ebstein anomaly (in some patients) \- Mitral valve insufficiency (in some patients) \- Irregular and fragmented thin filaments of sarcomere seen on electron microscopy \- Scalloped appearance of sarcolemma seen on electron microscopy \- Left ventricular noncompaction at apex and/or midventricular wall (in some patients) MISCELLANEOUS \- Some patients require cardiac transplantation MOLECULAR BASIS \- Caused by mutation in the gene encoding tropomyosin-1 (TPM1, 191010.0004 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CARDIOMYOPATHY, DILATED, 1Y	c0340427	5,553	omim	https://www.omim.org/entry/611878	2019-09-22T16:02:46	{"doid": ["0110457"], "mesh": ["C536231"], "omim": ["611878"], "orphanet": ["154", "54260"], "genereviews": ["NBK1309"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is caused by homozygous mutation in the AIMP1 gene (603605) on chromosome 4q24. Description Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by Feinstein et al., 2010). The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080. Clinical Features ### Early Descriptions Nisenbaum et al. (1965) described a family in which 6 of 7 sibs (3 males and 3 females) died in the first months of life from an infantile disease resembling Pelizaeus-Merzbacher disease. The parents, Yemenite Jews, were apparently unrelated. All 6 affected children were born prematurely with low birth weights. The main clinical feature was vomiting beginning at 1 to 3 weeks after birth and progressing to continuous projectile vomiting. Sarnat and Adelman (1973) described a single case. Yokoi et al. (1985) reported 2 affected sisters and reviewed reports of other cases. Novotny (1988) reported a case with associated arthrogryposis multiplex congenita and death at age 19 days. Cassidy et al. (1987) referred to the classic X-linked form of Pelizaeus-Merzbacher disease as type I and reported a female with what they referred to as the connatal or Seitelberger type (type II). They found reports of 16 patients from 11 families, including the description of 3 affected brothers (Seitelberger, 1954). Begleiter and Harris (1989) reported a brother and sister with severe connatal PMD consistent with autosomal recessive inheritance. Clinical features included severe developmental delay, tonic-clonic seizures, ankle clonus, rigidity, and spastic quadriparesis. Optic discs were atrophic. Postmortem examination of the boy, who died at about age 5 years, showed poor myelination of the white matter and massive gliosis throughout the brain. The cerebellum showed severe neuronal loss and scarce myelin. Mild polymicrogyria was also observed. Wolf et al. (2004) reported 2 unrelated girls with infantile onset of nystagmus, hypotonia, microcephaly, and seizures. One child later developed spasticity and the other myoclonus and dystonia. Both had essentially absent psychomotor development. Brain MRI showed almost complete absence of myelination and magnetic resonance spectroscopy of CSF detected highly elevated concentrations of N-acetylaspartylglutamate (NAAG). Genetic analysis excluded mutations in the PLP1 gene and the gene coding for glutamate carboxypeptidase II (FOLH1; 600934), which catabolizes NAAG. ### Patients With Proven Mutations in the AIMP1 Gene Feinstein et al. (2010) reported 7 individuals from an extended consanguineous Israeli Bedouin kindred with infantile onset of a severe rapid hypomyelinating neurodegenerative disorder similar to Pelizaeus-Merzbacher disease. All affected individuals had severe failure to thrive, microcephaly, and severe global developmental delay with mental retardation and lack of speech. Fast horizontal or rotary nystagmus was often the presenting sign at age 2 to 3 months. Other neurologic features included axial hypotonia and progressive spastic paraparesis with wasting of lower limbs and positive pyramidal signs. This resulted in progressive joint contractures and kyphoscoliosis becoming apparent at about 2 to 3 years of age. All had coarse faces, most had slow pupillary reflexes, 2 had seizures, and 2 had pale fundi. Extensive laboratory testing ruled out metabolic diseases. Brain MRI and MRS showed global cerebral atrophy, atrophy of the corpus callosum, and arrest of myelination/hypomyelination associated with decreased N-acetylaspartate levels. At the time of the report, 5 of the patients were still alive, at ages ranging from 16 months to 26 years. In a comment on the report of Feinstein et al. (2010), Biancheri et al. (2011) stated that the clinical and neuroradiologic features of those patients seemed consistent with a cortical disease rather than a primary white matter disorder. Severe failure to thrive with a concordant reduced head circumference, a rapid neurologic deterioration progressing over the first months of life, and abnormal epileptiform EEG pattern suggested a cortical disease more than PMLD. Biancheri et al. (2011) further argued that in patients with true hypomyelination, brain atrophy is mild or absent, and this was not the case in the family presented by Feinstein et al. (2010). Boespflug-Tanguy et al. (2011) also commented on the article by Feinstein et al. (2010), suggesting that the patients described did not present the core clinical and neuroradiologic symptoms that define a hypomyelinating leukodystrophy since the patients had rapid neurologic deterioration, early microcephaly, dysmorphia, spastic paraparesis, limb deformities, and kyphoscoliosis. Boespflug-Tanguy et al. (2011) argued that these patients presented a complex phenotype and appeared to suffer from a primitive severe axonal disease rather than a hypomyelinating leukodystrophy. Feinstein et al. (2011) commented on the letters by Biancheri et al. (2011) and Boespflug-Tanguy et al. (2011), stating that their patients presented precisely as described in the severe (connatal) form of Pelizaeus-Merzbacher disease, and that their MRI results were well within the scope of a PMD-like phenotype. Armstrong et al. (2014) reported a Filipino girl with a severe neurodegenerative disorder resulting in death at age 15 months. She presented with microcephaly at birth and developed intractable seizures at age 3 weeks. EEG showed hypsarrhythmia and focal seizures arising from the occipital region. She also had no visual reaction to light. Brain imaging showed myelin deficiency and progressive cerebral atrophy, and MR spectroscopy showed decreased N-acetylaspartic acid (NAA). The patient had arrested psychomotor development and was hypotonic, areflexic, and immobile, with markedly decreased muscle mass at age 13 months. Armstrong et al. (2014) concluded that the phenotype was consistent with a primary neuronal degenerative disorder with secondary hypomyelination. Mapping By genomewide homozygosity mapping of a large consanguineous Israeli Bedouin kindred with autosomal recessive hypomyelinating leukodystrophy, Feinstein et al. (2010) found linkage to a region on chromosome 4q23-q25 (maximum lod score of 4.25). Molecular Genetics In affected members of a large consanguineous Israeli Bedouin kindred with infantile onset of hypomyelinating leukodystrophy-3, Feinstein et al. (2010) identified a homozygous mutation in the AIMP1 gene (603605.0001). In a Filipino girl with a severe neurodegenerative disorder resulting in early death, Armstrong et al. (2014) identified a homozygous truncating mutation in the AIMP1 gene (603605.0002). The mutation was found by whole-exome sequencing and segregated with the disorder. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Microcephaly Face \- Coarse facies Eyes \- Horizontal or rotary nystagmus \- Pale fundi \- Slow pupillary reflexes \- Impaired vision SKELETAL \- Joint contractures, progressive Spine \- Kyphoscoliosis MUSCLE, SOFT TISSUES \- Atrophy of the lower limbs NEUROLOGIC Central Nervous System \- Global developmental delay, severe \- No speech acquisition \- Axial hypotonia \- Spastic paraparesis \- Pyramidal signs \- Seizures (variable) \- Abnormal EEG \- Brain MRI shows arrest in myelination \- Decreased N-acetylaspartate \- Generalized brain atrophy \- Atrophy of the corpus callosum MISCELLANEOUS \- Onset in first months of life \- Progressive disorder \- Nystagmus is often the presenting sign MOLECULAR BASIS \- Caused by mutation in the aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 gene (AIMP1, 603605.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	LEUKODYSTROPHY, HYPOMYELINATING, 3	c1850053	5,554	omim	https://www.omim.org/entry/260600	2019-09-22T16:23:36	{"doid": ["0060790"], "mesh": ["C536319"], "omim": ["260600"], "orphanet": ["280270", "280293"], "synonyms": ["PMLD"]}
A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome arthrochalasia type 1 (EDSARTH1) is caused by heterozygous mutation in the COL1A1 (120150) on chromosome 17q21. Several forms of osteogenesis imperfecta (see, e.g., OI1, 166200) are also caused by mutation in the COL1A1 gene. Description Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (Byers et al., 1997; Giunta et al., 2008). ### Genetic Heterogeneity of Arthrochalasia-type Ehlers-Danlos Syndrome See EDSARTH2 (617821), caused by mutation in the COL1A2 gene (120160). Clinical Features Cole et al. (1986) reported a 3-month-old girl with type VII EDS. She was born with bilateral dislocation of the hips and knees and mildly hyperelastic skin. At 4 years 7 months, her face had a chubby appearance due to laxity of facial tissues. Height was at the 3rd centile, which was thought to be due in part to progressive right thoracolumbar scoliosis. She also had a large inguinal hernia. Collagen fibrils in the skin were irregular in outline and varied widely in diameter. Studies of her collagen showed a deletion of 24 amino acids (positions 136-159) from the pro-alpha-1(I) protein. The deleted segment normally contains the small globular region of the NH2-propeptide, the procollagen N-proteinase cleavage site, the NH2-telopeptide, and the first triplet of the helix of the alpha-1(I) collagen chain. Loss of the procollagen N-proteinase cleavage site accounted for the persistence of NH2-propeptide despite normal activity of N-proteinase. Collagen production by mutant fibroblasts was doubled, possibly due to reduced feedback inhibition by NH2-propeptide. Neither parent had the deletion, indicating a de novo event in the child. The deleted peptide corresponded precisely to the sequence coded by exon 6 of the normal pro-alpha-1(I) gene (Chu et al., 1984). Byers et al. (1997) reported a girl with EDS VIIA born of a 23-year-old Caucasian father and a 31-year-old mother of Japanese origin. She presented at birth with large fontanels, a small umbilical hernia, joint laxity, contractures of the digits of both hands, short femurs, and pendulous skin folds. Radiographs demonstrated bilateral hip dislocation. At the age of 5 months, patent and bulging fontanels with prominent frontal bossing were noted. She had a small chin, deep blue sclerae, a narrow chest with mild pectus excavatum, and a large umbilical hernia. Her large joints were hypermobile. Genetic analysis identified a heterozygous mutation in the COL1A1 gene (120150.0057) that resulted in the skipping of exon 6. Giunta et al. (2008) reported a 12-month-old girl who was noted at birth to have bilateral hip dislocation, subluxations of the shoulders, elbows, and knees, arthrogryposis of the hands and feet, clubfoot, and hypotonia. Other features included short stature, frontal bossing, hypertelorism, depressed nasal bridge, macrostomia, bluish sclerae, Moderate pectus excavatum, umbilical hernia, and velvety skin. Skin biopsy showed highly irregular collagen fibrils with variable diameters. The changes were more pronounced than those observed in EDS VIIB (EDSARTH2; 617821), but less severe than those present in EDS VIIC (EDSDERMS; 225410). Genetic analysis identified a heterozygous mutation in the COL1A1 gene (120150.0066), confirming EDS VIIA. Giunta et al. (2008) emphasized the importance of examining the collagen fibril ultrastructure for accurate diagnosis. Molecular Genetics In a girl with EDS VIIA reported by Cole et al. (1986), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A1 gene that resulted in the skipping of exon 6 (120150.0026). The deleted peptides included those encoding the N-proteinase cleavage site necessary for proper collagen processing. D'Alessio et al. (1991) identified the same COL1A1 mutation in another child with EDS VIIA. In affected members of 6 unrelated families with EDS type VIIB (617821), Byers et al. (1997) identified heterozygous mutations in the COL1A2 gene (see, e.g., 120160.0042) that resulted in the skipping of exon 6. Some patients had fractures, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. A patient with EDS VIIA had a more severe phenotype compared to those with EDS VIIB, and electron microscopy indicated a more severe disruption of collagen fibrils in EDS VIIA compared to EDS VIIB. Byers et al. (1997) noted that collagen I contains 2 COL1A1 chains and 1 COL1A2 chain; thus, mutations in the COL1A1 gene would affect 3/4 of the collagen molecules, whereas mutations in the COL1A2 gene would affect only half. Nomenclature Halila et al. (1986) referred to the enzymatic form of EDS VII as type VIIA and to the autosomal dominant form as type VIIB. Nusgens et al. (1992) referred to the 2 structural defects of procollagen polypeptides as EDS VIIA and EDS VIIB for the COL1A1 and COL1A2 defects, respectively. They used the designation EDS VIIC for the autosomal recessive enzymatic form (225410). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature, mild to moderate HEAD & NECK Face \- Midface hypoplasia SKELETAL \- Joint laxity, severe \- Recurrent joint subluxation \- Premature osteoarthritis \- Osteopenia \- Fractures Spine \- Kyphosis \- Scoliosis Pelvis \- Congenital bilateral hip dislocation SKIN, NAILS, & HAIR Skin \- Thin, velvety skin \- Hyperextensible skin \- Poor wound healing \- Atrophic scars \- Easy bruisability NEUROLOGIC Central Nervous System \- Hypotonia \- Delayed gross motor development PRENATAL MANIFESTATIONS Delivery \- Breech presentation MOLECULAR BASIS \- Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1, 120150.0026 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 1	c0268345	5,555	omim	https://www.omim.org/entry/130060	2019-09-22T16:41:47	{"omim": ["130060"], "orphanet": ["1899"], "synonyms": ["Alternative titles", "EHLERS-DANLOS SYNDROME, TYPE VIIA, AUTOSOMAL DOMINANT", "EDS VIIA", "ARTHROCHALASIS MULTIPLEX CONGENITA", "EDS VII, MUTANT PROCOLLAGEN TYPE"]}
Jumping Frenchmen of Maine is a condition characterized by an unusually extreme startle response. The exact cause of the condition is unknown. One theory is that the disorder occurs because of an extreme conditioned response to a particular situation influenced by cultural factors. It was first identified during the late nineteenth century in Maine and the Canadian province of Quebec in an isolated population of lumberjacks of French Canadian descent. Jumping Frenchmen of Maine is a type of startle-matching syndrome. These syndromes have been described in many different parts of the world. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Jumping Frenchmen of Maine	c1280764	5,556	gard	https://rarediseases.info.nih.gov/diseases/6803/jumping-frenchmen-of-maine	2021-01-18T17:59:40	{"omim": ["244100"], "synonyms": ["Exaggerated startle reflex", "Startle disease", "'jumpers' of Maine"]}
A number sign (#) is used with this entry because of evidence that it represents a contiguous gene syndrome caused by duplication at chromosome 17q12 (Chr17:31.5-33.6 Mb, NCBI35). Molecular Genetics In 290 individuals with mental retardation, Sharp et al. (2006) used BAC array CGH to investigate 130 candidate chromosomal regions for genomic disorders. They identified a 1.46-Mb duplication at 17q12 in 1 patient with mental retardation, and noted that both breakpoints of the duplication mapped to a pair of 66-kb flanking segmental duplications with 99.7% similarity. The duplication was also detected in an affected sib, but was not found in their unaffected mother. In a study of chromosomal regions predisposed to recurrent rearrangements, Mefford et al. (2007) identified 2 patients with mild to moderate mental retardation, epilepsy, and focal cortical dysplasia who had overlapping duplications on chromosome 17q12. Oligonucleotide microarray CGH analysis in 1 of these patients and the proband previously studied by Sharp et al. (2006) showed that they had duplications of the entire 17q12 region, with breakpoints mapping to the same duplication blocks associated with renal disease and MODY5 deletions (see 137920). However, this reciprocal duplication of 17q12 was also found in unaffected family members and in 1 of 960 unrelated Caucasian controls, making the pathologic significance of the duplication unclear. The third patient had a smaller and more complex duplication, in which there was a 27-kb duplication encompassing the LHX1 gene (601999) and a 259-kb duplication corresponding to the TCF2 gene (HNF1B; 189907). The patient's unaffected mother carried the TCF2 duplication, and interphase FISH analysis showed her to be mosaic for the LHX1 duplication (28% of 135 nuclei), whereas the patient had the LHX1 duplication in virtually all cells (98% of 138 nuclei). Mencarelli et al. (2008) used oligonucleotide array CGH to analyze 84 patients with mild to severe mental retardation associated with multiple congenital anomalies and identified a 1.8-Mb duplication at chromosome 17q12 in a 15-year-old boy with XX sex reversal, severe mental retardation, Peters anomaly, microphthalmia, glaucoma, cleft soft palate, atrial septal defect, mild brachydactyly, and fifth finger clinodactyly. His healthy father and a sister with isolated behavioral problems were also carriers of the duplication, which encompassed TCF2 and 18 other genes. Nagamani et al. (2010) studied 9 patients with genomic rearrangements in chromosome 17q12, including 4 patients with a deletion (see 614527) and 5 with a duplication. The 5 patients with a duplication all presented with cognitive impairment except 1, who had nonsyndromic esophageal atresia, age-appropriate development, normal renal function and imaging, and no diabetes; information on renal status and diabetes in the other 4 patients was not available. The duplications in all 5 patients encompassed a minimum of 1.06 Mb from the LHX1 gene to LOC28400, and a possible maximum of 2.46 Mb, extending from the CCL3L3 gene (609468) to the SNIP gene (610786). Caselli et al. (2010) reported a 6-year-old boy with mental retardation and a 12.4-Mb duplication of chromosome 17q11.2-q12, encompassing the NF1 gene (613113) and about 130 additional genes. Unilateral megacalicosis of the left kidney had been seen on prenatal ultrasound and was confirmed at 1 year of age; cerebral MRI at that time showed a thin corpus callosum. Dysmorphic features included dolichocephaly and a triangular, hypotonic face with deep-set eyes and downslanting palpebral fissures, large and anteverted ears, smooth philtrum, and micrognathia. He also displayed rotational tongue movements, axial hypotonia, and had short second fingers bilaterally and broad thumbs and toes. Caselli et al. (2010) stated that the description of additional cases is essential to delineate a specific phenotype for chromosome 17q11.2-q12 duplication. Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 17q12 duplication was identified in 21 cases and 4 controls for a p value of 0.022 and a frequency of 1 in 750 cases. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Dolicocephaly (rare) Face \- Triangular face (rare) \- Hypotonic facies (rare) \- Smooth philtrum (rare) \- Micrognathia (rare) Ears \- Large anteverted ears (rare) Eyes \- Deep-set eyes (rare) \- Downslanting palpebral fissures (rare) \- Microphthalmia (rare) \- Peters anomaly (rare) \- Glaucoma (rare) Mouth \- Cleft soft palate (rare) \- Rotational tongue movements (rare) CARDIOVASCULAR Heart \- Atrial septal defect (rare) ABDOMEN Gastrointestinal \- Esophageal atresia (rare) GENITOURINARY Kidneys \- Megacalicosis, unilateral (rare) SKELETAL Hands \- Brachydactyly, mild (rare) \- Broad thumbs (rare) \- Short second fingers bilaterally (rare) \- Clinodactyly, fifth finger (rare) Feet \- Broad toes (rare) NEUROLOGIC Central Nervous System \- Mental retardation \- Seizures (in some patients) \- Cortical dysplasia, focal (in some patients) \- Corpus callosum, thin (rare) \- Axial hypotonia (rare) MISCELLANEOUS \- Contiguous gene duplication syndrome MOLECULAR BASIS \- Caused by duplication of 1.0-2.5Mb on chromosome 17q12 ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	CHROMOSOME 17q12 DUPLICATION SYNDROME	c3281137	5,557	omim	https://www.omim.org/entry/614526	2019-09-22T15:54:54	{"doid": ["0060433"], "omim": ["614526"], "orphanet": ["261272"], "synonyms": ["Dup(17)(q12)", "Trisomy 17q12"], "genereviews": ["NBK344340"]}
Lujan syndrome is a condition characterized by intellectual disability, behavioral problems, and poor muscle tone (hypotonia). Affected people also tend to have characteristic physical features such as a tall and thin body; a large head (macrocephaly); and a thin face with distinctive facial features (prominent top of the nose, short space between the nose and the upper lip, narrow roof of the mouth, crowded teeth and a small chin). Most of the cases occur in males. Lujan syndrome is caused by changes (mutations) in the MED12 gene and is inherited in an X-linked manner. Treatment is based on the signs and symptoms present in each person and may include special education; physical therapy, occupational therapy, and speech therapy for developmental delays; and medications to control seizures. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Lujan syndrome	c0796022	5,558	gard	https://rarediseases.info.nih.gov/diseases/3307/lujan-syndrome	2021-01-18T17:59:19	{"mesh": ["C537724"], "omim": ["309520"], "umls": ["C0796022"], "orphanet": ["776"], "synonyms": ["Marfanoid habitus, mild general hypotonia, hypernasal voice, normal testicular size and distinct craniofacial anomalies"]}
Vision disorder Disability-adjusted life year for vision disorders (age-related) per 100,000 inhabitants in 2002.[1] no data less than 100 100–200 200–300 300–400 400–450 450–500 500–600 600–700 700–750 750–800 800–850 more than 850 SpecialtyOphthalmology A vision disorder is an impairment of the sense of vision. Vision disorder is not the same as an eye disease. Although many vision disorders do have their immediate cause in the eye, there are many other causes that may occur at other locations in the optic pathway. ## Contents * 1 Causes * 2 Epidemiology * 3 See also * 4 References * 5 External links ## Causes[edit] There are many eye conditions that can lead to vision disorder. Some of which are as follows: * Age-Related Macular Degeneration (ARMD): ARMD is a retinal degeneration disease specifically associated with macula blood vessels, which can result in central vision impairment. It is strongly linked to advancing age, as well as European ancestry.[2] * Bulging eyes: where the eye (one or both) protrudes or distends out of its orbit. Left untreated, bulging eyes may lead to eye dryness, pain and vision loss [3] * Cytomegalovirus (CMV) Retinitis: This is an inflammation of the retina caused by infection, which can result in blindness. It occurs in people experiencing suppressed immune systems, most commonly by Acquired Immunodeficiency Syndrome (AIDS).[4] * Diabetic Macular Edema (DME): is an eye disease specifically related to diabetes, occurring due to fluid build-up in the retina as a result of sustained high blood glucose levels. It can result in blurred vision and vision loss.[5] * Eye floaters and spots: where visible cloud-like images appear to "float" in an individual's field of vision.[6] Floaters and spots are most commonly related to ageing. They are generally harmless and do not cause blindness [7] * Eye flashing: characterised by bursts or streaks of light that appear in an individual's field of vision. As eye flashing may indicate impending retinal detachment, medical attention is required.[8] * Eyelid twitching: where the eye lid muscles contract in an irregular or abnormal pattern. Such movements can cause irritation and fatigue to the eyes.[9] * Glaucoma: occurs when the optic nerve is damaged and can result in irreversible vision loss, with the potential to pass undetected until this damage occurs. It is caused when aqueous humour fails to adequately drain from the eye, resulting in pressure build-up.[10] * Keratoconus: vision problems can be caused when the cornea thins and distorts into a conical shape. While the cause is unknown, Keratoconus is believed to be congenital, and can be exacerbated by allergies and eye rubbing.[11] * Uveitis: where the uveal (middle) layer of the eye is inflamed. Uveitis requires medical intervention as it can lead to blurry vision, eye pain, eye floaters, eye redness and vision loss [12][13] ## Epidemiology[edit] It was estimated by the WHO in 2004 that 314 million people worldwide are vision impaired (from all causes), of whom 45 million are blind.[14] Vision disorders are not often targeted by public health initiatives, as mortality causes take priority.[15] However, they can have significant impact on a person's quality of life, affecting performance at school and the workplace if not corrected. ## See also[edit] * Blindness, Recovery from blindness * Amblyopia, Nystagmus, Strabism, Stereoblindness, Stereopsis recovery * Visual field ## References[edit] 1. ^ "Mortality and Burden of Disease Estimates for WHO Member States in 2002" (xls). World Health Organization. 2002. 2. ^ "Age-related macular degeneration - EyeWiki". eyewiki.org. Retrieved 2020-01-23. 3. ^ "Bulging Eyes – Symptoms and treatments for Bulging Eyes : Bausch + Lomb". www.bausch.com. Retrieved 2020-01-22. 4. ^ "CMV Retinitis - EyeWiki". eyewiki.org. Retrieved 2020-01-23. 5. ^ "Diabetic Macular Edema - EyeWiki". eyewiki.org. Retrieved 2020-01-23. 6. ^ "Glossary of Common Eye & Vision Conditions". www.aoa.org. Retrieved 2020-01-22. 7. ^ "Common Eye Problems and Infections". OnHealth. Retrieved 2020-01-22. 8. ^ "Glossary of Common Eye & Vision Conditions". www.aoa.org. Retrieved 2020-01-22. 9. ^ "Eyelid Twitching – Causes and Symptoms of Eyelid Twitches : Bausch + Lomb". www.bausch.com. Retrieved 2020-01-22. 10. ^ "Glaucoma Treatment, Symptoms & Diagnosis". Lions Eye Institute. Retrieved 2020-01-23. 11. ^ "Keratoconus: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2020-01-23. 12. ^ "Uveitis – Symptoms and Treatments for Uveitis : Bausch + Lomb". www.bausch.com. Retrieved 2020-01-22. 13. ^ "Glossary of Common Eye & Vision Conditions". www.aoa.org. Retrieved 2020-01-22. 14. ^ Resnikoff S, Pascolini D, Mariotti SP, Pokharel GP (January 2008). "Global magnitude of visual impairment caused by uncorrected refractive errors in 2004". Bulletin of the World Health Organization. 86 (1): 63–70. doi:10.2471/BLT.07.041210. PMC 2647357. PMID 18235892. 15. ^ Ono K, Hiratsuka Y, Murakami A (September 2010). "Global Inequality in Eye Health: Country-Level Analysis From the Global Burden of Disease Study". American Journal of Public Health. 100 (9): 1784–8. doi:10.2105/AJPH.2009.187930. PMC 2920965. PMID 20634443. ## External links[edit] Classification D * MeSH: D014786 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Vision disorder	c0018975	5,559	wikipedia	https://en.wikipedia.org/wiki/Vision_disorder	2021-01-18T19:05:03	{"mesh": ["D014786"], "icd-9": ["368.8"], "icd-10": ["H53.8"], "wikidata": ["Q767669"]}
Sickle cell disease is a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disease have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent, shape. Signs and symptoms of sickle cell disease usually begin in early childhood. Characteristic features of this disorder include a low number of red blood cells (anemia), repeated infections, and periodic episodes of pain. The severity of symptoms varies from person to person. Some people have mild symptoms, while others are frequently hospitalized for more serious complications. The signs and symptoms of sickle cell disease are caused by the sickling of red blood cells. When red blood cells sickle, they break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children. The rapid breakdown of red blood cells may also cause yellowing of the eyes and skin, which are signs of jaundice. Painful episodes can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels. These episodes deprive tissues and organs, such as the lungs, kidneys, spleen, and brain, of oxygen-rich blood and can lead to organ damage. A particularly serious complication of sickle cell disease is high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension), which can lead to heart failure. Pulmonary hypertension occurs in about 10 percent of adults with sickle cell disease. ## Frequency Sickle cell disease affects millions of people worldwide. It is most common among people whose ancestors come from Africa; Mediterranean countries such as Greece, Turkey, and Italy; the Arabian Peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean. Sickle cell disease is the most common inherited blood disorder in the United States, affecting an estimated 100,000 Americans. The disease is estimated to occur in 1 in 500 African Americans and 1 in 1,000 to 1,400 Hispanic Americans. ## Causes Mutations in the HBB gene cause sickle cell disease. The HBB gene provides instructions for making one part of hemoglobin. Hemoglobin consists of four protein subunits, typically, two subunits called alpha-globin and two subunits called beta-globin. The HBB gene provides instructions for making beta-globin. Various versions of beta-globin result from different mutations in the HBB gene. One particular HBB gene mutation produces an abnormal version of beta-globin known as hemoglobin S (HbS). Other mutations in the HBB gene lead to additional abnormal versions of beta-globin such as hemoglobin C (HbC) and hemoglobin E (HbE). HBB gene mutations can also result in an unusually low level of beta-globin; this abnormality is called beta thalassemia. In people with sickle cell disease, at least one of the beta-globin subunits in hemoglobin is replaced with hemoglobin S. In sickle cell anemia (also called homozygous sickle cell disease), which is the most common form of sickle cell disease, hemoglobin S replaces both beta-globin subunits in hemoglobin. In other types of sickle cell disease, just one beta-globin subunit in hemoglobin is replaced with hemoglobin S. The other beta-globin subunit is replaced with a different abnormal variant, such as hemoglobin C. For example, people with sickle-hemoglobin C (HbSC) disease have hemoglobin molecules with hemoglobin S and hemoglobin C instead of beta-globin. If mutations that produce hemoglobin S and beta thalassemia occur together, individuals have hemoglobin S-beta thalassemia (HbSBetaThal) disease. Abnormal versions of beta-globin can distort red blood cells into a sickle shape. The sickle-shaped red blood cells die prematurely, which can lead to anemia. Sometimes the inflexible, sickle-shaped cells get stuck in small blood vessels and can cause serious medical complications. ### Learn more about the gene associated with Sickle cell disease * HBB ## 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Sickle cell disease	c0002895	5,560	medlineplus	https://medlineplus.gov/genetics/condition/sickle-cell-disease/	2021-01-27T08:25:24	{"gard": ["8614"], "mesh": ["D000755"], "omim": ["603903"], "synonyms": []}
Minimal mesangial glomerulonephritis SpecialtyNephrology Minimal mesangial glomerulonephritis is a type of glomerulonephritis is seen in 10% to 25% of SLE cases, and is associated with mild clinical symptoms. Immune complexes deposit in the mesangium, with a slight increase in the mesangial matrix and cellularity.[1] ## References[edit] 1. ^ Robbins, Stanley L.; Kumar, Vinay (2007). Robbins basic pathology. Saunders/Elsevier. p. 142. ISBN 978-0-8089-2366-4. * v * t * e Lupus nephritis * Class I (Minimal mesangial glomerulonephritis) * Class II (Mesangial proliferative lupus nephritis) * Class III (Focal proliferative nephritis) * Class IV (Diffuse proliferative nephritis) * Class V (Membranous nephritis) * Class VI (Glomerulosclerosis) * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy This article about a disease of the genitourinary system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Minimal mesangial glomerulonephritis	None	5,561	wikipedia	https://en.wikipedia.org/wiki/Minimal_mesangial_glomerulonephritis	2021-01-18T19:10:47	{"wikidata": ["Q6865321"]}
Distal monosomy 10q is a chromosomal anomaly involving terminal deletion of the long arm of chromosome 10 and is characterized by facial dysmorphism, pre- and postnatal growth retardation, cardiac and genital anomalies, and developmental delay. ## Epidemiology Prevalence is unknown but around 40 cases have been described in the literature so far. ## Clinical description There is no specific clinical feature associated with this chromosome anomaly. Craniofacial features include hypertelorism, strabismus, a prominent or broad nasal bridge, and posteriorly rotated low-set ears. Hypotonia is frequent, and limited joint extensions and early scoliosis have been reported in a few cases. Cardiac defects are not a constant finding and vary to include patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot and truncus arteriosus (see these terms). Genital abnormalities have been mostly reported in males and include undescended testis, micropenis and a posterior urethral valve. Bladder distension due to cervical dysfunction may occur in females and may be evident during the antenatal period. Severe genital abnormalities (ambiguous external genitalia) have been reported in a few cases. Psychomotor retardation (generally described as mild) was present in all reported cases. ## Etiology Distal monosomy 10q results from a subterminal 10q deletion with breakpoints in the 10q25 or 10q26 band leading to partial monosomy for the genes located in this area. Most of the reported cases involved de novo terminal deletions resulting from abnormal non-allelic homolog recombination during meiosis. ## Diagnostic methods Diagnosis is made by molecular analysis. Comparative genomic hybridization (CGH) microarray or subterminal chromosome multiplex ligation-dependent probe amplification (MLPA) may be necessary since conventional cytogenetic analysis may not be sensitive enough to detect very short subterminal deletions. ## Antenatal diagnosis Antenatal molecular testing for the presence of a subterminal 10q deletion may be proposed in case of suspicion of a posterior urethral valve in males (associated or not with genital abnormalities) or in case of bladder distension in female fetuses. The risk of recurrence is low but prenatal screening for chromosomal abnormalities must be proposed, with the use of FISH markers for the 10q subterminal region. ## Management and treatment Management is symptomatic only. Bladder dysfunction may require transient cystostomy. Special education programs to improve cognitive development are needed in most cases. ## Prognosis The prognosis is unclear as there are no available data concerning long-term follow up, especially up until adult age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Distal monosomy 10q	c2674937	5,562	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96148	2021-01-23T18:15:33	{"gard": ["3711"], "mesh": ["C567182"], "omim": ["609625"], "umls": ["C2674937"], "icd-10": ["Q93.5"], "synonyms": ["Distal deletion 10q", "Monosomy 10qter", "Telomeric deletion 10q"]}
Not to be confused with Leiomyosarcoma. Uterine fibroids Other namesUterine leiomyoma, uterine myoma, myoma, fibromyoma, fibroleiomyoma Uterine fibroids as seen during laparoscopic surgery SpecialtyGynecology SymptomsPainful or heavy periods[1] ComplicationsInfertility[1] Usual onsetMiddle and later reproductive years[1] CausesUnknown[1] Risk factorsFamily history, obesity, eating red meat[1] Diagnostic methodPelvic examination, medical imaging[1] Differential diagnosisLeiomyosarcoma, pregnancy, ovarian cyst, ovarian cancer[2] TreatmentMedications, surgery, uterine artery embolization[1] MedicationIbuprofen, paracetamol (acetaminophen), iron supplements, gonadotropin releasing hormone agonist[1] PrognosisImprove after menopause[1] Frequency~50% of women by age 50[1] Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus.[1] Most women have no symptoms while others may have painful or heavy periods.[1] If large enough, they may push on the bladder causing a frequent need to urinate.[1] They may also cause pain during sex or lower back pain.[1][3] A woman can have one uterine fibroid or many.[1] Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon.[1] The exact cause of uterine fibroids is unclear.[1] However, fibroids run in families and appear to be partly determined by hormone levels.[1] Risk factors include obesity and eating red meat.[1] Diagnosis can be performed by pelvic examination or medical imaging.[1] Treatment is typically not needed if there are no symptoms.[1] NSAIDs, such as ibuprofen, may help with pain and bleeding while paracetamol (acetaminophen) may help with pain.[1][4] Iron supplements may be needed in those with heavy periods.[1] Medications of the gonadotropin-releasing hormone agonist class may decrease the size of the fibroids but are expensive and associated with side effects.[1] If greater symptoms are present, surgery to remove the fibroid or uterus may help.[1] Uterine artery embolization may also help.[1] Cancerous versions of fibroids are very rare and are known as leiomyosarcomas.[1] They do not appear to develop from benign fibroids.[1] About 20% to 80% of women develop fibroids by the age of 50.[1] In 2013, it was estimated that 171 million women were affected worldwide.[5] They are typically found during the middle and later reproductive years.[1] After menopause, they usually decrease in size.[1] In the United States, uterine fibroids are a common reason for surgical removal of the uterus.[6] ## Contents * 1 Signs and symptoms * 2 Risk factors * 2.1 Diet * 2.2 Genetics * 2.3 Familial leiomyomata * 3 Pathophysiology * 3.1 Location and classification * 3.1.1 Extrauterine fibroids of uterine origin, metastatic fibroids * 3.2 Pathogenesis * 4 Diagnosis * 4.1 Coexisting disorders * 5 Treatment * 5.1 Medication * 5.2 Uterine artery * 5.3 Myomectomy * 5.4 Hysterectomy * 5.5 Endometrial ablation * 5.6 Other procedures * 6 Prognosis * 6.1 Metastasis * 7 Epidemiology * 7.1 Europe * 7.2 United States * 8 Related legislation * 8.1 United States * 9 Other animals * 10 Research * 11 References * 12 External links ## Signs and symptoms[edit] Some women with uterine fibroids do not have symptoms. Abdominal pain, anemia and increased bleeding can indicate the presence of fibroids.[7] There may also be pain during intercourse, depending on the location of the fibroid. During pregnancy, they may also be the cause of miscarriage,[8] bleeding, premature labor, or interference with the position of the fetus.[citation needed] A uterine fibroid can cause rectal pressure. The abdomen can grow larger mimicking the appearance of pregnancy.[1] Some large fibroids can extend out through the cervix and vagina.[7] While fibroids are common, they are not a typical cause for infertility, accounting for about 3% of reasons why a woman may not be able to have a child.[9] The majority of women with uterine fibroids will have normal pregnancy outcomes.[10][11] In cases of intercurrent uterine fibroids in infertility, a fibroid is typically located in a submucosal position and it is thought that this location may interfere with the function of the lining and the ability of the embryo to implant.[9] ## Risk factors[edit] Some risk factors associated with the development of uterine fibroids are modifiable.[12] Fibroids are more common in obese women.[13] Fibroids are dependent on estrogen and progesterone to grow and therefore relevant only during the reproductive years. ### Diet[edit] Diets high in fruits and vegetables tend to lower the risk of developing fibroids.[12] Fibers, vitamin A, C and E, phytoestrogens, carotenoids, meat, fish, and dairy products are of unclear effect.[12] Normal dietary levels of vitamin D may reduce the risk of developing fibroids.[12] ### Genetics[edit] Fifty percent of uterine fibroids demonstrate a genetic abnormality. Often a translocation is found on some chromosomes.[7] Fibroids are partly genetic. If a mother had fibroids, risk in the daughter is about three times higher than average.[14] Black women have a 3-9 times increased chance of developing uterine fibroids than white women.[15] Only a few specific genes or cytogenetic deviations are associated with fibroids.[16] 80-85% of fibroids have a mutation in the mediator complex subunit 12 (MED12) gene.[17][18] ### Familial leiomyomata[edit] Further information: Hereditary leiomyomatosis and renal cell cancer A syndrome (Reed's syndrome) that causes uterine leiomyomata along with cutaneous leiomyomata and renal cell cancer has been reported.[19][20][21] This is associated with a mutation in the gene that produces the enzyme fumarate hydratase, located on the long arm of chromosome 1 (1q42.3-43). Inheritance is autosomal dominant. ## Pathophysiology[edit] An enucleated uterine leiomyoma – external surface on left, cut surface on right. Fibroids are a type of uterine leiomyoma. Fibroids grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the abdominal wall.[1] Micrograph of a lipoleiomyoma, a type of leiomyoma. H&E stain. Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus) and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active. The appearance of prominent nucleoli with perinucleolar halos should alert the pathologist to investigate the possibility of the extremely rare hereditary leiomyomatosis and renal cell cancer (Reed) syndrome.[22] ### Location and classification[edit] Schematic drawing of various types of uterine fibroids: a=subserosal fibroids, b=intramural fibroids, c=submucosal fibroid, d=pedunculated submucosal fibroid, e=cervical fibroid, f=fibroid of the broad ligament Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.[6] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows: * Intramural fibroids are located within the muscular wall of the uterus. Unless they are large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity. * Subserosal fibroids are located on the surface of the uterus. They can also grow outward from the surface and remain attached by a small piece of tissue and then are called pedunculated fibroids.[1] * Submucosal fibroids are most common type, located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix. * Cervical fibroids are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue. Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes. They tend to calcify after menopause.[23] If the uterus contains too many to count, it is referred to as diffuse uterine leiomyomatosis. #### Extrauterine fibroids of uterine origin, metastatic fibroids[edit] Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizing leiomyoma. They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with an increased risk of this complication.[24][25][26] There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.