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Hereditary elliptocytosis (HE) refers to a group of inherited blood conditions where the red blood cells are abnormally shaped. Symptoms vary from very mild to severe and can include fatigue, shortness of breath, gallstones, and yellowing of the skin and eyes (jaundice). Some people with this condition have an enlarged spleen. Hereditary elliptocytosis is caused by a genetic change in either the EPB41, SPTA1, or SPTB gene, and is inherited in an autosomal dominant pattern. Hereditary pyropoikilocytosis is a related condition with more serious symptoms, and is inherited in an autosomal recessive pattern.[15369] Diagnosis of this condition is made by looking at the shape of the red blood cells under a microscope. Treatment is usually not necessary unless severe anemia occurs. In severe cases, surgery to remove the spleen may decrease the rate of red blood cell damage. HE is generally not life-threatening. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hereditary elliptocytosis	c0013902	1,100	gard	https://rarediseases.info.nih.gov/diseases/6621/hereditary-elliptocytosis	2021-01-18T18:00:03	{"mesh": ["D004612"], "umls": ["C0013902"], "orphanet": ["288"], "synonyms": []}
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a genetic condition that leads to the growth of both non-cancerous and cancerous tumors. Symptoms of BRRS may include large head size, increased birth weight, developmental delay, and intellectual disability. Other symptoms include the appearance of non-cancerous tumors in the digestive system, fatty tumors under the skin, and freckles on the penis. People with BRRS have an increased risk of developing breast, thyroid, and uterine cancer. This condition is part of a group of conditions known as the PTEN hamartoma tumor syndromes, which all share similar features and are caused by genetic changes (DNA variants) in the PTEN gene. BRRS is inherited in an autosomal dominant pattern. Diagnosis is based on clinical exam, the symptoms, and genetic testing. Treatment is aimed at managing the symptoms and careful monitoring for signs of cancer. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Bannayan-Riley-Ruvalcaba syndrome	c0265326	1,101	gard	https://rarediseases.info.nih.gov/diseases/5887/bannayan-riley-ruvalcaba-syndrome	2021-01-18T18:01:54	{"mesh": ["D006223"], "omim": ["158350"], "umls": ["C0265326"], "orphanet": ["109"], "synonyms": ["BRRS", "Riley-Smith syndrome", "Macrocephaly multiple lipomas and hemangiomata", "Ruvalcaba -Myhre-Smith syndrome", "RMSS", "Bannayan-Zonana syndrome", "BZS", "Macrocephaly pseudopapilledema and multiple hemangiomas"]}
Albuminuria SpecialtyNephrology Albuminuria is a pathological condition wherein the protein albumin is abnormally present in the urine. It is a type of proteinuria. Albumin is a major plasma protein (normally circulating in the blood); in healthy people, only trace amounts of it are present in urine, whereas larger amounts occur in the urine of patients with kidney disease. For a number of reasons, clinical terminology is changing to focus on albuminuria more than proteinuria.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] It is usually asymptomatic but whitish foam may appear in urine. Swelling of the ankles, hands, belly or face may occur if losses of albumin are significant and produce low serum protein levels (nephrotic syndrome). ## Causes[edit] The kidneys normally do not filter large molecules into the urine, so albuminuria can be an indicator of damage to the kidneys or excessive salt intake. It can also occur in patients with long-standing diabetes, especially type 1 diabetes. Recent international guidelines (KDIGO 2012) reclassified chronic kidney disease (CKD) based on cause, glomerular filtration rate category, and albuminuria category (A1, A2, A3).[1] Causes of albuminuria can be discriminated between by the amount of protein excreted. * The nephrotic syndrome usually results in the excretion of about 3.0 to 3.5 grams per 24 hours.[medical citation needed] * Nephritic syndrome results in far less albuminuria.[medical citation needed] * Microalbuminuria (between 30 and 300 mg/24h,[2] mg/l of urine[3] or μg/mg of creatinine[4]) can be a forerunner of diabetic nephropathy. The term albuminuria is now preferred in Nephrology since there is not a "small albumin" (microalbuminuria) or a "big albumin" (macroalbuminuria).[5] A1 represents normal to mildly increased urinary albumin/creatinine ratio (<30 mg/g or < 3 mg/mmmol); A2 represents moderately increased urinary albumin/creatinine ratio (30–300 mg/g or 3–30 mg/mmmol, previously known as microalbuminuria); and A3 reflects severely increased urinary albumin/creatinine ratio >300 mg/g or > 30 mg/mmol).[1] ## Diagnosis[edit] The amount of protein being lost in the urine can be quantified by collecting the urine for 24 hours, measuring a sample of the pooled urine, and extrapolating to the volume collected. Also a urine dipstick test for proteinuria can give a rough estimate of albuminuria. This is because albumin is by far the dominant plasma protein, and bromophenol blue the agent used in the dipstick is specific to albumin. ## Treatment[edit] Though there is some evidence that dietary interventions (to lower red meat intake) can be helpful in lowering albuminuria levels,[6] there is currently no evidence that low protein interventions correlate to improvement in kidney function.[7] Among other measures, blood pressure control, especially with the use of inhibitors of the renin-angiotensin-system, is the most commonly used therapy to control albuminuria. ## References[edit] 1. ^ a b c KDIGO (Kidney Disease Improving Global Outcomes (2013). "KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease" (PDF). Kidney International Supplements. 3 (1): 1–150. Archived from the original (PDF) on 4 March 2016. Retrieved 5 February 2016. 2. ^ Page 291 in: Lee, Mary (26 February 2009). Basic Skills in Interpreting Laboratory Data. ISBN 978-1-58528-180-0. Retrieved 23 May 2013. 3. ^ Person—microalbumin level (measured) at Australian Institute of Health and Welfare. 01/03/2005 4. ^ [1] Justesen, T.; Petersen, J.; Ekbom, P.; Damm, P.; Mathiesen, E. (2006). "Albumin-to-creatinine ratio in random urine samples might replace 24-h urine collections in screening for micro- and macroalbuminuria in pregnant woman with type 1 diabetes". Diabetes Care. 29 (4): 924–925. doi:10.2337/diacare.29.04.06.dc06-1555. PMID 16567839. 5. ^ KDIGO 2012. "Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease" (PDF). Archived from the original (PDF) on 2016-03-04. Cite journal requires `\|journal=` (help) 6. ^ de Mello, V. D. F. et al. "Withdrawal of red meat from the usual diet reduces albuminuria and improves serum fatty acid profile in type 2 diabetes patients with macroalbuminuria." American Journal of Clinical Nutrition 83.5 (2006): 1032. 7. ^ Pan Yu et al. "Low-protein diet for diabetic nephropathy: a meta-analysis of randomized controlled trials." American Journal of Clinical Nutrition 88 (2008): 660-666. ## External links[edit] Classification D * ICD-10: R80 * ICD-9-CM: 791.0 * MeSH: D000419 Wikisource has the text of the 1911 Encyclopædia Britannica article Albuminuria. * v * t * e Components and results of urine tests Components * Albumin * Myoglobin * hCG * Leukocyte esterase * Urine pregnancy test * Ketone bodies * Glucose * Urobilinogen * Bilirubin * Creatinine * RBC * WBC * Urinary casts Chemical properties * Urine specific gravity * Isosthenuria * Urine osmolality * Hypersthenuria * Urine pH * Urine anion gap Abnormal findings Red blood cells * Hematuria (Microscopic hematuria) White blood cells * Eosinophiluria Proteinuria * Albuminuria/Microalbuminuria * Albumin/creatinine ratio * Urine protein/creatinine ratio * Myoglobinuria * Hemoglobinuria * Bence Jones protein Small molecules * Glycosuria * Ketonuria * Bilirubinuria * Hyperuricosuria * Aminoaciduria Other * Bacteriuria * Chyluria * Crystalluria [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Albuminuria	c0001925	1,102	wikipedia	https://en.wikipedia.org/wiki/Albuminuria	2021-01-18T18:50:58	{"mesh": ["D000419"], "umls": ["C0001925"], "wikidata": ["Q974792"]}
A number sign (#) is used with this entry because of evidence that ventriculomegaly with cystic kidney disease (VMCKD) is caused by homozygous or compound heterozygous mutation in the CRB2 gene (609720) on chromosome 9q33. Biallelic mutation in the CRB2 gene can also cause isolated focal segmental glomerulosclerosis-9 (FSGS9; 616220), a less severe disorder. Description Ventriculomegaly with cystic kidney disease is a severe autosomal recessive developmental disorder characterized by onset in utero of dilated cerebral ventricles and microscopic renal tubular cysts. The pregnancies of affected individuals are associated with increased alpha-fetoprotein (AFP). Most affected pregnancies have been terminated (summary by Slavotinek et al., 2015). See also 602200 for a disorder characterized by ventriculomegaly and defects of the radius and kidney. Clinical Features Reuss et al. (1989) described a family in which in 2 consanguineous relationships a Cape Verdean man fathered 2 normal children and 6 infants or fetuses with hydrocephaly and cystic disease of the corticomedullary areas of the kidneys. All 6 affected infants were detected prenatally. The first was found at 32 weeks' gestation to have ventriculomegaly, normal-sized but echodense kidneys, and increased amniotic fluid, and was born stillborn at 32 weeks' gestation. The 5 other fetuses were found to be affected at 18 to 20 weeks' gestation, and were terminated during pregnancy. Amniocentesis during pregnancy in 5 of the 6 fetuses showed increased alpha-fetoprotein and