[27] * In leiomyoma with vascular invasion, an ordinary-appearing fibroid invades into a vessel but there is no risk of recurrence. * In intravenous leiomyomatosis, leiomyomata grow in veins with uterine fibroids as their source. Involvement of the heart can be fatal. * In benign metastasizing leiomyoma, leiomyomata grow in more distant sites such as the lungs and lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal. * In disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on the peritoneal and omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves benignly. ### Pathogenesis[edit] Multiple uterine leiomyoma Large subserosal fibroid Multiple uterine leiomyoma with calcification Fibroids are monoclonal tumors and approximately 40 to 50% show karyotypically detectable chromosomal abnormalities.When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids.[28] The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth.[29] It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.[30] Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium.[31] TGIF is a potential repressor of TGF-β pathways in myometrial cells.[31] Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that fibroids can convert circulating androstenedione into estradiol.[32] Similar mechanism of action has been elucidated in endometriosis and other endometrial diseases.[33] Aromatase inhibitors are currently considered for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is particularly pronounced in African-American women.[34] Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy compared to dizygotic twins.[35] Expansion of uterine fibroids occurs by a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix.[34] A small population of the cells in a uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor α and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signaling.[34] ## Diagnosis[edit] The presence of a uterine fibroid versus an adnexal tumor is made. Fibroids can be mistaken for ovarian neoplasms. An uncommon tumor which may be mistaken for a fibroid is Sarcoma botryoides. It is more common in children and adolescents. Like a fibroid, it can also protrude from the vagina and is distinguished from fibroids.[7] While palpation used in a pelvic examination can typically identify the presence of larger fibroids, gynecologic ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. The location can be determined and dimensions of the lesion measured. Also, magnetic resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the uterus.[citation needed] Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine leiomyosarcoma, however, the latter is quite rare. Fast growth or unexpected growth, such as enlargement of a lesion after menopause, raise the level of suspicion that the lesion might be a sarcoma. Also, with advanced malignant lesions, there may be evidence of local invasion. A biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis after ultrasounds and MRI imaging, surgery is generally indicated.[citation needed] Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine cavity are hysterosalpingography or sonohysterography.[citation needed] * A very large (9 cm) fibroid of the uterus which is causing pelvic congestion syndrome as seen on CT * A very large (9 cm) fibroid of the uterus which is causing pelvic congestion syndrome as seen on ultrasound * A relatively large submucosal leiomyoma; it fills out the major part of the endometrial cavity * A small uterine fibroid seen within the wall of the myometrium on a cross-sectional ultrasound view * Two calcified fibroids (in the uterus) * A subserosal uterine fibroid with a diameter of 5 centimeters. * MRI image with multiple uterine leiomiyomas * Giant leiomiyomas almost filling the abdomen. * Histopathology of uterine fibroids typically show smooth muscle in a whorled (fascicular) pattern.[36] * This variant of Van Gieson's stain distinguishes muscle (yellow) from connective tissue (red) ### Coexisting disorders[edit] Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects gastrointestinal problems such as constipation and bloatedness are possible. Compression of the ureter may lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause infertility. Adenomyosis may be mistaken for or coexist with fibroids. In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop.[37] In extremely rare cases uterine fibroids may present as part or early symptom of the hereditary leiomyomatosis and renal cell cancer syndrome. ## Treatment[edit] Most fibroids do not require treatment unless they are causing symptoms. After menopause, fibroids shrink, and it is unusual for them to cause problems. Symptomatic uterine fibroids can be treated by: * medication to control symptoms (i.e., symptomatic management) * medication aimed at shrinking tumors * ultrasound fibroid destruction * myomectomy or radiofrequency ablation * hysterectomy * uterine artery embolization In those who have symptoms, uterine artery embolization and surgical options have similar outcomes with respect to satisfaction.[38] ### Medication[edit] A number of medications may be used to control symptoms. NSAIDs can be used to reduce painful menstrual periods. Oral contraceptive pills may be prescribed to reduce uterine bleeding and cramps.[9] Anemia may be treated with iron supplementation. Levonorgestrel intrauterine devices are effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically few as the levonorgestrel (a progestin) is released in low concentration locally.[39] While most levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported good results specifically for women with fibroids including a substantial regression of fibroids.[40][41] Cabergoline in a moderate and well-tolerated dose has been shown in two studies to shrink fibroids effectively. The mechanism of action responsible for how cabergoline shrinks fibroids is unclear.[40] Ulipristal acetate is a synthetic selective progesterone receptor modulator (SPRM) that has tentative evidence to support its use for presurgical treatment of fibroids with low side-effects.[42] Long-term UPA-treated fibroids have shown volume reduction of about 70%.[43] In some cases UPA alone is used to relieve symptoms without surgery.[7] Danazol is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing.[40] Gonadotropin-releasing hormone analogs cause temporary regression of fibroids by decreasing estrogen levels. Because of the limitations and side effects of this medication, it is rarely recommended other than for preoperative use to shrink the size of the fibroids and uterus before surgery. It is typically used for a maximum of 6 months or less because after longer use they could cause osteoporosis and other typically postmenopausal complications. The main side effects are transient postmenopausal symptoms. In many cases the fibroids will regrow after cessation of treatment, however, significant benefits may persist for much longer in some cases. Several variations are possible, such as GnRH agonists with add-back regimens intended to decrease the adverse effects of estrogen deficiency. Several add-back regimes are possible, tibolone, raloxifene, progestogens alone, estrogen alone, and combined estrogens and progestogens.[40] Progesterone antagonists such as mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting.[44][45] Fibroid growth has recurred after antiprogestin treatment was stopped.[34] Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids.[40] However, fibroid growth has recurred after treatment was stopped.[34] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor. ### Uterine artery[edit] Uterine artery embolization (UAE) is a noninvasive procedure that blocks blood flow to fibroids, causing them to shrink.[46] Long-term outcomes with respect to how happy people are with the procedure are similar to that of surgery.[47] There is tentative evidence that traditional surgery may result in better fertility.[47] One review found that UAE doubles the future risk of miscarriage.[48] UAE also appears to require more repeat procedures than if surgery was done initially.[47] A person will usually recover from the procedure within a few days. Uterine artery ligation, sometimes also laparoscopic occlusion of uterine arteries are minimally invasive methods to limit blood supply of the uterus by a small surgery that can be performed transvaginally or laparoscopically. The principal mechanism of action may be similar like in UAE but is easier to perform and fewer side effects are expected.[49][non-primary source needed][50][non-primary source needed] The 2016 NICE (National Institute of Clinical Excellence – the non governmental public body that publishes guidelines in the use of health technologies and good clinical practice in the United Kingdom) guidelines state UAE/UFE can be offered to women with symptomatic fibroids (fibroids being usually >30mm in size). Women should be informed that UAE and myomectomy (the surgical removal of fibroids) may potentially allow them to retain their fertility.[51] ### Myomectomy[edit] Submucosal fibroid in hysteroscopy Treatment of an intramural fibroid by laparoscopic surgery After treatment of an intramural fibroid by laparoscopic surgery Myomectomy is a surgery to remove one or more fibroids. It is usually recommended when more conservative treatment options fail for women who want fertility preserving surgery or who want to retain the uterus.[52] There are three types of myomectomy: * In a hysteroscopic myomectomy (also called transcervical resection), the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device. * A laparoscopic myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic myomectomy.[53] * A laparotomic myomectomy (also known as an open or abdominal myomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus. Laparoscopic myomectomy has less pain and shorter time in hospital than open surgery.[54] ### Hysterectomy[edit] Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US. ### Endometrial ablation[edit] Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids. ### Other procedures[edit] Radiofrequency ablation is a minimally invasive treatments for fibroids.[55] In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy. Magnetic resonance guided focused ultrasound, is a non-invasive intervention (requiring no incision) that uses high intensity focused ultrasound waves to destroy tissue in combination with magnetic resonance imaging (MRI), which guides and monitors the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using MR thermal imaging.[56] Patients who have symptomatic fibroids, who desire a non-invasive treatment option and who do not have contraindications for MRI are candidates for MRgFUS. About 60% of patients qualify. It is an outpatient procedure and takes one to three hours depending on the size of the fibroids. It is safe and about 75% effective.[57] Symptomatic improvement is sustained for two plus years.[58] Need for additional treatment varies from 16-20% and is largely dependent on the amount of fibroid that can be safely ablated; the higher the ablated volume, the lower the re-treatment rate.[59] There are currently no randomized trial between MRgFUS and UAE. A multi-center trial is underway to investigate the efficacy of MRgFUS vs. UAE. ## Prognosis[edit] About 1 out of 1000 lesions are or become malignant, typically as a leiomyosarcoma on histology.[9] A sign that a lesion may be malignant is growth after menopause.[9] There is no consensus among pathologists regarding the transformation of leiomyoma into a sarcoma. ### Metastasis[edit] There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.[27] See extrauterine fibroids. ## Epidemiology[edit] About 20% to 80% of women develop fibroids by the age of 50.[12][1] Globally in 2013 it was estimated that 171 million women were affected.[5] They are typically found during the middle and later reproductive years.[1] After menopause they usually decrease in size.[1] Surgery to remove uterine fibroids occurs more frequently in women in "higher social classes".[12] Adolescents develop uterine fibroids much less frequently than older women.[7] Up to 50% of women with uterine fibroids have no symptoms. The prevalence of uterine fibroids among teenagers is 0.4%.[7] ### Europe[edit] The incidence of uterine fibroids in Europe is thought to be lower than the incidence in the US.[12] ### United States[edit] Eighty percent of African-American women will develop benign uterine fibroid tumors by their late 40s, according to the National Institute of Environmental Health Sciences.[60] African-American women are two to three times more likely to get fibroids than Caucasian women.[12][13][61] In African-American women fibroids seem to occur at a younger age, grow more quickly, and are more likely to cause symptoms.[62] This leads to higher rates of surgery for African Americans, both myomectomy, and hysterectomy.[63] Increased risk of fibroids in African- Americans causes them to fare worse in in-vitro fertility treatments and raises their risk of premature births and delivery by Cesarean section.[63] It is unclear why fibroids are more common in African American women. Some studies suggest that black women who are obese and who have high blood pressure are more likely to have fibroids.[63] Other suggested causes include the tendency of African American women to consume food with less than the daily requirements for vitamin D.[12] ## Related legislation[edit] ### United States[edit] The 2005 S.1289 bill was read twice and referred to the committee on Health, Labor, and Pensions but never passed for a Senate or House vote; the proposed Uterine Fibroid Research and Education Act of 2005 mentioned that $5 billion is spent annually on hysterectomy surgeries each year, which affect 22% of African Americans and 7% of Caucasian women. The bill also called for more funding for research and educational purposes. It also states that of the $28 billion issued to NIH, $5 million was allocated for uterine fibroids in 2004.[64] ## Other animals[edit] Uterine fibroids are rare in other mammals, although they have been observed in certain dogs and Baltic grey seals.[65] ## Research[edit] Selective progesterone receptor modulators, such as progenta, have been under investigation. Another selective progesterone receptor modulator asoprisnil is being tested with promising results as a possible use as a treatment for fibroids, intended to provide the advantages of progesterone antagonists without their adverse effects.[40] Low dietary intake of vitamin D is associated with the development of uterine fibroids.[12] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak "Uterine fibroids fact sheet". Office on Women's Health. January 15, 2015. Archived from the original on 7 July 2015. Retrieved 26 June 2015. 2. ^ Ferri, Fred F. (2010). 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Vet. Pathol. 40 (2): 175–80. doi:10.1354/vp.40-2-175. PMID 12637757. ## External links[edit] Classification D * ICD-10: D25 * ICD-9-CM: 218 * OMIM: 150699 * MeSH: D007889 * DiseasesDB: 4806 External resources * MedlinePlus: 000914 * eMedicine: radio/777 * Patient UK: Uterine fibroid Wikimedia Commons has media related to Uterine fibroids. * NIH Fibroid Treatment Study: Information and NIH research * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma Authority control * NDL: 00933629 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Uterine fibroid	c0042133	5,563	wikipedia	https://en.wikipedia.org/wiki/Uterine_fibroid	2021-01-18T18:52:17	{"mesh": ["D007889"], "umls": ["C0042133"], "wikidata": ["Q556281"]}
Acquired angioedema (AAE) is a rare disorder that causes recurrent episodes of swelling (edema) of the face or body, lasting several days. People with AAE may have swelling of the face, lips, tongue, limbs, or genitals. People with AAE can have edema of the lining of the digestive tract, which can cause abdominal pain and nausea, as well as edema of the upper airway, which can be life-threatening. Swelling episodes may have various triggers, such as mild trauma (such as dental work), viral illness, cold exposure, pregnancy, certain foods, or emotional stress. The frequency of episodes is unpredictable and can vary widely. There are two forms of AAE. Type 1 is associated with various other diseases including lymphoproliferative disorders, and autoimmune diseases that may not become apparent until years after the angioedema begins. Type 2 is associated with an autoimmune abnormality in which a person has autoantibodies against a protein in the blood called C1-INH. In some cases, it is hard to distinguish between AAE types 1 and 2. Treatment options depend on the severity of symptoms, the parts of the body affected, and the type of AAE a person has. Various medications may be used to relieve symptoms or prevent complications. When an underlying disease is present, episodes may stop if the underlying disease is treated, but some people continue to experience episodes despite treatment. During severe or life-threatening episodes, intensive support may be needed (such as IV fluids or intubation for a blocked airway). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Acquired angioedema	c2931758	5,564	gard	https://rarediseases.info.nih.gov/diseases/8605/acquired-angioedema	2021-01-18T18:02:22	{"mesh": ["C538173"], "umls": ["C2931758"], "orphanet": ["91385"], "synonyms": ["Angioedema, acquired", "Acquired C1 inhibitor deficiency"]}
Chondrocalcinosis X-ray of a knee with chondrocalcinosis SpecialtyRadiology Chondrocalcinosis or cartilage calcification is calcification (accumulation of calcium salts) in hyaline cartilage and/or fibrocartilage.[1] It can be seen on radiography. ## Causes[edit] Buildup of calcium phosphate in the ankle joints has been found in about 50% of the general population, and may be associated with osteoarthritis.[2] Another common cause of chondrocalcinosis is calcium pyrophosphate dihydrate crystal deposition disease (CPPD).[3] CPPD is estimated to affect 4% to 7% of the adult populations of Europe and the United States.[4] Previous studies have overestimated the prevalence by simply estimating the prevalence of chondrocalcinosis regardless of cause.[4] A magnesium deficiency may cause chondrocalcinosis, and magnesium supplementation may reduce or alleviate symptoms.[5] In some cases, arthritis from injury can cause chondrocalcinosis.[6] Other causes of chondrocalcinosis include:[3] * Hypercalcaemia, especially when caused by hyperparathyroidism * Arthritis * Pseudogout * Wilson disease * Hemochromatosis * Ochronosis * Hypophosphatasia * Hypothyroidism * Hyperoxalemia * Acromegaly * Gitelman syndrome. ## Diagnosis[edit] Chondrocalcinosis can be visualized on projectional radiography, CT scan, MRI, US, and nuclear medicine.[1] CT scans and MRIs show calcific masses (usually within the ligamentum flavum or joint capsule), however radiography is more successful.[1] At ultrasound, chondrocalcinosis may be depicted as echogenic foci with no acoustic shadow within the hyaline cartilage.[7] As with most conditions, chondrocalcinosis can present with similarity to other diseases such as ankylosing spondylitis and gout.[1] ## References[edit] 1. ^ a b c d Rothschild, Bruce M Calcium Pyrophosphate Deposition Disease (radiology) 2. ^ Hubert, Jan; Weiser, Lukas; Hischke, Sandra; Uhlig, Annemarie; Rolvien, Tim; Schmidt, Tobias; Butscheidt, Sebastian Karl; Püschel, Klaus; Lehmann, Wolfgang; Beil, Frank Timo; Hawellek, Thelonius (2018). "Cartilage calcification of the ankle joint is associated with osteoarthritis in the general population". BMC Musculoskeletal Disorders. 19 (1). doi:10.1186/s12891-018-2094-7. ISSN 1471-2474. PMC 5968601. 3. ^ a b Matt A. Morgan; Frank Gaillard; et al. "Chondrocalcinosis". Radiopedia. Retrieved 2017-08-11. 4. ^ a b Ann K. Rosenthal. "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease". UpToDate. This topic last updated: Jul 24, 2018. 5. ^ de Filippi JP, Diderich PP, Wouters JM (1992). "Hypomagnesemia and chondrocalcinosis". Ned Tijdschr Geneeskd. 136 (20): 139–41. PMID 1732847. 6. ^ Wright GD, Doherty M (1997). "Calcium pyrophosphate crystal deposition is not always 'wear and tear' or aging". Ann. Rheum. Dis. 56 (10): 586–8. doi:10.1136/ard.56.10.586. PMC 1752269. PMID 9389218. 7. ^ Arend CF. Ultrasound of the Shoulder. Master Medical Books, 2013. Free chapter on acromioclavicular chondrocalcinosis is available at ShoulderUS.com [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Chondrocalcinosis	c0553730	5,565	wikipedia	https://en.wikipedia.org/wiki/Chondrocalcinosis	2021-01-18T18:44:57	{"mesh": ["D002805"], "umls": ["C0033802", "C0553730", "C0157852"], "orphanet": ["1416"], "wikidata": ["Q559082"]}
A rare genetic neurological disorder characterized by neonatal onset of rigidity and intractable seizures, with episodic jerking already beginning in utero. Affected infants have small heads, remain visually inattentive, do not feed independently, and make no developmental progress. Frequent spontaneous apnea and bradycardia usually culminate in cardiopulmonary arrest and death in infancy, although some cases were described with a milder clinical course and survival into childhood. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Lethal neonatal spasticity-epileptic encephalopathy syndrome	c3281029	5,566	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435845	2021-01-23T18:02:55	{"omim": ["614498", "618056"], "icd-10": ["G40.4"], "synonyms": ["Lethal neonatal rigidity-multifocal seizure syndrome"]}
A rare overgrowth syndrome associated with multiple congenital anomalies characterized by tall stature, large hands and feet with large thumbs and halluces, spatulate digits, developmental delay and facial dysmorphism. ## Epidemiology To date only 4 cases from 2 families have been reported in the literature. ## Clinical description The overgrowth disorder is characterized by tall stature, large hands and feet with large thumbs/halluces. Facial features include round face with widely spaced and deep-set eyes, epicanthal folds, flat midface, long and downslanting palpebral fissures, large prominent ears, thick lips, macroglossia. Patients exhibit developmental delay. Intellect ranges from norrmal with learning difficulties to intellectual disability. A range of variable congenital anomalies have been reported and include ocular defects (retinal coloboma or refraction errors), cardiac anomalies (ventricular septal defect, mitral valve prolapse, double chamber right ventricle), kidney malformations (renal malrotation with left bifid ureter, nephromegaly, cystic dysplastic kidneys), connective tissue disorders (inguinal hernia), as well as orthopedic features (talipes equinovarus, internal rotation of the femurs and tibias, bowing of the legs, and spina bifida occulta). Other features may include early-onset varicose veins, transient or chronic benign neutropenia (with normal bone marrow examination), sensorineural hearing loss and Wilms tumor (one patient). ## Etiology Biallelic loss of function variants in FIBP (11q13.1) are responsible for this phenotype. ## Diagnostic methods Diagnosis is with next generation sequencing (exome, genome or panel for developmental disorders). ## Differential diagnosis Differential diagnosis includes other overgrowth disorders, such as Beckwith-Wiedeman syndrome or Simpson-Golabi-Behmel syndrome in the association with tall stature, nephromegaly, macroglossia, predisposition to Wilms tumor. ## Antenatal diagnosis Prenatal diagnosis can be proposed to parents with an affected child. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. ## Management and treatment Management is multidisciplinary and depends on the particular manifestations and may include ophthalmological, cardiac, hematological and orthopedic evaluation and follow-up. Social care requirements for learning disability should be assessed. Psychiatric symptoms should be evaluated, in particular in adulthood. Hearing evaluations are required with possible prescription for hearing aids. Surgery may be recommended in cases of inguinal hernia and early-onset varicose veins. Follow-up for Wilms tumor with kidney ultrasound every 3 months from diagnosis to 8-years-old is recommended. ## Prognosis The possible lethality of the disorder has been questioned because of an increased occurrence of stillbirths and miscarriage in one family. A predisposition for Wilms tumor is suspected. Neutropenia does not seem associated with recurrent infections. * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Tall stature-intellectual disability-renal anomalies syndrome	c4310715	5,567	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=500095	2021-01-23T17:54:41	{"omim": ["617107"], "synonyms": ["Thauvin-Robinet-Faivre syndrome"]}
Megarbane (2003) reported 2 male cousins, both with consanguineous parents, who presented with severe mental retardation, microcephaly with elongated faces, seizure disorders, short stature, hypertelorism, optic atrophy, ptosis, absent ear lobes, and thin upper lips. A brain MRI of 1 cousin showed only slight bilateral ventricular dilatation and small orbits. Extensive radiologic and laboratory investigations, including karyotypes, of both cousins were normal. Clinical examination and karyotypes of both sets of parents and clinical examinations of the collective 12 sibs were normal. Megarbane (2003) suggested that the disorder may represent a newly recognized autosomal recessive MCA/MR syndrome. INHERITANCE \- Isolated cases GROWTH Other \- Short stature HEAD & NECK Head \- Microcephaly Face \- Long face \- Smooth philtrum Ears \- Absent ear lobes Eyes \- Hypertelorism \- Optic atrophy \- Ptosis Nose \- Broad nasal tip Mouth \- Thin upper lip NEUROLOGIC Central Nervous System \- Psychomotor delay (evident at 3 months) \- Mental retardation, severe \- Abnormal EEG (abnormal slowing of background activity) \- Wide-based gait \- Seizures ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MENTAL RETARDATION WITH OPTIC ATROPHY, FACIAL DYSMORPHISM, MICROCEPHALY, AND SHORT STATURE	c1836915	5,568	omim	https://www.omim.org/entry/609037	2019-09-22T16:06:49	{"mesh": ["C563810"], "omim": ["609037"]}
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure. It usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family. ## Frequency It is estimated that 750,000 people in the United States have dilated cardiomyopathy; roughly half of these cases are familial. ## Causes Mutations in more than 30 genes have been found to cause familial dilated cardiomyopathy. These genes provide instructions for making proteins that are found in cardiac muscle cells called cardiomyocytes. Many of these proteins play important roles in the contraction of the cardiac muscle through their association with cell structures called sarcomeres. Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Many other proteins associated with familial dilated cardiomyopathy make up the structural framework (the cytoskeleton) of cardiomyocytes. The remaining proteins play various roles within cardiomyocytes to ensure their proper functioning. Mutations in one gene, TTN, account for approximately 20 percent of cases of familial dilated cardiomyopathy. The TTN gene provides instructions for making a protein called titin, which is found in the sarcomeres of many types of muscle cells, including cardiomyocytes. Titin provides structure, flexibility, and stability to sarcomeres. Titin also plays a role in chemical signaling and in assembling new sarcomeres. The TTN gene mutations that cause familial dilated cardiomyopathy result in the production of an abnormally short titin protein. It is unclear how the altered protein causes familial dilated cardiomyopathy, but it is likely that it impairs sarcomere function and disrupts chemical signaling. It is unclear how mutations in the other genes cause familial dilated cardiomyopathy. It is likely that the changes impair cardiomyocyte function and reduce the ability of these cells to contract, weakening and thinning cardiac muscle. People with familial dilated cardiomyopathy often do not have an identified mutation in any of the known associated genes. The cause of the condition in these individuals is unknown. Familial dilated cardiomyopathy is described as nonsyndromic or isolated because it typically affects only the heart. However, dilated cardiomyopathy can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic and are caused by mutations in other genes. Additionally, there are many nongenetic causes of dilated cardiomyopathy, including viral infection and chronic alcohol abuse. ### Learn more about the genes associated with Familial dilated cardiomyopathy * ABCC9 * DES * DMD * LDB3 * LMNA * MYBPC3 * MYH6 * MYH7 * PSEN1 * PSEN2 * SCN5A * SGCD * TAZ * TNNI3 * TNNT2 * TTN Additional Information from NCBI Gene: * ACTC1 * ACTN2 * ANKRD1 * BAG3 * CRYAB * CSRP3 * DSG2 * EYA4 * GATAD1 * LAMA4 * MYPN * PLN * RBM20 * TCAP * TMPO * TNNC1 * TPM1 * VCL ## Inheritance Pattern Familial dilated cardiomyopathy has different inheritance patterns depending on the gene involved. In 80 to 90 percent of cases, familial dilated cardiomyopathy 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. However, some people who inherit the altered gene never develop features of familial dilated cardiomyopathy. (This situation is known as reduced penetrance.) Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. In rare instances, 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. In other rare cases, this condition is inherited in an X-linked pattern. In these cases, the gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell increases the risk of developing heart disease, but females with such a mutation may not develop familial dilated cardiomyopathy. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes familial dilated cardiomyopathy. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Familial dilated cardiomyopathy	c1449563	5,569	medlineplus	https://medlineplus.gov/genetics/condition/familial-dilated-cardiomyopathy/	2021-01-27T08:25:32	{"gard": ["2905"], "mesh": ["D002311"], "omim": ["115200", "612158", "600884", "612877", "601493", "601494", "613172", "601154", "613252", "604145", "604288", "613881", "604765", "615184", "605362", "615235", "605582", "615248", "606685", "607482", "608569", "609909", "609915", "613424", "613426", "613694", "613697", "611407", "611878", "611879", "611880", "614672", "302045", "607487", "615396"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-22 with or without anosmia (HH22) is caused by homozygous mutation in the FEZF1 gene (613301) on chromosome 7q31. Description Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism is caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950. Clinical Features Kotan et al. (2014) studied 4 patients from 2 unrelated consanguineous Kurdish families with hypogonadotropic hypogonadism and anosmia. In the first family, the proband was a 19-year-old man who presented at 14 years of age with absent pubertal development. After he received treatment with testosterone and human chorionic gonadotropin (HCG; see 118850) and underwent orchiopexy for undescended testicles, his penis developed to normal adult size, but his testicles remained small. His 24-year-old sister had absent breast development and primary amenorrhea, and began estrogen replacement at 18 years of age. In the second family, a boy presented at 2 years of age with micropenis and undescended testicles and underwent HCG and testosterone treatments, followed by orchiopexy. At 14 years of age, he had 1-ml testicles bilaterally and a 4-cm phallus with stage 2 axillary and pubic hair; a GNRH stimulation test elicited a prepubertal response. His 8.5-year-old brother also had micropenis and undescended testicles, and underwent orchiopexy at 2 years of age after failure of HCG treatment. He was prepubertal with 1-ml testicles bilaterally and a 3.6-cm phallus with stage 1 axillary and pubic hair. All 4 affected individuals had anosmia, as documented by quantitative smell-identification analysis that included a culturally appropriate 20-item test, and brain MRI revealed bilateral aplasia of the olfactory bulbs in the probands from both families. None of the 4 patients had any other dysmorphic features or developmental anomalies, and their parents and other sibs had no history of problems in pubertal development or fertility. Molecular Genetics Kotan et al. (2014) performed whole-exome sequencing in a cohort of 30 individuals with hypogonadotropic hypogonadism and anosmia, in whom mutations in known Kallmann syndrome-associated genes had been excluded. In 4 affected individuals from 2 unrelated consanguineous Kurdish families, they identified homozygosity for a missense mutation (H278Y; 613301.0001) and a 1-bp deletion (c.651delT; 613301.0002), respectively, in the FEZF1 gene. The mutations, which segregated with disease in each family, were not found in 100 ethnically matched controls, 36 in-house whole exomes, or public SNP databases. In the affected sibs from the family with the FEZF1 missense mutation, Kotan et al. (2014) also identified homozygosity for a nonsense mutation (R724X) in the CCDC141 gene (616031); the unaffected parents and 3 unafected sibs were all heterozygous for both the FEZF1 and the CCDC141 mutations. INHERITANCE \- Autosomal recessive HEAD & NECK Nose \- Anosmia CHEST Breasts \- Delayed or absent thelarche GENITOURINARY \- Delayed or absent puberty External Genitalia (Male) \- Micropenis Internal Genitalia (Male) \- Small testes \- Cryptorchidism Internal Genitalia (Female) \- Primary amenorrhea NEUROLOGIC Central Nervous System \- Aplasia of olfactory bulbs, bilateral ENDOCRINE FEATURES \- Delayed or absent puberty \- Low follicle-stimulating hormone (FSH) \- Low luteinizing hormone (LH) \- Low testosterone levels in males \- Low estradiol levels in females MOLECULAR BASIS \- Caused by mutation in the FEZ family zinc finger protein-1 gene (FEZF1, 613301.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	HYPOGONADOTROPIC HYPOGONADISM 22 WITH OR WITHOUT ANOSMIA	c0162809	5,570	omim	https://www.omim.org/entry/616030	2019-09-22T15:50:05	{"doid": ["0090081"], "mesh": ["D017436"], "omim": ["616030"], "orphanet": ["478"], "genereviews": ["NBK1334"]}
Analgesic nephropathy Classically caused by mixed analgesics containing phenacetin, analgesic nephropathy was once a common cause of acute kidney injury. SpecialtyNephrology Analgesic nephropathy is injury to the kidneys caused by analgesic medications such as aspirin, bucetin, phenacetin, and paracetamol. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication. The specific kidney injuries induced by analgesics are renal papillary necrosis and chronic interstitial nephritis. They appear to result from decreased blood flow to the kidney, rapid consumption of antioxidants, and subsequent oxidative damage to the kidney. This kidney damage may lead to progressive chronic kidney failure, abnormal urinalysis results, high blood pressure, and anemia. A small proportion of individuals with analgesic nephropathy may develop end-stage kidney disease. Analgesic nephropathy was once a common cause of kidney injury and end-stage kidney disease in parts of Europe, Australia, and the United States. In most areas, its incidence has declined sharply since the use of phenacetin fell in the 1970s and 1980s. ## Contents * 1 Presentation * 1.1 Complications * 2 Pathophysiology * 2.1 Aspirin and NSAIDs * 2.2 Phenacetin and paracetamol * 3 Diagnosis * 4 Treatment * 5 History * 6 Terminology * 7 References * 8 External links ## Presentation[edit] Clinical findings in analgesic nephropathy[1] Finding Proportion affected Headache 35-100% Pyuria 50-100% Anemia 60-90% Hypertension 15-70% Gastrointestinal symptoms 40-60% Urinary tract infection 30-60% Common findings in people with analgesic nephropathy include headache, anemia, high blood pressure (hypertension), and white blood cells in the urine (leucocyturia, pyuria).[1] Some individuals with analgesic nephropathy may also have protein in their urine (proteinuria).[2] ### Complications[edit] Complications of analgesic nephropathy include pyelonephritis[3] and end-stage kidney disease.[4] Risk factors for poor prognosis include recurrent urinary tract infection and persistently elevated blood pressure.[5] Analgesic nephropathy also appears to increase the risk of developing cancers of the urinary system.[6] ## Pathophysiology[edit] The scarring of the small blood vessels, called capillary sclerosis, is the initial lesion of analgesic nephropathy.[7] Found in the renal pelvis, ureter, and capillaries supplying the nephrons, capillary sclerosis is thought to lead to renal papillary necrosis and, in turn, chronic interstitial nephritis.[8][7] How phenacetin and other analgesics lead to this damage is incompletely understood. It is currently thought that the kidney toxicities of NSAIDs and the antipyretics phenacetin and paracetamol may combine to give rise to analgesic nephropathy. A committee of investigators reported in 2000 that there was insufficient evidence to suggest that non-phenacetin analgesics by themselves are associated with analgesic nephropathy.[9] ### Aspirin and NSAIDs[edit] Proper kidney function depends upon adequate blood flow to the kidney. Kidney blood flow is a complex, tightly regulated process that relies on a number of hormones and other small molecules, such as prostaglandins. Under normal circumstances, prostaglandin E2 (PGE2) produced by the kidney is necessary to support adequate blood flow to the kidney. Like all prostaglandins, PGE2 synthesis depends upon the cyclooxygenases. Aspirin and other NSAIDs are inhibitors of the cyclooxygenases. In the kidney, this inhibition results in decreased PGE2 concentration causing a reduction in blood flow. Because blood flow to the kidney first reaches the renal cortex (outside) and then the renal medulla (inside), the deeper structures of the kidney are most sensitive to decreased blood flow. Thus the innermost structures of the kidney, known as the renal papillae, are especially dependent on prostaglandin synthesis to maintain adequate blood flow. Inhibition of cyclooxygenases therefore rather selectively damages the renal papillae, increasing the risk of renal papillary necrosis.[10] NSAIDs caused no adverse effects on renal function in healthy dogs subjected to anesthesia.[11][12][13] Most healthy kidneys contain enough physiologic reserve to compensate for this NSAID-induced decrease in blood flow. However, those subjected to additional injury from phenacetin or paracetamol may progress to analgesic nephropathy. ### Phenacetin and paracetamol[edit] It is unclear how phenacetin induces injury to the kidney.[10] Bach and Hardy have proposed that phenacetin's metabolites lead to lipid peroxidation that damages cells of the kidney.[14] Paracetamol is the major metabolite of phenacetin and may contribute to kidney injury through a specific mechanism. In cells of the kidney, cyclooxygenases catalyse the conversion of paracetamol into N-acetyl-p-benzoquinoneimine (NAPQI).[15] NAPQI depletes glutathione via non-enzymatic conjugation with glutathione, a naturally occurring antioxidant.[16] With depletion of glutathione, cells of the kidney become particularly sensitive to oxidative damage. ## Diagnosis[edit] Diagnosis is traditionally based on the clinical findings above in combination with excessive analgesic use. It is estimated that between 2 and 3 kg each of phenacetin or aspirin must be consumed before evidence of analgesic nephropathy becomes clinically apparent.[10] Once suspected, analgesic nephropathy can be confirmed with relative accuracy using computed tomography (CT) imaging without contrast.[17] One trial demonstrated that the appearance of papillary calcifications on CT imaging was 92% sensitive and 100% specific for the diagnosis of analgesic nephropathy.[18] ## Treatment[edit] Treatment of analgesic nephropathy begins with the discontinuation of analgesics, which often halts the progression of the disease and may even result in normalization of kidney function.[5] In Stage 5 chronic kidney disease patients renal replacement therapy may become necessary. ## History[edit] Main articles: Phenacetin and Analgesic Analgesics are a class of medications widely used in the treatment of pain. They include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs),[19] as well as the antipyretics paracetamol (known as acetaminophen in the United States) and phenacetin. Introduced in the late 19th century, phenacetin was once a common component of mixed analgesics in parts of Europe, Australia, and the United States.[20] These analgesics contained aspirin or other NSAIDs combined with phenacetin, paracetamol, or salicylamide, and caffeine or codeine.[10] In the 1950s, Spühler and Zollinger reported an association between kidney injury and the chronic use of phenacetin.[21] They noted that chronic users of phenacetin had an increased risk of developing specific kidney injuries, namely renal papillary necrosis and chronic interstitial nephritis. This condition was dubbed analgesic nephropathy and was attributed to phenacetin, although no absolute causative role was demonstrated. With further reports of the increased risk of kidney injury with prolonged and excessive phenacetin use, however, phenacetin was banned in several countries between the 1960s and 1980s.[20] As the use of phenacetin declined, so too did the prevalence of analgesic nephropathy as a cause of end-stage kidney disease. Data from Switzerland, for example, demonstrated a decline in the prevalence of analgesic nephropathy among people with end-stage kidney disease, from 28% in 1981 to 12% in 1990.[4] An autopsy study performed in Switzerland suggested that the prevalence of analgesic nephropathy in the general population has likewise decreased; the prevalence was 3% in 1980 and 0.2% in 2000.[8] While these data demonstrate that analgesic nephropathy has been all but eliminated in some regions, in other regions the condition persists. Notably, in Belgium, the prevalence of analgesic nephropathy among people having dialysis was 17.9% in 1984 and 15.6% in 1990.[22][23] Michielsen and de Schepper suggest that analgesic nephropathy persists among people in Belgium having dialysis not due to non-phenacetin analgesics, but because Belgium accepts a higher proportion of elderly people for dialysis. According to these authors, a greater proportion have analgesic nephropathy because a greater percentage of people in Belgium having dialysis have been exposed to long-term use of phenacetin.[24] ## Terminology[edit] The term analgesic nephropathy usually refers to damage induced by excessive use of combinations of these medications, specifically combinations that include phenacetin. For this reason, it is also called analgesic abuse nephropathy. Murray prefers the less judgmental analgesic-associated nephropathy.[1] Both terms are abbreviated to the acronym AAN, by which the condition is also commonly known. ## References[edit] 1. ^ a b c Murray TG, Goldberg M (January 1978). "Analgesic-associated nephropathy in the U.S.A.: epidemiologic, clinical and pathogenetic features". Kidney Int. 13 (1): 64–71. doi:10.1038/ki.1978.9. PMID 713270. 2. ^ Nanra RS, Stuart-Taylor J, de Leon AH, White KH (January 1978). "Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia". Kidney Int. 13 (1): 79–92. doi:10.1038/ki.1978.11. PMID 362034. 3. ^ Maisonneuve P, Agodoa L, Gellert R, et al. (January 2000). "Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study". Am. J. Kidney Dis. 35 (1): 157–65. doi:10.1016/S0272-6386(00)70316-7. PMID 10620560. 4. ^ a b Brunner FP, Selwood NH (1994). "End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. EDTA-ERA Registry Committee". Nephrol. Dial. Transplant. 9 (10): 1371–6. doi:10.1093/ndt/9.10.1371. PMID 7816247. 5. ^ a b Linton AL (October 1972). "I. Recognition of the problem of analgesic nephropathy". Can Med Assoc J. 107 (8): 749–51. PMC 1941002. PMID 4638849. 6. ^ Blohmé I, Johansson S (November 1981). "Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy". Kidney Int. 20 (5): 671–5. doi:10.1038/ki.1981.192. PMID 7045494. 7. ^ a b Mihatsch MJ, Hofer HO, Gudat F, Knüsli C, Torhorst J, Zollinger HU (December 1983). "Capillary sclerosis of the urinary tract and analgesic nephropathy". Clin. Nephrol. 20 (6): 285–301. PMID 6641031. 8. ^ a b Mihatsch MJ, Khanlari B, Brunner FP (November 2006). "Obituary to analgesic nephropathy--an autopsy study". Nephrol. Dial. Transplant. 21 (11): 3139–45. doi:10.1093/ndt/gfl390. PMID 16891638. 9. ^ Feinstein AR, Heinemann LA, Curhan GC, et al. (December 2000). "Relationship between nonphenacetin combined analgesics and nephropathy: a review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy". Kidney Int. 58 (6): 2259–64. doi:10.1046/j.1523-1755.2000.00410.x. PMID 11115060. 10. ^ a b c d de Broe, Marc E (2008). "Analgesic nephropathy". In Curhan, Gary C (ed.). UpToDate. Waltham, MA. 11. ^ Boström, IM; Nyman, G; Hoppe, A; Lord, P (January 2006). "Effects of meloxicam on renal function in dogs with hypotension during anaesthesia". Veterinary Anaesthesia and Analgesia. 33 (1): 62–9. doi:10.1111/j.1467-2995.2005.00208.x. PMID 16412133. 12. ^ Frendin, JH; Boström, IM; Kampa, N; Eksell, P; Häggström, JU; Nyman, GC (December 2006). "Effects of carprofen on renal function during medetomidine-propofol-isoflurane anesthesia in dogs". American Journal of Veterinary Research. 67 (12): 1967–73. doi:10.2460/ajvr.67.12.1967. PMID 17144795. 13. ^ Boström, IM; Nyman, GC; Lord, PE; Häggström, J; Jones, BE; Bohlin, HP (May 2002). "Effects of carprofen on renal function and results of serum biochemical and hematologic analyses in anesthetized dogs that had low blood pressure during anesthesia". American Journal of Veterinary Research. 63 (5): 712–21. doi:10.2460/ajvr.2002.63.712. PMID 12013473. 14. ^ Bach PH, Hardy TL (October 1985). "Relevance of animal models to analgesic-associated renal papillary necrosis in humans". Kidney Int. 28 (4): 605–13. doi:10.1038/ki.1985.172. PMID 3910912. 15. ^ Mohandas J, Duggin GG, Horvath JS, Tiller DJ (November 1981). "Metabolic oxidation of acetaminophen (paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney". Toxicol. Appl. Pharmacol. 61 (2): 252–9. doi:10.1016/0041-008X(81)90415-4. PMID 6798713. 16. ^ Duggin GG (July 1996). "Combination analgesic-induced kidney disease: the Australian experience". Am. J. Kidney Dis. 28 (1 Suppl 1): S39–47. doi:10.1016/S0272-6386(96)90568-5. PMID 8669429. 17. ^ de Broe ME, Elseviers MM (February 1998). "Analgesic nephropathy". N. Engl. J. Med. 338 (7): 446–52. doi:10.1056/NEJM199802123380707. PMID 9459649. 18. ^ Elseviers MM, De Schepper A, Corthouts R, et al. (October 1995). "High diagnostic performance of CT scan for analgesic nephropathy in patients with incipient to severe renal failure". Kidney Int. 48 (4): 1316–23. doi:10.1038/ki.1995.416. PMID 8569094. 19. ^ Buer JK (Oct 2014). "Origins and impact of the term 'NSAID'". Inflammopharmacology. 22 (5): 263–7. doi:10.1007/s10787-014-0211-2. hdl:10852/45403. PMID 25064056. 20. ^ a b McLaughlin JK, Lipworth L, Chow WH, Blot WJ (September 1998). "Analgesic use and chronic renal failure: a critical review of the epidemiologic literature". Kidney Int. 54 (3): 679–86. doi:10.1046/j.1523-1755.1998.00043.x. PMID 9734593. 21. ^ Spühler O, Zollinger HU (1953). "Die chronisch-interstitielle Nephritis". Z Klin Med (in German). 151 (1): 1–50. PMID 13137299. 22. ^ Elseviers MM, de Broe ME (1994). "Analgesic nephropathy in Belgium is related to the sales of particular analgesic mixtures". Nephrol. Dial. Transplant. 9 (1): 41–6. PMID 8177475. 23. ^ Noels LM, Elseviers MM, de Broe ME (1995). "Impact of legislative measures on the sales of analgesics and the subsequent prevalence of analgesic nephropathy: a comparative study in France, Sweden and Belgium". Nephrol. Dial. Transplant. 10 (2): 167–74. PMID 7753450. 24. ^ Michielsen P, de Schepper P (March 2001). "Trends of analgesic nephropathy in two high-endemic regions with different legislation". J. Am. Soc. Nephrol. 12 (3): 550–6. PMID 11181803. ## External links[edit] Classification D * ICD-10: N14.0 * ICD-9-CM: 583.89, 584.7 External resources * MedlinePlus: 000482 * eMedicine: med/2839 * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Analgesic nephropathy	c0149938	5,571	wikipedia	https://en.wikipedia.org/wiki/Analgesic_nephropathy	2021-01-18T18:42:07	{"icd-9": ["584.7", "583.89"], "icd-10": ["N14.0"], "wikidata": ["Q120062"]}