acetylcholinesterase (AChE) levels. All had ventriculomegaly and normal-sized but echodense kidneys. Histologic studies of the kidneys showed cystic tubular dilatation in the corticomedullary area and renal medulla; the cysts contained eosinophilic amorphous proteinaceous material. One fetus had postaxial polydactyly, but no other limb anomalies were noted in any of the fetuses. The families lived in the Netherlands (ten Kate, 1991). Slavotinek et al. (2015) reported 5 fetuses from 2 families and an unrelated infant with ventriculomegaly and cystic kidney disease. All pregnancies were abnormal and ascertained due to high AFP levels or abnormal ultrasound findings prior to the end of the second trimester; 5 of the affected pregnancies were terminated. Ultrasound showed severe cerebral ventriculomegaly and echogenic kidneys. Kidney examination showed numerous dilated tubules and microscopic cysts in the renal medulla. Electron microscopy of renal tissue from 1 fetus showed effacement of the epithelial foot processes and microvillous transformation of the podocytes. One affected infant, who was delivered at 35 weeks' gestation, died at age 7 months. This infant had massive ventriculomegaly, subependymal gray matter heterotopia, seizures, nephrotic syndrome, and small cardiac ventricular septal defect. Inheritance The transmission pattern of ventriculomegaly with cystic kidney disease in the family reported by Reuss et al. (1989) was consistent with autosomal recessive inheritance. Molecular Genetics In DNA from 3 fetuses from 2 families and a male infant from a third family with cerebral ventriculomegaly with cystic kidney disease, Slavotinek et al. (2015) identified homozygous or compound heterozygous mutations in the CRB2 gene (609720.0006-609720.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 3 missense mutations and 1 truncating mutation, all of which occurred in the extracellular region of the protein; none of these mutations was predicted to affect polarity. Functional studies of the variants were not performed. INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Ventricular septal defect (1 patient) GENITOURINARY Kidneys \- Renal failure \- Echodense kidneys on ultrasound \- Echogenic kidneys \- Cystic tubular dilatation in the corticomedullary area and medulla \- Cysts contain eosinophilic proteinaceous material \- Effacement of epithelial foot processes SKELETAL Hands \- Postaxial polydactyly (1 fetus) NEUROLOGIC Central Nervous System \- Hydrocephaly \- Ventriculomegaly \- Dilated ventricles \- Focal hyperplasia of the choroid plexus \- Seizures \- Gray matter heterotopia (in some patients) PRENATAL MANIFESTATIONS Amniotic Fluid \- Increased amniotic fluid \- Polyhydramnios Delivery \- Premature delivery (in some patients) LABORATORY ABNORMALITIES \- Increased alpha-fetoprotein in amniotic fluid \- Increased acetylcholinesterase (AChE) in amniotic fluid MISCELLANEOUS \- Onset in utero \- Most pregnancies with affected fetuses resulted in elective termination MOLECULAR BASIS \- Caused by mutation in the crumbs cell polarity complex component 2 gene (CRB2, 609720.0006 ) ▲ 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	VENTRICULOMEGALY WITH CYSTIC KIDNEY DISEASE	c1857423	1,103	omim	https://www.omim.org/entry/219730	2019-09-22T16:29:01	{"mesh": ["C565657"], "omim": ["219730"], "orphanet": ["443988"]}
Condition in which severely overweight people fail to breathe rapidly or deeply enough Obesity hypoventilation syndrome Other namesPickwickian syndrome Obesity hypoventilation syndrome often improves with positive airway pressure treatment administered overnight by a machine such as this device SpecialtyRespirology Obesity hypoventilation syndrome (OHS) is a condition in which severely overweight people fail to breathe rapidly or deeply enough, resulting in low oxygen levels and high blood carbon dioxide (CO2) levels. The syndrome is often associated with obstructive sleep apnea (OSA), which causes periods of absent or reduced breathing in sleep, resulting in many partial awakenings during the night and sleepiness during the day.[1] The disease puts strain on the heart, which may lead to heart failure and leg swelling. Obesity hypoventilation syndrome is defined as the combination of obesity and an increased blood carbon dioxide level during the day that is not attributable to another cause of excessively slow or shallow breathing.[2] The most effective treatment is weight loss, but this may require bariatric surgery to achieve.[3] Weight loss of 25 to 30% is usually required to resolve the disorder.[3] The other first line treatment is non-invasive positive airway pressure (PAP), usually in the form of continuous positive airway pressure (CPAP) at night.[4][5] The disease was known initially in the 1950s, as "Pickwickian syndrome" in reference to a Dickensian character.[5] ## Contents * 1 Signs and symptoms * 2 Mechanism * 3 Diagnosis * 3.1 Classification * 4 Treatment * 4.1 Positive airway pressure * 4.2 Other treatments * 5 Prognosis * 6 Epidemiology * 7 History * 8 References * 9 Further reading ## Signs and symptoms[edit] Most people with obesity hypoventilation syndrome have concurrent obstructive sleep apnea, a condition characterized by snoring, brief episodes of apnea (cessation of breathing) during the night, interrupted sleep and excessive daytime sleepiness. In OHS, sleepiness may be worsened by elevated blood levels of carbon dioxide, which causes drowsiness ("CO2 narcosis"). Other symptoms present in both conditions are depression, and hypertension (high blood pressure) that is difficult to control with medication.[4] The high carbon dioxide can also cause headaches, which tend to be worsening in the morning.[6] The low oxygen level leads to physiologic constriction of the pulmonary arteries to correct ventilation-perfusion mismatching, which puts excessive strain on the right side of the heart. When this leads to right sided heart failure, it is known as cor pulmonale.[4] Symptoms of this disorder occur because the heart has difficulty pumping blood from the body through the lungs. Fluid may, therefore, accumulate in the skin of the legs in the form of edema (swelling), and in the abdominal cavity in the form of ascites; decreased exercise tolerance and exertional chest pain may occur. On physical examination, characteristic findings are the presence of a raised jugular venous pressure, a palpable parasternal heave, a heart murmur due to blood leaking through the tricuspid valve, hepatomegaly (an enlarged liver), ascites and leg edema.[7] Cor pulmonale occurs in about a third of all people with OHS.[5] ## Mechanism[edit] It is not fully understood why some obese people develop obesity hypoventilation syndrome while others do not. It is likely that it is the result of an interplay of various processes. Firstly, work of breathing is increased as adipose tissue restricts the normal movement of the chest muscles and makes the chest wall less compliant, the diaphragm moves less effectively, respiratory muscles are fatigued more easily, and airflow in and out of the lung is impaired by excessive tissue in the head and neck area. Hence, people with obesity need to expend more energy to breathe effectively.[8][9] These factors together lead to sleep-disordered breathing and inadequate removal of carbon dioxide from the circulation and hence hypercapnia; given that carbon dioxide in aqueous solution combines with water to form an acid (CO2[g] + H2O[l] + excess H2O[l] --> H2CO3[aq]), this causes acidosis (increased acidity of the blood). Under normal circumstances, central chemoreceptors in the brain stem detect the acidity, and respond by increasing the respiratory rate; in OHS, this "ventilatory response" is blunted.[5][10] The blunted ventilatory response is attributed to several factors. Obese people tend to have raised levels of the hormone leptin, which is secreted by adipose tissue and under normal circumstances increases ventilation. In OHS, this effect is reduced.[5][10] Furthermore, episodes of nighttime acidosis (e.g. due to sleep apnea) lead to compensation by the kidneys with retention of the alkali bicarbonate. This normalizes the acidity of the blood. However, bicarbonate stays around in the bloodstream for longer, and further episodes of hypercapnia lead to relatively mild acidosis and reduced ventilatory response in a vicious circle.[5][10] Low oxygen levels lead to hypoxic pulmonary vasoconstriction, the tightening of small blood vessels in the lung to create an optimal distribution of blood through the lung. Persistently low oxygen levels causing chronic vasoconstriction leads to increased pressure on the pulmonary artery (pulmonary hypertension), which in turn puts strain on the right ventricle, the part of the heart that pumps blood to the lungs. The right ventricle undergoes remodeling, becomes distended and is less able to remove blood from the veins. When this is the case, raised hydrostatic pressure leads to accumulation of fluid in the skin (edema), and in more severe cases the liver and the abdominal cavity.[5] The chronically low oxygen levels in the blood also lead to increased release of erythropoietin and the activation of erythropoeisis, the production of red blood cells. This results in polycythemia, abnormally increased numbers of circulating red blood cells and an elevated hematocrit.