The topic of this article may not meet Wikipedia's general notability guideline. Please help to demonstrate the notability of the topic by citing reliable secondary sources that are independent of the topic and provide significant coverage of it beyond a mere trivial mention. If notability cannot be shown, the article is likely to be merged, redirected, or deleted. Find sources: "Vermiphobia" – news · newspapers · books · scholar · JSTOR (September 2016) (Learn how and when to remove this template message) Helminthophobia, scoleciphobia or vermiphobia is a specific phobia, the fear of worms, especially parasitic worms. The sight of a worm, or anything that looks like a worm, may cause someone with this phobia to have extreme anxiety or even panic attacks. ## See also[edit] * Ophidiphobia * Mongolian death worm * Graboid ## References[edit] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Vermiphobia	None	5,572	wikipedia	https://en.wikipedia.org/wiki/Vermiphobia	2021-01-18T18:42:21	{"wikidata": ["Q4422074"]}
Jacobsen (1968) concluded that low proteolytic capacity is inherited as an autosomal dominant. Increased tendency to thrombosis did not occur in these persons. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	PROTEOLYTIC CAPACITY OF PLASMA	c1867621	5,573	omim	https://www.omim.org/entry/176900	2019-09-22T16:35:40	{"omim": ["176900"]}
## Clinical Features Rafiq et al. (2010) reported a consanguineous Pakistani family in which 4 sibs had autosomal recessive nonsyndromic mental retardation. One of the patients had seizures. Mapping By genomewide analysis using SNP microarrays in a consanguineous Pakistani family segregating autosomal recessive nonsyndromic mental retardation, Rafiq et al. (2010) identified a 23.52-Mb region of homozygosity on chromosome 9p23-p13.3 between rs10738277 and rs12376565, designated MRT16. Linkage analysis yielded a lod score of 3.2. INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Hair \- Synophrys NEUROLOGIC Central Nervous System \- Mental retardation \- Seizures (some patients) \- No or delayed speech development MISCELLANEOUS \- Based on 1 consanguineous Pakistani family with 4 affected sibs ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	MENTAL RETARDATION, AUTOSOMAL RECESSIVE 16	c3280154	5,574	omim	https://www.omim.org/entry/614208	2019-09-22T15:56:02	{"doid": ["0060308"], "omim": ["614208"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}
A displaced supracondylar fracture in a child Distal humeral fractures are a group of humerus fracture which includes supracondylar fractures, single condyle fractures, bi-column fractures and coronal shear fractures.[1] ## References[edit] 1. ^ Attum, B (6 June 2019). "Humerus Fractures Overview". StatPearls. PMID 29489190. This human musculoskeletal system 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Distal humeral fracture	c0272613	5,575	wikipedia	https://en.wikipedia.org/wiki/Distal_humeral_fracture	2021-01-18T18:37:58	{"umls": ["C0272613"], "icd-10": ["S42.4"], "wikidata": ["Q1229341"]}
Inborn errors of purine–pyrimidine metabolism SpecialtyEndocrinology Inborn errors of purine–pyrimidine metabolism are a class of inborn error of metabolism disorders specifically affecting purine metabolism and pyrimidine metabolism. An example is Lesch–Nyhan syndrome. Urine tests may be of use in identifying some of these disorders.[1] ## References[edit] 1. ^ Wevers RA, Engelke UF, Moolenaar SH, et al. (April 1999). "1H-NMR spectroscopy of body fluids: inborn errors of purine and pyrimidine metabolism". Clin. Chem. 45 (4): 539–48. PMID 10102915. Retrieved 2008-05-07. ## External links[edit] Classification D * ICD-10: E79 * ICD-9-CM: 277.2 * MeSH: D011686 * v * t * e Inborn error of purine–pyrimidine metabolism Purine metabolism Anabolism * Adenylosuccinate lyase deficiency * Adenosine Monophosphate Deaminase Deficiency type 1 Nucleotide salvage * Lesch–Nyhan syndrome/Hyperuricemia * Adenine phosphoribosyltransferase deficiency Catabolism * Adenosine deaminase deficiency * Purine nucleoside phosphorylase deficiency * Xanthinuria * Gout * Mitochondrial neurogastrointestinal encephalopathy syndrome Pyrimidine metabolism Anabolism * Orotic aciduria * Miller syndrome Catabolism * Dihydropyrimidine dehydrogenase deficiency This article about an endocrine, nutritional, or metabolic disease 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Inborn errors of purine–pyrimidine metabolism	c0034139	5,576	wikipedia	https://en.wikipedia.org/wiki/Inborn_errors_of_purine%E2%80%93pyrimidine_metabolism	2021-01-18T18:43:20	{"mesh": ["D011686"], "umls": ["C0034139"], "orphanet": ["79224"], "wikidata": ["Q3281375"]}
Lichen aureus Other namesLichen purpuricus[1] SpecialtyDermatology Lichen aureus is a skin condition characterized by the sudden appearance of one or several golden or rust-colored, closely packed macules or lichenoid papules.[2]:830 ## See also[edit] * Pigmentary purpuric eruptions * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. ## External links[edit] Classification D * DiseasesDB: 31388 * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Lichen aureus	c0406514	5,577	wikipedia	https://en.wikipedia.org/wiki/Lichen_aureus	2021-01-18T18:28:52	{"umls": ["C0406514"], "wikidata": ["Q6543198"]}
Fibrin-associated diffuse large B-cell lymphoma SpecialtyHematology, oncology Diagnostic methodHistology of involved tissue Prognosisgood to excellent Frequencyextremely rare Deathsrare, none due directly to the diseae Fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) is an extremely rare form of the diffuse large B-cell lymphomas (DLBCL). DLBCL are lymphomas in which a particular type of lymphocyte, the B-cell, proliferates excessively, invades multiple tissues, and often causes life-threatening tissue damage. DLBCL have various forms as exemplified by one of its subtypes, diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI). DLBCL-CI is an aggressive malignancy that develops in sites of chronic inflammation that are walled off from the immune system. In this protected environment, the B-cells proliferate excessively, acquire malignant gene changes, form tumor masses, and often spread outside of the protected environment.[1] In 2016, the World Health Organization provisionally classified FA-DLBCL as a DLBCL-CI.[2] Similar to DLBCL-CI, FA-DLBCL involves the proliferation of EBV-infected large B-cells in restricted anatomical spaces that afford protection from an individual's immune system. However, FA-DLBCL differs from DLBCL-CI in many other ways, including, most importantly, its comparatively benign nature.[3] Some researchers have suggested that this disease should be regarded as a non-malignant or pre-malignant lymphoproliferative disorder rather than a malignant DLBCL-CI.[2][3][4] FA-DLBCL is an Epstein–Barr virus-associated lymphoproliferative disease (EBV+ LPD), i.e. disease in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers develop any one of various EBV-associated benign or malignant diseases.[5] In FA-DLBCL as well as DLBCL-CI, EBV infects B-cells to promote their proliferation and thereby the development of either disease.[6] FA-DLBCL most commonly develops within immunologically sequestered sites such as body cavities (e.g. pseudocysts) and foreign bodies (e.g. artificial heart valves) where fibrin, a breakdown product of the blood clotting factor, fibrinogen, has deposited. It is almost always discovered as an incidental finding in specimens taken from these sites when they are examined for reasons not directly related to the FA-DLBCL infiltrates.[2] As reviewed in a publication of 2019, the disorder has been diagnoses in 47 individuals who are predominantly elderly males; it is almost uniformly amenable to various treatments and takes a benign course.[6] However, the disease, when occurring within vascular or cardiac sites, does have a risk of being complicated by the development of embolisms due to the dislodgement of blood clots that travel through the vascular system to cause, e.g. strokes.[3] ## Contents * 1 Pathogenesis * 2 Presentation * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 References ## Pathogenesis[edit] Current studies suggest that EBV transforms the B-cells which it infects into rapidly proliferating cells that in the case of FA-DLBCL are able to avoid attack by the immune system because they are in sites devoid of small blood vessels, overloaded with fibrin thrombi and/or debris resulting from the death of cells, and therefore lack inflammatory cells[2] including cytotoxic T-cells,[7] a specialized type of lymphocyte that can kill EBV-infected cells.[2][5] These immune privileged sites are typically located in certain body cavities or on foreign bodies. Since the EBV-infected cells are subject to immune attack when they leave these sites, FA-DLBCL remains, it is thought, an otherwise non-invasive, non-metastasizing, site-limited disease.[2] Unlike most other forms of DLBCL, including DLBCL-CI, the neoplastic cells in FA-DLBCL have relatively few gene abnormalities,[2] or abnormal expressions of genes such as MYC[3] and p53[7] which are implicated in the development of malignancy. However, programmed death-ligand 1 (PD-L1), which acts to suppress the adaptive arm of the immune system, is overexpressed in the neoplastic B-cells of FA-DLBCL and may contribute further to the ability of these cells to avoid immune attack.[7] ## Presentation[edit] Individuals with FA-DLBCL are typically males (~70% of cases) aged 25–96 years (~75% of cases are >50 years old).[6] They present with abnormalities associated with a long-standing (1–20 years[6]): a) cardiac myxoma (i.e. a myxoid tumor of primitive connective tissue in the heart's atrium); b) subdural hematoma (i.e. a collection of blood between the inner layer of the dura mater and the arachnoid mater of the meninges surrounding the brain; c) testicular hyrocoele (i.e. fluid accumulation within the potential space between the two layers of the cavum vaginale, of a testicle); d) pseudocyst[8] (i.e. a cyst that lacks epithelial or endothelial cells) or cyst[4] of the kidneys, spleen, ovary, adrenal gland, retroperitoneal space, or other tissue; and e) intravascular thrombi; f) implants of a foreign body such as an artificial heart valve, joint replacement,[8] or metal stent (i.e. a tube placed within a blood vessel to keep it open).[6] Most cases have involved atrial myxomas (~31%), pseudocysts (~28%), prosthetic devices (23%), and chronic hematoma (18%).[2] Symptoms of the disease are attributable to the pre-existing condition, not the FA-DLBCL that has developed in the immune-sequestered site.[2] ## Diagnosis[edit] FA-DLBCL is an incidental finding made by histological examination of tissues obtained at surgery conducted for reasons not related to FA-DLBCL. Microscopically, these tissues are composed of small foci of infiltrates composed of large lymphoid cells embedded in a background of fibrin[6] or debris.[7] Immunohistochemistry analyses reveals that the large neoplastic cells are B-cells by their expression of B-cell marker proteins (e.g. CD20, CD30, CD45, CD79a, PAX5, and MUM1)[2] and are infected with the EBV by their expression of this virus's proteins, e.g. EBNA2 and LMP1.[6] Typically, these cells evidence a high rate of proliferation[6] and are activated rather than non-activated B-cells (i.e. germinal center B-cells or unclassifiable B-cells) as identified by immunohistochemical analyses (see activated B-cells). The lesions show relatively little or no evidence of chronic inflammation[2] except for some cases arising in pseudocysts or chronic hematomas which may show lymphoplasmacytic cells (i.e. cells with combined morphologic features of lymphocytes and plasma cells) surrounding the neoplastic B cell infiltrates.[3] The lesions also show no evidence of tumor mass formation[1] at the site of disease and do not extend beyond their sites of origin.[6] ### Differential diagnosis[edit] FA-DLBCL-CI and (FA-DLBCL) are B-cell lymphomas. Both diseases appear driven by EBV-infected (latency stage III), large, activated B-cells and develop in spaces known or thought to be sequestered from the immune system. Unlike DLBCL-CI, FA-DLBCL is discovered as an incidental infiltrate[1] that develops in or around sites that are not involved in chronic inflammation such as pseudocysts,[3] cysts[9] foreign bodies, hematomas, thrombi formed in large arteries, and myxomas.[3] Also unlike DLBCL-CI, the lesions in FA-DLBCL do not form masses and, in almost all cases, do not extend beyond their site of origin; typically, FA-DLBCL lesions are small infiltrates composed of sheets, ribbons, or clusters of proliferating large B cells within avascular tissues that are often coated with or contain abundant fibrin and usually have few or no other types of inflammatory cells.[3] The disease often appears to be a non-malignant proliferation of EBV+ large B cells that are unable to survive outside of the sequestered sites:[2] DLBCL-CI is an aggressive lymphoma with a five-year overall survival rate of 20–35% while FA-DLBCL, usually has a highly favorable outcome.[1] ## Treatment[edit] Cases of FA-DLBCL have been treated by surgery; chemotherapy regimens such as CHOP (i.e. cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone or prednisolone) or R-CHOP (i.e. rituximab plus CHOP); radiotherapy; or a combination of these modalities. Regardless of treatment type, 30 of the 36 cases of FA-DBCL for which there is follow-up results had a benign course with no disease recurrence over 1 to 130 months. All cases arising in pseudocysts had favorable results. Local recurrences of the disease in non-pseudocyst sites did occur but responded to further treatment. Three individuals with disease located in thrombi had serious thromboembolic complications; two of them died from this complication. One individual who had a FA-DLBCL removed from a subdural hematoma developed an Epstein-Barr virus-associated diffuse large B-cell lymphoma (EBV+DLBCL) at a site in the brain near the original hematoma; this case suggests that FA-DLBCL may transform into the far more malignant Epstein-Barr virus-associated lymphoproliferative disease, EBV+ DLBCL. The limited number of FA-DLBCL cases reported as of 2019 does not definitively show which of their treatment(s) is superior.[6] However, the findings do suggest that cases amenable to complete surgical removal are cured by surgery alone and should be considered as an Epstein-Barr positive lymphoproliferative disease while disease in the heart, vasculature, or hematoma may be associated with serious complications and require chemotherapy.[3] ## References[edit] 1. ^ a b c d Grimm KE, O'Malley DP (2019). "Aggressive B cell lymphomas in the 2017 revised WHO classification of tumors of hematopoietic and lymphoid tissues". Annals of Diagnostic Pathology. 38: 6–10. doi:10.1016/j.anndiagpath.2018.09.014. PMID 30380402. 2. ^ a b c d e f g h i j k l Dojcinov SD, Fend F, Quintanilla-Martinez L (March 2018). "EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts". Pathogens (Basel, Switzerland). 7 (1): 28. doi:10.3390/pathogens7010028. PMC 5874754. PMID 29518976. 3. ^ a b c d e f g h i Boyer DF, McKelvie PA, de Leval L, Edlefsen KL, Ko YH, Aberman ZA, Kovach AE, Masih A, Nishino HT, Weiss LM, Meeker AK, Nardi V, Palisoc M, Shao L, Pittaluga S, Ferry JA, Harris NL, Sohani AR (March 2017). "Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation". The American Journal of Surgical Pathology. 41 (3): 299–312. doi:10.1097/PAS.0000000000000775. PMID 28195879. 4. ^ a b Korkolopoulou P, Vassilakopoulos T, Milionis V, Ioannou M (July 2016). "Recent Advances in Aggressive Large B-cell Lymphomas: A Comprehensive Review". Advances in Anatomic Pathology. 23 (4): 202–43. doi:10.1097/PAP.0000000000000117. PMID 27271843. 5. ^ a b Rezk SA, Zhao X, Weiss LM (June 2018). "Epstein—Barr virus-associated lymphoid proliferations, a 2018 update". Human Pathology. 79: 18–41. doi:10.1016/j.humpath.2018.05.020. PMID 29885408. 6. ^ a b c d e f g h i j Zanelli M, Zizzo M, Montanaro M, Gomes V, Martino G, De Marco L, Fraternali Orcioni G, Martelli MP, Ascani S (September 2019). "Fibrin-associated large B-cell lymphoma: first case report within a cerebral artery aneurysm and literature review". BMC Cancer. 19 (1): 916. doi:10.1186/s12885-019-6123-1. PMC 6743119. PMID 31519155. 7. ^ a b c d King RL, Goodlad JR, Calaminici M, Dotlic S, Montes-Moreno S, Oschlies I, Ponzoni M, Traverse-Glehen A, Ott G, Ferry JA (December 2019). "Lymphomas arising in immune-privileged sites: insights into biology, diagnosis, and pathogenesis". Virchows Archiv. doi:10.1007/s00428-019-02698-3. PMID 31863183. 8. ^ a b Sukswai N, Lyapichev K, Khoury JD, Medeiros LJ (November 2019). "Diffuse large B-cell lymphoma variants: an update". Pathology. 52: 53–67. doi:10.1016/j.pathol.2019.08.013. PMID 31735345. 9. ^ Boroumand N, Ly TL, Sonstein J, Medeiros LJ (July 2012). "Microscopic diffuse large B-cell lymphoma (DLBCL) occurring in pseudocysts: do these tumors belong to the category of DLBCL associated with chronic inflammation?". The American Journal of Surgical Pathology. 36 (7): 1074–80. doi:10.1097/PAS.0b013e3182515fb5. PMID 22472958. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Fibrin-associated diffuse large B-cell lymphoma	None	5,578	wikipedia	https://en.wikipedia.org/wiki/Fibrin-associated_diffuse_large_B-cell_lymphoma	2021-01-18T18:30:53	{"umls": ["CL552155"], "wikidata": ["Q96377889"]}
Abnormally small mouth Microstomia SpecialtyMedical genetics Microstomia is a small mouth (micro- a combining form meaning small + -stomia a combining form meaning mouth = (abnormally) "small mouth" in Greek.) ## Contents * 1 Congenital * 2 Acquired * 3 References * 4 External links ## Congenital[edit] It is a feature of many craniofacial syndromes, including Freeman–Sheldon syndrome and Sheldon-Hall syndromes (or distal arthrogryposis multiplex congenita). It may present with whistling-face feature, as well, as in Freeman-Sheldon syndrome. In this syndrome, it impairs alimentation and may require repeated oral surgeries (called commissurotomy) to improve function.[citation needed] ## Acquired[edit] Microstomia can occur as a result of scarring due to many conditions. It is seen as complication of facial burns.[1] It can also be a feature of systemic scleroderma.[2] ## References[edit] 1. ^ Hagberg and Benumof's Airway Management (4e ed.). Elsevier. pp. 608–639. 2. ^ Jameson, J. Larry. Harrison's Principles of Internal Medicine (20 ed.). McGraw-Hill Education. pp. ch 353. ## External links[edit] Classification D * ICD-10: Q18.5 * ICD-9-CM: 744.84 * MeSH: D008865 * DiseasesDB: 29609 * SNOMED CT: 14582003 External resources * eMedicine: ent/148 * v * t * e Congenital malformations and deformations of face and neck Face * jaw: Otocephaly * mouth: Macrostomia * Microstomia * lip: Macrocheilia * Microcheilia * chin: Microgenia * multiple/other: Hallermann–Streiff syndrome * Branchial cleft cyst Neck * Webbed neck Ungrouped * Preauricular sinus and cyst [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	Microstomia	c0026034	5,579	wikipedia	https://en.wikipedia.org/wiki/Microstomia	2021-01-18T18:29:26	{"mesh": ["D008865"], "umls": ["C0026034"], "icd-9": ["744.84"], "icd-10": ["Q18.5"], "wikidata": ["Q6840355"]}
A number sign (#) is used with this entry because Waardenburg syndrome type 4B (WS4B) is caused by homozygous and heterozygous mutation in the endothelin-3 gene (EDN3; 131242) on chromosome 20q13. Description Waardenburg syndrome type 4 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the eye, deafness, and Hirschsprung disease (review by Read and Newton, 1997). WS type 4B is caused by mutation in the EDN3 gene (131242). WS type 4 is genetically heterogeneous (see WS4A; 277580). For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS2 (193510), and WS3 (148820). Clinical Features Edery et al. (1996) reported a 4-year-old girl with Waardenburg-Shah syndrome. She had colonic aganglionosis, bilateral sensorineural hearing loss, and pigmentary anomalies, including achromic patches of the skin, white eyelashes, pale blue retina, but absence of dystopia canthorum found in Waardenburg syndrome type 1 (193500). Hofstra et al. (1996) reported a patient, born of consanguineous parents, with WS4B. A previous child in this family had been diagnosed with a similar combination of Hirschsprung disease, depigmentation, and deafness. Depigmentation and deafness were present in other relatives. Molecular analysis identified a homozygous mutation in the EDN3 gene (C159F; 131242.0002) Vinuela et al. (2009) reported a Spanish boy, born of consanguineous parents, with Waardenburg syndrome type 4B. The patient had pale blue irides, white forelock, depigmented skin patches, total colonic aganglionosis, and profound sensorineural hearing loss treated successfully with a cochlear implant. Shamseldin et al. (2010) reported an 8-year-old Egyptian boy with WS4B confirmed by genetic analysis (R93G; 131242.0009). He was noted to have a white forelock, grayish blue eyes, hypoplastic ears, and intrauterine growth retardation at birth. Hirschsprung disease was diagnosed soon after. He also had mixed hearing loss with absence of brainstem auditory-evoked response. Family history revealed 2 sibs who died as neonates from complications related to Hirschsprung disease. At age of 8 years, the proband was doing well at a school for the deaf, but no formal IQ testing had been done. He still showed poor physical growth. From a systematic literature search, Song et al. (2016) determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS4 due to EDN3 mutations was 75.0%. Molecular Genetics In a patient with WS4, Edery et al. (1996) identified a homozygous substitution/deletion mutation of the EDN3 gene (131242.0001). In a child with WS4, Pingault et al. (2001) identified a heterozygous nonsense mutation in the EDN3 gene (C169X; 131242.0007). Three unaffected relatives and a fetus terminated at 29 weeks' gestation because of intestinal obstruction also had the mutation. The fetus was found to have Hirschsprung disease affecting the ileum and colon, but no features of Waardenburg syndrome. In a Spanish boy with WS4B, Vinuela et al. (2009) identified a homozygous mutation in the EDN3 gene (H112R; 131242.0008). The patient's father and paternal grandmother, who were each heterozygous for the mutation, had white forelocks. Vinuela et al. (2009) were not able to distinguish whether the mild manifestations in the heterozygous carriers were due to haploinsufficiency or a mild dominant-negative effect. Animal Model Baynash et al. (1994) found that targeted disruption of the mouse endothelin-B ligand (Edn3) gene produces a recessive phenotype of megacolon and coat color spotting. INHERITANCE \- Autosomal dominant \- Autosomal recessive HEAD & NECK Ears \- Deafness, sensorineural Eyes \- Hypopigmented irides \- Bright blue irides ABDOMEN Gastrointestinal \- Hirschsprung disease \- Decreased myenteric and submucosal ganglia in the bowel SKIN, NAILS, & HAIR Skin \- Hypopigmented skin patches Hair \- White forelock \- White eyelashes \- White eyebrows \- Premature graying MISCELLANEOUS \- Variable severity, intrafamilial \- Incomplete penetrance of some features \- Both homozygous and heterozygous EDN3 mutations have been found \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the endothelin-3 gene (EDN3, 131242.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	WAARDENBURG SYNDROME, TYPE 4B	c3266898	5,580	omim	https://www.omim.org/entry/613265	2019-09-22T15:59:09	{"doid": ["0110954"], "mesh": ["D014849"], "omim": ["613265"], "orphanet": ["897"], "synonyms": ["Alternative titles", "WAARDENBURG SYNDROME, TYPE 4B, WITH HIRSCHSPRUNG DISEASE", "WAARDENBURG SYNDROME, TYPE IVB"]}
## Description Anton-Lamprecht (1978) stated that 4 genetic disorders of keratinization are known to have a structural defect of tonofibrils. (1) In the harlequin fetus (242500), an abnormal x-ray diffraction pattern of the horn material points to a cross-beta-protein structure instead of the normal alpha-protein structure of keratin. (2) Bullous ichthyosiform erythroderma (EHK; 113800) is characterized by an early formation of clumps and perinuclear shells due to an abnormal arrangement of tonofibrils. (3) In the Curth-Macklin form of ichthyosis hystrix (146590), concentric unbroken shells of abnormal tonofilaments form around the nucleus. (4) In ichthyosis hystrix gravior, only rudimentary tonofilaments are found with compensatory production of mucous granules. Goldsmith (1976) used the designation of epidermolytic hyperkeratosis for the condition that is called bullous congenital ichthyosiform erythroderma (BCIE) when generalized and ichthyosis hystrix when localized. Clinical Features Penrose and Stern (1958) stated that between 1731 and 1851, the Lambert family of Suffolk, England, had 11 members in 4 generations with ichthyosis hystrix gravior. It was the Lambert pedigree from which the term 'porcupine man' arose. In their review, Penrose and Stern (1958) showed that females in this family were also affected. The skin, normal at birth, developed dark warty scaling after 7 weeks of age. There was no blistering, and the face, palms, and soles were spared. Epstein (1992) suggested that the disorder in the historic 'porcupine man' may have been bullous congenital ichthyosiform erythroderma. Inheritance Y-linkage was suggested on the basis of the famous Lambert pedigree. Penrose and Stern (1958) disproved this, however, and concluded that autosomal dominant inheritance is likely. Diagnosis Anton-Lamprecht (1978) pointed out that electron microscopy is particularly revealing in dominant disorders in which structural abnormality of a protein is likely to be found, whereas biochemistry is more likely to be revealing in recessive disorders. The examples he used from dermatology to illustrate electron microscopic abnormalities in dominant disorders were: structural defects of tonofibrils in hystrix-like ichthyoses, of the anchoring fibrils in dominant dystrophic epidermolysis bullosa of Pasini, and of keratohyalin in autosomal dominant ichthyosis vulgaris. Inheritance \- Autosomal dominant Skin \- Ichthyosis hystrix gravior ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ICHTHYOSIS HYSTRIX GRAVIOR	c0432311	5,581	omim	https://www.omim.org/entry/146600	2019-09-22T16:39:38	{"mesh": ["C536087"], "omim": ["146600"], "orphanet": ["79504"], "synonyms": ["Alternative titles", "ICHTHYOSIS, LAMBERT TYPE", "PORCUPINE MAN"]}
A number sign (#) is used with this entry because of evidence that the harlequin fetus type of congenital ichthyosis, here symbolized ARCI4B, is caused by homozygous or compound heterozygous mutation in the ABCA12 gene (607800) on chromosome 2q35. Mutation in the ABCA12 gene can cause another form of ichthyosis, ARCI4A (601277). Description Harlequin ichthyosis is a rare severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an 'armor' of thick scale plates separated by deep fissures. There is bilateral ectropion and eclabium, and the nose and ears are flattened and appear rudimentary. Constricting bands around the extremities can restrict movement and cause digital necrosis. As the skin barrier is severely compromised, neonates are more prone to sepsis, dehydration, and impaired thermoregulation. Treatment with oral retinoids encourages shedding of the grossly thickened skin. Babies who survive into infancy and beyond develop skin changes resembling severe nonbullous congenital ichthyosiform erythroderma (see 242300) (summary by Rajpopat et al., 2011). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass lamellar ichthyosis (LI), nonbullous congenital ichthyosis erythroderma (NCIE), and harlequin ichthyosis (Oji et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300). Clinical Features Nix et al. (1963) claimed that this recessive form of ichthyosis is distinct from the lamellar exfoliative type of congenital ichthyosis (see 242300). Goldsmith (1976) agreed with the distinctness of this entity from lamellar ichthyosis. It carries a more grave prognosis (Shelmire, 1955). The baby is usually of low birth weight for dates and, as a rule, dies under 1 week of age. Plaques, measuring up to 4 or 5 cm on a side, have a diamond-like configuration resembling the suit of a harlequin clown. Tonofibrils are fibrillar structural proteins in keratinocytes which, although already present in dividing basal cells, are formed in increasing amounts by the differentiating cells. They are the morphologic equivalent of the biochemically well-characterized prekeratin and precursors of the alpha-keratin of horn cells. Four genetic disorders of keratinization are known to have a structural defect of tonofibrils (Anton-Lamprecht, 1978): (1) In the harlequin fetus, an abnormal x-ray diffraction pattern of the horn material points to a cross-beta-protein structure instead of the normal alpha-protein structure of keratin. (2) Bullous ichthyosiform erythroderma (113800) is characterized by an early formation of clumps and perinuclear shells due to an abnormal arrangement of tonofibrils. (3) In the Curth-Macklin form of ichthyosis hystrix (146590), concentric unbroken shells of abnormal tonofilaments form around the nucleus. (4) In ichthyosis hystrix gravior (146600) only rudimentary tonofilaments are found with compensatory production of mucous granules. Unamuno et al. (1987) described 3 affected males and 1 affected female from a consanguineous mating. The infants were covered with an enormous horny shell, similar to armor, with deep creases which fragmented the hard surface into large polygonal plates. The limbs remained in rigid semiflexion. The nose and external ear were hidden in the keratotic layer. Severe ectropion and eclabion were present. All 4 sibs were born prematurely. Two were alive at birth but 1 died soon after delivery and the other 4 days after delivery. Lawlor (1988) presented an experience suggesting that harlequin fetus may be a severe form of nonbullous ichthyosiform erythroderma. All except 1 previously reported harlequin fetus died during the first few weeks of life. Lawlor (1988) described an infant who survived to 2 and a half years, progressing to the picture of nonbullous ichthyosiform erythroderma. Temtamy (1989) described a family with 3 affected sibs and first-cousin parents; the eyes were bulging in the infants and a typically characteristic feature was markedly hypoplastic fingers. It appeared that the tight skin did not permit growth of the fingers. Diagnosis ### Prenatal Diagnosis Blanchet-Bardon et al. (1983) achieved prenatal diagnosis of harlequin fetus by skin biopsies done by fetoscopy at 22 weeks' gestation. The parents were second cousins; of 4 previously born children, 2 had the harlequin syndrome and died at birth. Arnold and Anton-Lamprecht (1985) concluded that prenatal diagnosis of the ichthyosis congenita group cannot be based on disturbance of keratinization because of the late onset of normal keratinization. Biochemical Features Biochemical and ultrastructural abnormalities have suggested genetic heterogeneity and division into 3 subtypes of harlequin ichthyosis (Dale et al., 1990; Akiyama et al., 1998). In types 1 and 2 profilaggrin is expressed but not processed to filaggrin, whereas type 3 lacks profilaggrin; types 2 and 3 both have keratins 6 (see 148041) and 16 (148067) in addition to normal keratins 5/14 (148040, 148066) and 1/10 (139350, 148080) seen in all 3 subtypes. Clinical Management Saunders et al. (1992) reported 2 patients with harlequin ichthyosis. From the photographs taken in the neonatal period, they looked very similar; however, whereas one died in the first day or so of life, the second required assisted ventilation for 5 days but survived thereafter and was alive at the age of almost 6 years at the time of report. Investigation at 15 months for failure to thrive indicated protein malnutrition as a consequence of enormous losses of protein in desquamated skin. Institution of a very high intake of protein led to satisfactory growth and development. Prasad et al. (1994) reported the follow-up and management of 2 affected male Saudi sibs. The first sib was cared for with the frequent application of paraffin ointment to the whole body and oral etretinate. The skin gradually softened. Improvement in the skin around the mouth allowed the infant to suck from a bottle by day 4 and to breastfeed by the age of 1 week. The range of movement in all the limbs improved and the fingers and toes assumed a more normal shape. The baby was discharged home at the age of 51 days. Although his weight gain was poor, with weight remaining below the third percentile, at the age of 18 months he was alert, able to make cooing and babbling sounds, and had normal hearing and vision. He had good neck control, but could not crawl or sit up unaided. At the age of 22 months, he was admitted to hospital where he was found to have blood cultures positive for Staphylococcus aureus and died 24 hours after admission. The second sib succumbed to infection complicated by disseminated intravascular coagulation at the age of 44 days. The second sib had developed areas of ischemia and gangrene on bony prominences and the tips of the fingers and toes. Culican and Custer (2002) reported the successful use of an Apligraf human skin equivalent for repair of bilateral cicatricial ectropion in a patient with harlequin ichthyosis. Inheritance Evidence for recessive inheritance of this disorder was provided by several reports (Bustamente and Tejeda, 1950; Kingery, 1926; Lattuada and Parker, 1951; Smith, 1880; Thomson and Wakeley, 1921), and by parental consanguinity (Edmonds and Dolan, 1951). Castiglia et al. (2009) reported a female newborn with harlequin ichthyosis due to complete paternal isodisomy as shown by parental segregation studies and microsatellite analysis. Chorionic villus karyotyping of the fetus had revealed a nonmosaic chromosome 2 trisomy, whereas postnatal peripheral blood karyotype was normal, indicating trisomic rescue. Cytogenetics Stewart et al. (2001) reported a male with harlequin ichthyosis with a de novo deletion of the long arm of chromosome 18; the karyotype was 46,XY,del(18)(q21.3). The authors proposed that a gene for this condition may lie within the deleted region. Mapping Using SNP chip technology and homozygosity mapping, Kelsell et al. (2005) identified a common region of homozygosity in the chromosomal region 2q35 in 5 patients with harlequin ichthyosis. Molecular Genetics By sequencing of the ABCA12 gene, which maps within the critical region of chromosome 2q35 for harlequin ichthyosis, Kelsell et al. (2005) identified disease-associated mutations, including large intragenic deletions and frameshift deletions (see, e.g., 607800.0006-607800.0009) in 11 of the 12 screened individuals with harlequin ichthyosis. Since the epidermis in harlequin ichthyosis displays abnormal lamellar granule formation, Kelsell et al. (2005) suggested that ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. In 5 patients with harlequin ichthyosis from 4 unrelated families, Akiyama et al. (2005) identified either compound heterozygosity or homozygosity for 5 mutations in the ABCA12 gene. Thomas et al. (2006) sequenced the ABCA12 gene in 14 patients with harlequin ichthyosis and identified mutations in all of them: 9 patients were homozygotes, 2 were compound heterozygotes, and in 3 patients, mutations were found on only 1 allele. The authors noted that the vast majority of ABCA12 mutations associated with harlequin ichthyosis are predicted to result in a truncated protein, although 1 patient was homozygous for a missense mutation (607800.0010). In a Caucasian British child born with severe ichthyosiform erythroderma, in whom Kelsell et al. (2005) did not identify any mutations by sequencing of the ABCA12 gene, Thomas et al. (2006) used a combination of oligonucleotide arrays, multiplex PCR analysis, and SNP genotyping to identify a heterozygous deletion (607800.0011). Thomas et al. (2006) concluded that ABCA12 is the major harlequin ichthyosis gene. ### Exclusion Studies Cystatin M/E (CST6; 601891) has a restricted expression pattern in humans which is largely limited to cutaneous epithelia. Zeeuwen et al. (2003) evaluated the involvement of the CST6 gene in harlequin ichthyosis by sequencing the entire coding region and intron-exon boundaries for mutations in 11 sporadic harlequin ichthyosis patients. No CST6 mutations were detected in this group, which comprised type 1 and type 2 harlequin ichthyosis patients. Disturbed transcription/translation due to mutations in regulatory and noncoding regions of cystatin M/E was unlikely because cystatin M/E protein expression was observed in all patients examined, as assessed by immunohistochemistry. Genotype/Phenotype Correlations Akiyama (2010) reviewed mutations in the ABCA12 gene and stated that a total of 56 mutations had been reported in 66 ARCI families, including 48 with harlequin ichthyosis (HI), 10 with lamellar ichthyosis (LI), and 8 with ichthyosis of the congenital ichthyosiform erythroderma (CIE) type. Most of the mutations in HI patients were truncation mutations, and homozygosity or compound heterozygosity for truncating mutations in ABCA12 always resulted in the HI phenotype. In CIE families, at least 1 mutation on each allele was typically a missense mutation, and combinations of missense mutations in the first ATP-binding cassette of ABCA12 caused the LI phenotype. Animal Model The harlequin ichthyosis (ichq) mouse mutation arose spontaneously in 1989 in a colony of BALB/cJ mice at the Jackson Laboratory, Bar Harbor, Maine. Sundberg et al. (1997) described the phenotypic features and showed that the mutant gene locus maps to the proximal end of mouse chromosome 19. The disorder is inherited as a fully penetrant autosomal recessive and in general, its features are very similar to those of human harlequin ichthyosis. Zeeuwen et al. (2002) reported the isolation and characterization of the mouse Cst6 ortholog and the assignment of the chromosomal localization to the proximal end of mouse chromosome 19. This region corresponds to the locus of the spontaneous harlequin ichthyosis (ichq) mouse mutation. Zeeuwen et al. (2002) found a frameshift deletion resulting in premature termination in the Cst6 gene of BALB/cJ-ichq/+ mice, which precluded the synthesis of functional protein. Immunohistochemistry confirmed the absence of cystatin M/E at the protein level in ichq/ichq mice. Mice that were homozygous for 2 null alleles displayed a hyperplastic, hyperkeratotic epidermis and abnormal hair follicles, and died between 5 and 12 days of age. In wildtype mice, cystatin M/E was found in the stratum granulosum and in the infundibulum of the hair follicle, indicating that the anatomic site in the skin where cystatin M/E is normally expressed correlates with the abnormalities at the tissue level in ichq/ichq mice. Zeeuwen et al. (2002) suggested that cystatin M/E is required for viability and for correct formation of cornified layers in the epidermis and hair follicles. In the ichq (Cst6-null) mouse, Zeeuwen et al. (2004) reported unrestricted activity of the target protease legumain (602620) in hair follicles and epidermis. Analysis of stratum corneum proteins revealed a strong decrease of soluble loricrin (152445) monomers in skin extracts of ichq mice, although normal levels of loricrin were present in the stratum granulosum and stratum corneum. This suggested a premature or enhanced crosslinking of loricrin monomers in ichq mice by transglutaminase-3 (TGM3; 600238). Increased levels of TGM3 were processed into activated 30- and 47-kD subunits, compared to wildtype mice. The authors concluded that cystatin M/E and legumain form a functional dyad in epidermis in vivo. They further proposed that disturbance of this protease-antiprotease balance may cause increased enzyme activity of TGM3 that could explain the observed abnormal cornification. History Waring (1932) pointed to an early mention of a harlequin fetus in the diary of the Reverend O. Hart in 1750. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Flattened \- Rudimentary Eyes \- Severe ectropion \- Bulging eyes Nose \- Flattened \- Rudimentary Mouth \- Eclabium SKELETAL Limbs \- Constricting bands around extremities at birth \- Semiflexed rigid limbs Hands \- Hypoplastic fingers \- Necrotic fingertips Feet \- Necrotic distal toes SKIN, NAILS, & HAIR Skin \- Collodion membrane at birth \- Harlequin fetus \- Large diamond-shaped plaques Skin Histology \- Abnormal lamellar granule formation PRENATAL MANIFESTATIONS Delivery \- Premature birth LABORATORY ABNORMALITIES \- Tonofibril defect (cross-beta-protein structure) MISCELLANEOUS \- Patients are susceptible to sepsis and dehydration \- Patients are prone to impaired thermoregulation \- Usually fatal within the first few weeks of life \- Surviving infants develop severe nonbullous ichthyosiform erythroderma MOLECULAR BASIS \- Caused by mutation in the ATP-binding cassette, subfamily A, member 12 gene (ABCA12, 607800.0006 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid	ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 4B	c0239849	5,582	omim	https://www.omim.org/entry/242500	2019-09-22T16:26:30	{"doid": ["0060713"], "mesh": ["D017490"], "omim": ["242500"], "icd-10": ["Q80.4"], "orphanet": ["457"], "synonyms": ["Alternative titles", "ICHTHYOSIS CONGENITA, HARLEQUIN FETUS TYPE", "HARLEQUIN ICHTHYOSIS", "'HARLEQUIN FETUS'"], "genereviews": ["NBK1420"]}
2009 global H1N1 influenza virus pandemic 2009 swine flu pandemic 50,000+ confirmed cases 5,000–49,999 confirmed cases 500–4,999 confirmed cases 50–499 confirmed cases 5–49 confirmed cases 1–4 confirmed cases No confirmed cases DiseaseInfluenza Virus strainPandemic H1N1/09 virus LocationWorldwide First outbreakNorth America[1][2] Index caseVeracruz, Mexico[1][3] Arrival dateSeptember 2008[4][5] DateJanuary 2009 – 10 August 2010[6][7] Confirmed cases491,382 (lab-confirmed)[8] Suspected cases‡700 million to 1.4 billion (estimate)[9] Deaths Lab confirmed deaths: 18,449 (reported to the WHO)[10] Estimated death toll: 284,000[11] ‡Suspected cases have not been confirmed by laboratory tests as being due to this strain, although some other strains may have been ruled out. Influenza (Flu) Types * Avian * A/H5N1 subtype * Canine * Equine * Swine * A/H1N1 subtype Vaccines * 2009 pandemic * Pandemrix * Live attenuated * Seasonal flu vaccine brands Treatment * Amantadine * Baloxavir marboxil * Laninamivir * Oseltamivir * Peramivir * Rimantadine * Umifenovir * Zanamivir Pandemics * 1918 Spanish flu * 1957 Asian flu * 1968–1969 Hong Kong flu * 2009 swine flu Outbreaks * 1976 swine flu * 2006 H5N1 India * 2007 Australian equine * 2007 Bernard Matthews H5N1 * 2008 West Bengal * 2015 United States H5N2 outbreak See also * Flu season * Influenza evolution * Influenza research * Influenza-like illness * Vaccine reformulations * v * t * e The 2009 swine flu pandemic was an influenza pandemic that lasted about 19 months, from January 2009 to August 2010, and was the second of two pandemics involving H1N1 influenza virus (the first being the 1918–1920 Spanish flu pandemic). First described in April 2009, the virus appeared to be a new strain of H1N1 that resulted from a previous triple reassortment of bird, swine, and human flu viruses and that further combined with a Eurasian pig flu virus,[12] leading to the term "swine flu".[13] Some studies estimated that the actual number of cases including asymptomatic and mild cases could be 700 million to 1.4 billion people—or 11 to 21 percent of the global population of 6.8 billion at the time.[9] The lower value of 700 million is more than the 500 million people estimated to have been infected by the Spanish flu pandemic.[14] However, the Spanish flu infected a much higher proportion of the world population at the time, with the Spanish flu infecting an estimated 500 million people, which was roughly equivalent to a third of the world population at the time of the pandemic.[15] The number of lab-confirmed deaths reported to the World Health Organization (WHO) is 18,449,[10] though the 2009 H1N1 flu pandemic is estimated to have actually caused about 284,000 (range from 150,000 to 575,000) deaths.[16] A follow-up study done in September 2010 showed that the risk of serious illness resulting from the 2009 H1N1 flu was no higher than that of the yearly seasonal flu.[17] For comparison, the WHO estimates that 250,000 to 500,000 people die of seasonal flu annually.[18] Unlike most strains of influenza, the Pandemic H1N1/09 virus does not disproportionately infect adults older than 60 years; this was an unusual and characteristic feature of the H1N1 pandemic.[19] Even in the case of previously healthy people, a small percentage develop pneumonia or acute respiratory distress syndrome (ARDS). This manifests itself as increased breathing difficulty and typically occurs three to six days after initial onset of flu symptoms.[20][21] The pneumonia caused by flu can be either direct viral pneumonia or a secondary bacterial pneumonia. A November 2009 New England Journal of Medicine article recommended that flu patients whose chest X-ray indicates pneumonia receive both antivirals and antibiotics.[22] In particular, it is a warning sign if a child seems to be getting better and then relapses with high fever, as this relapse may be bacterial pneumonia.[23] ## Contents * 1 Name * 2 History * 3 Signs and symptoms * 3.1 Severe cases * 3.2 Complications * 4 Diagnosis * 5 Cause * 5.1 Transmission * 6 Prevention * 6.1 Public health response * 6.2 Vaccines * 6.3 Accusations of conflict of interest * 6.4 Infection control * 6.4.1 Travel precautions * 6.4.2 Schools * 6.4.3 Workplace * 6.4.4 Face masks * 6.4.5 Quarantine * 6.4.6 Pigs and food safety * 7 Treatment * 7.1 Side effects * 7.2 Resistance * 7.3 Antivirals effectiveness questioned in healthy adults * 8 Epidemiology * 8.1 Mexico * 8.2 United States * 8.3 Data reporting and accuracy * 8.4 Follow-up * 9 Comparisons to other pandemics and epidemics * 10 See also * 11 References * 12 Further reading * 13 External links ## Name[edit] Further information: Pandemic H1N1/09 virus § Nomenclature The World Health Organization uses the term "(H1N1) 2009 pandemic" when referring to the event, and officially adopted the name "A(H1N1)pdm09" for the virus in 2010, after the conclusion of the pandemic.[24] Controversy arose early on regarding the wide assortment of terms used by journalists, academics, and officials. Labels like "H1N1 flu", "Swine flu", "Mexican flu", and variations thereof were typical. Criticism centered on how these names may confuse or mislead the public. It was argued that the names were overly technical (e.g. "H1N1"), incorrectly implying that the disease is caused by contact with pigs or pig products, or provoking stigmatization against certain communities (e.g. "Mexican"). Some academics of the time asserted there is nothing wrong with such names,[25] while research published years later (in 2013) concluded that Mexican Americans and Latino Americans had indeed been stigmatized due to the frequent use of term "Mexican flu" in the news media.[26] Official entities adopted terms with varying consistency over the course of the pandemic. The CDC used names like "novel influenza A (H1N1)" or "2009 H1N1 flu".[27] The Netherlands National Institute for Public Health and the Environment used the term "Pig Flu" early on. Officials in Taiwan suggested use of the names "H1N1 flu" or "new flu".[28] The World Organization for Animal Health, an IGO based in Europe, proposed the name "North American influenza".[29] The European Commission adopted the term "novel flu virus". Officials in Israel and South Korea briefly considered adoption of the name "Mexican virus" due to concern about the use of the word "swine".[30] In Israel, objections stemmed from sensitivity to religious restrictions on eating pork in the Jewish and Muslim populations,[31] in South Korea, concerns were influenced by the importance of pork and domestic pigs. As terminology changed to deal with these and other such issues, further criticism was made that the situation was unnecessarily confusing. For example, the news department at the journal Science produced an article with the humorous title "Swine Flu Names Evolving Faster Than Swine Flu Itself".[32] ## History[edit] Analysis of the genetic divergence of the virus in samples from different cases indicated that the virus jumped to humans in 2008, probably after June, and not later than the end of November,[33] likely around September 2008.[4][5] The research also indicated the virus had been latent in pigs for several months prior to the outbreak, suggesting a need to increase agricultural surveillance to prevent future outbreaks.[34] In 2009, U.S. agricultural officials speculated, although emphasizing that there was no way to prove their hypothesis, that "contrary to the popular assumption that the new swine flu pandemic arose on factory farms in Mexico, [the virus] most likely emerged in pigs in Asia, but then traveled to North America in a human."[35] However, a subsequent report[36] by researchers at the Mount Sinai School of Medicine in 2016 found that the 2009 H1N1 virus likely originated from pigs in a very small region of central Mexico.[37] Mexican soldiers distributing protective masks to citizens Initially called an "outbreak", widespread H1N1 infection was first recognized in the state of Veracruz, Mexico, with evidence that the virus had been present for months before it was officially called an "epidemic".[35] The Mexican government closed most of Mexico City's public and private facilities in an attempt to contain the spread of the virus; however, it continued to spread globally, and clinics in some areas were overwhelmed by infected people. The new virus was first isolated in late April by American and Canadian laboratories from samples taken from people with flu in Mexico, Southern California, and Texas. Soon the earliest known human case was traced to a case from 9 March 2009 in a 5-year-old boy in La Gloria, Mexico, a rural town in Veracruz.[38][35] In late April, the World Health Organization (WHO) declared its first ever "public health emergency of international concern," or PHEIC,[39] and in June, the WHO and the U.S. CDC stopped counting cases and declared the outbreak a pandemic.[40] Despite being informally called "swine flu", the H1N1 flu virus cannot be spread by eating pork products;[41][42] similar to other influenza viruses, it is typically contracted by person to person transmission through respiratory droplets.[43] Symptoms usually last 4–6 days.[44] Antivirals (oseltamivir or zanamivir) were recommended for those with more severe symptoms or those in an at-risk group.[45] The pandemic began to taper off in November 2009,[46] and by May 2010, the number of cases was in steep decline.[47][48][49][50] On 10 August 2010, the Director-General of the WHO, Margaret Chan, announced the end of the H1N1 pandemic[7] and announced that the H1N1 influenza event had moved into the post-pandemic period.[51] According to WHO statistics (as of July 2010), the virus had killed more than 18,000 people since it appeared in April 2009; however, they state that the total mortality (including deaths unconfirmed or unreported) from the H1N1 strain is "unquestionably higher".[47][52] Critics claimed the WHO had exaggerated the danger, spreading "fear and confusion" rather than "immediate information".[53] The WHO began an investigation to determine[54] whether it had "frightened people unnecessarily".[55] A flu follow-up study done in September 2010, found that "the risk of most serious complications was not elevated in adults or children."[56] In a 5 August 2011 PLOS ONE article, researchers estimated that the 2009 H1N1 global infection rate was 11% to 21%, lower than what was previously expected.[57] However, by 2012, research showed that as many as 579,000 people could have been killed by the disease, as only those fatalities confirmed by laboratory testing were included in the original number, and meant that many without access to health facilities went uncounted. The majority of these deaths occurred in Africa and Southeast Asia. Experts, including the WHO, have agreed that an estimated 284,500 people were killed by the disease, much higher than the initial death toll.[58][59] ## Signs and symptoms[edit] Main article: Influenza § Signs and symptoms The symptoms of H1N1 flu are similar to those of other influenzas, and may include fever, cough (typically a "dry cough"), headache, muscle or joint pain, sore throat, chills, fatigue, and runny nose. Diarrhea, vomiting, and neurological problems have also been reported in some cases.[60][61] People at higher risk of serious complications include people over 65, children younger than 5, children with neurodevelopmental conditions, pregnant women (especially during the third trimester),[20][62] and people of any age with underlying medical conditions, such as asthma, diabetes, obesity, heart disease, or a weakened immune system (e.g., taking immunosuppressive medications or infected with HIV).[63] More than 70% of hospitalizations in the U.S. have been people with such underlying conditions, according to the CDC.[64] In September 2009, the CDC reported that the H1N1 flu "seems to be taking a heavier toll among chronically ill children than the seasonal flu usually does".[23] Through 8 August 2009, the CDC had received 36 reports of paediatric deaths with associated influenza symptoms and laboratory-confirmed pandemic H1N1 from state and local health authorities within the United States, with 22 of these children having neurodevelopmental conditions such as cerebral palsy, muscular dystrophy, or developmental delays.[65] "Children with nerve and muscle problems may be at especially high risk for complications because they cannot cough hard enough to clear their airways".[23] From 26 April 2009, to 13 February 2010, the CDC had received reports of the deaths of 277 children with laboratory-confirmed 2009 influenza A (H1N1) within the United States.[66] ### Severe cases[edit] The World Health Organization reports that the clinical picture in severe cases is strikingly different from the disease pattern seen during epidemics of seasonal influenza. While people with certain underlying medical conditions are known to be at increased risk, many severe cases occur in previously healthy people. In severe cases, patients generally begin to deteriorate around three to five days after symptom onset. Deterioration is rapid, with many patients progressing to respiratory failure within 24 hours, requiring immediate admission to an intensive care unit. Upon admission, most patients need immediate respiratory support with mechanical ventilation.[67] ### Complications[edit] Most complications have occurred among previously unhealthy individuals, with obesity and respiratory disease as the strongest risk factors. Pulmonary complications are common. Primary influenza pneumonia occurs most commonly in adults and may progress rapidly to acute lung injury requiring mechanical ventilation. Secondary bacterial infection is more common in children. Staphylococcus aureus, including methicillin-resistant strains, is an important cause of secondary bacterial pneumonia with a high mortality rate; Streptococcus pneumoniae is the second most important cause of secondary bacterial pneumonia for children and primary for adults. Neuromuscular and cardiac complications are unusual but may occur.[68] A United Kingdom investigation of risk factors for hospitalisation and poor outcome with pandemic A/H1N1 influenza looked at 631 patients from 55 hospitals admitted with confirmed infection from May through September 2009. 13% were admitted to a high dependency or intensive care unit and 5% died; 36% were aged <16 years and 5% were aged ≥65 years. Non-white and pregnant patients were over-represented. 45% of patients had at least one underlying condition, mainly asthma, and 13% received antiviral drugs before admission. Of 349 with documented chest x-rays on admission, 29% had evidence of pneumonia, but bacterial co-infection was uncommon. Multivariate analyses showed that physician-recorded obesity on admission and pulmonary conditions other than asthma or chronic obstructive pulmonary disease (COPD) were associated with a severe outcome, as were radiologically confirmed pneumonia and a raised C-reactive protein (CRP) level (≥100 mg/l). 59% of all in-hospital deaths occurred in previously healthy people.[69] Fulminant (sudden-onset) myocarditis has been linked to infection with H1N1, with at least four cases of myocarditis confirmed in patients also infected with A/H1N1. Three out of the four cases of H1N1-associated myocarditis were classified as fulminant, and one of the patients died.[70] Also, there appears to be a link between severe A/H1N1 influenza infection and pulmonary embolism. In one report, five out of 14 patients admitted to the intensive care unit with severe A/H1N1 infection were found to have pulmonary emboli.[71] An article published in JAMA in September 2010[72] challenged previous reports and stated that children infected in the 2009 flu pandemic were no more likely to be hospitalised with complications or get pneumonia than those who catch seasonal strains. Researchers found that about 1.5% of children with the H1N1 swine flu strain were hospitalised within 30 days, compared with 3.7% of those sick with a seasonal strain of H1N1 and 3.1% with an H3N2 virus.[56] ## Diagnosis[edit] Confirmed diagnosis of pandemic H1N1 flu requires testing of a nasopharyngeal, nasal, or oropharyngeal tissue swab from the patient.[73] Real-time RT-PCR is the recommended test as others are unable to differentiate between pandemic H1N1 and regular seasonal flu.[73] However, most people with flu symptoms do not need a test for pandemic H1N1 flu specifically, because the test results usually do not affect the recommended course of treatment.[74] The U.S. CDC recommend testing only for people who are hospitalized with suspected flu, pregnant women, and people with weakened immune systems.[74] For the mere diagnosis of influenza and not pandemic H1N1 flu specifically, more widely available tests include rapid influenza diagnostic tests (RIDT), which yield results in about 30 minutes, and direct and indirect immunofluorescence assays (DFA and IFA), which take 2–4 hours.[75] Due to the high rate of RIDT false negatives, the CDC advises that patients with illnesses compatible with novel influenza A (H1N1) virus infection but with negative RIDT results should be treated empirically based on the level of clinical suspicion, underlying medical conditions, severity of illness, and risk for complications, and if a more definitive determination of infection with influenza virus is required, testing with rRT-PCR or virus isolation should be performed.[76] The use of RIDTs has been questioned by researcher Paul Schreckenberger of the Loyola University Health System, who suggests that rapid tests may actually pose a dangerous public health risk.[77] Nikki Shindo of the WHO has expressed regret at reports of treatment being delayed by waiting for H1N1 test results and suggests, "[D]octors should not wait for the laboratory confirmation but make diagnosis based on clinical and epidemiological backgrounds and start treatment early."[78] On 22 June 2010, the CDC announced a new test called the "CDC Influenza 2009 A (H1N1)pdm Real-Time RT-PCR Panel (IVD)". It uses a molecular biology technique to detect influenza A viruses and specifically the 2009 H1N1 virus. The new test will replace the previous real-time RT-PCR diagnostic test used during the 2009 H1N1 pandemic, which received an emergency use authorization from the U.S. Food and Drug Administration in April 2009. Tests results are available in four hours and are 96% accurate.[79] ## Cause[edit] Main article: Pandemic H1N1/09 virus The virus was found to be a novel strain of influenza for which existing vaccines against seasonal flu provided little protection. A study at the U.S. Centers for Disease Control and Prevention published in May 2009 found that children had no preexisting immunity to the new strain but that adults, particularly those older than 60, had some degree of immunity. Children showed no cross-reactive antibody reaction to the new strain, adults aged 18 to 60 had 6–9%, and older adults 33%.[80][81] While it has been thought that these findings suggest the partial immunity in older adults may be due to previous exposure to similar seasonal influenza viruses, a November 2009 study of a rural unvaccinated population in China found only a 0.3% cross-reactive antibody reaction to the H1N1 strain, suggesting that previous vaccinations for seasonal flu and not exposure may have resulted in the immunity found in the older U.S. population.[82] Analyses of the genetic sequences of the first isolates, promptly shared on the GISAID database according to Nature and WHO,[83][84] soon determined that the strain contains genes from five different flu viruses: North American swine influenza, North American avian influenza, human influenza, and two swine influenza viruses typically found in Asia and Europe. Further analysis has shown that several proteins of the virus are most similar to strains that cause mild symptoms in humans, leading virologist Wendy Barclay to suggest on 1 May 2009, that the initial indications are that the virus was unlikely to cause severe symptoms for most people.[85] The virus was less lethal than previous pandemic strains and killed about 0.01–0.03% of those infected; the 1918 influenza was about one hundred times more lethal and had a case fatality rate of 2–3%.[86] By 14 November 2009, the virus had infected one in six Americans with 200,000 hospitalisations and 10,000 deaths—as many hospitalizations and fewer deaths than in an average flu season overall, but with much higher risk for those under 50. With deaths of 1,100 children and 7,500 adults 18 to 64, these figures were deemed "much higher than in a usual flu season" during the pandemic.[87] In June 2010, scientists from Hong Kong reported discovery of a new swine flu virus: a hybrid of the pandemic H1N1 virus and viruses previously found in pigs. It was the first report of a reassortment of the pandemic virus, which in humans had been slow to evolve. Nancy Cox, head of the influenza division at the U.S. Centers for Disease Control and Prevention, has said, "This particular paper is extremely interesting because it demonstrates for the first time what we had worried about at the very onset of the pandemic, and that is that this particular virus, when introduced into pigs, could reassort with the resident viruses in pigs and we would have new gene constellations. And bingo, here we are." Pigs have been termed the mixing vessel of flu because they can be infected both by avian flu viruses, which rarely directly infect people, and by human viruses. When pigs become simultaneously infected with more than one virus, the viruses can swap genes, producing new variants which can pass to humans and sometimes spread amongst them.[88] "Unlike the situation with birds and humans, we have a situation with pigs and humans where there's a two-way street of exchange of viruses. With pigs it's very much a two-way street."[89] ### Transmission[edit] Spread of the H1N1 virus is thought to occur in the same way that seasonal flu spreads. Flu viruses are spread mainly from person to person through coughing or sneezing by people with influenza. Sometimes people may become infected by touching something—such as a surface or object—with flu viruses on it and then touching their face.[41] The basic reproduction number (the average number of other individuals whom each infected individual will infect, in a population which has no immunity to the disease) for the 2009 novel H1N1 is estimated to be 1.75.[90] A December 2009 study found that the transmissibility of the H1N1 influenza virus in households is lower than that seen in past pandemics. Most transmissions occur soon before or after the onset of symptoms.[91] The H1N1 virus has been transmitted to animals, including swine, turkeys, ferrets, household cats, at least one dog, and a cheetah.[92][93][94][95] ## Prevention[edit] See also: Influenza prevention, 2009 swine flu pandemic vaccine, and Influenza vaccine § 2009-2010 Northern Hemisphere winter season Because the H1N1 vaccine was initially in short supply in the U.S., the CDC recommended that initial doses should go to priority groups such as pregnant women, people who live with or care for babies under six months old, children six months to four years old and health-care workers.[96] In the UK, the NHS recommended vaccine priority go to people over six months old who were clinically at risk for seasonal flu, pregnant women and households of people with compromised immunity.[97] Although it was initially thought that two injections would be required, clinical trials showed that the new vaccine protected adults "with only one dose instead of two;" thus the limited vaccine supplies would go twice as far as had been predicted.[98][99] Health officials worldwide were also concerned because the virus was new and could easily mutate and become more virulent, even though most flu symptoms were mild and lasted only a few days without treatment. Officials also urged communities, businesses, and individuals to make contingency plans for possible school closures, multiple employee absences for illness, surges of patients in hospitals, and other effects of potentially widespread outbreaks.[100] Disaster response organizations such as Direct Relief helped by providing protective items to clinical workers to help them stay healthy throughout flu season.[101][102] In February 2010, the CDC's Advisory Committee on Immunization Practices voted for "universal" flu vaccination in the U.S. to include all people over six months of age. The 2010–2011 vaccine will protect against the 2009 H1N1 pandemic virus and two other flu viruses.[103] ### Public health response[edit] See also: 2009 swine flu pandemic by country On 27 April 2009, the European Union health commissioner advised Europeans to postpone nonessential travel to the United States or Mexico. This followed the discovery of the first confirmed case in Spain.[104] On 6 May 2009, the Public Health Agency of Canada announced that their National Microbiology Laboratory (NML) had mapped the genetic code of the swine flu virus, the first time that had been done.[105] In the U.K., the National Health Service launched a website, the National Pandemic Flu Service,[106] allowing patients to self-assess and get an authorisation number for antiviral medication. The system was expected to reduce the burden on general practitioners.[97] U.S. officials observed that six years of concern about H5N1 avian flu did much to prepare for the current H1N1 outbreak, noting that after H5N1 emerged in Asia, ultimately killing about 60% of the few hundred people infected over the years, many countries took steps to try to prevent any similar crisis from spreading further.[107] The CDC and other U.S. governmental agencies[108] used the summer lull to take stock of the United States response to H1N1 flu and attempt to patch any gaps in the public health safety net before flu season started in early autumn.[109] Preparations included planning a second influenza vaccination program in addition to the one for seasonal flu, and improving coordination between federal, state, and local governments and private health providers.[109] On 24 October 2009, U.S. President Obama declared swine flu a national emergency, giving Secretary of Health and Human Services Kathleen Sebelius authority to grant waivers to requesting hospitals from usual federal requirements.[110] ### Vaccines[edit] Main article: 2009 swine flu pandemic vaccine President Barack Obama being vaccinated against H1N1 flu on 20 December 2009 By 19 November 2009, doses of vaccine had been administered in over 16 countries. A 2009 review by the U.S. National Institutes of Health (NIH) concluded that the 2009 H1N1 vaccine has a safety profile similar to that of seasonal vaccine. In 2011, a study from the US Flu Vaccine Effectiveness Network estimated the overall effectiveness of all pandemic H1N1 vaccines at 56%. A CDC study released 28 January 2013, estimated that the Pandemic H1N1 vaccine saved roughly 300 lives and prevented about a million illnesses in the US. The study concluded that had the vaccination program started two weeks earlier, close to 60% more cases could have been prevented. The study was based on an effectiveness in preventing cases, hospitalizations, and deaths of 62% for all subgroups except people over 65, for whom the effectiveness was estimated at 43%. The effectiveness was based on European and Asian studies and expert opinion. The delay in vaccine administration demonstrated the shortcomings of the world's capacity for vaccine-production, as well as problems with international distribution. Some manufacturers and wealthy countries had concerns regarding liability and regulations, as well as the logistics of transporting, storing, and administering vaccines to be donated to poorer countries.[111] ### Accusations of conflict of interest[edit] In January 2010, Wolfgang Wodarg, a German deputy who trained as a physician and now chairs the health committee at the Council of Europe, claimed major firms had organized a "campaign of panic" to put pressure on the World Health Organization (WHO) to declare a "false pandemic" to sell vaccines. Wodarg said the WHO's "false pandemic" flu campaign is "one of the greatest medicine scandals of the century". He said that the "false pandemic" campaign began in May 2009 in Mexico City, when a hundred or so "normal" reported influenza cases were declared to be the beginning of a threatening new pandemic, although he said there was little scientific evidence for it. Nevertheless, he argued that the WHO, "in cooperation with some big pharmaceutical companies and their scientists, re-defined pandemics," removing the statement that "an enormous amount of people have contracted the illness or died" from its existing definition and replacing it by stating simply that there has to be a virus, spreading beyond borders and to which people have no immunity.[112] The WHO responded by stating that they take their duty to provide independent advice seriously and guarded against interference from outside interests. Announcing a review of the WHO's actions, spokeswoman Fadela Chaib stated: "Criticism is part of an outbreak cycle. We expect and indeed welcome criticism and the chance to discuss it".[113][114] In March 2010, the Council of Europe launched an enquiry into "the influence of the pharmaceutical companies on the global swine flu campaign", and a preliminary report is in preparation.[115] On 12 April 2010, Keiji Fukuda, the WHO's top influenza expert, stated that the system leading to the declaration of a pandemic led to confusion about H1N1 circulating around the world and he expressed concern that there was a failure to communicate in regard to uncertainties about the new virus, which turned out to be not as deadly as feared. WHO Director-General Margaret Chan appointed 29 flu experts from outside the organization to conduct a review of WHO's handling of the H1N1 flu pandemic. She told them, "We want a frank, critical, transparent, credible and independent review of our performance."[116] In June 2010, Fiona Godlee, editor-in-chief of the BMJ, published an editorial which criticised the WHO, saying that an investigation had disclosed that some of the experts advising WHO on the pandemic had financial ties with drug companies which were producing antivirals and vaccines.[117] Margaret Chan, Director-General of the WHO, replied stating, "Without question, the BMJ feature and editorial will leave many readers with the impression that WHO's decision to declare a pandemic was at least partially influenced by a desire to boost the profits of the pharmaceutical industry. The bottom line, however, is that decisions to raise the level of pandemic alert were based on clearly defined virological and epidemiological criteria. It is hard to bend these criteria, no matter what the motive".[116] ### Infection control[edit] #### Travel precautions[edit] Flu inspection on a flight arriving in China Thermal imaging camera and screen, photographed in an airport terminal in Greece. Thermal imaging can detect elevated body temperature, one of the signs of swine flu. On 7 May 2009, the WHO stated that containment was not feasible and that countries should focus on mitigating the effect of the virus. They did not recommend closing borders or restricting travel.[118] On 26 April 2009, the Chinese government announced that visitors returning from flu-affected areas who experienced flu-like symptoms within two weeks would be quarantined.[119] U.S. airlines had made no major changes as of the beginning of June 2009, but continued standing practices which include looking for passengers with symptoms of flu, measles or other infections, and relying on in-flight air filters to ensure that aircraft were sanitised.[120] Masks were not generally provided by airlines and the CDC did not recommend that airline crews wear them.[120] Some non-U.S. airlines, mostly Asian, including Singapore Airlines, China Eastern Airlines, China Southern Airlines, Cathay Pacific and Aeromexico, took measures such as stepping up cabin cleaning, installing state-of-the-art air filters and allowing in-flight staff to wear face masks.[120] According to studies conducted in Australia and Japan, screening individuals for influenza symptoms at airports during the 2009 H1N1 outbreak was not an effective method of infection control.[121][122] #### Schools[edit] U.S. government officials were especially concerned about schools because the H1N1 flu virus appears to disproportionately affect young and school-age people, between six months and 24 years of age.[123] The H1N1 outbreak led to numerous precautionary school closures in some areas. Rather than closing schools, the CDC recommended that students and school workers with flu symptoms should stay home for either seven days total, or until 24 hours after symptoms subsided, whichever was longer.[124] The CDC also recommended that colleges should consider suspending fall 2009 classes if the virus began to cause severe illness in a significantly larger share of students than the previous spring. They also urged schools to suspend rules, such as penalties for late papers or missed classes or requirements for a doctor's note, to enforce "self-isolation" and prevent students from venturing out while ill;[125] schools were advised to set aside a room for people developing flu-like symptoms while they waited to go home and to have ill students or staff and those caring for them use face masks.[126] In California, school districts and universities were on alert and worked with health officials to launch education campaigns. Many planned to stockpile medical supplies and discuss worst-case scenarios, including plans to provide lessons and meals for low-income children in case elementary and secondary schools closed.[127] University of California campuses stockpiled supplies, from paper masks and hand sanitizer to food and water.[127] To help prepare for contingencies, University of Maryland School of Medicine professor of pediatrics James C. King Jr. suggested that every county should create an "influenza action team" to be run by the local health department, parents, and school administrators.[128] By 28 October 2009, about 600 schools in the United States had been temporarily closed, affecting over 126,000 students in 19 states.[129] #### Workplace[edit] Fearing a worst-case scenario, the U.S. Department of Health and Human Services (HHS), the Centers for Disease Control and Prevention and the Department of Homeland Security (DHS) developed updated guidance[130] and a video for employers to use as they developed plans to respond to the H1N1 outbreak. The guidance suggested that employers consider and communicate their objectives, such as reducing transmission among staff, protecting people who are at increased risk of influenza-related complications from becoming infected, maintaining business operations, and minimising adverse effects on other entities in their supply chains.[130] The CDC estimated that as much as 40% of the workforce might be unable to work at the peak of the pandemic due to the need for many healthy adults to stay home and care for an ill family member,[131] and advised that individuals should have steps in place should a workplace close down or a situation arise that requires working from home.[132] The CDC further advised that persons in the workplace should stay home sick for seven days after getting the flu, or 24 hours after symptoms end, whichever is longer.[124] In the UK, the Health and Safety Executive (HSE) also issued general guidance for employers.[133] #### Face masks[edit] Mexico City Metro Osaka Loop Line, Japan The U.S. CDC did not recommend the use of face masks or respirators in non-health care settings, such as schools, workplaces, or public places, with a few exceptions: people who were ill with the virus when around other people, and people who were at risk for severe illness while caring for someone with the flu.[134] There was some disagreement about the value of wearing face masks, as some experts feared that masks may have given people a false sense of security and should not have replaced other standard precautions.[135] Yukihiro Nishiyama, professor of virology at Nagoya University's School of Medicine, commented that the masks are "better than nothing, but it's hard to completely block out an airborne virus since it can easily slip through the gaps".[136][137] According to mask manufacturer 3M, masks will filter out particles in industrial settings, but "there are no established exposure limits for biological agents such as swine flu virus".[135] However, despite the lack of evidence of effectiveness, the use of such masks is common in Asia.[136] [137] [138] They are particularly popular in Japan, where cleanliness and hygiene are highly valued and where etiquette obligates those who are sick to wear masks to avoid spreading disease.[136][137] #### Quarantine[edit] During the height of the fear of a pandemic, some countries initiated or threatened to initiate quarantines of foreign visitors suspected of having or being in contact with others who may have been infected. In May 2009, the Chinese government confined 21 U.S. students and three teachers to their hotel rooms.[139] As a result, the US State Department issued a travel alert about China's anti-flu measures and warned travellers against travelling to China if ill.[140] In Hong Kong, an entire hotel was quarantined with 240 guests;[141] Australia ordered a cruise ship with 2,000 passengers to stay at sea because of a swine flu threat.[142] Egyptian Muslims who went on the annual pilgrimage to Mecca risked being quarantined upon their return.[143] Russia and Taiwan said they would quarantine visitors with fevers who come from areas where the flu was present.[144] Japan quarantined 47 airline passengers in a hotel for a week in mid-May,[145] then in mid-June India suggested pre-screening "outbound" passengers from countries thought to have a high rate of infection.[146] #### Pigs and food safety[edit] Main article: 2009 swine flu pandemic actions concerning pigs The pandemic virus is a type of swine influenza, derived originally from a strain which lived in pigs, and this origin gave rise to the common name of "swine flu". This term is widely used by mass media, though the Paris-based World Organisation for Animal Health as well as industry groups such as the U.S. National Pork Board, the American Meat Institute, and the Canadian Pork Council objected to widespread media use of the name "swine flu" and suggested it should be called "North American flu" instead, while the World Health Organization switched its designation from "swine influenza" to "influenza A (H1N1)" in late April 2009.[147][148] The virus has been found in U.S. hogs,[149] and Canadian[150] as well as in hogs in Northern Ireland, Argentina, and Norway.[151] Leading health agencies and the United States Secretary of Agriculture have stressed that eating properly cooked pork or other food products derived from pigs will not cause flu.[152][153] Nevertheless, on 27 April Azerbaijan imposed a ban on the importation of animal husbandry products from the entire Americas.[154] The Indonesian government also halted the importation of pigs and initiated the examination of 9 million pigs in Indonesia.[155] The Egyptian government ordered the slaughter of all pigs in Egypt on 29 April.[156] ## Treatment[edit] Further information: Influenza treatment A number of methods have been recommended to help ease symptoms, including adequate liquid intake and rest.[157] Over-the-counter pain medications such as acetaminophen and ibuprofen do not kill the virus; however, they may be useful to reduce symptoms.[158] Aspirin and other salicylate products should not be used by people under 16 with any flu-type symptoms because of the risk of developing Reye's Syndrome.[159] If the fever is mild and there are no other complications, fever medication is not recommended.[158] Most people recover without medical attention, although ones with pre-existing or underlying medical conditions are more prone to complications and may benefit from further treatments.[160] People in at-risk groups should be treated with antivirals (oseltamivir or zanamivir) as soon as possible when they first experience flu symptoms. The at-risk groups include pregnant and post partum women, children under two years old, and people with underlying conditions such as respiratory problems.[45] People who are not in an at-risk group who have persistent or rapidly worsening symptoms should also be treated with antivirals. People who have developed pneumonia should be given both antivirals and antibiotics, as in many severe cases of H1N1-caused illness, bacterial infection develops.