[5] ## Diagnosis[edit] Formal criteria for diagnosis of OHS are:[4][5][11] * Body mass index over 30 kg/m2 (a measure of obesity, obtained by taking one's weight in kilograms and dividing it by one's height in meters squared) * Arterial carbon dioxide level over 45 mmHg or 6.0 kPa as determined by arterial blood gas measurement * No alternative explanation for hypoventilation, such as use of narcotics, severe obstructive or interstitial lung disease, severe chest wall disorders such as kyphoscoliosis, severe hypothyroidism (underactive thyroid), neuromuscular disease or congenital central hypoventilation syndrome If OHS is suspected, various tests are required for its confirmation. The most important initial test is the demonstration of elevated carbon dioxide in the blood. This requires an arterial blood gas determination, which involves taking a blood sample from an artery, usually the radial artery. Given that it would be complicated to perform this test on every patient with sleep-related breathing problems, some suggest that measuring bicarbonate levels in normal (venous) blood would be a reasonable screening test. If this is elevated (27 mmol/l or higher), blood gasses should be measured.[5] To distinguish various subtypes, polysomnography is required. This usually requires brief admission to a hospital with a specialized sleep medicine department where a number of different measurements are conducted while the subject is asleep; this includes electroencephalography (electronic registration of electrical activity in the brain), electrocardiography (same for electrical activity in the heart), pulse oximetry (measurement of oxygen levels) and often other modalities.[4] Blood tests are also recommended for the identification of hypothyroidism and polycythemia.[4][5] To distinguish between OHS and various other lung diseases that can cause similar symptoms, medical imaging of the lungs (such as a chest X-ray or CT/CAT scan), spirometry, electrocardiography and echocardiography may be performed. Echo- and electrocardiography may also show strain on the right side of the heart caused by OHS, and spirometry may show a restrictive pattern related to obesity.[5] ### Classification[edit] Obesity hypoventilation syndrome is a form of sleep disordered breathing. Two subtypes are recognized, depending on the nature of disordered breathing detected on further investigations. The first is OHS in the context of obstructive sleep apnea; this is confirmed by the occurrence of 5 or more episodes of apnea, hypopnea or respiratory-related arousals per hour (high apnea-hypopnea index) during sleep. The second is OHS primarily due to "sleep hypoventilation syndrome"; this requires a rise of CO2 levels by 10 mmHg (1.3 kPa) after sleep compared to awake measurements and overnight drops in oxygen levels without simultaneous apnea or hypopnea.[4][11] Overall, 90% of all people with OHS fall into the first category, and 10% in the second.[5] ## Treatment[edit] In people with stable OHS, the most important treatment is weight loss—by diet, through exercise, with medication, or sometimes weight loss surgery (bariatric surgery). This has been shown to improve the symptoms of OHS and resolution of the high carbon dioxide levels. Weight loss may take a long time and is not always successful.[4] If the symptoms are significant, nighttime positive airway pressure (PAP) treatment is tried; this involves the use of a machine to assist with breathing. PAP exists in various forms, and the ideal strategy is uncertain. Some medications have been tried to stimulate breathing or correct underlying abnormalities; their benefit is again uncertain.[5] While many people with obesity hypoventilation syndrome are cared for on an outpatient basis, some deteriorate suddenly and when admitted to the hospital may show severe abnormalities such as markedly deranged blood acidity (pH<7.25) or depressed level of consciousness due to very high carbon dioxide levels. On occasions, admission to an intensive care unit with intubation and mechanical ventilation is necessary. Otherwise, "bi-level" positive airway pressure (see the next section) is commonly used to stabilize the patient, followed by conventional treatment.[12] ### Positive airway pressure[edit] Positive airway pressure, initially in the form of continuous positive airway pressure (CPAP), is a useful treatment for obesity hypoventilation syndrome, particularly when obstructive sleep apnea coexists. CPAP requires the use during sleep of a machine that delivers a continuous positive pressure to the airways and preventing the collapse of soft tissues in the throat during breathing; it is administered through a mask on either the mouth and nose together or if that is not tolerated on the nose only (nasal CPAP). This relieves the features of obstructive sleep apnea and is often sufficient to remove the resultant accumulation of carbon dioxide. The pressure is increased until the obstructive symptoms (snoring and periods of apnea) have disappeared. CPAP alone is effective in more than 50% of people with OHS.[5] In some occasions, the oxygen levels are persistently too low (oxygen saturations below 90%). In that case, the hypoventilation itself may be improved by switching from CPAP treatment to an alternate device that delivers "bi-level" positive pressure: higher pressure during inspiration (breathing in) and a lower pressure during expiration (breathing out). If this too is ineffective in increasing oxygen levels, the addition of oxygen therapy may be necessary. As a last resort, tracheostomy may be necessary; this involves making a surgical opening in the trachea to bypass obesity-related airway obstruction in the neck. This may be combined with mechanical ventilation with an assisted breathing device through the opening.[5] ### Other treatments[edit] People who fail first-line treatments or have very severe, life-threatening disease may sometimes be treated with tracheotomy, which is a reversible procedure.[13] Treatments without proven benefit, and concern for harm, include oxygen alone or respiratory stimulant medications. Medroxyprogesterone acetate, a progestin, and acetazolamide are both associated with an increased risk of thrombosis and are not recommended.[4][5] ## Prognosis[edit] Obesity hypoventilation syndrome is associated with a reduced quality of life, and people with the condition incur increased healthcare costs, largely due to hospital admissions including observation and treatment on intensive care units. OHS often occurs together with several other disabling medical conditions, such as asthma (in 18–24%) and type 2 diabetes (in 30–32%). Its main complication of heart failure affects 21–32% of patients.[5] Those with abnormalities severe enough to warrant treatment have an increased risk of death reported to be 23% over 18 months and 46% over 50 months. This risk is reduced to less than 10% in those receiving treatment with PAP. Treatment also reduces the need for hospital admissions and reduces healthcare costs.[5] ## Epidemiology[edit] The exact prevalence of obesity hypoventilation syndrome is unknown, and it is thought that many people with symptoms of OHS have not been diagnosed.[4] About a third of all people with morbid obesity (a body mass index exceeding 40 kg/m2) have elevated carbon dioxide levels in the blood.[5] When examining groups of people with obstructive sleep apnea, researchers have found that 10–20% of them meet the criteria for OHS as well. The risk of OHS is much higher in those with more severe obesity, i.e. a body mass index (BMI) of 40 kg/m2 or higher. It is twice as common in men compared to women. The average age at diagnosis is 52. American Black people are more likely to be obese than American whites, and are therefore more likely to develop OHS, but obese Asians are more likely than people of other ethnicities to have OHS at a lower BMI as a result of physical characteristics.[5] It is anticipated that rates of OHS will rise as the prevalence of obesity rises. This may also explain why OHS is more commonly reported in the United States, where obesity is more common than in other countries.[5] ## History[edit] The discovery of obesity hypoventilation syndrome is generally attributed to the authors of a 1956 report of a professional poker player who, after gaining weight, became somnolent and fatigued and prone to fall asleep during the day, as well as developing edema of the legs suggesting heart failure. The authors coined the condition "Pickwickian syndrome" after the character Joe from Dickens' The Posthumous Papers of the Pickwick Club (1837), who was markedly obese and tended to fall asleep uncontrollably during the day.[14] This report, however, was preceded by other descriptions of hypoventilation in obesity.[5][15] In the 1960s, various further discoveries were made that led to the distinction between obstructive sleep apnea and sleep hypoventilation.[16] The term "pickwickian syndrome" has fallen out of favor because it does not distinguish obesity hypoventilation syndrome and sleep apnea as separate disorders (which may coexist).[17][18] ## References[edit] 1. ^ Casey KR, Cantillo KO, Brown LK. Sleep-related hypoventilation/hypoxemic syndromes. Chest. 2007;131(6):1936-48. 2. ^ American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. 3. ^ a b Mokhlesi, B; Masa, JF; Brozek, JL; Gurubhagavatula, I; Murphy, PB; Piper, AJ; Tulaimat, A; Afshar, M; Balachandran, JS; Dweik, RA; Grunstein, RR; Hart, N; Kaw, R; Lorenzi-Filho, G; Pamidi, S; Patel, BK; Patil, SP; Pépin, JL; Soghier, I; Tamae Kakazu, M; Teodorescu, M (1 August 2019). "Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline". American Journal of Respiratory and Critical Care Medicine. 200 (3): e6–e24. doi:10.1164/rccm.201905-1071ST. PMC 6680300. PMID 31368798. 4. ^ a b c d e f g h i j Olson AL, Zwillich C (2005). "The obesity hypoventilation syndrome". Am. J. Med. 118 (9): 948–56. doi:10.1016/j.amjmed.2005.03.042. PMID 16164877. 5. ^ a b c d e f g h i j k l m n o p q r s t u v w Mokhlesi B, Tulaimat A (October 2007). "Recent advances in obesity hypoventilation syndrome". Chest. 132 (4): 1322–36. doi:10.1378/chest.07-0027. PMID 17934118. 6. ^ McNicholas, WT; Phillipson EA (2001). Breathing Disorders in Sleep. Saunders Ltd. pp. 80. ISBN 978-0-7020-2510-5. 7. ^ Braunwald E (2005). "Chapter 216: heart failure and cor pulmonale". In Kasper DL, Braunwald E, Fauci AS, et al. (eds.). Harrison's Principles of Internal Medicine (16th ed.). New York, NY: McGraw-Hill. pp. 1367–78. ISBN 978-0-07-139140-5. 8. ^ Bray, GA; Bouchard C; James WPT (1998). Handbook of Obesity. Marcel Dekker Inc. p. 726. ISBN 978-0-8247-9899-4. 9. ^ Björntorp, P; Brodoff BN (1992). Obesity. JB Lippincott. p. 569. ISBN 978-0-397-50999-7. 10. ^ a b c Piper AJ, Grunstein RR (November 2007). "Current perspectives on the obesity hypoventilation syndrome". Current Opinion in Pulmonary Medicine. 13 (6): 490–6. doi:10.1097/MCP.0b013e3282ef6894. PMID 17901754. 11. ^ a b Anonymous (1999). "Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force". Sleep. 22 (5): 667–89. doi:10.1093/sleep/22.5.667. PMID 10450601. 12. ^ Mokhlesi B, Kryger MH, Grunstein RR (February 2008). "Assessment and management of patients with obesity hypoventilation syndrome". Proc Am Thorac Soc. 5 (2): 218–25. doi:10.1513/pats.200708-122MG. PMC 2645254. PMID 18250215. 13. ^ Martin TJ, Badr M Safwan, and Finlay G. Treatment and prognosis of the obesity hypoventilation syndrome. UpToDate Aug 6, 2019. https://www.uptodate.com/contents/treatment-and-prognosis-of-the-obesity-hypoventilation-syndrome 14. ^ Burwell CS, Robin ED, Whaley RD, Bicklemann AG (1956). "Extreme obesity associated with alveolar hypoventilation; a Pickwickian syndrome". Am. J. Med. 21 (5): 811–8. doi:10.1016/0002-9343(56)90094-8. PMID 13362309. Reproduced in Burwell CS, Robin ED, Whaley RD, Bickelmann AG (1994). "Extreme obesity associated with alveolar hypoventilation--a Pickwickian Syndrome". Obes. Res. 2 (4): 390–7. doi:10.1002/j.1550-8528.1994.tb00084.x. PMID 16353591. 15. ^ Auchincloss JH, Cook E, Renzetti AD (October 1955). "Clinical and physiological aspects of a case of obesity, polycythemia and alveolar hypoventilation". J. Clin. Invest. 34 (10): 1537–45. doi:10.1172/JCI103206. PMC 438731. PMID 13263434. 16. ^ Pack AI (January 2006). "Advances in sleep-disordered breathing". Am. J. Respir. Crit. Care Med. 173 (1): 7–15. doi:10.1164/rccm.200509-1478OE. PMID 16284108. 17. ^ Pack AI (January 2006). "Advances in sleep-disordered breathing". Am. J. Respir. Crit. Care Med. 173 (1): 7–15. doi:10.1164/rccm.200509-1478OE. PMID 16284108. 18. ^ Bray, George A. (July 1994). "What's in a Name? Mr. Dickens' "Pickwickian" Fat Boy Syndrome". Obesity Research. 2 (4): 380–383. doi:10.1002/j.1550-8528.1994.tb00079.x. ## Further reading[edit] * Mokhlesi, B; Masa, JF; Brozek, JL; Gurubhagavatula, I; Murphy, PB; Piper, AJ; Tulaimat, A; Afshar, M; Balachandran, JS; Dweik, RA; Grunstein, RR; Hart, N; Kaw, R; Lorenzi-Filho, G; Pamidi, S; Patel, BK; Patil, SP; Pépin, JL; Soghier, I; Tamae Kakazu, M; Teodorescu, M (1 August 2019). "Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline". American Journal of Respiratory and Critical Care Medicine. 200 (3): e6–e24. doi:10.1164/rccm.201905-1071ST. PMC 6680300. PMID 31368798. Classification D * ICD-10: E66.2 * ICD-9-CM: 278.03 * OMIM: 257500 * MeSH: D010845 * DiseasesDB: 32243 External resources * MedlinePlus: 000085 * eMedicine: ped/1627 med/3470 * v * t * e Obesity * Overweight * Childhood obesity * Abdominal obesity * Weight gain * Obesity hypoventilation syndrome * Bariatric surgery * Obesity and walking * Overnutrition * v * t * e Sleep and sleep disorders Stages of sleep cycles * Rapid eye movement (REM) * Non-rapid eye movement * Slow-wave Brain waves * Alpha wave * Beta wave * Delta wave * Gamma wave * K-complex * Mu rhythm * PGO waves * Sensorimotor rhythm * Sleep spindle * Theta wave Sleep disorders Dyssomnia * Excessive daytime sleepiness * Hypersomnia * Insomnia * Kleine–Levin syndrome * Narcolepsy * Night eating syndrome * Nocturia * Sleep apnea * Catathrenia * Central hypoventilation syndrome * Obesity hypoventilation syndrome * Obstructive sleep apnea * Periodic breathing * Sleep state misperception Circadian rhythm disorders * Advanced sleep phase disorder * Cyclic alternating pattern * Delayed sleep phase disorder * Irregular sleep–wake rhythm * Jet lag * Non-24-hour sleep–wake disorder * Shift work sleep disorder Parasomnia * Bruxism * Nightmare disorder * Night terror * Periodic limb movement disorder * Rapid eye movement sleep behavior disorder * Sleepwalking * Somniloquy Benign phenomena * Dreams * Exploding head syndrome * Hypnic jerk * Hypnagogia / Sleep onset * Hypnopompic state * Sleep paralysis * Sleep inertia * Somnolence * Nocturnal clitoral tumescence * Nocturnal penile tumescence * Nocturnal emission Treatment * Sleep diary * Sleep hygiene * Sleep induction * Hypnosis * Lullaby * Somnology * Polysomnography Other * Sleep medicine * Behavioral sleep medicine * Sleep study Daily life * Bed * Bunk bed * Daybed * Four-poster bed * Futon * Hammock * Mattress * Sleeping bag * Bed bug * Bedding * Bedroom * Bedtime * Bedtime story * Bedtime toy * Biphasic and polyphasic sleep * Chronotype * Dream diary * Microsleep * Mouth breathing * Nap * Nightwear * Power nap * Second wind * Siesta * Sleep and creativity * Sleep and learning * Sleep deprivation / Sleep debt * Sleeping while on duty * Sleepover * Snoring [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Obesity hypoventilation syndrome	c0031880	1,104	wikipedia	https://en.wikipedia.org/wiki/Obesity_hypoventilation_syndrome	2021-01-18T18:37:40	{"mesh": ["D010845"], "umls": ["C0031880"], "icd-9": ["278.03"], "icd-10": ["E66.2"], "wikidata": ["Q202394"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant dilated cardiomyopathy-1G (CMD1G) is caused by heterozygous mutation in the titin gene (TTN; 188840) on chromosome 2q31. For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see CMD1A (115200). Mapping Siu et al. (1999) clinically evaluated 3 generations of a Native American kindred with autosomal dominant transmission of dilated cardiomyopathy. Nine surviving affected individuals had early-onset disease (ventricular chamber dilatation during the teenage years and congestive heart failure during the third decade of life). The disease was nonpenetrant in 2 obligate carriers. By linkage analysis, Siu et al. (1999) identified a novel disease locus at marker D2S1244 on 2q31 (maximum lod = 4.06 at theta = 0.0) between the glucagon gene (138030) and marker D2S72; they designated this locus CMD1G. Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, the authors analyzed sequences encoding 900-amino acid residues of the cardiac-specific (N2-B) domain of the gene. Although 5 sequence variants were identified, none segregated with the disease in this family. Molecular Genetics In 2 unrelated families with autosomal dominant dilated cardiomyopathy, Gerull et al. (2002) identified 2 different heterozygous mutations in the titin gene (188840.0002; 188840.0003). Both families showed reduced penetrance and no involvement of noncardiac muscle. The latter was surprising since exons of TTN that contain the 2 CMD-causing mutations are both expressed in cardiac and noncardiac muscle isoforms. In 4 patients with dilated cardiomyopathy, Itoh-Satoh et al. (2002) identified 4 different mutations in the TTN gene (188840.0007-188840.0010). Two of the cases were familial. Herman et al. (2012) used next-generation sequencing to analyze the TTN gene in 203 individuals with dilated cardiomyopathy, 231 with hypertrophic cardiomyopathy (CMH), and 249 controls. The frequency of TTN mutations was significantly higher among individuals with CMD (27%) than among those with CMH (1%) or controls (3%). In CMD families, TTN mutations cosegregated with dilated cardiomyopathy, with highly observed penetrance (greater than 95%) after the age of 40 years. Mutations associated with CMD were overrepresented in the titin A-band but were absent from the Z-disc and M-band regions of titin. Overall, rates of cardiac outcomes were similar in individuals with or without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers. Herman et al. (2012) concluded that TTN truncating mutations are the most common known genetic cause of dilated cardiomyopathy, occurring in approximately 25% of familial CMD cases and in 18% of sporadic cases. Pathogenesis In assays of contractile function using cardiac microtissues (CMTs) engineered from human induced pluripotent stem (iPS) cells, Hinson et al. (2015) found that, like TTN-truncating variants (TTNtvs), certain missense mutations (e.g., W976R, 188840.0003) diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, Hinson et al. (2015) explained why truncations in the A-band domain of TTN cause dilated cardiomyopathy, whereas truncations in the I-band are better tolerated. Finally, the authors demonstrated that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress, and attenuated growth factor and cell signaling activation. Hinson et al. (2015) concluded that titin mutations cause dilated cardiomyopathy by disrupting critical linkages between sarcomerogenesis and adaptive remodeling. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	CARDIOMYOPATHY, DILATED, 1G	c0340427	1,105	omim	https://www.omim.org/entry/604145	2019-09-22T16:12:27	{"doid": ["0110430"], "mesh": ["C536231"], "omim": ["604145"], "orphanet": ["154"], "genereviews": ["NBK1309"]}