[78] Antivirals are most useful if given within 48 hours of the start of symptoms and may improve outcomes in hospitalised patients.[161] In those beyond 48 hours who are moderately or severely ill, antivirals may still be beneficial.[43] If oseltamivir (Tamiflu) is unavailable or cannot be used, zanamivir (Relenza) is recommended as a substitute.[45][162] Peramivir is an experimental antiviral drug approved for hospitalised patients in cases where the other available methods of treatment are ineffective or unavailable.[163] To help avoid shortages of these drugs, the U.S. CDC recommended oseltamivir treatment primarily for people hospitalised with pandemic flu; people at risk of serious flu complications due to underlying medical conditions; and patients at risk of serious flu complications. The CDC warned that the indiscriminate use of antiviral medications to prevent and treat influenza could ease the way for drug-resistant strains to emerge, which would make the fight against the pandemic that much harder. In addition, a British report found that people often failed to complete a full course of the drug or took the medication when not needed.[164] ### Side effects[edit] Both medications mentioned above for treatment, oseltamivir and zanamivir, have known side effects, including lightheadedness, chills, nausea, vomiting, loss of appetite, and trouble breathing. Children were reported to be at increased risk of self-injury and confusion after taking oseltamivir.[157] The WHO warned against buying antiviral medications from online sources and estimated that half the drugs sold by online pharmacies without a physical address were counterfeit.[165] ### Resistance[edit] In December 2012, the World Health Organization (WHO) reported 314 samples of the 2009 pandemic H1N1 flu tested worldwide have shown resistance to oseltamivir (Tamiflu).[166] It is not totally unexpected as 99.6% of the seasonal H1N1 flu strains tested have developed resistance to oseltamivir.[167] No circulating flu has yet shown any resistance to zanamivir (Relenza), the other available anti-viral.[168] ### Antivirals effectiveness questioned in healthy adults[edit] On 8 December 2009, the Cochrane Collaboration, which reviews medical evidence, announced in a review published in BMJ that it had reversed its previous findings that the antiviral drugs oseltamivir (Tamiflu) and zanamivir (Relenza) can ward off pneumonia and other serious conditions linked to influenza. They reported that an analysis of 20 studies showed oseltamivir offered mild benefits for healthy adults if taken within 24 hours of onset of symptoms, but found no clear evidence it prevented lower respiratory tract infections or other complications of influenza.[169][170] Of note, their published finding related only to use in healthy adults with influenza but not in patients judged to be at high risk of complications (pregnant women, children under five and those with underlying medical conditions), and uncertainty over its role in reducing complications in healthy adults still left it as a useful drug for reducing the duration of symptoms. In general, the Cochrane Collaboration concluded "Paucity of good data".[170][171] ## Epidemiology[edit] Further information: 2009 swine flu pandemic timeline, 2009 swine flu pandemic timeline summary, 2009 swine flu pandemic tables, and 2009 swine flu pandemic by country 2009 flu pandemic data Area Lab confirmed deaths reported to WHO Worldwide (total) At least 18,449 Africa 168 Americas At least 8,533 Eastern Mediterranean 1,019 Europe At least 4,079 South-East Asia 1,992 Western Pacific 1,858 Source: World Health Organization – August 6, 2010[10] Further information: Cases and deaths by country Note: The ratio of confirmed deaths to total deaths due to the pandemic is unknown. For more information, see "Data reporting and accuracy". While it is not known precisely where or when the virus originated,[4][172] analyses in scientific journals have suggested that the H1N1 strain responsible for the 2009 outbreak first evolved in September 2008 and circulated amongst humans for several months, before being formally recognised and identified as a novel strain of influenza.[4][5] ### Mexico[edit] Further information: 2009 swine flu pandemic in Mexico The virus was first reported in two U.S. children in March 2009, but health officials have reported that it apparently infected people as early as January 2009 in Mexico.[6] The outbreak was first identified in Mexico City on 18 March 2009;[173] immediately after the outbreak was officially announced, Mexico notified the U.S. and World Health Organization, and within days of the outbreak Mexico City was "effectively shut down".[174] Some countries cancelled flights to Mexico while others halted trade. Calls to close the border to contain the spread were rejected.[174] Mexico already had hundreds of non-lethal cases before the outbreak was officially discovered, and was therefore in the midst of a "silent epidemic". As a result, Mexico was reporting only the most serious cases which showed more severe signs different from those of normal flu, possibly leading to a skewed initial estimate of the case fatality rate.[173] ### United States[edit] Further information: 2009 swine flu pandemic in the United States President Obama at Homeland Security Council meeting in Cabinet Room to discuss the H1N1 flu on May 1, 2009 The new strain was first identified by the CDC in two children, neither of whom had been in contact with pigs. The first case, from San Diego County, California, was confirmed from clinical specimens (nasopharyngeal swab) examined by the CDC on 14 April 2009. A second case, from nearby Imperial County, California, was confirmed on 17 April. The patient in the first confirmed case had flu symptoms including fever and cough upon clinical examination on 30 March and the second on 28 March.[175] The first confirmed H1N1/09 pandemic flu death, which occurred at Texas Children's Hospital in Houston, Texas, was of a toddler from Mexico City who was visiting family in Brownsville, Texas, before being air-lifted to Houston for treatment.[176] The Infectious Diseases Society of America estimated that the total number of deaths in the U.S. was 12,469.[177] ### Data reporting and accuracy[edit] See also: GISAID, National Influenza Centers, Disease surveillance, and Clinical surveillance Influenza surveillance information "answers the questions of where, when, and what influenza viruses are circulating. Sharing of such information is especially crucial during an emergent pandemic as in April 2009, when the genetic sequences of the initial viruses were rapidly and openly shared via the GISAID Initiative within days of identification,[178] playing a key role in facilitating an early response to the evolving pandemic.[179][180][181] Surveillance is used to determine if influenza activity is increasing or decreasing, but cannot be used to ascertain how many people have become ill with influenza."[182] For example, as of late June, influenza surveillance information showed the U.S. had nearly 28,000 laboratory-confirmed cases including 3,065 hospitalizations and 127 deaths. But mathematical modelling showed an estimated 1 million Americans had the 2009 pandemic flu at the time, according to Lyn Finelli, a flu surveillance official with the CDC.[183] Estimating deaths from influenza is also a complicated process. In 2005, influenza only appeared on the death certificates of 1,812 people in the US. The average annual US death toll from flu is, however, estimated to be 36,000.[184] The CDC explains:[185] "[I]nfluenza is infrequently listed on death certificates of people who die from flu-related complications" and hence, "Only counting deaths where influenza was included on a death certificate would be a gross underestimation of influenza's true impact." Influenza surveillance information on the 2009 H1N1 flu pandemic is available, but almost no studies attempted to estimate the total number of deaths attributable to H1N1 flu. Two studies were carried out by the CDC; the later of them estimated that between 7,070 and 13,930 deaths were attributable to H1N1 flu from April to 14 November 2009.[186] During the same period, 1,642 deaths were officially confirmed as caused by H1N1 flu.[187][188] The WHO stated in 2010 that total mortality (including unconfirmed or unreported deaths) from H1N1 flu was "unquestionably higher" than their own confirmed death statistics.[189] The initial outbreak received a week of near-constant media attention. Epidemiologists cautioned that the number of cases reported in the early days of an outbreak can be very inaccurate and deceptive, due to several causes, among them selection bias, media bias and incorrect reporting by governments. Inaccuracies could also be caused by authorities in different countries looking at differing population groups. Furthermore, countries with poor health care systems and older laboratory facilities may take longer to identify or report cases.[190] "[E]ven in developed countries the [numbers of flu deaths] are uncertain, because medical authorities don't usually verify who actually died of influenza and who died of a flu-like illness".[191] Joseph S. Bresee, then CDC flu division's epidemiology chief and Michael Osterholm, director of the Center for Infectious Disease Research and Policy pointed out that millions of people have had H1N1 flu, usually in a mild form, so the numbers of laboratory-confirmed cases were actually meaningless, and in July 2009, the WHO stopped keeping count of individual cases and focused more on major outbreaks.[192] ### Follow-up[edit] A Wisconsin study published in the Journal of the American Medical Association in September 2010, reported that findings showed that the 2009 H1N1 flu was no more severe than the seasonal flu. "The risk of most serious complications was not elevated in adults or children", the study's authors wrote. "Children were disproportionately affected by 2009 H1N1 infection, but the perceived severity of symptoms and risk of serious outcomes were not increased." Children infected in the 2009 H1N1 flu pandemic were no more likely to be hospitalized with complications or get pneumonia than those who catch seasonal strains. About 1.5% of children with the H1N1 swine flu strain were hospitalized within 30 days, compared with 3.7% of those sick with a seasonal strain of H1N1 and 3.1% with an H3N2 virus.[193] CDC illness and death estimates from April 2009 to April 2010, in the US are as follows: * between 43 million and 89 million cases of 2009 H1N1 occurred between April 2009 and 10 April 2010. The mid-level in this range is about 61 million people infected with 2009 H1N1. * between about 195,000 and 403,000 H1N1-related hospitalizations occurred between April 2009 and 10 April 2010. The mid-level in this range is about 274,000 2009 H1N1-related hospitalizations. * between about 8,870 and 18,300 2009 H1N1-related deaths occurred between April 2009 and 10 April 2010. The mid-level in this range is about 12,470 2009 H1N1-related deaths.[194][195][196] It has been stated that about 36,000 die from the seasonal flu in the U.S. each year,[197] and this is frequently understood as an indication that the H1N1 strain was not as severe as seasonal influenza. The 36,000 estimate was presented in a 2003 study by CDC scientists and refers to a period from 1990 to 1991 through 1998–99. During those years, the number of estimated deaths ranged from 17,000 to 52,000, with an average of about 36,000. Throughout that decade, influenza A (H3N2) was the predominant virus during most of the seasons, and H3N2 influenza viruses are typically associated with higher death rates. The JAMA study also looked at seasonal influenza-associated deaths over a 23-year period, from 1976 to 1977 and 1998–99 with estimates of respiratory and circulatory influenza-associated deaths ranging from about 5,000 to about 52,000, and an average of about 25,000. CDC believes that the range of deaths over the past 31 years (~3,000 to ~49,000) is a more accurate representation of the unpredictability and variability of flu-associated deaths.[198] The annual toll from seasonal influenza in the US between 1979 and 2001 is estimated at 41,400 deaths on average.[199] Therefore, the H1N1 pandemic estimated mortality of 8,870 to 18,300 is just below the mid-range of estimates.[200] The 2009 pandemic caused US hospitals to make significant preparations in terms of hospital surge capacities, especially within the emergency department and among vulnerable populations. In many cases, hospitals were relatively successful in making sure that those patients most severely affected by the influenza strain were able to be seen, treated, and discharged in an efficient manner. A case-study of the preparation, planning, mitigation, and response efforts during the fall of 2009 is that of the Children's Hospital of Philadelphia (CHOP) which took several steps to increase the emergency department (ED) surge capacity response. CHOP used portions of the main lobby area as an ED waiting room; several of the region's hospital-based outpatient facilities were in use during evening and weekend hours for non-emergency cases; the ED's 24-hour short-stay unit was utilized to care for ED patients in a longer-term capacity; non-board certified physicians (in pediatric emergency medicine) and inpatient-unit medical nurses were utilized for ED patient care; hospital units normally utilized for other medical or therapeutic purposes were transformed into ED patient rooms; and rooms normally used for only one patient were expanded to at least a capacity of 2.[201] ## Comparisons to other pandemics and epidemics[edit] Annual influenza epidemics are estimated to affect 5–15% of the global population. Although most cases are mild, these epidemics still cause severe illness in 3–5 million people and 290,000–650,000 deaths worldwide every year.[202] On average 41,400 people die of influenza-related illnesses each year in the United States, based on data collected between 1979 and 2001.[199] In industrialised countries, severe illness and deaths occur mainly in the high-risk populations of infants, the elderly and chronically ill patients,[202] although the H1N1 flu outbreak (like the 1918 Spanish flu) differs in its tendency to affect younger, healthier people.[203] In addition to these annual epidemics, Influenza A virus strains caused three global pandemics during the 20th century: the Spanish flu in 1918, Asian flu in 1957, and Hong Kong flu in 1968–69. These virus strains had undergone major genetic changes for which the population did not possess significant immunity.[204] Recent genetic analysis has revealed that three-quarters, or six out of the eight genetic segments, of the 2009 flu pandemic strain arose from the North American swine flu strains circulating since 1998, when a new strain was first identified on a factory farm in North Carolina, and which was the first-ever reported triple-hybrid flu virus.[205] The Spanish flu began with a wave of mild cases in the spring, followed by more deadly waves in the autumn, eventually killing hundreds of thousands in the United States and 50–100 million worldwide.[206] The great majority of deaths in the 1918 flu pandemic were the result of secondary bacterial pneumonia. The influenza virus damaged the lining of the bronchial tubes and lungs of victims, allowing common bacteria from the nose and throat to infect their lungs. Subsequent pandemics have had many fewer fatalities due to the development of antibiotic medicines which can treat pneumonia.[207] Major modern influenza pandemics[208][209] Name Date World pop. Subtype Reproduction number[210] Infected (est.) Deaths worldwide Case fatality rate Pandemic severity 1889–90 flu pandemic[211] 1889–90 1.53 billion Likely H3N8 or H2N2 2.10 (IQR, 1.9–2.4)[211] 20–60%[211] (300–900 million) 1 million 0.10–0.28%[211] 2 1918 flu[212] 1918–20 1.80 billion H1N1 1.80 (IQR, 1.47–2.27) 33% (500 million)[213] or >56% (>1 billion)[214] 17[215]–100[216][217] million 2–3%,[214] or ~4%, or ~10%[218] 5 Asian flu 1957–58 2.90 billion H2N2 1.65 (IQR, 1.53–1.70) >17% (>500 million)[214] 1–4 million[214] <0.2%[214] 2 Hong Kong flu 1968–69 3.53 billion H3N2 1.80 (IQR, 1.56–1.85) >14% (>500 million)[214] 1–4 million[214] <0.1%[214][219] 2 2009 flu pandemic[220][221] 2009–10 6.85 billion H1N1/09 1.46 (IQR, 1.30–1.70) 11–21% (0.7–1.4 billion)[222] 151,700–575,400[223] 0.01%[224][225] 1 Typical seasonal flu[t 1] Every year 7.75 billion A/H3N2, A/H1N1, B, ... 1.28 (IQR, 1.19–1.37) 5–15% (340 million – 1 billion)[226] 3–11% or 5–20%[227][228] (240 million – 1.6 billion) 290,000–650,000/year[229] <0.1%[230] 1 Notes 1. ^ Not pandemic, but included for comparison purposes. The influenza virus has caused several pandemic threats over the past century, including the pseudo-pandemic of 1947 (thought of as mild because although globally distributed, it caused relatively few deaths),[204] the 1976 swine flu outbreak and the 1977 Russian flu, all caused by the H1N1 subtype.[204] The world has been at an increased level of alert since the SARS epidemic in Southeast Asia (caused by the SARS coronavirus).[231] The level of preparedness was further increased and sustained with the advent of the H5N1 bird flu outbreaks because of H5N1's high fatality rate, although the strains currently prevalent have limited human-to-human transmission (anthroponotic) capability, or epidemicity.[232] People who contracted influenza before 1957 appeared to have some immunity to H1N1 flu. According to Daniel Jernigan, head of flu epidemiology for the U.S. CDC "Tests on blood serum from older people showed that they had antibodies that attacked the new virus ... That does not mean that everyone over 52 is immune, since Americans and Mexicans older than that have died of the new flu".[233] In June 2012, a model based study found that the number of deaths related to the H1N1 influenza may have been fifteen times higher than the reported laboratory confirmed deaths, with 80% of the respiratory and cardiovascular deaths in people younger than 65 years and 51% occurring in southeast Asia and Africa. A disproportionate number of pandemic deaths might have occurred in these regions and that efforts to prevent future influenza pandemics need to effectively target these regions.[234] A WHO-supported 2013 study estimated that the 2009 global pandemic respiratory mortality was ~10-fold higher than the World Health Organization's laboratory-confirmed mortality count (18.631). Although the pandemic mortality estimate was similar in magnitude to that of seasonal influenza, a marked shift toward mortality among persons less than 65 years of age occurred, so that many more life-years were lost. Between 123,000 and 203,000 pandemic respiratory deaths were estimated globally for the last nine months of 2009. The majority (62–85%) were attributed to persons under 65 years of age. The burden varied greatly among countries. There was an almost 20-fold higher mortality in some countries in the Americas than in Europe. The model attributed 148,000–249,000 respiratory deaths to influenza in an average pre-pandemic season, with only 19% in persons <65 years of age.[235] The current pandemic of coronavirus disease 2019 (COVID-19) is not caused by an influenza virus but SARS-CoV-2, a coronavirus which also primarily affects the respiratory system. 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Ithaca; London: Cornell University Press. ISBN 978-0-8014-7983-0. * Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, et al. (June 2009). "Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic". Nature. 459 (7250): 1122–25. Bibcode:2009Natur.459.1122S. doi:10.1038/nature08182. PMID 19516283. * Soundararajan V, Tharakaraman K, Raman R, Raguram S, Shriver Z, Sasisekharan V, Sasisekharan R (June 2009). "Extrapolating from sequence – the 2009 H1N1 'swine' influenza virus". Nature Biotechnology. 27 (6): 510–13. doi:10.1038/nbt0609-510. PMID 19513050. S2CID 22710439. * Centers for Disease Control Prevention (CDC) (October 2009). "Introduction and transmission of 2009 pandemic influenza A (H1N1) Virus – Kenya, June–July 2009". MMWR. Morbidity and Mortality Weekly Report. 58 (41): 1143–46. PMID 19847148. Archived from the original on 13 May 2011. ## External links[edit] Wikinews has news related to: Swine flu * Influenza: H1N1 at Curlie * Pandemic (H1N1) 2009 at the World Health Organization (WHO) * International Society for Infectious Diseases PROMED-mail news updates * H1N1 Flu Resource Centre of The Lancet * Novel H1N1 Influenza (Swine Flu) Overview from CIDRAP * Influenza Research Database * CDC 2009 H1N1 Influenza Vaccine Supply Status * The H1N1 Pandemic and Global Health Security, Dean Julio Frenk, 2009-09-17 * Health-EU Portal EU response to influenza * 2009 influenza A (H1N1) pandemic. European Centre for Disease Prevention and Control (ECDC). * Summaries of the pandemic. 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δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	2009 swine flu pandemic	None	5,583	wikipedia	https://en.wikipedia.org/wiki/2009_swine_flu_pandemic	2021-01-18T18:30:19	{"wikidata": ["Q101452"]}
Condition of markedly elevated blood pressure with diastolic pressure typically greater than 120 mm Hg Hypertensive emergency Other namesMalignant hypertension, hypertensive crises CT scan depicting intracranial hemorrhage, a possible complication of hypertensive emergency. Patients with spontaneous intracranial hemorrhage present with newfound headache and neurologic deficits. SpecialtyCardiology A hypertensive emergency is high blood pressure with potentially life-threatening symptoms and signs indicative of acute impairment of one or more organ systems (brain, eyes, heart, aorta, or kidneys).[1] Hypertensive urgency is defined as having a systolic blood pressure over 180 mmHg or a diastolic blood pressure over 110 mmHg. Hypertensive emergency is defined as elevated blood pressure consistent with hypertensive urgency, plus evidence of impending irreversible hypertension-mediated organ damage (HMOD). Signs of organ damage will be discussed below. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Fundoscopic view of an eye with diabetic retinopathy. Similar to hypertensive retinopathy, evidence of nerve fiber infarcts due to ischemia (cotton-wool spots) can be seen on physical exam. Symptoms may include headache, nausea, or vomiting. Chest pain may occur due to increased workload on the heart resulting in inadequate delivery of oxygen to meet the heart muscle's metabolic needs. The kidneys may be affected, resulting in blood or protein in the urine, and acute kidney failure. People can have decreased urine production, fluid retention, and confusion. Other signs and symptoms can include: * Chest pain * Abnormal heart rhythms * Headache * Nosebleeds that are difficult to stop * Dyspnea * Fainting or the sensation of the world spinning around them (vertigo) * Severe anxiety * Agitation * Altered mental status * Abnormal sensations The most common presentations of hypertensive emergencies are cerebral infarction (24.5%), pulmonary edema (22.5%), hypertensive encephalopathy (16.3%), and congestive heart failure (12%).[2] Less common presentations include intracranial bleeding, aortic dissection, and pre-eclampsia or eclampsia.[3] Massive, rapid elevations in blood pressure can trigger any of these symptoms, and warrant further work-up by physicians. Physical exam findings would be performed to be measurement of blood pressure in both arms. Laboratory tests to be conducted include urine toxicology, blood glucose, a basic metabolic panel evaluating kidney function, or a complete metabolic panel evaluating liver function, EKG, chest x-rays, and pregnancy screening.[4] The eyes may show bleeding in the retina, an exudate, cotton-wool spots, scattered splinter hemorrhages, or swelling of the optic disc called papilledema. ## Causes[edit] Many factors and causes are contributory in hypertensive crises. The most common cause is patients with diagnosed, chronic hypertension who have discontinued anti hypertensive medications.[5] Other common causes of hypertensive crises are autonomic hyperactivity such as pheochromocytoma, collagen-vascular diseases, drug use particularly stimulants, cocaine and amphetamines and their substituted analogues, monoamine oxidase inhibitors or food-drug interactions, spinal cord disorders, glomerulonephritis, head trauma, neoplasias, preeclampsia and eclampsia, hyperthyroidism and renovascular hypertension.[4][5] People withdrawing from medications such as clonidine or beta-blockers have been frequently found to develop hypertensive crises.[6] It is important to note that these conditions exist outside of hypertensive emergency, in that patients diagnosed with these conditions are at increased risk of hypertensive emergencies or end organ failure. ## Pathophysiology[edit] Kidney Biopsy showing thrombotic microangiopathy, a histomorphologic finding seen in malignant hypertension The pathophysiology of hypertensive emergency is not well understood. Failure of normal autoregulation and an abrupt rise in systemic vascular resistance are typical initial components of the disease process.[3] Hypertensive emergency pathophysiology includes: * Abrupt increase in systemic vascular resistance, likely related to humoral vasoconstrictors * Endothelial injury and dysfunction * Fibrinoid necrosis of the arterioles * Deposition of platelets and fibrin * Breakdown of normal autoregulatory function The resulting ischemia prompts further release of vasoactive substances including prostaglandins, free radicals, and thrombotic/mitotic growth factors, completing a vicious cycle of inflammatory changes.[3] If the process is not stopped, homeostatic failure begins, leading to loss of cerebral and local autoregulation, organ system ischemia and dysfunction, and myocardial infarction. Single-organ involvement is found in approximately 83% of hypertensive emergency patients, two-organ involvement in about 14% of patients, and multi-organ failure (failure of at least 3 organ systems) in about 3% of patients. In the brain, hypertensive encephalopathy \- characterized by hypertension, altered mental status, and swelling of the optic disc \- is a manifestation of the dysfunction of cerebral autoregulation. Cerebral autoregulation is the ability of the blood vessels in the brain to maintain a constant blood flow. People who suffer from chronic hypertension can tolerate higher arterial pressure before their autoregulation system is disrupted. Hypertensives also have an increased cerebrovascular resistance which puts them at greater risk of developing cerebral ischemia if the blood flow decreases into a normotensive range. On the other hand, sudden or rapid rises in blood pressure may cause hyperperfusion and increased cerebral blood flow, causing increased intracranial pressure and cerebral edema, with increased risk of intracranial bleeding.[4] In the heart, increased arterial stiffness, increased systolic blood pressure, and widened pulse pressures, all resulting from chronic hypertension, can cause significant damage. Coronary perfusion pressures are decreased by these factors, which also increase myocardial oxygen consumption, possibly leading to left ventricular hypertrophy. As the left ventricle becomes unable to compensate for an acute rise in systemic vascular resistance, left ventricular failure and pulmonary edema or myocardial ischemia may occur.[3] In the kidneys, chronic hypertension has a great impact on the kidney vasculature, leading to pathologic changes in the small arteries of the kidney. Affected arteries develop endothelial dysfunction and impairment of normal vasodilation, which alter kidney autoregulation. When the kidneys' autoregulatory system is disrupted, the intraglomerular pressure starts to vary directly with the systemic arterial pressure, thus offering no protection to the kidney during blood pressure fluctuations. The renin-aldosterone-angiotensin system can be activated, leading to further vasoconstriction and damage. During a hypertensive crisis, this can lead to acute kidney ischemia, with hypoperfusion, involvement of other organs, and subsequent dysfunction. After an acute event, this endothelial dysfunction has persisted for years.[3] ## Diagnosis[edit] The term hypertensive emergency is primarily used as a specific term for a hypertensive crisis with a diastolic blood pressure greater than or equal to 120 mmHg or systolic blood pressure greater than or equal to 180 mmHg.[7] Hypertensive emergency differs from hypertensive urgency in that, in the former, there is evidence of acute organ damage.[7] Both of these definitions had collectively been known as malignant hypertension, although this medical term is replaced. In the pregnant patient, the definition of hypertensive emergency (likely secondary to pre-eclampsia or eclampsia) is only a blood pressure exceeding 160 mmHg systolic blood pressure or 110 mmHg diastolic blood pressure.[8] ## Treatment[edit] In a hypertensive emergency, treatment should first be to stabilize the patient's airway, breathing, and circulation per ACLS guidelines. Patients should have their blood pressure slowly lowered over a period of minutes to hours with an antihypertensive agent. Documented goals for blood pressure include a reduction in the mean arterial pressure by less than or equal to 25% within the first 8 hours of emergency.[4] If blood pressure is lowered aggressively, patients are at increased risk of complications including stroke, blindness, or kidney failure.[3] Several classes of anti hypertensive agents are recommended, with the choice depending on the cause of the hypertensive crisis, the severity of the elevation in blood pressure, and the patient's baseline blood pressure prior to a hypertensive emergency. Physicians will attempt to identify a cause of the patient's hypertension, including chest radiograph, serum laboratory studies evaluating kidney function, urinalysis, as that will alter the treatment approach for a more patient-directed regimen. Hypertensive emergencies differ from hypertensive urgency in that they are treated parenterally, whereas in urgency it is recommended to use oral anti hypertensives to reduce the risk of hypotensive complications or ischemia.[3] Parenteral agents are classified into beta-blockers, calcium channel blockers, systemic vasodilators, or other (fenoldopam, phentolamine, clonidine). Medications include Labetalol, Nicardipine, Hydralazine, Sodium nitroprusside, Esmolol, Nifedipine, Minoxidil, Isradipine, and Clonidine. These medications work through a variety of mechanisms. Labetalol is a beta-blocker with mild alpha antagonism, decreasing the ability of catecholamine activity to increase systemic vascular resistance, while also decreasing heart rate and myocardial oxygen demand. Nicardipine, Nifedipine, and Isradipine are calcium channel blockers that work to decrease systemic vascular resistance and subsequently lower blood pressure. Hydralazine and Sodium nitroprusside are systemic vasodilators, thereby reducing afterload, however can be found to have reflex tachycardia, making them likely second or third line choices. Sodium nitroprusside was previously the first-line choice due to its rapid onset, although now it is less commonly used due to side effects, drastic drops in blood pressure, and cyanide toxicity. Sodium nitroprusside is also contraindicated in patients with myocardial infarction, due to coronary steal.[6] It is again important that the blood pressure is lowered slowly. The initial goal in hypertensive emergencies is to reduce the pressure by no more than 25% the mean arterial pressure. Excessive reduction in blood pressure can precipitate coronary, cerebral, or kidney ischemia and, possibly, infarction. A hypertensive emergency is not based solely on an absolute level of blood pressure, but also on a patient's baseline blood pressure before the hypertensive crisis occurs. Individuals with a history of chronic hypertension may not tolerate a "normal" blood pressure, and can therefore present symptomatically with hypotension, including fatigue, light-headedness, nausea, vomiting, or syncope. Blood pressure targets[4] <1 hr 25% reduction in the mean arterial pressure, diastolic blood pressure above 100 2-6 hr Systolic BP < 160 mmHg or Diastolic BP <110 mmHg 6-24 hr monitor BP targets, ensure non-rapid drop in BPs below 160 SBP or 100 DBP 1-2 d if no end-organ damage, monitor out-patient and JNC8 Guidelines for maintaining BP control ## Prognosis[edit] Severe hypertension is a serious and potentially life-threatening medical condition. It is estimated that people who do not receive appropriate treatment only live an average of about three years after the event.[8] The morbidity and mortality of hypertensive emergencies depend on the extent of end-organ dysfunction at the time of presentation and the degree to which blood pressure is controlled afterward. With good blood pressure control and medication compliance, the 10-year survival rate of patients with hypertensive crises approaches 70%.[1] The risks of developing a life-threatening disease affecting the heart or brain increase as the blood flow increases. Commonly, ischemic heart attack and stroke are the causes that lead to death in patients with severe hypertension. It is estimated that for every 20 mm Hg systolic or 10 mm Hg diastolic increase in blood pressures above 115/75 mm Hg, the mortality rate for both ischemic heart disease and stroke doubles. Consequences of hypertensive emergency result after prolonged elevations in blood pressure and associated end-organ dysfunction. Acute end-organ damage may occur, affecting the neurological, cardiovascular, kidney, or other organ systems. Some examples of neurological damage include hypertensive encephalopathy, cerebral vascular accident/cerebral infarction, subarachnoid hemorrhage, and intracranial bleeding. Cardiovascular system damage can include myocardial ischemia/infarction, acute left ventricular dysfunction, acute pulmonary edema, and aortic dissection. Other end-organ damage can include acute kidney failure or insufficiency, retinopathy, eclampsia, and microangiopathic hemolytic anemia. ## Epidemiology[edit] In 2000, it was estimated that approximately 1 billion people worldwide have hypertension, making it the most prevalent condition in the world.[2] Approximately 60 million Americans suffer from chronic hypertension, with 1% of these individuals having an episode of hypertensive urgency. In emergency departments and clinics around the U.S., the prevalence of hypertensive urgency is suspected to be between 3-5%.[6] 25% of hypertensive crises have been found to be hypertensive emergency versus urgency when presenting to the ER.[8] Risk factors for hypertensive emergency include age, obesity, noncompliance to anti hypertensive medications, female sex, Caucasian race, preexisting diabetes or coronary artery disease, mental illness, and sedentary lifestyle.[2] Several studies have concluded that African Americans have a greater incidence of hypertension and a greater morbidity and mortality from hypertensive disease than non-Hispanic whites, however hypertensive crises have a greater incidence in Caucasians.[9] Although severe hypertension is more common in the elderly, it may occur in children (though very rarely), likely due to metabolic or hormonal dysfunction. In 2014, a systematic review identified women as having slightly higher increased risks of developing hypertensive crises than do men.[2] With the usage of anti hypertensives, the rates of hypertensive emergencies has declined from 7% to 1% of patients with hypertensive urgency.[2] 16% of patients presenting with hypertensive emergency can have no known history of hypertension.[3] ## See also[edit] * Hypertensive retinopathy * Hypertensive encephalopathy * Preeclampsia * Eclampsia * Aortic dissection * Intracranial hemorrhage ## References[edit] 1. ^ a b Thomas L (October 2011). "Managing hypertensive emergencies in the ED". Canadian Family Physician. 57 (10): 1137–97. PMC 3192077. PMID 21998228. 2. ^ a b c d e Pak KJ, Hu T, Fee C, Wang R, Smith M, Bazzano LA (2014). "Acute hypertension: a systematic review and appraisal of guidelines". The Ochsner Journal. 14 (4): 655–63. PMC 4295743. PMID 25598731. "A summary of recommendations from the selected guidelines is presented in Table 2." 3. ^ a b c d e f g h Cline, David M.; John Ma, O.; Meckler, Garth D.; Tintinalli, Judith E.; Stephan Stapczynski, J.; Yealy, Donald (2015-11-10). Tintinalli's emergency medicine : a comprehensive study guide. Tintinalli, Judith E.,, Stapczynski, J. Stephan,, Ma, O. John,, Yealy, Donald M.,, Meckler, Garth D.,, Cline, David, 1956- (Eighth ed.). New York. ISBN 9780071794763. OCLC 915775025. 4. ^ a b c d e Larry Jameson, J.; Fauci, Anthony S.; Kasper, Dennis L.; Hauser, Stephen L.; Longo, Dan L.; Loscalzo, Joseph (2018-08-13). Harrison's principles of internal medicine. Jameson, J. Larry,, Kasper, Dennis L.,, Longo, Dan L. (Dan Louis), 1949-, Fauci, Anthony S., 1940-, Hauser, Stephen L.,, Loscalzo, Joseph (20th ed.). New York. ISBN 9781259644030. OCLC 1029074059. 5. ^ a b Saguner AM, Dür S, Perrig M, Schiemann U, Stuck AE, Bürgi U, Erne P, Schoenenberger AW (July 2010). "Risk factors promoting hypertensive crises: evidence from a longitudinal study". American Journal of Hypertension. 23 (7): 775–80. doi:10.1038/ajh.2010.71. PMID 20395943. 6. ^ a b c Campos CL, Herring CT, Ali AN, Jones DN, Wofford JL, Caine AL, Bloomfield RL, Tillett J, Oles KS (April 2018). "Pharmacologic Treatment of Hypertensive Urgency in the Outpatient Setting: A Systematic Review". Journal of General Internal Medicine. 33 (4): 539–550. doi:10.1007/s11606-017-4277-6. PMC 5880769. PMID 29340938. 7. ^ a b Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, et al. (June 2018). "2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Hypertension. 71 (6): e13–e115. doi:10.1161/HYP.0000000000000065. PMID 29133356. 8. ^ a b c Walls, Ron; Hockberger, Robert; Gausche-Hill, Marianne (2017-03-09). Rosen's emergency medicine : concepts and clinical practice. Walls, Ron M.,, Hockberger, Robert S.,, Gausche-Hill, Marianne (Ninth ed.). Philadelphia, PA. ISBN 9780323390163. OCLC 989157341. 9. ^ Howard J (1965). "Race Differences in Hypertension Mortality Trends: Differential Drug Exposure as a Theory". Systemic Hypertension. Milbank Mem Fund Q. 43 (2): 202–218. JSTOR 3349030. PMID 14283119. ## External links[edit] Classification D * ICD-10: I10 * ICD-9-CM: 401-405 * MeSH: D006974 * DiseasesDB: 7788 External resources * MedlinePlus: 000491 * eMedicine: article/241640 * Patient UK: Hypertensive emergency * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Hypertensive emergency	c0020540	5,584	wikipedia	https://en.wikipedia.org/wiki/Hypertensive_emergency	2021-01-18T18:49:05	{"mesh": ["D006974"], "umls": ["C0020540"], "icd-9": ["401", "405"], "icd-10": ["I16.1"], "wikidata": ["Q1641132"]}