Lachiewicz–Sibley syndrome is a rare autosomal dominant disorder characterized by preauricular pits and renal disease. Persons with this disease may have hypoplasic kidneys or proteinuria. This disease was first described in a Caucasian family of British and Irish descent that emigrated to Ohio in the 19th century before settling in Nebraska. Many of the members of this family still live in Nebraska, although the relatives are now scattered throughout the country. Unlike branchio-oto-renal (BOR) syndrome, Lachiewicz–Sibley syndrome is characterized by only preauricular pitting and renal disease. Persons with BOR syndrome also present with hearing loss, branchial fistulas or cysts, malformed ears, and lacrimal stenosis. Other anomalies in BOR syndrome may include a long narrow face, a deep overbite, and facial paralysis.[1] It was characterized in 1985.[1] ## See also[edit] * Branchio-oto-renal syndrome ## References[edit] 1. ^ a b Lachiewicz AM, Sibley R, Michael AF (June 1985). "Hereditary renal disease and preauricular pits: report of a kindred". The Journal of Pediatrics. 106 (6): 948–50. doi:10.1016/S0022-3476(85)80248-1. PMID 3998953. * 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	Lachiewicz–Sibley syndrome	c2931742	1,106	wikipedia	https://en.wikipedia.org/wiki/Lachiewicz%E2%80%93Sibley_syndrome	2021-01-18T18:54:07	{"gard": ["3157"], "mesh": ["C538131"], "umls": ["C2931742"], "wikidata": ["Q6468402"]}
For a general phenotypic description and a discussion of genetic heterogeneity of basal cell carcinoma, see BCC1 (605462). Mapping In a genomewide SNP association study of 930 Icelanders with BCC and 33,117 controls, Stacey et al. (2008) observed signals from loci at chromosomes 1p36 (BCC1; 605462) and 1q42. These associations were replicated in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, p = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, p = 5.9 x 10(-12)). Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Stacey et al. (2008) estimated that approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers. The linkage disequilibrium block on 1q42 containing rs801114 contained no known genes; the nearest gene is the Ras homolog RHOU (606366), which has been implicated in Wnt signaling. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	BASAL CELL CARCINOMA, SUSCEPTIBILITY TO, 2	c2751606	1,107	omim	https://www.omim.org/entry/613058	2019-09-22T15:59:54	{"omim": ["613058"]}
Aggressive periodontitis describes a type of periodontal disease and includes two of the seven classifications of periodontitis as defined by the 1999 classification system:[1] 1. Localized aggressive periodontitis (LAP) 2. Generalized aggressive periodontitis (GAP) LAP is localised to first molar or incisor interproximal attachment loss, whereas GAP is the interproximal attachment loss affecting at least three permanent teeth other than incisors and first molar.[2] The prevalence of LAP is less than 1% and that of GAP is 0.13%.[2] Approximately 0.1% of white Caucasians[3] (with 0.1% in northern and in central Europe, 0.5% in southern Europe, and 0.1-0.2% in North America[2]) and 2.6% of black Africans may suffer from LAP.[3] Estimates of the disease prevalence are 1-5% in the African population and in groups of African descent, 2.6% in African-Americans, 0.5-1.0% in Hispanics in North America, 0.3-2.0% in South America, and 0.2-1.0% in Asia.[2] On the other hand, in Asia, the prevalence rate of 1.2% for LAP and 0.6% for GAP in Baghdad and Iran population, and 0.47% in Japanese population.[2] Therefore, the prevalence of LAP varies considerably between continents, and differences in race or ethnicity seem to be a major contributing factor.[2] Aggressive periodontitis is much less common than chronic periodontitis and generally affects younger patients than does the chronic form.[2][3] Around 1 in every 1000 patients suffer more rapid loss of attachment.[4] Males seem to be at higher risk of GAP than females[2] The localized and generalized forms are not merely different in extent; they differ in etiology and pathogenesis. ## Contents * 1 Aetiology * 1.1 Microbiology * 1.2 Pathophysiology * 2 Features * 2.1 Primary features * 2.2 Secondary features * 3 Clinical & Radiographic Features of Localised and Generalized Aggressive Periodontitis * 3.1 Localised Aggressive Periodontitis * 3.1.1 Clinical Features * 3.1.2 Radiographic Features * 3.2 Generalized Aggressive Periodontitis * 3.2.1 Clinical Features * 3.2.2 Radiographic Features * 4 Screening * 4.1 Clinical examination * 4.2 Radiographs * 4.3 Strong family association * 5 Treatment * 5.1 Cause Related Therapy * 5.2 Re-examination/Response to Therapy * 5.3 Definitive Therapy * 5.4 Maintenance * 6 References ## Aetiology[edit] ### Microbiology[edit] Of the microflora characterised in aggressive periodontitis, approximately 65-75% of bacteria are Gram-negative bacilli, with few spirochaetes or motile rods present.[5] Aggressive periodontitis is often characterised by a rapid loss of periodontal attachment associated with highly pathogenic bacteria and an impaired immune response. Various studies have associated Aggregatibacter actinomycetemcomitans, formerly known as Actinobacillus actinomycetemcomitans, with aggressive periodontitis. An early study dating back to 1983 explains its prevalence and documents its role in localised aggressive periodontitis.[6] Virulence factors are the attributes of microorganisms that enable it to colonise a particular niche in its host, overcome the host defences and initiate a disease process.[7] Fives Taylor et al. (2000) have categorised the virulence factors of Aggregatibacter actinomycetemcomitans as follows.[7] Promote colonization and persistence in the oral cavity: Interfere with host defences: Destroy host tissues: Inhibit host repair of tissues: Adhesins Leukotoxin Cytotoxins Inhibitors of fibroblast proliferation Invasins Chemotactic inhibitors Collagenase Bacteriocins Immunosuppressive proteins Bone resorption agents Inhibitors of bone formation Antibiotic resistance Fc-binding proteins Stimulators of inflammatory mediators Samaranayake notes the evidence for the specific involvement of Aggregatibacter actinomycetemcomitans includes: an increased incidence of it found in subgingival plaque obtained from lesional sites, high level of its antibody which tends to fall following successful treatment, its possession of a wide range of potentially pathogenic products and its elimination with concordant disease regression, following treatment with successful periodontal therapy and adjunctive tetracycline.[5] Porphyromonas gingivalis is a Gram-negative anaerobe associated with the pathogenicity of periodontal disease,[8] and aggressive periodontitis is no exception. Greater numbers of both Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were found in active, destructive periodontal lesions in comparison to non-active sites.[8] Capnocytophaga spp are implicated as prime periodontal pathogens, especially in localised aggressive periodontitis.[5] Both Capnocytophaga spp and Prevotella intermedia were the most frequently detected microorganisms in a study,[9] which also noted that Capnocytophaga spp was the most prominent bacteria in subgingival samples of aggressive periodontitis sufferers.[9][10] An impaired ability of peripheral blood lymphocytes to react to chemotactic stimuli is found in the majority of patients suffering from aggressive periodontitis. As well as Aggregatibacter actinomycetemcomitans being associated with this, the synergism of the disease also accounts for both Capnocytophaga spp and Porphyromonas gingivalis.[5] ### Pathophysiology[edit] Aggressive periodontitis is a multifactorial disease with many complex interactions including host factors, microbiology and genetics. Host defences involve multiple factors; saliva, epithelium, inflammatory response, immune response and chemical mediators. The inflammatory exudate in the gingival tissues and gingival crevicular fluid is mostly polymorph neutrophils but also includes B cells and plasma cells. The neutrophils may show an intrinsic functional defect and respond abnormally when challenged by certain pathogens.[11] The plasma cells produce specific antibodies in response to the periodontal pathogens, which diffuse into the gingival crevicular fluid. They produce mainly IgG, with some IgA.[11] It has been suggested that these gingival crevicular fluid antibody levels could be potentially useful in the development of a vaccine.[12] Patients with localised aggressive periodontitis have large amount of Aggregatibacter actinomycetemcomitans specific IgG2. This is suggested to be protective against wider spread periodontal breakdown. However, patients with generalized aggressive periodontitis have decreased ability to mount high titres of IgG to Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has also been found that a low T-helper to T-suppressor ratio is found in aggressive periodontitis which may alter local immune regulation. Monocytes respond to bacterial and inflammatory stimuli with very high levels of local release inflammatory mediators and induce hyper-inflammatory reaction with activation of tissue degrading matrix-metalloproteinases. These is also evidence they produce increased amounts IL-1α and IL-1β which cause osteoclastic bone resorption. These amounts are greatly reduced following treatment.[11] Studies of families, twins and sibling pairs have provided strong evidence for a genetic basis for aggressive periodontitis.[13] A person's genetic predisposition to the condition is determined by a single gene of major effect, inherited as an autosomal dominant trait. However, for the disease process to initiate the person must be exposed to the presence of periodontal pathogens and potentially also various environmental factors. Smoking is a generalized risk factor for generalized forms of aggressive periodontitis. Studies found that smokers have more affected teeth than non-smokers and high levels of attachment loss. This is due to the suppression of serum IgG2 and antibody against Aggregatibacter actinomycetemcomitans found in smokers.