Tibial plateau fracture Other namesFractures of the tibial plateau A severe tibial plateau fracture with an associated fibular head fracture SpecialtyOrthopedics SymptomsPain, swelling, decreased ability to move the knee[1] ComplicationsInjury to the artery or nerve, compartment syndrome[1] TypesType I to Type VI[2] CausesTrauma (fall, motor vehicle collision)[1] Risk factorsOsteoporosis, skiing[2] Diagnostic methodSuspected based on symptoms, confirmed with X-rays and CT scan[1] Differential diagnosisPatella fracture, fibular fracture, anterior cruciate ligament injury[2] TreatmentSurgery, splinting[1][2] MedicationNSAIDs, opioids[1][2] PrognosisArthritis is common[2] Frequency~1% of fractures[2] A tibial plateau fracture is a break of the upper part of the tibia (shinbone) that involves the knee joint.[1] Symptoms include pain, swelling, and a decreased ability to move the knee.[1] People are generally unable to walk.[2] Complication may include injury to the artery or nerve, arthritis, and compartment syndrome.[1] The cause is typically trauma such as a fall or motor vehicle collision.[1] Risk factors include osteoporosis and certain sports such as skiing.[2] Diagnosis is typically suspected based on symptoms and confirmed with X-rays and a CT scan.[1] Some fractures may not be seen on plain X-rays.[2] Pain may be managed with NSAIDs, opioids, and splinting.[1][2] In those who are otherwise healthy, treatment is generally by surgery.[1] Occasionally, if the bones are well aligned and the ligaments of the knee are intact, people may be treated without surgery.[2] They represent about 1% of broken bones.[2] They occur most commonly in middle aged males and older females.[3] In the 1920s they were called a "fender fracture" due to their association with people being hit by a motor vehicle while walking.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Mechanism * 4 Diagnosis * 4.1 Classification * 5 Treatment * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Tibial plateau fractures typically presents with knee effusion, swelling of the knee soft tissues and inability to bear weight. The knee may be deformed due to displacement and/or fragmentation of the tibia which leads to loss of its normal structural appearance. Blood in the soft tissues and knee joint (hemarthrosis) may lead to bruising and a doughy feel of the knee joint. Due to the tibial plateau's proximity to important vascular (i.e. arteries, veins) and neurological (i.e. nerves such as peroneal and tibial) structures, injuries to these may occur upon fracture. A careful examination of the neurovascular systems is imperative. A serious complication of tibial plateau fractures is compartment syndrome in which swelling causes compression of the nerves and blood vessels inside the leg and may ultimately lead to necrosis or cell death of the leg tissues.[citation needed] ## Cause[edit] Tibial plateau fractures may be divided into low energy or high energy fractures. Low energy fractures are commonly seen in older females due to osteoporotic bone changes and are typically depressed fractures. High energy fractures are commonly the result of motor vehicle accidents, falls or sports related injuries. These causes constitute the majority of tibial plateau fractures in young individuals.[citation needed] ## Mechanism[edit] Fractures of the tibial plateau are caused by a varus (inwardly angulating) or valgus (outwardly angulating) force combined with axial loading or weight bearing on knee. The classically described situation in which this occurs is from a car striking a pedestrian's fixed knee ("bumper fracture"). However most of these fractures occur from motor vehicle accidents or falls. Injury can be due to a fall from height in which knee forced into valgus or varus. The tibial condyle is crushed or split by the opposing femoral condyle, which remains intact. The knee anatomy provides insight into predicting why certain fracture patterns occur more often than others. The medial plateau is larger and significantly stronger than the lateral pleateau. Also, there is a natural valgus or outward angulation alignment to the limb which coupled with the often valgus or outwardly angulating force on impact will injure the lateral side. This explains how 60% of plateau fractures involve the lateral pleateau, 15% medial plateau, 25% bicondylar lesions. Partial or complete ligamentous ruptures occur in 15-45%, meniscal lesions in about 5-37% of all tibial plateau fractures.[4] ## Diagnosis[edit] In all injuries to the tibial plateau radiographs (commonly called x-rays) are imperative. Computed tomography scans are not always necessary but are sometimes critical for evaluating degree of fracture and determining a treatment plan that would not be possible with plain radiographs.[5] Magnetic Resonance images are the diagnositic modality of choice when meniscal, ligamentous and soft tissue injuries are suspected.[6][7] CT angiography should be considered if there is alteration of the distal pulses or concern about arterial injury. * Lipohemarthrosis (presence of fat and blood from bone marrow in the joint space after an intraarticular fracture) seen on X-ray in a person with a subtle tibial plateau fracture * Lipohemarthrosis due to a tibial plateau fracture * 3D reconstruction of a CT image of a tibial plateau fracture * Subtle tibial plateau fracture on an AP X ray of the knee * Lipohemarthrosis due to a tibial plateau fracture * A tibial plateau fracture seen on X-ray ### Classification[edit] Physicians use classification types to assess the degree of injury, treatment plan and predict prognosis. Multiple classifications of tibial plateau fractures have been developed. Currently, the Schatzker classification system is the most widely accepted and used.[6] It is composed of six condyle fracture types classified by fracture pattern and fragment anatomy.[8] Each increasing numeric fracture type denotes increasing severity. The severity correlates with the amount of energy imparted to the bone at the time of injury and prognosis. Schatzker classification for tibial plateau fracture:[citation needed] * Type I = Lateral Tibial plateau fracture without depression. This is a wedge-shaped pure cleavage fracture and involves a vertical split of the lateral tibial plateau. It is usually the result of a low energy injury in young individuals with normal mineralization. May be caused by a valgus force combined with axial loading that leads to the lateral femoral condyle being driven into the articular surface of the tibial plateau. Represent 6% of all tibial plateau fractures. * Type II = Lateral tibial plateau fracture with depression, This is a combined cleavage and compression fracture and involves vertical split of the lateral condyle combined with depression of the adjacent load bearing part of the condyle. Caused by a valgus force on the knee; it is a low energy injury, typically seen in individuals of the 4th decade or older with osteoporotic changes in bone. Most common, and make up 75% of all tibial plateau fractures. There is a 20% risk of distraction injuries to the medial collateral ligament. May include distraction injury to the medial collateral ligament or anterior cruciate ligament. * Type III: Focal depression of articular surface with no associated split. This is a pure compression fracture of the lateral or central tibial plateau in which the articular surface of the tibial plateau is depressed and driven into the lateral tibial mataphysis by axial forces.3 A low energy injury, these fractures are more frequent in the 4th and 5th decades of life and individuals with osteoporotic changes in bone. They are extremely rare. Can be further divided into two subtypes: IIIA Compression Fracture of the lateral tibial plateau IIIB Compression Fracture of the central tibial plateau May result in joint instability. * Type IV = Medial tibial plateau fracture, with or without depression; may involve tibial spines; associated soft tissue injuries. This is a medial tibial plateau fracture with a split or depressed component. It is usually the result of a high energy injury and involves a varus force with axial loading at the knee. Represent 10% of all tibial plateau fractures. There is high risk of damage to the popliteal artery and peroneal nerve and therefore carry a worse prognosis. May include distraction injuries to lateral collateral ligament, fibular dislocation/fracture, posterolateral corner. * Type V = Bicondylar tibial plateau fracture, Consists of a split fracture of the medial and lateral tibial plateau. It is usually the result of a high energy injury with complex varus and valgus forces acting upon the tibial plateau. May include injuries to the anterior cruciate ligament and collateral ligaments. Make up 3% of all tibial plateau fractures. * Type VI = Tibial plateau fracture with diaphyseal discontinuity Main feature of this type of fracture is a transverse subcondylar fracture with dissociation of the metaphysis from the diaphysis. The fracture pattern of the condyles is variable and all types of fractures can occur. This is a high energy injury with a complex mechanism that includes varus and valgus forces. Up to 33% of these fractures may be open, often with extensive soft tissue injuries and risk of compartment syndrome. Represents 20% of all tibial plateau fractures. ## Treatment[edit] Repair of a tibial plateau fracture Pain may be managed with NSAIDs, opioids, and splinting.[1][2] In those who are otherwise healthy, treatment is generally by surgery.[1] Occasionally, if the bones are well aligned and the ligaments of the knee are intact, people may be treated without surgery.[2] The surgery usually involves reducing the fractured fragments of the tibia plateau to their anatomical position and fixing them in place with screws only or fixed angle anatomical plates ensuring absolute stability. Implant selection is based on the type of injury. Generally, simple or incomplete fractures (Schatzker type 1) of the plateau are compressed with 6.5mm partially threaded cancellous screws. Complex type fractures will require a plate for enhanced stability. As the tibia condyles articulate with the femur (thigh bone) to form knee joint, any incongruity in the articular surface is unacceptable as it leads to early arthritis. Prolonged immobilization of the knee joint is also not recommended which result in stiffness of the joint and difficult recovery.[citation needed] ## Epidemiology[edit] Tibial plateau fractures constitute 1% of all fractures. Peak age is 30–40 years old in men and 60-70 in women. Approximately half of the people who sustain a tibial plateau fracture are aged over 50 years old.[9] ## References[edit] 1. ^ a b c d e f g h i j k l m n o "Fractures of the Proximal Tibia (Shinbone)". OrthoInfo - AAOS. Archived from the original on 17 June 2017. Retrieved 15 October 2017. 2. ^ a b c d e f g h i j k l m n o p Bracker, Mark D. (2012). The 5-Minute Sports Medicine Consult. Lippincott Williams & Wilkins. p. 242. ISBN 9781451148121. Archived from the original on 2017-10-15. 3. ^ Karadsheh, Mark. "Tibial Plateau Fractures". www.orthobullets.com. Archived from the original on 28 June 2017. Retrieved 15 October 2017. 4. ^ Clifford R. Wheeless III, MD. Wheeless' Textbook of Orthopaedics. Duke University Medical Center's Division of Orthopedic Surgery. Data Trace Internet Publishing, LLC. Archived from the original on 2008-03-29.CS1 maint: uses authors parameter (link) 5. ^ "K. Markhardt, MD. Schatkzker Classification of Tibial Plateau Fractures: Use of CT and MR Imaging Improves Assessment. Radiographics 2009". Cite journal requires `\|journal=` (help) 6. ^ a b Scuderi G, Tria A (2010). The Knee: A Comprehensive Review. 1 edition. World Scientific Publishing Company. pp. 209–301. 7. ^ Barrow B (1994). "Tibial Plateau Fractures: Evualuation with MR Imaging". Radiographics. 14 (3): 553–9. doi:10.1148/radiographics.14.3.8066271. PMID 8066271. 8. ^ Zeltser D, Leopold S (2013). "Classifications in Brief: Schatzker Classification of Tibial Plateau Fractures". Clinical Orthopaedics and Related Research. 471 (2): 371–374. doi:10.1007/s11999-012-2451-z. PMC 3549155. PMID 22744206. 9. ^ Pires R (2013). "Epidemiological study on tibial plateau fractures at a level I trauma center". Acta Ortop Bras. 21 (2): 109–15. doi:10.1590/S1413-78522013000200008. PMC 3861961. PMID 24453653. ## External links[edit] Classification D * ICD-10: S82.1 External resources * AO Foundation: \- 41-C3 41-B1 - 41-C3 * OrthoInfo: A00393 Wikimedia Commons has media related to Tibial plateau fractures. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Tibial plateau fracture	c0262489	5,585	wikipedia	https://en.wikipedia.org/wiki/Tibial_plateau_fracture	2021-01-18T19:00:04	{"wikidata": ["Q7800447"]}
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Homophobia * Intersex discrimination * Lesbophobia * Migration * Non-binary discrimination * Rhetoric * Sexualism * Transphobia * Violence Academic fields and discourse * Lesbian feminism * Lavender linguistics * Queer studies * Queer theory * Transfeminism LGBT portal * v * t * e Biphobia is aversion toward bisexuality and bisexual people as individuals. It can take the form of denial that bisexuality is a genuine sexual orientation, or of negative stereotypes about people who are bisexual (such as the beliefs that they are promiscuous or dishonest). Other forms of biphobia include bisexual erasure.[1] Specific people of any sexual orientation can experience or perpetuate biphobia. ## Contents * 1 Etymology and usage * 2 Forms * 2.1 Denial and erasure * 2.1.1 Allegations that bisexual men are homophobic * 2.1.2 Claims of bisexuals adapting to heteronormativity * 2.2 Negative stereotypes * 3 Effects * 4 Intersectional perspectives * 4.1 Women's issues * 4.2 Race * 5 See also * 6 References * 7 Further reading * 8 External links ## Etymology and usage[edit] Biphobia is a portmanteau word patterned on the term homophobia. It derives from the English neo-classical prefix bi- (meaning "two") from bisexual and the root -phobia (from the Greek: φόβος, phóbos, "fear") found in homophobia. Along with transphobia and homophobia, it is one of a family of terms used to describe intolerance and discrimination against LGBT people. The adjectival form biphobic describes things or qualities related to biphobia, and the less-common noun biphobe is a label for people thought to harbor biphobia.[2] The term biphobia was first[3][4] introduced in 1992 by researcher Kathleen Bennett to mean "prejudice against bisexuality"[5] and "the denigration of bisexuality as a life-choice."[5] It has subsequently been defined as "any portrayal or discourse denigrating or criticizing men or women on the sole ground of their belonging to this [bisexual] socio-sexual identity, or refusing them the right to claim it."[6] Biphobia need not be a phobia as defined in clinical psychology (i.e., an anxiety disorder). Its meaning and use typically parallel those of xenophobia. ## Forms[edit] ### Denial and erasure[edit] Biphobia can lead people to deny that bisexuality is real, asserting that people who identify as bisexual are not genuinely bisexual, or that the phenomenon is far less common than they claim. One form of this denial is based on the heterosexist view that heterosexuality is the only true or natural sexual orientation. Thus anything that deviates from that is instead either a psychological pathology or an example of anti-social behavior. Another form of denial stems from binary views of sexuality: that people are assumed monosexual, i.e. homosexual (gay/lesbian) or heterosexual (straight). Throughout the 1980s, modern research on sexuality was dominated by the idea that heterosexuality and homosexuality were the only legitimate orientations, dismissing bisexuality as "secondary homosexuality".[7] In that model, bisexuals are presumed to be either closeted lesbian/gay people wishing to appear heterosexual,[8] or individuals (of "either" orientation) experimenting with sexuality outside of their "normal" interest.[9] Maxims such as "people are either gay, straight, or lying" embody this dichotomous view of sexual orientation.[10] Some people accept the theoretical existence of bisexuality but define it narrowly, as being only the equal sexual attraction towards both men and women.[10] Thus the many bisexual individuals with unequal attractions are instead categorized as either homosexual or heterosexual. Others acknowledge the existence of bisexuality in women, but deny that men can be bisexual.[11] Some denial asserts that bisexual behavior or identity is merely a social trend – as exemplified by "bisexual chic" or gender bending – and not an intrinsic personality trait.[12] Same-gender sexual activity is dismissed as merely a substitute for sex with members of the opposite sex, or as a more accessible source of sexual gratification. Situational homosexuality in sex-segregated environments is presented as an example of this behavior.[citation needed] Biphobia is common from the heterosexual community, but is frequently exhibited by gay and lesbian people as well, usually with the notion that bisexuals are able to escape oppression from heterosexuals by conforming to social expectations of opposite-gender sex and romance. This leaves some that identify as bisexual to be perceived as "not enough of either" or "not real."[13] An Australian study conducted by Roffee and Waling in 2016 established that bisexual people faced microaggressions, bullying, and other anti-social behaviors from people within the lesbian and gay community.[14] Bisexual erasure (also referred to as bisexual invisibility) is a phenomenon that tends to omit, falsify, or re-explain evidence of bisexuality in history, academia, the news media, and other primary sources,[15][16] sometimes to the point of denying that bisexuality exists.[17][18] Yoshino (2000) writes that there are three concepts that cause invisibility within bisexuality: "The three invisibilities can be seen as nested within each other; the first affects straights, gays, and bisexuals; the second affects only gays and bisexuals; and the third affects only bisexuals."[19] Forms of social standards and expectations, religion, and integrating the same-sex attraction aspect of bisexuality with homosexuality contribute to invisibility.[19] #### Allegations that bisexual men are homophobic[edit] One cause of biphobia in the gay male community is that there is an identity political tradition to assume that acceptance of male homosexuality is linked to the belief that men's sexuality is specialized. This causes many members of the gay male community to assume that the very idea that men can be bisexual is homophobic to gay men. A number of bisexual men feel that such attitudes force them to keep their bisexuality in the closet and that it is even more oppressive than traditional heteronormativity. These men argue that the gay male community have something to learn about respect for the individual from the lesbian community, in which there is not a strong tradition to assume links between notions about the origins of sexual preferences and the acceptance thereof. These views are also supported by some gay men who do not like anal sex (sides, as opposed to both tops and bottoms) and report that they feel bullied by other gay men's assumption that their dislike for anal sex is "homophobic" and want more respect for the individuality in which a gay man who does not hate himself may simply not like anal sex and instead prefer other sex acts such as mutual fellatio and mutual male masturbation.[20][21] #### Claims of bisexuals adapting to heteronormativity[edit] Some forms of prejudice against bisexuals are claims that bisexuality is an attempt in persecuted homosexuals to adapt to heteronormative societies by adopting a bisexual identity. Such claims are criticized by bisexuals and researchers studying the situation of bisexuals for falsely assuming that same-sex relationships would somehow escape persecution in heteronormative cultures by simply identifying as bisexual instead of homosexual. These researchers cite that all countries with laws against sex between people of the same sex give the same punishment regardless of what sexual orientation the people found guilty identify as, that any countries where same-sex marriage is illegal never allow marriages between people of the same sex no matter if they identify as bisexual instead of homosexual, and that laws against "gay" male blood donors invariably prohibit any man who had sex with other men from donating blood no matter if he identifies as homosexual or as bisexual. The conclusion made by these researchers is that since there is no societal benefit in identifying as bisexual instead of identifying as homosexual, the claim that bisexuals are homosexuals trying to adapt to a heteronormative society is simply false and biphobic and causes bisexuals to suffer a two-way discrimination from both LGBT society and heteronormative society that is worse than the one-way discrimination from heteronormative society that is faced by homosexuals. It is also argued that such two-way discrimination causes many bisexuals to hide their bisexuality to an even greater extent than homosexuals hide their sexuality, leading to underestimations of the prevalence of bisexuality especially in men for whom such assumptions of "really being completely gay" are the most rampant.[22][23] In the book Bi: Notes for a Bisexual Revolution,[24] Eisner (2013) mentions Obradors-Campos' argument that bisexual individuals endure stigma by heterosexuals as well as gay and lesbian individuals. Eisner (2013) also writes, "some forms of biphobic stigma frequently observed in gay and lesbian communities: that bisexuals are privileged, that bisexuals will ultimately choose heterosexual relationships and lifestyles, that bisexual women are reinforcing patriarchy, that bisexuality is not a political identity, that bisexual women carry HIV to lesbian communities, and so on."[24] ### Negative stereotypes[edit] Many stereotypes about people who identify as bisexual stem from denial or bisexual erasure. Because their orientation is not recognized as valid, they are stereotyped as confused, indecisive, insecure, experimenting, or "just going through a phase".[25] The association of bisexuality with promiscuity stems from a variety of negative stereotypes targeting bisexuals as mentally or socially unstable people for whom sexual relations only with men, only with women, or only with one person at a time is not enough. These stereotypes may result from cultural assumptions that "men and women are so different that desire for one is an entirely different beast from desire for the other" ("a defining feature of heterosexism"), and that "verbalizing a sexual desire inevitably leads to attempts to satisfy that desire."[26] As a result, bisexuals may bear a social stigma from accusations of cheating on or betraying their partners, leading a double life, being "on the down-low", and spreading sexually transmitted diseases such as HIV/AIDS. This presumed behavior is further generalized as dishonesty, secrecy, and deception. Bisexuals can be characterized as being "slutty", "easy", indiscriminate, and nymphomaniacs. Furthermore, they are strongly associated with polyamory, swinging, and polygamy,[27] the last being an established heterosexual tradition sanctioned by some religions and legal in several countries. This is despite the fact that bisexual people are as capable of monogamy or serial monogamy as homosexuals or heterosexuals.[28] ## Effects[edit] The mental and sexual health effects of biphobia on bisexual people are numerous. One study showed that bisexuals are often trapped in between the binaries of heterosexuality and homosexuality, creating a form of invalidation around their sexual identity. This often leads to recognized indicators of mental health issues such as low self-esteem and self-worth. These indicators and pressures to "choose" a sexual identity can, in many cases, lead to depression as they may feel they live in a culture that does not recognize their existence.[29] While doing research on women at high-risk of HIV infection, one study, from the Journal of Bisexuality, concluded that bisexual women in the high-risk cohort studied were more likely to engage in various high risk behaviors and were at a higher risk of contracting HIV and other sexually transmitted diseases.[30] These behaviors have been attributed to the unlikeliness of bisexuals to discuss their sexuality and proper protection with health professionals for fear of judgement or discrimination, leaving them uneducated.[31] In the book, Bi: Notes for a Bisexual Revolution,[32] Eisner (2013) discusses the suicidality statistics amongst bisexual identifying individuals as compared to heterosexuals, gays, and lesbians. Eisner (2013) referred to a Canadian study that found bisexual women had higher rates of suicidality as compared to heterosexual and lesbian women; the study also found that bisexual men also had increased rates of suicidality as compared to heterosexual and gay men[33] Bisexual-identified people may face disparities in harsher degrees than their gay and lesbian peers. In the U.S. in particular, for example, they may face: * Lower success rates for refugee applications; may also be the case in Canada and Australia[34] * Higher levels of intimate partner violence[35] * Higher likelihood of youth risk behavior amongst high school students[36] * Higher likelihood of anxiety and mood disorders amongst bisexual women and men who report having sex with both sexes[37] * Higher likelihood of living on less than $30,000 a year[38] * Lower levels of reporting feeling "very accepted" in the workplace[38] * Lower likelihood of being out to the important people in their lives[38] * "Bisexuals report higher rates of hypertension, poor or fair physical health, smoking, and risky drinking than heterosexuals or lesbians/gays"[24] * "Bisexual women in relationships with monosexual partners have an increased rate of domestic violence compared to women in other demographic categories"[24] * "Many, if not most, bisexual people do not come out to their healthcare providers. This means they are getting incomplete information (for example, about safer sex practices)"[24] * "Bisexual women were more likely to be current smokers and acute drinkers"[24] ## Intersectional perspectives[edit] ### Women's issues[edit] Feminist positions on bisexuality range greatly, from acceptance of bisexuality as a feminist issue to rejection of bisexuality as reactionary and anti-feminist backlash to lesbian feminism.[39] A bisexual woman filed a lawsuit against the lesbian feminist magazine Common Lives/Lesbian Lives, alleging discrimination against bisexuals when her submission was not published.[40] A widely studied example of lesbian-bisexual conflict within feminism was the Northampton Pride March during the years between 1989 and 1993, where many feminists involved debated over whether bisexuals should be included and whether or not bisexuality was compatible with feminism. Common lesbian-feminist critiques leveled at bisexuality were that bisexuality was anti-feminist, that bisexuality was a form of false consciousness, and that bisexual women who pursue relationships with men were "deluded and desperate". However, tensions between bisexual feminists and lesbian feminists have eased since the 1990s, as bisexual women have become more accepted within the feminist community.[41] Nevertheless, some lesbian feminists such as Julie Bindel are still critical of bisexuality. Bindel has described female bisexuality as a "fashionable trend" being promoted due to "sexual hedonism" and broached the question of whether bisexuality even exists.[42] She has also made tongue-in-cheek comparisons of bisexuals to cat fanciers and devil worshippers.[43] Lesbian feminist Sheila Jeffreys writes in The Lesbian Heresy (1993) that while many feminists are comfortable working alongside gay men, they are uncomfortable interacting with bisexual men. Jeffreys states that while gay men are unlikely to sexually harass women, bisexual men are just as likely to be bothersome to women as heterosexual men.[44] Donna Haraway was the inspiration and genesis for cyberfeminism with her 1985 essay "A Cyborg Manifesto: Science, Technology, and Socialist-Feminism in the Late Twentieth Century" which was reprinted in Simians, Cyborgs and Women: The Reinvention of Nature (1991). Haraway's essay states that the cyborg "has no truck with bisexuality, pre-oedipal symbiosis, unalienated labor, or other seductions to organic wholeness through a final appropriation of all powers of the parts into a higher unity."[45] ### Race[edit] While the general bisexual population as a whole faces biphobia, this oppression is also aggravated by other factors such as race. In a study conducted by Grady L. Garner Jr. titled Managing Heterosexism and Biphobia: A Revealing Black Bisexual Male Perspective, the author interviews 14 self-identified black bisexual men to examine how they cope with heterosexism and biphobia in order to formulate coping strategies. Data from the interviews revealed that 33% of the participants reported heterosexism and biphobia experiences, while 67% did not. He explains that the internalization of negative sociocultural messages, reactions, and attitudes can be incredibly distressing as bisexual black males attempted to translate or transform these negative experiences into positive bisexual identity sustaining ones.[46] ## See also[edit] * LGBT portal * Bisexuality in the United States * Bisexual community * Duclod Man * Heteronormativity * History of bisexuality * International Day Against Homophobia, Transphobia and Biphobia (biphobia was added to the name of the day in 2015) * List of media portrayals of bisexuality * List of phobias ## References[edit] 1. ^ Yoshino, Kenji (2000). "The Epistemic Contract of Bisexual Erasure". 52 (2): 353–461. doi:10.2307/1229482. Retrieved November 12, 2020. Cite journal requires `\|journal=` (help) 2. ^ Eliason, MJ (1997). "The prevalence and nature of biphobia in heterosexual undergraduate students". Archives of Sexual Behavior. 26 (3): 317–26. doi:10.1023/A:1024527032040. PMID 9146816. S2CID 30800831. 3. ^ Monro, Surya (2015). Bisexuality: Identities, Politics, and Theories. Basingstoke: Palgrave Macmillan. p. 23. ISBN 9781137007308. 4. ^ Greenesmith, Heron (April 25, 2018). "We Know Biphobia Is Harmful. But Do We Know What's Behind It?". Rewire.News. Retrieved October 22, 2019. 5. ^ a b Weise, Elizabeth Reba (1992). Closer to Home: Bisexuality and Feminism. Seattle: Seal Press. pp. 207. ISBN 1-878067-17-6. 6. ^ Welzer-Lang, Daniel (October 11, 2008). "Speaking Out Loud About Bisexuality: Biphobia in the Gay and Lesbian Community". Journal of Bisexuality. 8 (1–2): 82. doi:10.1080/15299710802142259. S2CID 144416441. 7. ^ Managing Heterosexism and Biphobia: A Revealing Black Bisexual Male Perspective. 2008-01-01. ISBN 9780549622482. 8. ^ Michael Musto, April 7, 2009. Ever Meet a Real Bisexual? Archived April 13, 2010, at the Wayback Machine, The Village Voice 9. ^ Yoshino, Kenji (January 2000). "The Epistemic Contract of Bisexual Erasure" (PDF). Stanford Law Review. Stanford Law School. 52 (2): 353–461. doi:10.2307/1229482. JSTOR 1229482. 10. ^ a b Dworkin, SH (2001). "Treating the bisexual client". Journal of Clinical Psychology. 57 (5): 671–80. doi:10.1002/jclp.1036. PMID 11304706. 11. ^ "Do Bisexual Men Really Exist?". Retrieved 2017-02-12. 12. ^ Ka'ahumanu, Lani; Yaeger, Rob. "Biphobia". LGBT Resource Center UC San Diego. UC San Diego. Archived from the original on September 20, 2016. Retrieved September 22, 2016. 13. ^ Fahs, Breanne (2009-11-13). "Compulsory Bisexuality?: The Challenges of Modern Sexual Fluidity". Journal of Bisexuality. 9 (3–4): 431–449. doi:10.1080/15299710903316661. ISSN 1529-9716. 14. ^ Roffee, James A.; Waling, Andrea (2016-10-10). "Rethinking microaggressions and anti-social behaviour against LGBTIQ+ youth". Safer Communities. 15 (4): 190–201. doi:10.1108/SC-02-2016-0004. S2CID 151493252. 15. ^ Word Of The Gay: BisexualErasure May 16, 2008 "Queers United" 16. ^ The B Word Suresha, Ron. "The B Word," Options (Rhode Island), November 2004 17. ^ Hutchins, Loraine (2005). "Sexual Prejudice: The erasure of bisexuals in academia and the media". American Sexuality. 3 (4). National Sexuality Resource Center. Archived from the original on 2007-12-16. 18. ^ Hutchins, Loraine. "Sexual Prejudice—The erasure of bisexuals in academia and the media". American Sexuality Magazine. San Francisco, CA 94103, United States: National Sexuality Resource Center, San Francisco State University. Archived from the original on 2007-12-16. Retrieved 2007-07-19.CS1 maint: location (link) 19. ^ a b Yoshino, Kenji (2000). "The Epistemic Contract of Bisexual Erasure". 52 (2): 353–461. doi:10.2307/1229482. Retrieved November 12, 2020. Cite journal requires `\|journal=` (help) 20. ^ Bi Men: Coming Out Every Which Way, Ron Jackson Suresha, Pete Chvany - 2013 21. ^ Social Work Practice with Lesbian, Gay, Bisexual, and Transgender People, Gerald P. Mallon—2017 22. ^ Fritz Klein, Karen Yescavage, Jonathan Alexander (2012) "Bisexuality and Transgenderism: InterSEXions of the Others" 23. ^ Abbie E. Goldberg (2016) "The SAGE Encyclopedia of LGBTQ Studies" 24. ^ a b c d e f Eisner, Shiri (2013). Bi: Notes for a Bisexual Revolution (English ed.). Seal Press. p. 345. ISBN 1580054757. Retrieved November 12, 2020. 25. ^ "It's Just A Phase" Is Just A Phrase, The Bisexual Index 26. ^ "Bisexuals and the Slut Myth", presented at the 9th International Conference on Bisexuality 27. ^ GLAAD: Cultural Interest Media Archived April 19, 2006, at the Wayback Machine 28. ^ "Are Bisexuals Really Less Monogamous Than Everyone Else?". Psychology Today. Retrieved 2017-02-12. 29. ^ Dodge, Brian; Schnarrs, Phillip W.; Reece, Michael; Martinez, Omar; Goncalves, Gabriel; Malebranche, David; Van Der Pol, Barbara; Nix, Ryan; Fortenberry, J. Dennis (2012-01-01). "Individual and Social Factors Related to Mental Health Concerns among Bisexual Men in the Midwestern United States". Journal of Bisexuality. 12 (2): 223–245. doi:10.1080/15299716.2012.674862. ISSN 1529-9716. PMC 3383005. PMID 22745591. 30. ^ Gonzales, V; Washienko, K M; Krone, M R; Chapman, L I; Arredondo, E M; Huckeba, H J; Downer, A (1999). "Sexual and drug-use risk factors for HIV and STDs: a comparison of women with and without bisexual experiences". American Journal of Public Health. 89 (12): 1841–1846. doi:10.2105/ajph.89.12.1841. PMC 1509027. PMID 10589313. 31. ^ Makadon MD, Harvey J; Ard MD, MPH, Kevin L (2012-07-09). "Improving the Health Care of Lesbian, Gay, Bisexual and Transgender People: Understanding and Eliminating Health Disparities" (PDF). Fenway Institute. U.S. Department of Health and Human Services. 32. ^ Eisner, Shiri (2013). Bi: Notes for a Bisexual Revolution (English ed.). Seal Press. p. 345. ISBN 1580054757. Retrieved November 12, 2020. 33. ^ Eisner, Shiri (2013). Bi: Notes for a Bisexual Revolution (English ed.). Seal Press. p. 345. ISBN 1580054757. Retrieved November 12, 2020. 34. ^ Rehaag, Sean (2009). "Bisexuals need not apply: a comparative appraisal of refugee law and policy in Canada, the United States, and Australia". The International Journal of Human Rights. 13 (2–3): 415–436. doi:10.1080/13642980902758226. hdl:10315/8022. S2CID 55379531. 35. ^ Mikel L. Walters, Jieru Chen, and Matthew J. Breiding, “The National Intimate Partner and Sexual Violence Survey: 2010 Findings on Victimization by Sexual Orientation” (Atlanta, GA: National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, January 2013). 36. ^ Kann, Laura; Olsen, Emily O'Malley; McManus, Tim; Harris, William A.; Shanklin, Shari L.; Flint, Katherine H.; Queen, Barbara; Lowry, Richard; Chyen, David; Whittle, Lisa; Thornton, Jemekia; Lim, Connie; Yamakawa, Yoshimi; Brener, Nancy; Zaza, Stephanie (2016). "Sexual Identity, Sex of Sexual Contacts, and Health-Related Behaviors Among Students in Grades 9–12 — United States and Selected Sites, 2015". MMWR Surveillance Summaries. 65 (9): 1–202. doi:10.15585/mmwr.ss6509a1. PMID 27513843. 37. ^ Bostwick, Wendy B.; Boyd, Carol J.; Hughes, Tonda L.; McCabe, Sean Esteban (2010). "Dimensions of Sexual Orientation and the Prevalence of Mood and Anxiety Disorders in the United States". American Journal of Public Health. 100 (3): 468–475. doi:10.2105/AJPH.2008.152942. PMC 2820045. PMID 19696380. 38. ^ a b c "A Survey of LGBT Americans: The LGBT Population and Its Sub-Groups” (Pew Research Center, June 13, 2013). 39. ^ Wilkinson, Sue (1996). "Bisexuality as Backlash". In Harne, Lynne (ed.). All the Rage: Reasserting Radical Lesbian Feminism. Elaine Miller. New York City: Teacher's College Press. pp. 75–89. ISBN 978-0-807-76285-1. OCLC 35202923. 40. ^ Common Lives/Lesbian Lives Records, Iowa Women's Archives, University of Iowa Libraries, Iowa City, Iowa Archived 2015-08-21 at the Wayback Machine 41. ^ Gerstner, David A. (2006). Routledge International Encyclopedia of Queer Culture. United Kingdom: Routledge. pp. 82–3. ISBN 978-0-415-30651-5. Retrieved October 3, 2012. 42. ^ Bindel, Julie (June 12, 2012). "Where's the Politics in Sex?". The Huffington Post. Retrieved 2012-10-03. 43. ^ Bindel, Julie (November 8, 2008). "It's not me. It's you". The Guardian. London. Retrieved 2012-10-03. 44. ^ Jeffreys, Sheila (1993). The Lesbian Heresy. Melbourne, Australia: Spinifex Press Pty Ltf. p. 124. ISBN 978-1-875559-17-6. Retrieved October 4, 2012. 45. ^ "Donna Haraway - A Cyborg Manifesto". Egs.edu. Archived from the original on 2013-09-22. Retrieved 2015-09-15. 46. ^ Garner, Grady L. (2011-09-02). Managing Heterosexism and Biphobia: A Revealing Black Bisexual Male Perspective. ISBN 9781243513434. ## Further reading[edit] * Garber, Marjorie (1995). Bisexuality and the Eroticism of Everyday Life, pp. 20–21, 28, 39. * Fraser, M., Identity Without Selfhood: Simone de Beauvoir and Bisexuality, Cambridge and New York: Cambridge University Press 1999. p. 124–140. * Rankin, Sam; Morton, James; Bell, Matthew (May 2015). "Complicated? Bisexual people's experiences of and ideas for improving services" (PDF). Equality Network. * The fencesitters? 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antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Biphobia	None	5,586	wikipedia	https://en.wikipedia.org/wiki/Biphobia	2021-01-18T18:43:25	{"wikidata": ["Q747592"]}
A number sign (#) is used with this entry because Miyoshi muscular dystrophy-1 (MMD1) can be caused by homozygous mutation in the gene encoding dysferlin (DYSF; 603009) on chromosome 2p13. A form of limb-girdle muscular dystrophy (LGMD2B; 253601) is also caused by mutation in the dysferlin gene. Description Miyoshi muscular dystrophy is an autosomal recessive skeletal muscle disorder characterized by onset in young adulthood of distal muscle weakness affecting the upper and lower limbs but sparing the intrinsic hand muscles. Muscle weakness and atrophy particularly affects the gastrocnemius and soleus muscles, and can later spread to involve the thigh and gluteal muscles. Patients showed impaired tiptoe standing, difficulty in climbing stairs, and difficulty walking, but usually remain ambulatory. Serum creatine kinase is increased and muscle biopsies show myopathic and dystrophic changes with necrosis (summary by Miyoshi et al., 1986). ### Genetic Heterogeneity of Miyoshi Muscular Dystrophy Miyoshi muscular dystrophy is a genetically heterogeneous disorder: MMD2 (613318) has been mapped to chromosome 10p, and MMD3 (613319) is caused by mutation in the ANO5 gene (608662) on chromosome 11p14. See also Welander myopathy (604454), an autosomal dominant form of late-onset distal myopathy. Clinical Features Miyoshi et al. (1967) reported 4 patients from 2 Japanese families with distal myopathy inherited in an autosomal recessive pattern. Sasaki et al. (1969) and Ideta et al. (1973) each reported 4 affected patients. Kuhn and Schroder (1981) reported 2 affected Caucasian brothers born of consanguineous parents. They had early-adult onset in the distal leg muscles and elevated creatine kinase. Miyoshi et al. (1986) described in detail 17 cases from 8 families including an autopsy case. Consanguinity was found in 7 of the 8 families and in 2 families there was pseudodominance, i.e., affected father and children. Eighty percent of the cases had onset between 16 and 20 years with long survival. Serum CK activity was markedly elevated in all except 1 patient, aged 56 years; CK was mildly elevated in preclinical stages. The pattern of muscle involvement was distinctive; the muscles of the lower legs and forearms were involved, whereas the small muscles of the feet and hands were relatively spared. Skilled movements of the fingers were not disturbed, but grip strength was decreased early in the disease. No lesions were detected in the brain, spinal cord, or peripheral nerves. Miyoshi et al. (1986) noted that the disorder could be distinguished from Welander myopathy, which shows atrophy of small muscles of the hands and extensor muscles of the legs with inability to stand on the heels but ability to stand on tiptoes, whereas in Miyoshi myopathy, impaired toe-standing was an early symptom and heel-standing was normal. Isaacs et al. (1988) described 5 patients with autosomal recessive distal myopathy of late onset; 3 of the patients belonged to a single sibship. One of the cases resembled the Nonaka form (605820). The authors concluded that autosomal recessive distal myopathy can occur in different ethnic groups. Yamanouchi et al. (1994) examined 19 muscle biopsies from 14 patients with autosomal recessive distal muscular dystrophy. The histologic features were similar to those of Duchenne muscular dystrophy (DMD; 310200) with active muscle fiber necrosis and regeneration, as well as disorganization of the intermyofibrillar network. In half of the patients, small angular fibers and scattered rimmed vacuoles were found. However, dystrophin (300377) and utrophin (128240) were expressed normally, even in severely affected gastrocnemius muscles. In a large, inbred, aboriginal Canadian kindred with 9 muscular dystrophy patients, Weiler et al. (1996) found that the ancestry of all but 2 of the carrier parents could be traced to a founder couple 7 generations earlier. Seven patients presented with proximal myopathy consistent with limb-girdle muscular dystrophy, whereas 2 patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy. Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MD was consistent with autosomal recessive inheritance. Rowin et al. (1999) described 2 patients with a clinical diagnosis of Miyoshi myopathy who demonstrated marked inflammatory changes on muscle biopsy of clinically less affected muscles. The findings illustrated the importance of recognizing the marked variability in histopathology of Miyoshi myopathy, which may include an inflammatory infiltrate on muscle biopsy, mimicking the histopathologic picture of an inflammatory myopathy. One patient was a 25-year-old Pakistani man, born of consanguineous parents, with a 1.5-year history of progressive atrophy of both calves associated with 'limping.' He denied involvement of the upper extremities. The second patient was a 29-year-old woman who had had progressive difficulty in walking, particularly in high-heeled shoes, beginning at the age of 18 and progressing to include difficulty walking up stairs and stumbling over her feet. Ro et al. (2004) reported 4 Chinese patients from 2 unrelated families living in Taiwan with MM confirmed by molecular identification of mutations in the dysferlin gene. Three sibs in 1 family experienced difficulty in toe walking beginning at ages 17 to 18 years. In the following 2 to 5 years, all had difficulty in climbing stairs and rising from a squatting position accompanied by moderate to severe weakness in the gastrocnemius and soleus muscles and mild weakness in the hamstring and quadriceps muscles. The tibialis anterior muscle was relatively spared. Two patients had muscle wasting and weakness in the lower legs. Reflexes were decreased or absent in the ankles. CK was elevated and muscle biopsies showed dystrophic patterns with decreased or absent dysferlin staining. MRI showed a mild to moderate increase of signal intensity in the affected muscles of the lower legs, reflecting fatty infiltration. The 1 patient from the other family had a similar clinical course and MRI findings. Illa et al. (2007) reported 2 sibs with Miyoshi myopathy due to a homozygous mutation in the DYSF gene (G519R; 603009.0015). Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder. Spuler et al. (2008) reported 2 sibs with Miyoshi myopathy caused by mutation in the DYSF gene (G299W; 603009.0018). Skeletal muscle biopsy of 1 showed amyloid fibrils on skeletal muscle biopsy. Amyloid was located in the sarcolemma of muscle cells as well as in blood vessel walls and interstitium. Spuler et al. (2008) postulated that the mutation destabilized the protein structure of dysferlin and increased the propensity to form amyloid fibrils. Diagnosis Cacciottolo et al. (2011) found that all of 55 patients with an undetermined LGMD clinical phenotype and 10 patients with a Miyoshi myopathy phenotype who had less than 20% dysferlin on skeletal muscle biopsy determined by Western blot analysis had pathogenic mutations in the DYSF gene. Exhaustive mutation analysis was performed, including genomic DNA sequencing, mRNA analysis, array CGH, and PCR. Sixty-five different mutations were identified throughout the gene and there were no mutation hotspots. Cacciottolo et al. (2011) noted the difficulty of sequencing the DYSF gene because of its larger size, and concluded that protein analysis showing a dysferlin reduction to 20% of normal values in skeletal muscle or in peripheral blood monocytes can be used to identify LGMD2B/MMD1 caused by DYSF mutations with 100% accuracy. Mapping Bejaoui et al. (1995) identified a putative Miyoshi myopathy disease locus on chromosome 2p14-p12 (lod score of 15.3 at marker D2S291) by a study of 12 families with MM. Five of the families were consanguineous. Weiler et al. (1996) linked a Canadian family in which some members had features of limb-girdle muscular dystrophy and others had features of distal myopathy to 2p (lod score greater than 3.0). The putative region included the LGMD2B locus on 2p. Analysis of microsatellite markers surrounding the disease locus disputed the original hypothesis that the affected patients would be homozygous by descent. Rather, 2 different core haplotypes, encompassing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with the disease, indicating 2 mutant alleles of independent origin. There was no association between phenotype and haplotype. Weiler et al. (1996) concluded that LGMD and MM in this population were caused by the same mutation at the LGMD2B locus and that additional factors, both genetic and nongenetic, contributed to the clinical phenotype. By examining critical recombination events in 2 consanguineous families of Tunisian origin with MM, Bejaoui et al. (1998) refined the MM locus to a 360-kb segment. They mapped the cytoskeletal protein beta-adducin gene (102681) within the MM candidate region, but failed to find a consistent pattern of mutation of this gene in MM patients. Although Welander distal myopathy also links to 2p13, von Tell et al. (2003) used extended linkage analysis to exclude the dysferlin gene as the cause of that disease. Molecular Genetics In 9 families with either Miyoshi myopathy or LGMD2B, Liu et al. (1998) identified 9 mutations in the dysferlin gene (see, e.g., 603009.0001), indicating that they are allelic disorders. Nomenclature In a review of limb-girdle muscular dystrophies, Bushby (1999) referred to LGMD2B and Miyoshi myopathy as dysferlinopathies. INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Difficulty in toe walking \- Preserved heel standing \- Difficulty climbing stairs \- Difficulty rising from a squatting position \- Muscle weakness in lower limbs \- Muscle wasting in lower limbs \- Gastrocnemius and soleus muscles most affected \- Hamstring and quadriceps muscles mildly affected \- Sparing of anterior tibialis muscle \- Decreased or absent ankle reflexes \- Muscle weakness in forearm muscles \- Mild muscle atrophy in forearm muscles \- Decreased grip strength \- Sparing of small hand and finger muscles \- MRI shows increased signal intensity in affected muscles consistent with fatty infiltration \- Muscle biopsy shows dystrophic changes \- Muscle biopsy may show inflammatory changes \- Muscle biopsy shows decreased or absent dysferlin staining \- Fibrillations in affected muscles \- Amyloid deposition in muscle fibers occurs rarely LABORATORY ABNORMALITIES \- Increased creatine kinase MISCELLANEOUS \- Onset age 15-25 years \- Genetic heterogeneity \- Allelic disorder to Limb-Girdle Muscular Dystrophy type 2B (LGMD2B, 253601 ) MOLECULAR BASIS \- Caused by mutation in the dysferlin gene (DYS, 603009.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	MIYOSHI MUSCULAR DYSTROPHY 1	c1850808	5,587	omim	https://www.omim.org/entry/254130	2019-09-22T16:24:42	{"doid": ["0070199"], "omim": ["254130"], "orphanet": ["45448"], "synonyms": ["Alternative titles", "MIYOSHI MYOPATHY", "MUSCULAR DYSTROPHY, DISTAL, LATE-ONSET, AUTOSOMAL RECESSIVE"], "genereviews": ["NBK1303"]}