[14] ## Features[edit] According to the 1999 International Workshop for the Classification of Periodontal Diseases, aggressive periodontitis was defined according to 3 primary features, in contrast to chronic periodontitis. These features are common for both localized and generalized form of disease.[15][16] ### Primary features[edit] * Patients are clinically healthy.[15] Patients do not have any underlying systemic disease that would contribute to aggressive periodontitis.[17] For instance, diabetes is proved to be associated with periodontitis- it is a major risk factor when glycaemic control is poor.[18] * The rate of loss of attachment and bone loss is rapid.[15] Loss of attachment refers to the destruction of periodontium whereas the bone refers to the alveolar bone supporting the teeth.[19] The loss can be determined by using a calibrated periodontal probe and taking radiographs of the dentition.[20] Usually the loss of attachment is greater than 2mm per year. * Aggressive periodontitis runs in the patient's family.[15] Familial aggregation of aggressive periodontitis is often discovered by taking a thorough medical history of the patient. The patient is said to have a high genetic susceptibility to aggressive periodontitis. Many studies have shown that genetic factors contribute to the pathogenesis of this disease.[21] In this case, the manifestation of aggressive periodontitis is believed to be the result of genetic mutation, combined with environmental factors.[21] ### Secondary features[edit] Secondary features are characteristics which are frequently seen but not always present in every patient diagnosed with aggressive periodontitis. * The severity of periodontal tissue destruction is out of proportion to amount of bacteria present .[15] The amount of bacteria is often indicated by the level of dental plaque.[22] This feature implies that when aggressive periodontitis is present, loss of attachment and bone loss tend to occur even if the plaque level is low. * High levels of Aggregatibacter (or Actinobacillus) actinomycetemcomitans and, in some populations, Porphyromonas gingivalis.[15] These gram-negative microbes are considered the chief aetiological agent of aggressive periodontitis. They are implicated in the development of aggressive periodontitis by triggering inflammatory response in periodontal tissue. * There are abnormalities associated with phagocytes.[15] Phagocytes are essential in resolving inflammation. The impairment of their phagocytic activity results in persistent inflammation in periodontal tissues.[23] * Hyper-responsive macrophage phenotype.[15] Due to the increased responsiveness, the macrophages produce excessive levels of inflammatory mediator and cytokine, such as prostaglandin E2 (PGE2) and interleukin-1β (IL-1B).[15] Their hyperactivity is associated with periodontal tissue destruction and bone loss.[24] * Progression of attachment loss and bone loss may be self-arresting.[15] In some patients, the disease may burnout without any cause-related therapy.[25] ## Clinical & Radiographic Features of Localised and Generalized Aggressive Periodontitis[edit] ### Localised Aggressive Periodontitis[edit] #### Clinical Features[edit] LAP begins around the age of puberty where there is interproximal loss of attachment of the first molar, and or incisors[26] on at least two permanent teeth (one which is a first molar) and no involvement of more than two teeth other than the first molars and incisors,[26][27] lack of inflammation and evidence of deep periodontal pocket with advanced bone loss.[26] There is also a relatively fast progression of periodontal tissue loss.[27] With an increase in the age of the patient, there may be progression of the disease involving the adjacent teeth and lead to the patient developing GAP.[28][29] The periodontal tissue also exhibits minimal signs of inflammation clinically[30] and show a robust response with serum antibodies to pathogens.[27] The amount of plaque present is inconsistent with the amount and severity of tissue destruction [26][27] but with a high plaque pathogenicity due to the presence of increased levels of bacteria like Aggregatibacter actinomycetemcomitans (A.a) and Porphyromonas Gingivalis (P.g).[26] Secondary features of LAP may also be present including;[26] * diastema formation with disto-labial migration of the incisors * increased mobility of the affected teeth, sensitivity due to exposed root, * deep dull pain that radiates to the jaw * periodontal abscess with lymph node enlargement #### Radiographic Features[edit] Radiographically, the periodontal lesion often presents with alveolar bone loss in a horizontal pattern at the interproximal surface of the permanent first molars [26][27][28] and usually horizontal bone pattern of bone loss at the interproximal surface of the incisors as the bone is thinner than at the interproximal surface of the molars.[27] The alveolar bone loss patterns are usually bilateral and similar on both sides and has been referred to as being a ‘mirror-image’ pattern.[28][27] In advanced cases the alveolar bone loss may be depicted as a horizontal bone loss pattern radiographically.[27][28] ### Generalized Aggressive Periodontitis[edit] #### Clinical Features[edit] * Mostly in individuals under 30 years old[31] * In GAP, the clinical appearance of the disease resembles chronic periodontitis. The difference is that individuals affected by GAP are much younger and the progression of disease appears more rapid.[30] * There is a poor serum response against infecting agents[31]: * Destruction is present that is not in balance with the amount of local irritants present[30] * Generalized inter-proximal attachment loss on 3 or more permanent teeth, excluding the first molars or incisors[31]: * The main distinction between the localized and generalized form of AgP lies in the number of teeth affected. GAP brings about attachment loss involving more than 30% of sites on teeth;[1] effectively being at least three permanent teeth other than the first molars or incisors.[16] * Episodic nature of attachment loss: Two main tissue responses have been found in GAP cases:[31] * Tissue may have severe acute inflammation and often presents with an angry red appearance and ulceration. There may be spontaneous bleeding or suppuration. This response is known to be present in the destructive phase, where there is presence of bone and attachment loss. * The other response is known as a period of quiescence, where gingival tissue may appear with no inflammation, pink appearance with some possible stippling. In addition to this mild appearance there may be deep pockets upon probing. #### Radiographic Features[edit] * The key diagnostic feature of AgP is vertical bone loss around teeth including the first molars and incisors. This tends to begin around puberty in otherwise healthy individuals.[31] There may be an appearance of “arc-shaped loss of alveolar bone extending from the distal surface of the second premolar to the mesial surface of the second molar”.[32] * In GAP, generalized bone destruction is present that ranges from mild crestal bone resorption to severe alveolar bone destruction, depending on the severity of the disease.[32] There may be a combination of vertical and horizontal bone loss defects.[32] ## Screening[edit] Early diagnosis of aggressive periodontitis is important as it can cause rapid permanent destruction of the periodontal tissues. It is essential that all patients undergo a routine periodontal examination to screen for any form of periodontal disease during a dental checkup. ### Clinical examination[edit] At the start of the clinical examination of the gingival and periodontal tissues, the dental practitioner would look at the appearance of the gingiva first. A healthy periodontium in a Caucasian would appear stippled and pink with a knife edge margin where it abuts the tooth (pigmentation may differ in other races).[33] After that, gingival probing depths would be checked. This would normally be carried out using a basic periodontal probe (WHO CPI).[34] On probing, patients with AgP should have evidence of significant periodontal pocket depths and loss of attachment (LOA). Dental practitioners should also be aware of false pocketing around erupting/newly erupted teeth in the mixed dentition phase and also in the presence of gingival inflammation.[34][35] The presence of bleeding on probing (BOP) should be noted which is an indicator of active disease. ### Radiographs[edit] Radiographic assessment should be carried out for patients with evidence of periodontitis to observe alveolar bone levels which can help to identify signs of AgP.[34] In healthy periodontal tissues, the distance from the amelocemental junction (ACJ) to the alveolar bone crest is typically in the order of 1mm in young people.[36] If the distance between the ACJ and alveolar bone crest is more than 2-3mm then there is a possible suggestion of AgP. In addition to that, presence of angular or vertical bone loss (especially at 6's) and arrowhead or furcation lesions are also a strong suggestion of AgP. ### Strong family association[edit] It is also important for a dental practitioner to check for family history of periodontal disease for each patient. This is because AgP may have an autosomal dominant inheritance pattern which suggests that up to 50% of siblings could be affected if one parent has the disease.[37] Careful interpretation of the history is required but it may provide vital evidence in diagnosing AgP. If a case of Agp is diagnosed, it is important to screen the patient's family members as well for AgP.