## Summary ### Clinical characteristics. PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: * Infantile neuroaxonal dystrophy (INAD) * Atypical neuroaxonal dystrophy (atypical NAD) * PLA2G6-related dystonia-parkinsonism INAD usually begins between ages six months and three years with psychomotor regression or delay, hypotonia, and progressive spastic tetraparesis. Many affected children never learn to walk or lose the ability shortly after attaining it. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid, resulting in severe spasticity, progressive cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade. Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability, ataxia, or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. Strabismus, nystagmus, and optic atrophy are common. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years. PLA2G6-related dystonia-parkinsonism has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability. ### Diagnosis/testing. The diagnosis of PLA2G6-associated neurodegeneration is established in a proband by identification of biallelic pathogenic variants in PLA2G6 on molecular genetic testing. The diagnosis of INAD or atypical NAD can be established in a proband with no identified PLA2G6 pathogenic variants by electron microscopic examination of nerve biopsies for dystrophic axons (axonal spheroids). ### Management. Treatment of manifestations: * Individuals with INAD and atypical NAD. Routine pharmacologic treatment of spasticity and seizures; trial of oral or intrathecal baclofen for dystonia associated with atypical INAD; treatment by a psychiatrist for those with later-onset neuropsychiatric symptoms; fiber supplements and/or stool softener treatment for constipation; control of secretions with transdermal scopolamine patch as needed; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition. * Individuals with PLA2G6-related dystonia-parkinsonism. Consider treatment with dopaminergic agents; treatment of neuropsychiatric symptoms by a psychiatrist; evaluation by physical therapy for management of postural instability and gait difficulties; occupational therapy to assist with activities of daily living; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition. Prevention of secondary complications: Early physical therapy and orthopedic management to prevent contractures as the disease progresses; body temperature monitors may be required for individuals with progressive autonomic involvement to identify dangerous fluctuations in core body temperature. Surveillance: Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits. ### Genetic counseling. PLA2G6-associated neurodegeneration is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known. ## Diagnosis ### Suggestive Findings PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: * Infantile neuroaxonal dystrophy (INAD) * Atypical neuroaxonal dystrophy (atypical NAD) * PLA2G6-related dystonia-parkinsonism #### Infantile Neuroaxonal Dystrophy (INAD) PLA2G6-associated INAD should be suspected in individuals with the following clinical, laboratory, radiographic, and neurophysiologic features. Clinical * Onset before age three years * Psychomotor regression (most common presenting feature) * Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course) * Visual abnormalities: strabismus, nystagmus, optic atrophy Laboratory * Elevated aspartate aminotransferase / alanine aminotransferase ratio * Elevated lactate dehydrogenase Radiographic * Cerebellar atrophy (see Figure 1) * T2-weighted MRI of the brain: hypointense globus pallidus (indicating iron accumulation), cortical cerebellar hyperintensities consistent with cerebellar gliosis, white matter abnormalities, thin vertically oriented corpus callosum (see Figure 1), and hypertrophy of the clava [Illingworth et al 2014, Al-Maawali et al 2016] #### Figure 1 A. Left axial image shows high brain iron in the globus pallidus (see arrow) on T2-weighted MRI. B. Right sagittal image shows cerebellar atrophy (see arrow). Neurophysiologic * EMG (electromyogram). Evidence of denervation * EEG (electroencephalogram). Fast rhythms * VEP (visual evoked potential). Delayed with reduced amplitudes * NCV (nerve conduction velocity). Distal axonal-type sensorimotor neuropathy * Seizures that may present early or late in the disease course [Wu et al 2009] #### Atypical Neuroaxonal Dystrophy (NAD) PLA2G6-associated atypical NAD) should be suspected in individuals with the following clinical, radiographic, and neurophysiologic features. Clinical * Onset before age 20 years * Psychomotor regression * Gait abnormalities * Prominent expressive language difficulties * Psychiatric/behavioral abnormalities including autistic-like behavior * Visual abnormalities: nystagmus, optic atrophy * Spasticity (without preceding hypotonia) * Joint contractures * Progressive dystonia and dysarthria * Disease progression slower than in INAD Radiographic * Cerebellar atrophy * T2-weighted MRI of the brain: hypointense globus pallidus (indicating iron accumulation) Neurophysiologic * VEP. Delayed with reduced amplitudes * Seizures #### PLA2G6-Related Dystonia-Parkinsonism PLA2G6-related dystonia-parkinsonism should be suspected in individuals with the following clinical and radiographic features. Clinical * Onset varying from childhood to young adulthood * Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses) * Dystonia * Dysarthria * Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation) * Cognitive decline * Neuropsychiatric changes * Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias Radiographic * Cerebral atrophy * Cerebellar atrophy * Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum; findings are variable and may not be evident on MRI studies until late in the disease course for some individuals. * Reduced dopamine transporter labeling similar to that seen in idiopathic Parkinson disease * In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography ### Establishing the Diagnosis The diagnosis of PLA2G6-associated neurodegeneration (PLAN) is established in a proband by identification of biallelic pathogenic variants in PLA2G6 on molecular genetic testing (see Table 1). Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of PLA2G6 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. * A multigene panel that includes PLA2G6 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in PLA2G6-Associated Neurodegeneration View in own window Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method PLA2G6Sequence analysis 3~85% 4 Gene-targeted deletion/duplication analysis 5≤12.5% 6 Unknown 7NA 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\. Of all individuals identified with PLA2G6 pathogenic variants, approximately 10% have only one pathogenic variant identified [NBIA International Mutation Database, unpublished data]. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Deletion and duplication of multiple exons have been identified Crompton et al [2010] (see Molecular Genetics, Pathogenic variants). 7\. Linkage data support the presence of at least one additional INAD locus [Morgan et al 2006]. Tissue biopsy. If no PLA2G6 pathogenic variants are identified but the evolving phenotype remains most consistent with INAD or atypical NAD, a biopsy for identification of dystrophic axons (axonal spheroids) can be considered. Electron microscopic (EM) examination of nerve ultrastructure should be done on one of the following preferred tissues: conjunctiva, skin, rectum, muscle, or other peripheral nerve (sural). Histopathologic evidence of dystrophic axons on biopsy from one or more of the following tissues, viewed by EM, includes: * Membranotubular profiles; * Mitochondrial aggregates; * Increased axonal diameter and thinned membrane. Note: (1) Because axonal spheroids accumulate with age and may not be evident in all tissues, individuals suspected to have INAD or atypical NAD without identifiable PLA2G6 pathogenic variants may require multiple biopsies over time before axonal spheroids are identified. (2) Peripheral spheroids have not been described in pathologic specimens from persons with PLA2G6-associated dystonia-parkinsonism; however, limited pathologic material has been available thus far from this group. ## Clinical Characteristics ### Clinical Description Infantile neuroaxonal dystrophy (INAD). Onset of INAD usually occurs between ages six months and three years. The disease presents with psychomotor regression (i.e., loss of previously acquired milestones) or delay, delayed walking, or gait disturbance. A single individual with neonatal onset has been reported, with severe hypotonia and marked weakness [Fusco et al 2015]. Truncal hypotonia is observed early in the disease course. Over time, affected persons develop a spastic tetraparesis, with symmetric pyramidal tract signs on clinical examination. Visual signs and symptoms are common. Strabismus and nystagmus are early features of the disease. Later optic atrophy occurs in most individuals. Optic atrophy may be observed early as optic nerve pallor; thin optic chiasm and tracts have also been reported on brain MRI [Farina et al 1999]. Seizures occur in a minority of individuals as a later symptom [Nardocci et al 1999, Wu et al 2009]. Autonomic involvement may present early as constipation or cold extremities. With progression, some individuals require body temperature monitors because of dangerous fluctuations in core body temperature. The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications. Atypical NAD. Whereas the features of INAD are relatively homogeneous, atypical disease is quite varied. In general, onset in atypical NAD is in early childhood but can be as late as the late teens. In a series of 13 individuals, four had onset by age three years but a fairly stable course during early childhood resembling static encephalopathy, followed by neurologic deterioration between ages seven and 12 years [Nardocci et al 1999]. The presenting signs and symptoms may be similar to INAD, including gait instability or ataxia. Others may present with speech delay and autistic features, which may remain as the only evidence of disease for a year or more, given the slow progression of atypical NAD compared to INAD [Gregory et al 2008]. Although spastic tetraparesis is evident late in the disease, it is rarely preceded by early truncal hypotonia. In contrast to classic disease, extrapyramidal findings (i.e., dystonia and dysarthria) predominate in atypical NAD. Eye findings are similar to those seen in classic INAD. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common [Gregory et al 2008]. Atypical NAD is rare, and the life span is not known; however, it is expected to be longer than that observed in classic disease. PLA2G6-related dystonia-parkinsonism. To date, only a small number of affected individuals have been described [Karkheiran et al 2015]. Age at onset has varied from four to 37 years [Paisán-Ruiz et al 2009, Paisán-Ruiz et al 2010, Yoshino et al 2010, Bower et al 2011, Paisán-Ruiz et al 2012, Virmani et al 2014]; however, the majority have presented in early adulthood (late teens to 20s). Of those with childhood onset, one presented with foot drag and dystonia at age ten years and the other two children presented with an unsteady gait at ages six and eight years. The youngest individual presented with stuttering speech, clumsiness, and dyslexia at age four years – findings that may not be related to the PLA2G6-associated neurodegeneration (PLAN). In young adults, initial symptoms are frequently neuropsychiatric, including depression, personality changes, aggression, delusions, or paranoia. Gait disturbance is also common at presentation. Regardless of the age at onset, affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Neuropsychiatric changes may precede the movement disorder or occur concomitantly. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability. Of note, it is common to have an initially dramatic positive response to dopaminergic agents; however, this tends to be short-lived and followed quickly by the development of motor fluctuations and dyskinesias. Neuropathology. Paisán-Ruiz et al [2012] described the neuropathologic findings in seven individuals who spanned the three forms of PLAN. Numerous axonal swellings in the basal ganglia and brain stem were observed in individuals with infantile-onset and adult-onset PLAN. They were also found in the spinal cord in the two individuals for whom cord tissue was available. Lewy bodies were widespread in both those with adult-onset and those with infantile-onset PLAN. In two affected individuals, one with onset at 18 years and the other only specified as "childhood," the Lewy body pathology was comparable to that seen in severe, end-stage Parkinson disease. Tau pathology, to varying degrees, was also found across the PLAN spectrum. ### Genotype-Phenotype Correlations Genotype correlates with phenotype to a limited extent: * All individuals with two null alleles of PLA2G6 have INAD. * The less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants. * Common pathogenic variants associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with PLA2G6-related dystonia-parkinsonism did not [Engel et al 2010]. ### Nomenclature Outdated terms * Seitelberger [1952] first described this condition, which was originally named Seitelberger disease. * Karak syndrome was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. Brain MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [Mubaidin et al 2003]. Morgan et al [2006] identified pathogenic variants in PLA2G6 in individuals with Karak syndrome, which is now included in the phenotypic spectrum of PLAN and no longer considered a clinically distinct entity; what had been described as Karak syndrome is now referred to as atypical NAD. Current nomenclature. In addition to INAD, later-onset variants have been called late-infantile, juvenile, or atypical neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (NBIA). The authors propose the following usage: * INAD for early-onset, rapidly progressive disease * Atypical NAD for later childhood-onset disease with slower progression and predominant extrapyramidal findings (dystonia, dysarthria). The atypical NAD phenotype is expected to include a broad range of presentations including Karak syndrome. * PLA2G6-related dystonia-parkinsonism for adult-onset dystonia-parkinsonism accompanied by cognitive decline and neuropsychiatric changes ### Prevalence Disease prevalence is not established; it is estimated at 1:1,000,000. ## Differential Diagnosis ### Infantile Neuroaxonal Dystrophy (INAD) Early diagnosis is challenging because the initial symptoms of psychomotor regression and progression are also observed in other conditions. The observation of an elevated aspartate aminotransferase / alanine aminotransferase ratio and elevated lactate dehydrogenase in combination with these findings is more suspicious for INAD [Kraoua et al 2016]. The degree of weakness early in the disease course may initially direct the clinician toward a myopathy or spinal muscular atrophy. Cerebellar atrophy can be detected by brain MRI before age two years in some children [Farina et al 1999]. The differential diagnosis for childhood cerebellar atrophy includes infantile neuronal ceroid-lipofuscinosis (CLN1 disease, Santavuori-Haltia), ataxia-telangiectasia, KIF1A-associated hereditary spastic paraplegia (OMIM 610357; see also Hereditary Spastic Paraplegia Overview), and hereditary ataxia; however, cerebellar atrophy usually presents later in individuals with these disorders. An estimated 40%-50% of individuals with INAD have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T2-weighted MRI. For this reason, conditions included in the neurodegeneration with brain iron accumulation (NBIA) category should also be considered in the differential diagnosis of INAD. Individuals with INAD have not been found to have an eye-of-the-tiger sign, which correlates very highly with pantothenate kinase-associated neurodegeneration (PKAN) [Hayflick et al 2003]. Since the identification of PLA2G6 pathogenic variants as causative of INAD, the need for invasive nerve biopsy to aid in diagnosis has decreased. While the presence of axonal spheroids in peripheral tissues remains specific to INAD, spheroids are found in the brain in a few other conditions, including PKAN, idiopathic NBIA, infantile GM2 gangliosidosis (see Hexosaminidase A Deficiency), Niemann-Pick disease type C, and Menkes disease (see ATP7A-Related Copper Transport Disorders). ### Atypical Neuroaxonal Dystrophy (NAD) Initial speech delay and limited social interaction may be consistent with autism. Spasticity, dystonia, and dysarthria – findings similar to those of other forms of NBIA – eventually predominate; high brain iron in the globus pallidus and substantia nigra has been observed in nearly all individuals, although ascertainment is likely to be biased [Gregory et al 2008]. Therefore, idiopathic NBIA should also be considered in the differential diagnosis of atypical NAD. PKAN may present with similar features. ### PLA2G6-Related Dystonia-Parkinsonism When high brain iron is present and pathogenic variants in PLA2G6 have not been identified, other forms of NBIA should be considered in the differential diagnosis. Atypical PKAN, Kufor-Rakeb syndrome (OMIM 606693), MPAN (mitochondrial membrane protein-associated neurodegeneration), and BPAN (beta-propeller protein-associated neurodegeneration) can present with neuropsychiatric changes, parkinsonism, and dystonia in late childhood or early adulthood. As in PLA2G6-related dystonia-parkinsonism, individuals with MPAN, BPAN, and Kufor-Rakeb syndrome also exhibit cognitive decline. Other forms of early-onset dystonia-parkinsonism must also be considered, including: dopa-responsive dystonia; Wilson disease; Parkinson disease 2 (PARK2); PARK6, PARK7, and PARK15 (see Parkinson Disease Overview); SLC6A3-related dystonia-parkinsonism; X-linked dystonia-parkinsonism (DYT-TAF1); DYT-ATP1A3; DYT16; and spastic paraplegia 11 (SPG11) [Schneider & Bhatia 2010]. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PLA2G6-associated neurodegeneration (PLAN), the following evaluations are recommended if they have not already been completed: * Thorough ophthalmologic examination to assess for optic atrophy * EEG for the possibility of unrecognized seizure activity * Consultation with a clinical geneticist and/or genetic counselor Note: The extent of disease is often well characterized by the time of diagnosis, since the diagnostic workup frequently includes neurophysiologic studies (EEG, EMG, nerve conduction studies, ERG [electroretinogram], and/or VEP) and brain MRI. ### Treatment of Manifestations The following treatments for infantile neuroaxonal dystrophy (INAD) and atypical NAD are palliative: * Pharmacologic treatment of spasticity and seizures * Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (see Dystonia Overview) Deep brain stimulation has been successfully utilized in one individual with atypical NAD who had intractable dystonia [Cif et al 2014]. * Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms * Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications * Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions * Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia Treatments for PLA2G6-related dystonia-parkinsonism are also palliative but differ somewhat: * Treatment with dopaminergic agents is likely to be beneficial for the motor symptoms of parkinsonism and dystonia and may initially produce a dramatic response. In individuals treated to date, this response diminished over time, and affected individuals often developed prominent early dyskinesias, complicating medical management. Despite the dyskinesias, treatment with dopaminergic agents may still be indicated, as affected individuals typically experience benefit for a period of time and the dyskinesias are expected to decline after discontinuation of treatment. In one case report, an individual age 32 years with dystonia-parkinsonism developed episodes of non-painful, fixed upward gaze with neck extension that started shortly after levodopa administration and persisted until the drug wore off [Virmani et al 2014]. The use of deep brain stimulation for PLA2G6-associated dystonia-parkinsonism has not been reported. * Treatment by a psychiatrist for neuropsychiatric symptoms is indicated. * Evaluation by physical therapy may guide the management of postural instability and gait difficulties. * Occupational therapy may offer tools to assist with activities of daily living. * Interventions such as a gastric feeding tube or tracheostomy may be needed to reduce the risk of aspiration pneumonia. ### Prevention of Secondary Complications A rehabilitation program including physical therapy and orthopedic management should be initiated early in the disease course to prevent contractures when the individual is permanently nonambulatory. Body temperature monitors may be required for individuals with progressive autonomic involvement to identify dangerous fluctuations in core body temperature. ### Surveillance Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Women with the INAD and atypical NAD forms of PLAN have not been known to reproduce due to the relatively early onset and severity of disease. Two women with PLA2G6-related dystonia-parkinsonism have been reported to reproduce [Paisán-Ruiz et al 2010, Virmani et al 2014]. Since onset of manifestations of PLAN has been reported as late as age 30 years, some women may become pregnant before onset of symptoms or early in the disease course. For those who may be symptomatic, the main issue is the potential for teratogenic effects of medications taken during pregnancy. It is not known whether pregnancy itself may have short- or long-term effects on the disease course for the affected pregnant woman. ### Therapies Under Investigation Because some individuals with PLAN have high brain iron and this disorder falls into the category of NBIA, the option of chelation therapy is sometimes raised. The chelator deferiprone is currently under investigation for the PKAN form of NBIA. Results may inform its use in PLAN and/or lead to additional trials. A proof-of-concept gene therapy strategy is currently under investigation in murine disease models of PLAN [Dr. Manju Kurian, personal communication]. Development of small molecule therapies is also under investigation in cell and murine disease models [Dr. Paul Kotzbauer, personal communication]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. ### Other Docosahexaenoic acid (DHA) is selectively hydrolyzed from phospholipids by the action of the iPLA2-beta enzyme, the protein encoded by PLA2G6. Although not yet tested as an intervention in individuals with PLAN, a Pla2g6-mutant mouse model showed reduced DHA metabolism and signaling [Basselin et al 2010]; evidence from a more recent study showed that DHA can reverse selective iPLA2-beta inhibition [Mazzocchi-Jones 2015]. Given the low risk of harm from DHA supplementation, the authors recommend its administration at a dose that is age appropriate. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	PLA2G6-Associated Neurodegeneration	c0270724	5,588	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1675/	2021-01-18T21:06:12	{"mesh": ["D019150"], "synonyms": ["NBIA2", "PLA2G6-Related Disorders", "PLAN"]}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Effective safety training" – news · newspapers · books · scholar · JSTOR (January 2011) (Learn how and when to remove this template message) Effective safety training is an unofficial phrase used to describe the training materials designed to teach occupational safety and health standards developed by the United States government labor organization, Occupational Safety and Health Administration (OSHA). OSHA has produced many standards and regulations that affect employers and employees in the United States. United States employers have a legal responsibility to educate employees on all workplace safety standards and the hazards that their employees may face while on the job, and providing effective safety training meets that responsibility. ## Contents * 1 AS ENTERPRISES * 2 Benefits of a training program * 3 OSHA's voluntary training guidelines * 4 Computer and video training * 5 OSHA Medical Safety * 6 See also * 7 References ## AS ENTERPRISES[edit] Employers must have an overall safety program including relative site specific safety information where applicable. The safety training program should cover topics such as:[1] * accident prevention and safety promotion * safety compliance * accident and emergency response * personal protective equipment * safety practices * equipment and machinery * chemical and hazardous materials safety * workplace hazards * employee involvement Employers must document all training. Creating a training matrix will help keep track of who has been trained, when they were trained, the training topic, and when it is time for refresher training. Employees must also sign an official sign-in sheet provided by the employer that can serve as proof that employees received proper training. The sign in sheet must have a broad description of what is being covered in the training. Tests or quizzes on the presented material can help gauge employee understanding of the material and highlight topics that need to be reviewed. The non-English speaking population is consistently growing in many industries and it is important that employers provide bilingual training for those workers, as OSHA requires that all employees be properly trained. Most employees display attitudes of disinterest and dread at the thought of attending a safety training, which can leave the trainer feeling frustrated and unappreciated. It is the trainer's duty to make safety training fun and educational, which will help the trainees to retain the information, enjoy the course, and apply the learning to their work and lives.[2] ## Benefits of a training program[edit] An effective training program can reduce the number of injuries and deaths, property damage, legal liability, illnesses, workers' compensation claims, and missed time from work. An effective safety training program can also help a trainer keep the required OSHA-mandated safety training courses organized and up-to-date. Safety training classes help establish a safety culture in which employees themselves help promote proper safety procedures while on the job. It is important that new employees be properly trained and embrace the importance of workplace safety as it is easy for seasoned workers to negatively influence the new hires. That negative influence however, can be purged with the establishment of new, hands-on, innovative effective safety training which will ultimately lead to an effective safety culture. A 1998 NIOSH study concluded that the role of training in developing and maintaining effective hazard control activities is a proven and successful method of intervention.[3] ## OSHA's voluntary training guidelines[edit] OSHA issued voluntary training guidelines in 1992. These guidelines serve as a model for trainers to use in developing, organizing, evaluating, and editing their safety training programs. It is important for trainers to tailor the OSHA guidelines to their specific work site so that the training is relevant to the specific working conditions and not just a long generalized informational session. > Many standards promulgated by OSHA explicitly require the employer to train employees in the safety and health aspects of their jobs. Other OSHA standards make it the employer's responsibility to limit certain job assignments to employees who are "certified," "competent," or "qualified"—meaning that they have had special previous training, in or out of the workplace. The term "designated" personnel means selected or assigned by the employer or the employer's representative as being qualified to perform specific duties. These requirements reflect OSHA's belief that training is an essential part of every employer's safety and health program for protecting workers from injuries and illnesses.[4] OSHA's training guidelines follow a model that consists of: * A. Determining if Training is Needed * B. Identifying Training Needs * C. Identifying Goals and Objectives * D. Developing learning activities * E. Conducting the training * F. Evaluating program effectiveness * G. Improving the program * H. Training must align with job tasks. * A. Determining if training is needed You first have to determine if a situation can be solved using training. Training, or retraining as the case may be, could be required by an OSHA standard. Training is an effective solution to problems such as employee lack of understanding, unfamiliarity with equipment, incorrect execution of a task, lack of attention, or lack of motivation. Sometimes, however, the situation cannot be mitigated through the use of training and other methods, such as the establishment of engineering controls, may be needed to ensure worker safety. * B. Identifying training needs A job safety analysis and/or a job hazard analysis should be conducted with every employee so that it is understood what is needed to do the job safely and what hazards are associated with the job. A safety trainer may observe the worker in his/her environment to adequately assess the worker's training needs. Certain employees may need extra training due to the hazards associated with their particular job. These employees should be trained not only on how to perform their job safely but also on how to operate within a hazardous environment. * C. Identifying Goals and Objectives It is important for the Trainer to identify necessary training material. It is equally important that the trainer identify training material that is not needed to avoid unnecessary training and frustration from their trainees. At the beginning of every safety training session the trainer should clearly iterate the objectives of the class. The objectives should be delivered using action oriented words like: the employee "will be able to demonstrate" or "will know when to" which will help the audience understand what he/she should know by the end of the class or what to information to assimilate during the class. Clearly established objectives also help focus the evaluation process on those skill sets and knowledge requirements necessary to perform the job safely. * D. Developing Learning Activities Training should be hands-on and simulate the job as closely as possible. Trainers can use instructional aids such as charts, manuals, PowerPoint presentations, and films. Trainers can also include role-playing, live demonstrations, and round-table group discussions to stimulate employee participation. Games like "what's wrong with this picture" (it is usually good to use pictures of situations found at their specific location)" or "safety jeopardy" can be useful ways to make the training fun yet educational. * E. Conducting the Training Trainers should provide employees with an overview of the material to be learned and relate the training to the employees' experiences. Employers should also reinforce what the employees have learned by summarizing the program's objectives and key points of training. At the beginning of the training program, the trainer should show the employees why the material is important and relevant to their jobs. Employees are more likely to pay attention and apply what they've learned if they know the benefits of the training.[1] * F. Evaluating Program Effectiveness Evaluation will help employers or supervisors determine the amount of learning achieved and whether an employee's performance has improved on the job. Among the methods of evaluating training are:[4] * (1) Student opinion. Questionnaires or informal discussions with employees can help employers determine the relevance and appropriateness of the training program * (2) Supervisors' observations. Supervisors are in good positions to observe an employee's performance both before and after the training and note improvements or changes * (3) Workplace improvements. The ultimate success of a training program may be changes throughout the workplace that result in reduced injury or accident rates * (4) Formal assessments. Practical and written exams also assist in evaluating understanding of training material. For example, for a lift-truck operator, a written and a practical exam would identify areas of training that may need to be revisited. Furthermore administering a pre-test and post-test will establish a knowledge base line or reference point to measure training effectiveness. * G. Improving the Program As evaluations are reviewed, it may be evident the training was not adequate and that the employees did not reach the expected level of knowledge and skill. As the program is evaluated, the trainer should ask:[4] * (1) If a job analysis was conducted, was it accurate? * (2) Was any critical feature of the job overlooked? * (3) Were the important gaps in knowledge and skill included? * (4) Was material already known by the employees intentionally omitted? * (5) Were the instructional objectives presented clearly and concretely? * (6) Did the objectives state the level of acceptable performance that was expected of employees? * (7) Did the learning activity simulate the actual job? * (8) Was the learning activity appropriate for the kinds of knowledge and skills required on the job? * (9) When the training was presented, was the organization of the material and its meaning made clear? * (10) Were the employees motivated to learn? * (11) Were the employees allowed to participate actively in the training process? * (12) Was the employer's evaluation of the program thorough? ## Computer and video training[edit] Computers and videos can be a great addition to a company's safety training program. As stand alone resources, they may not be adequate in meeting OSHA's training requirements as they are not site specific. Computer-based training can help meet the following training challenges[5] * Training employees in remote sites * Employees who become bored with the same safety training * Safety managers lack of time and resources to effectively train employees * Providing a means of documenting and tracking student progress * Lowering trainer fees or travel costs * A self-paced, relaxed learning environment ## OSHA Medical Safety[edit] There is no more important places to regard the positive impact the OSHA regulations than in the healthcare and clinical settings. OSHA has been revolutionary in the medical field due to its ability to prevent the spread of diseases. Every clinical facility on US land, civilian or military is governed by OSHA's directives. To remain in accordance to the Federal regulations enacted by OSHA healthcare administrators must maintain an OSHA safety program and train their employees on an annual basis. Some of the topics that employees must be trained on include: * Bloodborne Pathogen Standard * Chemical Hazard Communications * Tuberculosis Exposure Control * Mercury Exposure * Ionizing Radiation Exposure * Fire Escape Plan * Emergency Action Plan * Electricity Safety * Fire Safety Standard ## See also[edit] * Department of Public Safety * Loss-control consultant * National Safety Council ## References[edit] 1. ^ a b Barnett, Lawrence (2000). Safety Management Handbook: CCH Safety Professional Series. 2. Chicago, IL: Health and Human Resources. pp. 9301–9307. 2. ^ Hilyer, Barbara; Veasey, Alan; Oldfield, Kenneth; Craft-McCormick, Lisa (2000). Effective Safety and Health Training. CRC Press. ISBN 1-56670-396-4. 3. ^ Assessing Occupational Safety and Health Training: a Literature Review. NIOSH Publication No. 98-145. 1998. 4. ^ a b c Training Requirements in OSHA Standards and Training Guidelines (PDF). OSHA 2254 1998 (Revised). US Department of Labor. 5. ^ Hubiak, Stacy (September 1998). "Click On to Effective Training". Safety and Health Magazine. p. 116. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Effective safety training	None	5,589	wikipedia	https://en.wikipedia.org/wiki/Effective_safety_training	2021-01-18T18:53:48	{"wikidata": ["Q5347280"]}
For other uses, see Ptosis (disambiguation). Gastroptosis SpecialtyGastroenterology Risk factorsFemale gender[1] Diagnostic methodX-ray with barium contrast[1] Gastroptosis is the abnormal downward displacement of the stomach. It is not a life-threatening condition. The condition frequently causes digestive symptoms and constipation. It is much more prominent in women than men.[2][1] Gastroptosis is diagnosed with x-ray using barium contrast.[1] ## See also[edit] * Visceroptosis ## References[edit] 1. ^ a b c d Kusano, M; Moki, F; Hosaka, H; Shimoyama, Y; Kawamura, O; Nagoshi, A; Maeda, M; Kuribayashi, S; Zai, H; Mizuide, M; Horikoshi, T; Mori, M; Akuzawa, M (2011). "Gastroptosis is associated with less dyspepsia, rather than a cause of dyspepsia, in Japanese persons". Internal medicine (Tokyo, Japan). 50 (7): 667–71. doi:10.2169/internalmedicine.50.4582. PMID 21467696. 2. ^ Gould, George Milbry (1899). The Philadelphia Monthly Medical Journal. Philadelphia Medical Publishing Company. p. 150. Retrieved 13 November 2017. ## External links[edit] Classification D * ICD-10: K31.8 * ICD-9-CM: 537.5 * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum Authority control * NDL: 00564016 This human digestive system 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Gastroptosis	c0156088	5,590	wikipedia	https://en.wikipedia.org/wiki/Gastroptosis	2021-01-18T18:40:51	{"icd-9": ["537.5"], "icd-10": ["K31.8"], "wikidata": ["Q5526882"]}
Selmanowitz et al. (1970) suggested that fibrosis is associated with hydronephrosis and urinary tract abnormalities on a familial basis. They reported a single case, a 44-year-old woman with multiple nodules on the legs and two elsewhere and a double collecting system of the right kidney. Gelfarb and Hyman (1962) described mother and daughter with multiple nodules and associated hydronephrosis. GU \- Hydronephrosis \- Urinary tract abnormalities \- Double collecting system Inheritance \- Autosomal dominant Skin \- Nodular cutaneous fibrosis ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	NODULI CUTANEI, MULTIPLE, WITH URINARY TRACT ABNORMALITIES	c1834143	5,591	omim	https://www.omim.org/entry/163850	2019-09-22T16:37:20	{"mesh": ["C563512"], "omim": ["163850"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (February 2013) Retrocolic hernia SpecialtyGastroenterology A retrocolic hernia is a medical condition consisting of the entrapment of portions of the small intestine behind the mesocolon. It has been observed to occur as a complication of a left hemicolectomy.[1] ## References[edit] 1. ^ Angelone, G; Giardiello, C; Francica, G (October 2005). "Retrocolic small bowel herniation as a complication of laparascopic left hemicolectomy". Retrieved 21 October 2011. This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Retrocolic hernia	None	5,592	wikipedia	https://en.wikipedia.org/wiki/Retrocolic_hernia	2021-01-18T18:33:00	{"wikidata": ["Q7317002"]}
A number sign (#) is used with this entry because of evidence that autosomal visceral heterotaxy-6 (HTX6) is caused by homozygous mutation in the CCDC11 gene (614759) on chromosome 18q21. For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955). Clinical Features Perles et al. (2012) reported 2 brothers, born of consanguineous Arab-Muslim parents, with variable manifestations of visceral heterotaxy. The younger brother, aged 14 years, presented with congenital heart disease and severe cyanosis. Echocardiography showed a complex cardiovascular defect and abdominal situs abnormalities. He died after corrective surgery. Radiographs showed midline liver and inverted stomach and spleen. His heart malformation included dextrocardia, a complete unbalanced atrioventricular canal defect with single atrium and common atrioventricular valve, hypoplastic left ventricle with bulboventricular foramen, double outlet right ventricle with transposition of the great arteries, severe pulmonary stenosis, right aortic arch, abnormal systemic venous return, and total anomalous pulmonary venous drainage. In contrast, his 17-year-old, apparently healthy brother was found to have situs inversus totalis with normal cardiac anatomy and function. He had no respiratory symptoms, and sperm count, structure, and motility were normal. Light microscopy examination of a nasal sample showed beating ciliated cells, and electron microscopy showed normal ciliary ultrastructure with typical 9:2 doublet microtubules, excluding a ciliary defect. Narasimhan et al. (2015) reported a patient (OP-1069-II1), born of consanguineous parents, with situs inversus totalis. He had mild respiratory symptoms, including recurrent cough and sinusitis, but normal nasal nitric oxide levels. Further clinical details were not provided. Inheritance The transmission pattern of heterotaxy-6 in the family reported by Perles et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics By homozygosity mapping followed by candidate gene analysis of 2 brothers with heterotaxy-6, Perles et al. (2012) identified a homozygous splice site mutation in the CCDC11 gene (614759.0001). In a patient, born of consanguineous parents, with HTX6, Narasimhan et al. (2015) identified a homozygous truncating mutation in the CCDC11 gene (R41X; 614759.0002). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was found in heterozygous state in the unaffected father. CCDC11 was undetectable in patient respiratory cilia, consistent with a loss of function, but patient respiratory cilia showed no morphologic defects. Animal Model In zebrafish embryos, Narasimhan et al. (2015) found expression of ccdc11 in the cilia in Kupffer vesicle (KV), in the floor plate of the spinal cord, and in the pronephric ducts. Ccdc11 localized along the axoneme of cilia in pronephric kidney tubules but localized exclusively to the ciliary base in KV and motile cilia in the neural tube. Visualization studies indicated that ccdc11 was required for proper cilia motility in the spinal canal and KV, but not for motility in the pronephric cilia. Ultrastructural studies of the KV showed a reduction in the numbers of outer dynein arms in zebrafish with morpholino knockdown of ccdc11. Morpholino knockdown of ccdc11 resulted in phenotypes consistent with defective motile cilia, including curved body axis, hydrocephalus, edema, and abnormalities in left-right asymmetry. There were no obvious defects in the gross morphology of motile cilia. The findings indicated that ccdc11 activity is differentially required for distinct cilia types. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Dextrocardia \- Complex congenital heart malformation (in 1 patient) Vascular \- Transposition of the great arteries \- Anomalous pulmonary drainage RESPIRATORY \- Recurrent cough, mild (1 patient) ABDOMEN \- Situs inversus viscerum Liver \- Midline liver Spleen \- Inverted spleen LABORATORY ABNORMALITIES \- Normal ciliary structure and function MISCELLANEOUS \- Three patients from 2 unrelated families have been reported (last curated August 2015) \- Variable severity MOLECULAR BASIS \- Caused by mutation in the coiled-coil domain-containing protein 11 gene (CCDC11, 614759.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	HETEROTAXY, VISCERAL, 6, AUTOSOMAL	c3178805	5,593	omim	https://www.omim.org/entry/614779	2019-09-22T15:54:16	{"doid": ["0050545"], "mesh": ["D059446"], "omim": ["614779"], "orphanet": ["450"]}
A rare primordial growth disorder characterized by low birth weight, reduced birth length, severe postnatal growth restriction, large head size, a spectrum of minor anomalies (including facial dysmorphism) and normal intelligence. ## Epidemiology Approximately 200 cases have been reported to date and the condition is rare. However, the phenotype is likely under-recognized. ## Clinical description Infants present with severe prenatal and postnatal growth retardation, birth weight usually at or below the 2nd centile. Growth impairment is greater in those with CUL7 variants. The head circumference is relatively large. Characteristic facial features include: triangular-shaped face, pointed chin, frontal bossing, hypoplastic midface, fleshy, upturned nose , prominent mouth and lips. These features often become less noticeable with age. Short broad neck and thorax, prominent trapezii, winged scapulae, square shoulders, hyperlordosis and clinodactyly of the fifth finger are seen in some children. Prominent fleshy heels in infancy are a common and distinctive feature. Joint hypermobility and an increased risk of congenital hip dislocation may be present. Hyperlordosis can cause back pain. Intelligence is unaffected and development is usually normal. Some cases of impaired fertility and hypospadias have been noted in males , though this is not universal, while females have normal ovarian function. Patients reach a final adult height of about 120-130 cm (5-6 standard deviations below the mean). ## Etiology Pathogenic variants in three different genes are known to cause 3M syndrome. Variants in in the CUL7 at 6p21.1 are found in around 75% patients. Other genes known to be involved are OBSL1(2q35), in 20% of cases and CCDC8 (19q13.33) in 5% of cases. The precise mechanisms leading to growth failure in 3M syndrome remain unclear although the poor response to growth hormone in many patients indicates a degree of resistance to the GH/IGF1 pathway. ## Diagnostic methods Diagnosis is based primarily on clinical features (e.g. low birth weight, severe growth retardation, prominent fleshy heels). In some, specific radiological findings will be found, including slender/ 'gracile' long bones, relatively tall vertebral bodies, foreshortening of vertebral bodies, small pelvic bones and a broad thorax with slender and horizontal ribs. The occurrence of these radiological findings, however, is highly variable. Children with 3M syndrome usually have normal GH levels. Molecular genetic testing can identify pathogenic variants in one of the causal genes, confirming diagnosis in the majority of cases. Some children with 3M syndrome demonstrate normal-high baseline insulin-like growth factor (IGF-I) concentrations. ## Differential diagnosis Differential diagnoses include Silver-Russell syndrome, Dubowitz syndrome, Mulibrey nanism, fetal alcohol syndrome, and microdeletion of chromosome 20p13p12. ## Antenatal diagnosis Prenatal and preimplantation diagnosis is possible in families with a known disease causing variant. ## Genetic counseling 3M syndrome is inherited autosomal recessively and genetic counseling is recommended for affected families. In a family with an index patient, the sibling recurrence risk is 25%. ## Management and treatment Once diagnosed the child should be seen by a pediatric endocrinologist for monitoring of growth and pubertal progress and for consideration of recombinant human growth hormone (GH) therapy. Monitoring of growth every 6-12 months is recommended until achievement of final height. Adaptive aids for people with short stature and physiotherapy are possible treatment options. Newborns should have a hip ultrasound scan to screen for developmental dysplasia of the hip. Children can be treated with recombinant human growth hormone. In general, the response to treatment is relatively poor, however a trial of treatment over 1 year may show a reasonable response. Overall treatment with growth hormone is more successful if started early and continued long term. The issue of fertility should be discussed with male patients at the end of puberty and semen analysis offered. ## Prognosis 3M syndrome is not a life-threatening condition and the prognosis is good. * 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	3M syndrome	c1848862	5,594	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2616	2021-01-23T19:09:23	{"gard": ["5667"], "mesh": ["C535314"], "omim": ["273750", "612921", "614205"], "umls": ["C1848862", "C1851996", "C2678312"], "icd-10": ["Q87.1"], "synonyms": ["3-M syndrome", "Yakut short stature syndrome"]}
Unexplained infertility is infertility that is idiopathic in the sense that its cause remains unknown even after an infertility work-up, usually including semen analysis in the man and assessment of ovulation and fallopian tubes in the woman.[1] ## Contents * 1 Possible causes * 2 Prevalence * 3 Management * 4 Prognosis * 5 See also * 6 References ## Possible causes[edit] In unexplained infertility abnormalities are likely to be present but not detected by current methods. Possible problems could be that the egg is not released at the optimum time for fertilization, that it may not enter the fallopian tube, sperm may not be able to reach the egg, fertilization may fail to occur, transport of the zygote may be disturbed, or implantation fails. It is increasingly recognized that egg quality is of critical importance and women of advanced maternal age have eggs of reduced capacity for normal and successful fertilization. Also, polymorphisms in folate pathway genes could be one reason for fertility complications in some women with unexplained infertility.[2] Aberrant reproductive immunology such as decreased maternal immune tolerance towards the embryo may also be a possible explanation. However, a growing body of evidence suggests that epigenetic modifications in sperm may be partially responsible.[3][4] ## Prevalence[edit] Data from UK, 2009.[5] Globally, about 10% of infertile couples have unexplained infertility.[6] ## Management[edit] Potential methods in unexplained infertility include oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) as well as intrauterine insemination (IUI), intracervical insemination (ICI) and in vitro fertilization (IVF). In women who have not had previous treatment, ovarian stimulation combined with IUI achieves approximately the same live birth rate as IVF.[7] On the other hand, in women who have had previous unsuccessful treatment, IVF achieves a live birth rate approximately 2–3 times greater than ovarian stimulation combined with IUI.[7] IUI and ICI has higher pregnancy rates when combined with ovarian stimulation in couples with unexplained infertility, for IUI being 13% unstimulated and 15% stimulated, and for ICI being 8% unstimulated and 15% stimulated. However, the rate of twin birth increases substantially with IUI or ICI combined with ovarian stimulation, for IUI being 6% unstimulated and 23% stimulated, and for ICI being 6% unstimulated and 23% stimulated.[8] According to NICE guidelines, oral ovarian stimulation agents should not be given to women with unexplained infertility.[9] Rather, it is recommended that in vitro fertilization should be offered to women with unexplained infertility when they have not conceived after two years of regular unprotected sexual intercourse.[9] IVF avails for embryo transfer of the appropriate number of embryos to give good chances of pregnancy with minimal risk of multiple birth. A review of randomized studies came to the result that IVF in couples with a high chance of natural conception, as compared to IUI/ICI with or without ovarian stimulation, was more effective in three studies and less effective in two studies.[8] There is no evidence for an increased risk of ovarian hyperstimulation syndrome (OHSS) with IVF when compared with ovarian stimulation combined with IUI.[7] ## Prognosis[edit] Prognosis in unexplained infertility depends on many factors, but can roughly be estimated by e.g. the Hunault model, which takes into account female age, duration of infertility/subfertility, infertility/subfertility being primary or secondary, percentage of motile sperm and being referred by a general practitioner or gynecologist.[8][10] ## See also[edit] * Male infertility * Female infertility ## References[edit] 1. ^ merckmanuals > Unexplained Infertility Last full review/revision November 2008 by Robert W. Rebar, MD 2. ^ Altmäe S, Stavreus-Evers A, Ruiz JR, Laanpere M, Syvänen T, Yngve A, Salumets A, Nilsson TK (Jun 2010). "Variations in folate pathway genes are associated with unexplained female infertility". Fertility and Sterility. 94 (1): 130–7. doi:10.1016/j.fertnstert.2009.02.025. PMID 19324355. 3. ^ Kenneth I. Aston; Philip J. Uren; Timothy G. Jenkins; Alan Horsager; Bradley R. Cairns; Andrew D. Smith; Douglas T. Carrell (December 2015). "Aberrant sperm DNA methylation predicts male fertility status and embryo quality". Fertility and Sterility. 104 (6): 1388–1397. doi:10.1016/j.fertnstert.2015.08.019. PMID 26361204. 4. ^ Dada R, Kumar M, Jesudasan R, Fernández JL, Gosálvez J, Agarwal A (2012). "Epigenetics and its role in male infertility". J. Assist. Reprod. Genet. 29: 213–23. doi:10.1007/s10815-012-9715-0. PMC 3288140. PMID 22290605. 5. ^ Regulated fertility services: a commissioning aid - June 2009, from the Department of Health UK 6. ^ [1] Merck Manuals 7. ^ a b c "IVF for unexplained infertility". Human Reproduction Update. 19 (5): 431. 2013. doi:10.1093/humupd/dmt005. 8. ^ a b c van den Boogaard NM, Bensdorp AJ, Oude Rengerink K, Barnhart K, Bhattacharya S, Custers IM, Coutifaris C, Goverde AJ, Guzick DS, Hughes EC, Factor-Litvak P, Steures P, Hompes PG, van der Veen F, Mol BW, Bossuyt P (2013). "Prognostic profiles and the effectiveness of assisted conception: secondary analyses of individual patient data". Human Reproduction Update. 20 (1): 141–51. doi:10.1093/humupd/dmt035. PMID 24173882. 9. ^ a b Fertility: assessment and treatment for people with fertility problems. NICE clinical guideline CG156 - Issued: February 2013 10. ^ Quaas A, Dokras A (2008). "Diagnosis and Treatment of Unexplained Infertility". 1 (2). Reviews in Obstetrics and Gynecology. PMID 18769664. Retrieved 10 Sep 2020. Cite journal requires `\|journal=` (help) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Unexplained infertility	c0404585	5,595	wikipedia	https://en.wikipedia.org/wiki/Unexplained_infertility	2021-01-18T18:48:28	{"umls": ["C0404585"], "wikidata": ["Q686627"]}
ADNP syndrome, also known as Helsmoortel-van der Aa syndrome, is a complex neuro-developmental disorder that affects the brain and many other areas and functions of the body. ADNP syndrome can affect muscle tone, feeding, growth, hearing, vision, sleep, fine and gross motor skills, as well as the immune system, heart, endocrine system, and gastrointestinal tract.[1] ADNP syndrome causes behavior disorders such as Autism Spectrum Disorder (ASD). ADNP is caused by a non-inherited (de novo) ADNP gene mutation. ADNP syndrome is thought to be one of the most common causes of non-inherited genetic autism.[1] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	ADNP syndrome	c4014538	5,596	gard	https://rarediseases.info.nih.gov/diseases/12931/adnp-syndrome	2021-01-18T18:02:16	{"omim": ["615873"], "orphanet": ["404448"], "synonyms": ["Helsmoortel-Van Der Aa Syndrome", "ADNP-related syndromic intellectual disability-autism spectrum disorder", "HVDAS", "Helsmoortel-van der Aa Syndrome"]}
A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) due to pterin-4-alpha-carbinolamine dehydratase deficiency (HPABH4D) is caused by homozygous or compound heterozygous mutation in the PCBD gene (126090), which encodes an enzyme involved in the salvage pathway for BH4, on chromosome 10q22. Description Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) D is an autosomal recessive disorder characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported (Thony et al., 1998). Patients may also develop hypomagnesemia and nonautoimmune diabetes mellitus during puberty (summary by Ferre et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640). Clinical Features Primapterinuria, a variant form of hyperphenylalaninemia, is characterized by excretion of 7-substituted pterins in urine (Curtius et al., 1988). Patients were reported by Dhondt et al. (1987, 1988), Blaskovics and Giudici (1988), and Blau et al. (1988). Patients with primapterinuria show an increased ratio of neopterin to biopterin in the urine, excretion of subnormal levels of biopterins, and normal levels of biogenic amines in cerebrospinal fluid. In all cases, hyperphenylalaninemia was transient. Loading tests with tetrahydrobiopterin and sepiapterin suggested that 7-biopterin (primapterin) is formed by rearrangement from 6-substituted pterins (Giudici et al., 1991). Blau et al. (1992) proposed that carbinolamine dehydratase deficiency is responsible for the findings in a female patient studied in detail. A brother showed a similar pterin pattern, had had a transient plasma phenylalanine elevation in the neonatal period, and was later clinically normal. Adler et al. (1992) independently suspected that carbinolamine dehydratase is the site of the deficiency. Furthermore, they performed kinetic experiments to verify that tetrahydroprimapterin inhibits phenylalanine hydroxylase. Thony et al. (1998) reported 6 patients with mild hyperphenylalaninemia on neonatal screening who were found to have increased serum and urinary 7-biopterin. Ferre et al. (2014) reported follow-up of 1 of the patients (BIODEF 272) reported by Thony et al. (1998), and noted that he had developed nonautoimmune diabetes mellitus in his late teens. He was initially treated with insulin, but was later managed well on oral agents. The patient also had hypomagnesemia and hypermagnesuria. Thony et al. (1998) reported 4 unrelated children with HPABH4D confirmed by genetic analysis. Three patients were detected by neonatal screening, whereas 1 had normal neonatal screening but developed hyperphenylalaninemia at age 1 month. All patients also showed increased urinary 7-biopterin levels. Treatment of 2 patients with BH4 resulted in decreased phenylalanine levels. All patients had normal psychomotor development between ages 2 and 6 years. Ferre et al. (2014) reported follow-up of 2 of the patients (BIODEF 329 and BIODEF 319) reported by Thony et al. (1998). One had hypomagnesemia and hypermagnesuria but did not develop diabetes mellitus, whereas the other had borderline hypomagnesemia and developed nonautoimmune diabetes mellitus at age 16 years. Simaite et al. (2014) reported a girl from a consanguineous Turkish family who developed nonautoimmune diabetes mellitus at age 14 years. Linkage analysis and whole-genome sequencing identified a homozygous truncating mutation in the PCBD1 gene in this patient, consistent with a diagnosis of HPABH4D. However, the patient had no history of hyperphenylalaninemia, even as a newborn. By reevaluation of patients with neonatal hyperphenylalaninemia caused by PCBD1 mutations who were included in a database, they found that 3 of 7 children from 6 families developed antibody-negative diabetes mellitus with normal pancreatic morphology during puberty. Two of the 7 patients were younger than 5 years of age. Several of these patients had previously been reported by Thony et al. (1998) and Thony et al. (1998). The patients showed a good response to oral sulfonylureas or glinides. Eight family members in 4 families developed type 2 diabetes as adults; heterozygous PCBD1 mutations were confirmed in 4 of these individuals, all of whom were obese or overweight. No heterozygous mutation carriers with a normal body mass index developed type 2 diabetes. Simaite et al. (2014) suggested that patients with biallelic PCBD1 mutations be monitored for early-onset diabetes, and that even heterozygous PCBD1 mutations may increase susceptibility to type 2 diabetes when combined with other risk factors. Inheritance The transmission pattern of HPABH4D in the families reported by Simaite et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics Citron et al. (1993) identified mutations in the 4-alpha-carbinolamine dehydratase gene in a mildly hyperphenylalaninemic child who excreted large amounts of 7-biopterin (126090.0001; 126090.0002). In the family reported by Citron et al. (1993), no phenotypic manifestations were evident other than the presence of 7-biopterin and elevated blood levels of phenylalanine in the proband. Clinical liver function tests yielded results within the normal range. In 6 patients with hyperphenylalaninemia with high levels of 7-biopterin, Thony et al. (1998) demonstrated homozygous mutations in the PCBD gene (see 126090.0001, 126090.0003, and 126090.0005). Ferre et al. (2014) found that 5 previously reported PCBD1 mutations in HPABH4D patients (e.g., Q87X, 126090.0001; E27X, 126090.0006; Q98X, 126090.0005) resulted in proteolytic instability, leading to reduced FXYD2 (601814) promoter activity and increased renal magnesium loss. Cytosolic localization of PCBD1 increased when coexpressed with HNF1B (189907) mutants. The findings established PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the renal distal collecting tubule. Animal Model Simaite et al. (2014) found that Pcbd1 is expressed in the developing pancreas in both mouse and Xenopus embryos. Morpholino knockdown of pcbd1 in Xenopus resulted in a significant reduction in the expression of pancreatic progenitor genes, as well as reduced expression of hnf1b. The finding suggested that pcbd1 activity in the endoderm is required for proper establishment of the pancreas. In mice, Ferre et al. (2014) found expression of Pcbd1 mostly in the distal convoluted tubule of the kidney. Pcbd1 expression increased when mice were fed a low magnesium diet, suggesting that Pcbd1 is important for renal magnesium reabsorption. In vitro studies showed that PCBD1 regulated HNF1B-mediated transcription of FXYD2, influencing active renal magnesium absorption. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Hypotonia, mild, transient \- Hypertonia, mild, transient \- Delayed motor development, mild, transient \- Tremor, mild, transient ENDOCRINE : Nonautoimmune diabetes mellitus, juvenile-onset LABORATORY ABNORMALITIES \- Hyperphenylalaninemia \- Increased urinary 7-biopterin (primapterin) \- Increased urinary neopterin \- Low serum magnesium \- Increased urinary magnesium \- Normal CSF neurotransmitters MISCELLANEOUS \- Generally mild phenotype \- Neurologic signs are present in the neonatal period only \- Neurologic signs may not be present \- Defect in tetrahydrobiopterin (BH4) synthesis \- Favorable response to BH4 therapy \- Diabetes mellitus develops in adolescence MOLECULAR BASIS \- Caused by mutation in the pterin-4-alpha-carbinolamine dehydratase 1 gene (PCBD1, 126090.0001 ) ▲ 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	HYPERPHENYLALANINEMIA, BH4-DEFICIENT, D	c0751436	5,597	omim	https://www.omim.org/entry/264070	2019-09-22T16:23:13	{"mesh": ["D010661"], "omim": ["264070"], "orphanet": ["238583", "1578"], "synonyms": ["Alternative titles", "HYPERPHENYLALANINEMIA, TETRAHYDROBIOPTERIN-DEFICIENT, DUE TO PTERIN-4-ALPHA-CARBINOLAMINE DEHYDRATASE DEFICIENCY", "HYPERPHENYLALANINEMIA WITH PRIMAPTERINURIA", "CADH DEFICIENCY", "PCBD DEFICIENCY"]}
Abdominal cystic lymphangioma is a benign (noncancerous) malformation of the lymphatic vessels in the abdomen. These vessels carry lymph, a fluid that contains white blood cells that fight infection, throughout the body. The severity of the condition and the associated features vary from person to person. When present, signs and symptoms may include abdominal pain, an increase in waist circumference, an abdominal mass, intestinal obstruction, and/or volvulus (a twisting of the intestines). The cause of abdominal cystic lymphangioma is poorly understood; however, scientists suspect that it is a congenital anomaly. Most cases are diagnosed in people with no family history of the condition. Treatment varies based on the severity of the condition. People with small malformations that do not cause any symptoms may simply be followed with regular imaging studies to monitor for progression. Some of these cases may resolve spontaneously without treatment. When necessary, surgical excision is often the treatment of choice since it is associated with the lowest risk 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 inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Abdominal cystic lymphangioma	c2930929	5,598	gard	https://rarediseases.info.nih.gov/diseases/439/abdominal-cystic-lymphangioma	2021-01-18T18:02:24	{"mesh": ["C535553"], "umls": ["C2930929"], "synonyms": ["Retroperitoneal cystic lymphangioma", "RCL", "Abdominal retroperitoneal lymphangioma"]}
Metal toxicity or metal poisoning is the toxic effect of certain metals in certain forms and doses on life. Some metals are toxic when they form poisonous soluble compounds. Certain metals have no biological role, i.e. are not essential minerals, or are toxic when in a certain form.[1] In the case of lead, any measurable amount may have negative health effects.[2] Often heavy metals are thought as synonymous, but lighter metals may also be toxic in certain circumstances, such as beryllium and lithium. Not all heavy metals are particularly toxic, and some are essential, such as iron. The definition may also include trace elements when in abnormally high doses may be toxic. An option for treatment of metal poisoning may be chelation therapy, which is a technique which involves the administration of chelation agents to remove metals from the body. Toxic metals sometimes imitate the action of an essential element in the body, interfering with the metabolic process resulting in illness. Many metals, particularly heavy metals are toxic, but some heavy metals are essential, and some, such as bismuth, have a low toxicity. Most often the definition of toxic metals includes at least thallium, cadmium, manganese, lead, mercury and the radioactive metals.[3] Metalloids (arsenic, polonium) may be included in the definition. Radioactive metals have both radiological toxicity and chemical toxicity. Metals in an oxidation state abnormal to the body may also become toxic: chromium(III) is an essential trace element, but chromium(VI) is a carcinogen. Toxicity is a function of solubility. Insoluble compounds as well as the metallic forms often exhibit negligible toxicity. The toxicity of any metal depends on its ligands. In some cases, organometallic forms, such as methylmercury and tetraethyl lead, can be extremely toxic. In other cases, organometallic derivatives are less toxic such as the cobaltocenium cation. Decontamination for toxic metals is different from organic toxins: because toxic metals are elements, they cannot be destroyed. Toxic metals may be made insoluble or collected, possibly by the aid of chelating agents, or through bioremediation. Alternatively, they can be diluted into a sufficiently large reservoir, such as the sea, because immediate toxicity is a function of concentration rather than amount. Toxic metals can bioaccumulate in the body and in the food chain.[citation needed] Therefore, a common characteristic of toxic metals is the chronic nature of their toxicity. This is particularly notable with radioactive heavy metals such as radium, which imitates calcium to the point of being incorporated into human bone, although similar health implications are found in lead or mercury poisoning. ## Contents * 1 Testing for poisoning * 2 Treatment for poisoning * 3 Specific types of poisoning * 3.1 Aluminium phosphide poisoning * 3.2 Arsenic poisoning * 3.3 Beryllium poisoning * 3.4 Cadmium poisoning * 3.5 Copper toxicity * 3.6 Iron poisoning * 3.7 Lead poisoning * 3.8 Lithium poisoning * 3.9 Manganese poisoning, or manganism * 3.10 Mercury poisoning * 3.11 Silver poisoning (Argyria) * 3.12 Thallium poisoning * 3.13 Tin poisoning * 3.14 Zinc toxicity * 4 Society and culture * 5 References * 6 External links ## Testing for poisoning[edit] People are continually exposed to metals in the environment.[4] Medical tests can detect metals often, but this is to be expected and alone is not evidence that a person is poisoned.[4] Metal screening tests should not be used unless there is reason to believe that a person has had excessive exposure to metals.[4] People should seek medical testing for poisoning only if they are concerned for a particular reason, and physicians should consider a patient's history and physical examination before conducting tests to detect metals. ## Treatment for poisoning[edit] Chelation therapy is a medical procedure that involves the administration of chelating agents to remove heavy metals from the body. Chelating agents are molecules that have multiple electron-donating groups, which can form stable coordination complexes with metal ions. Complexation prevents the metal ions from reacting with molecules in the body, and enable them to be dissolved in blood and eliminated in urine. It should only be used in people who have a diagnosis of metal intoxication.[5] That diagnosis should be validated with tests done in appropriate biological samples.[5] Chelation therapy is administered under very careful medical supervision due to various inherent risks.[6] Even when the therapy is administered properly, the chelation drugs can have significant side effects.[5] Chelation administered inappropriately can cause neurodevelopmental toxicity, increase risk of developing cancer, and cause death;[5] chelation also removes essential metal elements and requires measures to prevent their loss. ## Specific types of poisoning[edit] ### Aluminium phosphide poisoning[edit] Main article: Aluminium phosphide poisoning Aluminium has no known biological role and its classification into toxic metals is controversial. Acute aluminium phosphide poisoning (AAlPP) is a large, though under-reported, problem in the Indian subcontinent. Aluminium phosphide (AlP), which is readily available as a fumigant for stored cereal grains, sold under various brand names such as QuickPhos and Celphos, is highly toxic, especially when consumed from a freshly opened container.[7][8] Death results from profound shock, myocarditis and multi-organ failure.[9] Aluminium phosphide has a fatal dose of between 0.15 and 0.5 grams (0.0053 and 0.0176 oz).[10] It has been reported to be the most common cause of suicidal death in North India.[11] The very high toxicity of aluminium phosphide is attributed to the phosphine content and is not related to aluminium. Calcium phosphide and zinc phosphide are similar poisons. ### Arsenic poisoning[edit] Main article: Arsenic poisoning Arsenic poisoning is a medical condition caused by elevated levels of arsenic in the body. The dominant basis of arsenic poisoning is from ground water that naturally contains high concentrations of arsenic. A 2007 study found that over 137 million people in more than 70 countries are probably affected by arsenic poisoning from drinking water.[12] ### Beryllium poisoning[edit] Main article: Beryllium poisoning Beryllium poisoning is illness resulting from the toxic effect of beryllium in its elemental form or in various chemical compounds. The toxicity of beryllium depends upon the duration, intensity and frequency of exposure (features of dose), as well as the form of beryllium and the route of exposure (i.e. inhalation, dermal, ingestion). According to the International Agency for Research on Cancer (IARC), beryllium and beryllium compounds are Category 1 carcinogens; they are carcinogenic to both animals and humans.[13] ### Cadmium poisoning[edit] Main article: Cadmium poisoning Cadmium is an extremely toxic metal commonly found in industrial workplaces. Due to its low permissible exposure limit, overexposures may occur even in situations where trace quantities of cadmium are found. Cadmium is used extensively in electroplating, although the nature of the operation does not generally lead to overexposures. Cadmium is also found in some industrial paints and may represent a hazard when sprayed. Operations involving removal of cadmium paints by scraping or blasting may pose a significant hazard. Cadmium is also present in the manufacturing of some types of batteries. Exposures to cadmium are addressed in specific standards for the general industry, shipyard employment, construction industry, and the agricultural industry.[14] ### Copper toxicity[edit] Main article: Copper toxicity Copper toxicity, also called copperiedus, refers to the consequences of an excess of copper in the body. Copperiedus can occur from eating acid foods cooked in uncoated copper cookware, or from exposure to excess copper in drinking water, as a side-effect of estrogen birth control pills, or other environmental sources. It can also result from the genetic condition Wilson's disease. ### Iron poisoning[edit] Main article: Iron poisoning Iron poisoning is an iron overload caused by a large excess of iron intake and usually refers to an acute overload rather than a gradual one. The term has been primarily associated with young children who consumed large quantities of iron supplement pills, which resemble sweets and are widely used, including by pregnant women—see overnutrition (approximately 3 grams is lethal for a 2 year old).[15] Targeted packaging restrictions in the US for supplement containers with over 250 mg elemental iron have existed since 1978, and recommendations for unit packaging have reduced the several iron poisoning fatalities per year to almost nil since 1998.[16][17] No known cases of iron poisoning have been identified that are associated with iron mining.[citation needed] ### Lead poisoning[edit] Main article: Lead poisoning Lead poisoning is a medical condition in humans and other vertebrates caused by increased levels of the heavy metal lead in the body. Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems. It interferes with the development of the nervous system and is therefore particularly toxic to children, causing potentially permanent learning and behavior disorders. Symptoms include abdominal cramping, constipation, tremors, mood changes, infertility, anemia, and toxic psychosis.[18] ### Lithium poisoning[edit] Lithium is used in some medications, specifically to treat bipolar disorder. The level of "sufficient" medication is thought by many physicians to be close to toxic tolerance for kidney function. Therefore, the patient is often monitored for this purpose.[19][20] ### Manganese poisoning, or manganism[edit] Main article: Manganism Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese and first identified in 1837 by James Couper.[21] ### Mercury poisoning[edit] Main article: Mercury poisoning Mercury poisoning is a disease caused by exposure to mercury or its compounds. Mercury (chemical symbol Hg) is a heavy metal occurring in several forms, all of which can produce toxic effects in high enough doses. Its zero oxidation state Hg0 exists as vapor or as liquid metal, its mercurous state Hg22+ exists as inorganic salts, and its mercuric state Hg2+ may form either inorganic salts or organomercury compounds; the three groups vary in effects. Toxic effects include damage to the brain, kidney, and lungs. Mercury poisoning can result in several diseases, including acrodynia (pink disease), Hunter-Russell syndrome, and Minamata disease.[citation needed] Symptoms typically include sensory impairment (vision, hearing, speech), disturbed sensation and a lack of coordination. The type and degree of symptoms exhibited depend upon the individual toxin, the dose, and the method and duration of exposure.[citation needed] ### Silver poisoning (Argyria)[edit] A 92-year-old Caucasian man (right) with pigmentary changes had used nose drops containing silver for many years. His skin biopsy showed silver deposits in the dermis, confirming the diagnosis of generalized argyria.[22] Main article: Argyria Argyria or argyrosis is a condition caused by inappropriate exposure to chemical compounds of the element silver, or to silver dust.[23] The most dramatic symptom of argyria is that the skin turns blue or bluish-grey. It may take the form of generalized argyria or local argyria. Generalized argyria affects large areas over much of the visible surface of the body. Local argyria shows in limited regions of the body, such as patches of skin, parts of the mucous membrane or the conjunctiva.[24] ### Thallium poisoning[edit] Main article: Thallium poisoning Thallium and its compounds are often highly toxic.[25] Contact with skin is dangerous, and adequate ventilation should be provided when melting this metal.[26] Many thallium(I) compounds are highly soluble in water and are readily absorbed through the skin.[citation needed] Exposure to them should not exceed 0.1 mg per m2 of skin in an 8-hour time-weighted average (40-hour work week). Thallium is a suspected human carcinogen.[26] ### Tin poisoning[edit] Main article: Tin poisoning Tin poisoning refers to the toxic effects of tin and its compounds. Cases of poisoning from tin metal, its oxides, and its salts are "almost unknown"; on the other hand certain organotin compounds are almost as toxic as cyanide.[27] ### Zinc toxicity[edit] Main article: Zinc toxicity Even though zinc is an essential requirement for a healthy body, excess zinc can be harmful, and cause zinc toxicity. Such toxicity levels have been seen to occur at ingestion of greater than 225 mg of Zinc.[28] Excessive absorption of zinc can suppress copper and iron absorption. The free zinc ion in solution is highly toxic to bacteria, plants, invertebrates, and even vertebrate fish.[29][30][31] ## Society and culture[edit] It is difficult to differentiate the effects of low level metal poisoning from the environment with other kinds of environmental harms, including nonmetal pollution.[32] Generally, increased exposure to heavy metals in the environment increases risk of developing cancer.[33] Without a diagnosis of metal toxicity and outside of evidence-based medicine, but perhaps because of worry about metal toxicity, some people seek chelation therapy to treat autism, cardiovascular disease, Alzheimer's disease, or any sort of neurodegeneration.[5] Chelation therapy does not improve outcomes for those diseases.[5] ## References[edit] 1. ^ "A Metals Primer". Dartmouth Toxic Metals Superfund Research Program. 2012-05-30. Archived from the original on 2013-12-30. Retrieved 2013-12-29. 2. ^ "Announcement: Response to the Advisory Committee on Childhood Lead Poisoning Prevention Report, Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention". Centers for Disease Control and Prevention. 2012-05-25. Archived from the original on 2017-04-30. 3. ^ "Radium". Toxic Substances Portal. Agency for Toxic Substances and Disease Registry. March 3, 2011. 4. ^ a b c American College of Medical Toxicology; American Academy of Clinical Toxicology (February 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American College of Medical Toxicology and American Academy of Clinical Toxicology, archived from the original on 4 December 2013, retrieved 5 December 2013 5. ^ a b c d e f American College of Medical Toxicology; American Academy of Clinical Toxicology (February 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American College of Medical Toxicology and American Academy of Clinical Toxicology, archived from the original on 4 December 2013, retrieved 5 December 2013, which cites * Medical Letter consultants (September 20, 2010). "Nonstandard uses of chelation therapy". The Medical Letter on Drugs and Therapeutics. 52 (1347): 75–6. PMID 20847718. Archived from the original on July 14, 2014. * Kosnett, M J (2010). "Chelation for Heavy Metals (Arsenic, Lead, and Mercury): Protective or Perilous?". Clinical Pharmacology & Therapeutics. 88 (3): 412–415. doi:10.1038/clpt.2010.132. ISSN 0009-9236. PMID 20664538. 6. ^ Atwood, K.C., IV; Woeckner, E.; Baratz, R.S.; Sampson, W.I. (2008). "Why the NIH Trial to Assess Chelation Therapy (TACT) should be abandoned". Medscape Journal of Medicine. 10 (5): 115. PMC 2438277. PMID 18596934. 7. ^ Chugh, SN; Dushyant; Ram, S; Arora, B; Malhotra, KC (1991). "Incidence & outcome of aluminium phosphide poisoning in a hospital study". The Indian Journal of Medical Research. 94: 232–5. PMID 1937606. 8. ^ Singh S, Singh D, Wig N, Jit I, Sharma BK; Singh; Wig; Jit; Sharma (1996). "Aluminum phosphide ingestion—a clinico-pathologic study". J Toxicol Clin Toxicol. 34 (6): 703–6. doi:10.3109/15563659609013832. PMID 8941200.CS1 maint: multiple names: authors list (link) 9. ^ Mathai, Ashu; Bhanu, Madhuritasingh (2010). "Acute aluminium phosphide poisoning: Can we predict mortality?". Indian Journal of Anaesthesia. 54 (4): 302–7. doi:10.4103/0019-5049.68372. PMC 2943698. PMID 20882171. 10. ^ A Wahab; MS Zaheer; S Wahab; RA Khan. "Acute aluminium phosphide poisoning: an update" (PDF). Hong Kong Journal of Emergency Medicine: 152. Archived (PDF) from the original on 2012-01-31. 11. ^ Siwach, SB; Gupta, A (1995). "The profile of acute poisonings in Harayana-Rohtak Study". The Journal of the Association of Physicians of India. 43 (11): 756–9. PMID 8773034. 12. ^ See: * "Arsenic in drinking water seen as threat," USAToday.com, August 30, 2007. * See page 6 of: Peter Ravenscroft, "Predicting the global distribution of arsenic pollution in groundwater." Archived 2013-07-01 at the Wayback Machine Paper presented at: "Arsenic -- The Geography of a Global Problem," Archived 2013-07-01 at the Wayback Machine Royal Geographic Society Arsenic Conference held at: Royal Geographic Society, London, England, August 29, 2007. This conference is part of The Cambridge Arsenic Project Archived 2012-11-17 at the Wayback Machine. 13. ^ "IARC Monograph, Volume 58". International Agency for Research on Cancer. 1993. Archived from the original on 2012-07-31. Retrieved 2008-09-18. 14. ^ "Safety and Health Topics \| Cadmium". Osha.gov. Archived from the original on 2013-06-06. Retrieved 2013-07-08. 15. ^ "Plants Poisonous to Livestock - Cornell University Department of Animal Science". Ansci.cornell.edu. Archived from the original on 2012-02-05. Retrieved 2012-04-09. 16. ^ Tenenbein, Milton (2005). "Unit-Dose Packaging of Iron Supplements and Reduction of Iron Poisoning in Young Children". Archives of Pediatrics & Adolescent Medicine. 159 (6): 557–60. doi:10.1001/archpedi.159.6.557. PMID 15939855. 17. ^ AAPCC Annual Reports, American Association of Poison Control Centers.[failed verification] Archived May 22, 2008, at the Wayback Machine 18. ^ O’Malley, R.; O’Malley, G. (February 2018). "Lead Poisoning (Plumbism)". Merck Manual. 19. ^ Lithium Nephropathy at eMedicine 20. ^ Markowitz, Glen S.; Radhakrishnan, Jai; Kambham, Neeraja; Valeri, Anthony M.; Hines, William H.; D'Agati, Vivette D. (2000). "Lithium Nephrotoxicity: A Progressive Combined Glomerular and Tubulointerstitial Nephropathy". Journal of the American Society of Nephrology. 11 (8): 1439–48. PMID 10906157. 21. ^ Couper, J. (1837). "Sur les effets du peroxide de manganèse". Journal de chimie médicale, de pharmacie et de toxicologie. 3: 223–225. Archived from the original on 2014-07-22. 22. ^ Fred, Herbert (2008). Images of Memorable Cases: 50 Years at the Bedside. ISBN 9780892630004. 23. ^ James, William D.; Berger, Timothy G.; Elston, Dirk M.; Odom, Richard B. (2006). Andrews' diseases of the skin: clinical dermatology. Saunders Elsevier. p. 858. ISBN 0-7216-2921-0. OCLC 62736861. 24. ^ Isak, Beerli, Cozzio, Flatz (January–April 2019). A Rare Case of Localized Argyria on the Face (Report). Case Reports in Dermatology. Retrieved 23 January 2020.CS1 maint: uses authors parameter (link) 25. ^ Thallium Toxicity at eMedicine 26. ^ a b "Biology of Thallium". webelemnts. Archived from the original on 2008-04-10. Retrieved 2008-11-11. 27. ^ Graf, Günter G. (2000). "Tin, Tin Alloys, and Tin Compounds". Ullmann's Encyclopedia of Industrial Chemistry. Wiley. doi:10.1002/14356007.a27_049. ISBN 978-3-527-30673-2. 28. ^ Fosmire, Gary J (1990). "Zinc toxicity". The American Journal of Clinical Nutrition. 51 (2): 225–7. doi:10.1093/ajcn/51.2.225. PMID 2407097. 29. ^ Rout, Gyana Ranjan; Das, Premananda (2009). "Effect of Metal Toxicity on Plant Growth and Metabolism: I. Zinc". In Lichtfouse, Eric; Navarrete, Mireille; Debaeke, Philippe; Véronique, Souchere; Alberola, Caroline (eds.). Sustainable Agriculture. pp. 873–84. doi:10.1007/978-90-481-2666-8_53. ISBN 978-90-481-2666-8. INIST:14709198. 30. ^ Smith, SE; Larson, EJ (1946). "Zinc toxicity in rats; antagonistic effects of copper and liver". The Journal of Biological Chemistry. 163: 29–38. PMID 21023625. 31. ^ Muyssen, Brita T.A.; De Schamphelaere, Karel A.C.; Janssen, Colin R. (2006). "Mechanisms of chronic waterborne Zn toxicity in Daphnia magna". Aquatic Toxicology. 77 (4): 393–401. doi:10.1016/j.aquatox.2006.01.006. PMID 16472524. 32. ^ Liu, J; Lewis, G (Jan–Feb 2014). "Environmental toxicity and poor cognitive outcomes in children and adults". Journal of environmental health. 76 (6): 130–8. PMID 24645424. 33. ^ Tabrez, Shams; Priyadarshini, Medha; Priyamvada, Shubha; Khan, Mohd Shahnawaz; NA, Arivarasu; Zaidi, Syed Kashif (2014). "Gene–environment interactions in heavy metal and pesticide carcinogenesis". Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 760: 1–9. doi:10.1016/j.mrgentox.2013.11.002. ## External links[edit] * Dartmouth Toxic Metals Superfund Research Program * Toxic Metals (OSHA) * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: 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 [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid *[pop.]: population	Metal toxicity	c0274869	5,599	wikipedia	https://en.wikipedia.org/wiki/Metal_toxicity	2021-01-18T18:59:55	{"mesh": ["D000075322", "D020260"], "umls": ["C0274869"], "icd-10": ["T56"], "wikidata": ["Q4215775"]}

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