[38][39] Early detection of AgP allows intervention to be carried out before extensive periodontal destruction has taken place which further simplifies treatment. ## Treatment[edit] Following the initial assessment and diagnosis of AgP, a treatment plan is usually developed for each individual undergoing therapy. As the overall treatment concepts and goals for AgP are not significantly different from that of chronic periodontitis, the different treatment phases (cause related therapy; re-examination for response to therapy; definitive therapy; and maintenance) are similar for both types of periodontitis. Nevertheless, the considerable amount of bone loss relative to the young age of the individual in AgP necessitates an often more aggressive treatment approach, to halt further periodontal destruction and regain as much periodontal attachment as possible. The objective of treatment is to create a conducive clinical condition for retaining as many teeth, for as long as possible.[40] ### Cause Related Therapy[edit] This stage involves discussion of the disease with the patient. * Oral Hygiene Instructions: The clinician should advise the patient of his intrinsic susceptibility to plaque, which his body induces a strong, pro-inflammatory response to.[41] It is thus essential to keep his oral hygiene immaculate. This involve going over both smooth surfaces (tooth brushing instructions) and the use of interproximal aids (e.g. floss). * Smoking cessation (if applicable): Smoking is a significant risk factor for AgP, with patients who smoke having more affected teeth with loss of clinical attachment and more bone loss than non-smoking patients with AgP.[42] Non-smokers also tend to have a better response to periodontal therapy as compared to smokers. As such, individuals must be advised of the benefits of smoking cessation and the otherwise potential risks of a worsening periodontal condition.[32] * Removal of plaque retentive factors: Local plaque retentive factors such as mal-positioned teeth, overhanging restorations, crown and bridgework, partial dentures and fixed/removable orthodontic appliances can increase the risk of periodontal disease and prevent successful treatment and resolution of associated pockets. Prior to starting periodontal treatment, any overhanging or poorly contoured restorations should be modified or replaced. Instructions should also be given on how to clean adequately around fixed restorations and appliances, and how to clean removable prostheses. These intra-oral appliances should also be well-designed and fitting.[43] The periodontal therapy carried out at this stage is of a non-surgical approach, which is aimed at the removal of supra- and sub-gingival plaque and calculus deposits, to decrease the microbial load, bacteria biofilm, and calculus from the periodontally involved sites.[44] * Scale and Polish * Root Surface Debridement (RSD) * Antibiotics: There is evidence that the additional use of systemic antibiotics in conjunction with non-surgical periodontal treatment results in a more favourable clinical response, as compared to just periodontal treatment alone, as it helps to suppress pathogenic bacteria and create a health-associated biofilm.[45] There have been many antibiotic regimes proposed for the treatment of AgP. However, the combination of choice according to current research is a combination of amoxicillin (500 mg, thrice/day) and metronidazole (200 mg, thrice/day), for 7 days, starting on the day of the final debridement. Doxycycline (100 mg, once/day, with a starting first dose of 200 mg) is the choice of antibiotics for patients allergic to penicillin.[46] * Light Amplification by Stimulated Emission of Radiation (LASER) Therapy * Photodynamic Therapy (PDT): This potentially has all the advantages of low-level LASER therapy, which allows the disinfection of periodontal pocket and the eradication of bacteria in areas of difficult access, without the thermal damage to tissues associated with the high-powered LASER. A significant reduction in the aggregatibacter actinomycetemcomitans count following PDT suggests that the use of PDT in conjunction with conventional non-surgical periodontal treatment can potentially result in a more effective treatment.[47] Considering the global issue of antibiotic resistance, further development and research in PDT successes may prove to present it an ideal adjunct to conventional non-surgical periodontal therapy, as compared to the use of systemic antibiotics. ### Re-examination/Response to Therapy[edit] This stage of treatment involves the reassessment of the individual's compliance (i.e. level of oral hygiene) and the tissue response to the treatment. This is carried out 10–12 weeks following RSD. If the disease is stabilised, the treatment progresses on to the maintenance stage. In the case where the disease is not stabilised, the cause of failure should be considered, and the treatment progresses on to the stage of definitive therapy, if the cause is correctable. ### Definitive Therapy[edit] * Further RSD at sites which require treatment * Use of Locally Delivered Antimicrobials (LDA) as an adjunct to non-surgical periodontal treatment: For use in deep pockets which fail to respond to repeated non-surgical treatment in patients with adequate oral hygiene. Currently, the available LDA include tetracycline, minocycline, chlorhexidine gluconate and doxycycline, with the mode of delivery being in the form of fibers, chips, polymers and trays.[48] There has yet to be much research into the effects of LDA in AgP, but current studies report an insignificant difference to the adjunctive effect of systemic antibiotics.[40] * Periodontal surgery: If it is a localised problem and if the case is non-response to non-surgical treatment despite the oral hygiene being consistently excellent. This could involve an open flap debridement with or without regenerative procedures, with the aim of gaining access and visibility to root and furcation areas so that a thorough instrumentation and debridement can be carried out. * Regenerative surgical therapy currently available include the use of bone replacement grafts, barrier membranes or guided tissue regeneration (GTR), biologic modifiers like growth and differentiation factors (GDF), and extracellular matrix proteins like enamel matrix proteins (EMD).[32] There is however, a great variation in periodontal gains reported in the literature available, signifying that results are not entirely predictable. ### Maintenance[edit] Periodontal treatment may help to stabilise the disease, but it does not change one's susceptibility to the disease. Given the high susceptibility for disease progression of the individual with AgP, there is a higher risk of disease recurrence.[49] It is thus necessary to attend frequent review appointments at the dentist to ensure there is no relapse of the disease, and that the periodontal health is maintained after active periodontal therapy.[40] ## References[edit] 1. ^ a b Armitage GC (December 1999). "Development of a classification system for periodontal diseases and conditions". Ann. Periodontol. 4 (1): 1–6. doi:10.1902/annals.1999.4.1.1. PMID 10863370. 2. ^ a b c d e f g Joshipura, Vaibhavi; Yadalam, Umesh; Brahmavar, Bhavya (2015-01-01). "Aggressive periodontitis: A review". Journal of the International Clinical Dental Research Organization. 7 (1): 11. doi:10.4103/2231-0754.153489. 3. ^ a b Clerehugh, Valerie (2012). "Guidelines for periodontal screening and management of children and adolescents under 18 years of age" (PDF). British Society of Periodontology and The British Society of Paediatric Dentistry. Retrieved 6 Dec 2017. 4. ^ Needleman, Ian (2016). "The Good Practitioner's Guide to Periodontology" (PDF). British Society of Periodontology. Retrieved 6 Dec 2017. 5. ^ a b c d Whiley, R A (2006-11-25). "Essential microbiology for dentistry (3rd edition)". British Dental Journal. 201 (10): 679. doi:10.1038/sj.bdj.4814299. 6. ^ Zambon, J. J.; Christersson, L. A.; Slots, J. (December 1983). "Actinobacillus actinomycetemcomitans in human periodontal disease. Prevalence in patient groups and distribution of biotypes and serotypes within families". Journal of Periodontology. 54 (12): 707–711. doi:10.1902/jop.1983.54.12.707. ISSN 0022-3492. PMID 6358452. 7. ^ a b Fives-Taylor, P. M.; Meyer, D. H.; Mintz, K. P.; Brissette, C. (June 1999). "Virulence factors of Actinobacillus actinomycetemcomitans". Periodontology 2000. 20: 136–167. doi:10.1111/j.1600-0757.1999.tb00161.x. ISSN 0906-6713. PMID 10522226. 8. ^ a b Thiha, K.; Takeuchi, Y.; Umeda, M.; Huang, Y.; Ohnishi, M.; Ishikawa, I. (June 2007). "Identification of periodontopathic bacteria in gingival tissue of Japanese periodontitis patients". Oral Microbiology and Immunology. 22 (3): 201–207. doi:10.1111/j.1399-302X.2007.00354.x. ISSN 0902-0055. PMID 17488447. 9. ^ a b Nonnenmacher, C.; Mutters, R.; de Jacoby, L. F. (April 2001). "Microbiological characteristics of subgingival microbiota in adult periodontitis, localized juvenile periodontitis and rapidly progressive periodontitis subjects". Clinical Microbiology and Infection. 7 (4): 213–217. doi:10.1046/j.1469-0691.2001.00210.x. ISSN 1198-743X. PMID 11422244. 10. ^ Genco, R. J.; Zambon, J. J.; Christersson, L. A. (November 1986). "Use and interpretation of microbiological assays in periodontal diseases". Oral Microbiology and Immunology. 1 (1): 73–81. doi:10.1111/j.1399-302X.1986.tb00324.x. ISSN 0902-0055. PMID 3295682. 11. ^ a b c Wilson, Thomas G.; Kornman, Kenneth S. (2003). fundamentals of periodontics (2nd ed.). ISBN 978-0867154054. 12. ^ Author, UTHSCSA Dental School CATs. "UTCAT2409, Found CAT view, CRITICALLY APPRAISED TOPICs". cats.uthscsa.edu. Retrieved 2017-12-07. 13. ^ Kinane, D. F.; Hart, T. C. (2003). "Genes and gene polymorphisms associated with periodontal disease". Critical Reviews in Oral Biology and Medicine. 14 (6): 430–449. doi:10.1177/154411130301400605. ISSN 1544-1113. PMID 14656898. 14. ^ SCHENKEIN, HARVEY A.; GUNSOLLEY, JOHN C.; KOERTGE, THOMAS E.; SCHENKEIN, JEREMY G.; TEW, JOHN G. (1995-08-01). "SMOKING and its Effects on Early-Onset Periodontitis". The Journal of the American Dental Association. 126 (8): 1107–1113. doi:10.14219/jada.archive.1995.0327. ISSN 0002-8177. PMID 7560567. 15. ^ a b c d e f g h i j Armitage, Gary C. (2004). "Periodontal diagnoses and classification of periodontal diseases". Periodontology 2000. 34: 9–21. doi:10.1046/j.0906-6713.2002.003421.x. ISSN 0906-6713. PMID 14717852. 16. ^ a b Lang, Niklaus; Bartold, P. Mark; Cullinan, Mary; Jeffcoat, Marjorie; Mombelli, Andrea; Murakami, Shinya; Page, Roy; Papapanou, Panos; Tonetti, Maurizio (1999-12-01). "Consensus Report: Aggressive Periodontitis". Annals of Periodontology. 4 (1): 53. doi:10.1902/annals.1999.4.1.53. ISSN 1553-0841. 17. ^ "Managing Aggressive Periodontitis - Decisions in Dentistry". Decisions in Dentistry. Retrieved 2017-12-07. 18. ^ Preshaw, P. M.; Alba, A. L.; Herrera, D.; Jepsen, S.; Konstantinidis, A.; Makrilakis, K.; Taylor, R. (2012). "Periodontitis and diabetes: a two-way relationship". Diabetologia. 55 (1): 21–31. doi:10.1007/s00125-011-2342-y. ISSN 0012-186X. PMC 3228943. PMID 22057194. 19. ^ "Periodontitis, aggressive - Oxford Reference". Retrieved 2017-12-07. 20. ^ Armitage, Gary C. (2004). "The complete periodontal examination". Periodontology 2000. 34: 22–33. doi:10.1046/j.0906-6713.2002.003422.x. ISSN 0906-6713. PMID 14717853. 21. ^ a b Vieira, Alexandre R.; Albandar, Jasim M. (June 2014). "Role of genetic factors in the pathogenesis of aggressive periodontitis". Periodontology 2000. 65 (1): 92–106. doi:10.1111/prd.12021. ISSN 1600-0757. PMID 24738588. 22. ^ Schaeken, M. J.; Creugers, T. J.; Van der Hoeven, J. S. (September 1987). "Relationship between dental plaque indices and bacteria in dental plaque and those in saliva". Journal of Dental Research. 66 (9): 1499–1502. doi:10.1177/00220345870660091701. ISSN 0022-0345. PMID 3476622. 23. ^ Fredman, Gabrielle; Oh, Sungwhan F.; Ayilavarapu, Srinivas; Hasturk, Hatice; Serhan, Charles N.; Van Dyke, Thomas E. (2011). "Impaired phagocytosis in localized aggressive periodontitis: rescue by Resolvin E1". PLOS One. 6 (9): e24422. Bibcode:2011PLoSO...624422F. doi:10.1371/journal.pone.0024422. ISSN 1932-6203. PMC 3173372. PMID 21935407. 24. ^ Shaddox, L.; Wiedey, J.; Bimstein, E.; Magnuson, I.; Clare-Salzler, M.; Aukhil, I.; Wallet, S.M. (2010). "Hyper-responsive Phenotype in Localized Aggressive Periodontitis". Journal of Dental Research. 89 (2): 143–148. doi:10.1177/0022034509353397. ISSN 0022-0345. PMC 3096871. PMID 20042739. 25. ^ Asano, Masahiro; Asahara, Yoji; Kirino, Akinori; Ohishi, Mika; Akimaru, Noriko; Hama, Hideki; Sury, Yono; Shionoya, Akemi; Kido, Jun-ichi (2003-09-28). "Case Report of an Early-onset Periodontitis Patient Showing Self-Arrest of Alveolar Bone Loss after Puberty". Nihon Shishubyo Gakkai Kaishi (Journal of the Japanese Society of Periodontology) (in Japanese). 45 (3): 279–288. doi:10.2329/perio.45.279. ISSN 0385-0110. 26. ^ a b c d e f g Joshipura, Vaibhavi; Yadalam, Umesh; Brahmavar, Bhavya (2015-01-01). "Aggressive periodontitis: A review". Journal of the International Clinical Dental Research Organization. 7 (1): 11. doi:10.4103/2231-0754.153489. 27. ^ a b c d e f g h Albandar, Jasim M. (June 2014). "Aggressive periodontitis: case definition and diagnostic criteria". Periodontology 2000. 65 (1): 13–26. doi:10.1111/prd.12014. ISSN 1600-0757. PMID 24738584. 28. ^ a b c d Albandar, Jasim M. (June 2014). "Aggressive and acute periodontal diseases". Periodontology 2000. 65 (1): 7–12. doi:10.1111/prd.12013. ISSN 1600-0757. PMID 24738583. 29. ^ Caton, Jack G. (December 1999). "1999 International International Workshop for a Classification of Periodontal Diseases and Conditions. Papers. Oak Brook, Illinois, October 30-November 2, 1999". Annals of Periodontology. 4 (1): i, 1–112. doi:10.1902/annals.1999.4.1.i. ISSN 1553-0841. PMID 10896458. 30. ^ a b c Armitage, Gary C.; Cullinan, Mary P. (June 2010). "Comparison of the clinical features of chronic and aggressive periodontitis". Periodontology 2000. 53: 12–27. doi:10.1111/j.1600-0757.2010.00353.x. ISSN 1600-0757. PMID 20403102. 31. ^ a b c d e Newman, Michael G.; Takei, Henry H.; Klokkevold, Perry R.; Carranza, Fermin A. (2015). Carranza's clinical periodontology. Newman, Michael G.,, Takei, Henry H., 1938-, Klokkevold, Perry R.,, Carranza, Fermin A. (Twelfth ed.). St. Louis, Missouri. ISBN 978-0323188241. OCLC 885376294. 32. ^ a b c d e Roshna, T.; Nandakumar, K. (2012). "Generalized Aggressive Periodontitis and Its Treatment Options: Case Reports and Review of the Literature". Case Reports in Medicine. 2012: 535321. doi:10.1155/2012/535321. ISSN 1687-9627. PMC 3265097. PMID 22291715. 33. ^ Highfield, J (2009-09-01). "Diagnosis and classification of periodontal disease". Australian Dental Journal. 54: S11–S26. doi:10.1111/j.1834-7819.2009.01140.x. ISSN 1834-7819. PMID 19737262. 34. ^ a b c Preshaw, Philip M (2015-09-15). "Detection and diagnosis of periodontal conditions amenable to prevention". BMC Oral Health. 15 (Suppl 1): S5. doi:10.1186/1472-6831-15-S1-S5. ISSN 1472-6831. PMC 4580822. PMID 26390822. 35. ^ Clerehugh, Valerie; Kindelan, Susan (2012). "Guidelines for Periodontal Screening and Management of Children and Adolescents Under 18 Years of Age" (PDF). British Society of Periodontology. 36. ^ Jonasson, Grethe (2015-07-01). "Five-year alveolar bone level changes in women of varying skeletal bone mineral density and bone trabeculation". Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 120 (1): 86–93. doi:10.1016/j.oooo.2015.04.009. ISSN 2212-4403. PMID 26093684. 37. ^ Melnick, M.; Shields, E. D.; Bixler, D. (July 1976). "Periodontosis: a phenotypic and genetic analysis". Oral Surgery, Oral Medicine, and Oral Pathology. 42 (1): 32–41. doi:10.1016/0030-4220(76)90029-3. ISSN 0030-4220. PMID 1065840. 38. ^ Nibali, L.; Donos, N.; Brett, P. M.; Parkar, M.; Ellinas, T.; Llorente, M.; Griffiths, G. S. (December 2008). "A familial analysis of aggressive periodontitis - clinical and genetic findings". Journal of Periodontal Research. 43 (6): 627–634. doi:10.1111/j.1600-0765.2007.01039.x. ISSN 1600-0765. PMID 18752567. 39. ^ Llorente, M. A.; Griffiths, G. S. (February 2006). "Periodontal status among relatives of aggressive periodontitis patients and reliability of family history report". Journal of Clinical Periodontology. 33 (2): 121–125. doi:10.1111/j.1600-051X.2005.00887.x. ISSN 0303-6979. PMID 16441736. 40. ^ a b c Teughels, Wim; Dhondt, Rutger; Dekeyser, Christel; Quirynen, Marc (2014-06-01). "Treatment of aggressive periodontitis". Periodontology 2000. 65 (1): 107–133. doi:10.1111/prd.12020. ISSN 1600-0757. PMID 24738589. 41. ^ Shahabuddin, Nishat; Boesze-Battaglia, Kathleen; Lally, Edward T (2016). "Trends in Susceptibility to Aggressive Periodontal Disease". International Journal of Dentistry and Oral Health. 2 (4). doi:10.16966/2378-7090.197. ISSN 2378-7090. PMC 5172390. PMID 28008419. 42. ^ Mullally, Brian H.; Breen, Blanaid; Linden, Gerard J. (1999-04-01). "Smoking and Patterns of Bone Loss in Early-Onset Periodontitis". Journal of Periodontology. 70 (4): 394–401. doi:10.1902/jop.1999.70.4.394. ISSN 0022-3492. PMID 10328651. 43. ^ (SDCEP), Scottish Dental Clinical Effectiveness Programme (June 2014). "Prevention and Treatment of Periodontal Diseases in Primary Care, Dental Clinical Guidance" (PDF). Retrieved 7 Dec 2017. 44. ^ Aimetti, Mario (2014). "Nonsurgical periodontal treatment". The International Journal of Esthetic Dentistry. 9 (2): 251–267. ISSN 2198-591X. PMID 24765632. 45. ^ Keestra, J. a. J.; Grosjean, I.; Coucke, W.; Quirynen, M.; Teughels, W. (2015-12-01). "Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and meta-analysis". Journal of Periodontal Research. 50 (6): 689–706. doi:10.1111/jre.12252. ISSN 1600-0765. PMID 25522248. 46. ^ (BSP), British Society of Periodontology (Mar 2016). "The Good Practitioner's Guide to Periodontology" (PDF). Retrieved 7 Dec 2017. 47. ^ Vohra, Fahim; Akram, Zohaib; Safii, Syarida Hasnur; Vaithilingam, Rathna Devi; Ghanem, Alexis; Sergis, Konstantinos; Javed, Fawad (2016). "Role of antimicrobial photodynamic therapy in the treatment of aggressive periodontitis: A systematic review". Photodiagnosis and Photodynamic Therapy. 13: 139–147. doi:10.1016/j.pdpdt.2015.06.010. PMID 26184762. 48. ^ Collins, Fiona. "Periodontal Treatment: The Delivery and Role of Locally Applied Therapeutics" (PDF). Retrieved 7 Dec 2017. 49. ^ Kamma, Joanna J.; Baehni, Pierre C. (2003-06-01). "Five-year maintenance follow-up of early-onset periodontitis patients". Journal of Clinical Periodontology. 30 (6): 562–572. doi:10.1034/j.1600-051x.2003.00289.x. ISSN 1600-051X. PMID 12795796. * v * t * e Dentistry involving supporting structures of teeth (Periodontology) Anatomy * Periodontium * Alveolar bone * Biologic width * Bundle bone * Cementum * Free gingival margin * Gingiva * Gingival fibers * Gingival sulcus * Junctional epithelium * Mucogingival junction * Periodontal ligament * Sulcular epithelium * Stippling Disease Diagnoses * Chronic periodontitis * Localized aggressive periodontitis * Generalized aggressive periodontitis * Periodontitis as a manifestation of systemic disease * Periodontosis * Necrotizing periodontal diseases * Abscesses of the periodontium * Combined periodontic-endodontic lesions Infection * A. actinomycetemcomitans * Capnocytophaga sp. * F. nucleatum * P. gingivalis * P. intermedia * T. forsythia * T. denticola * Red complex * Entamoeba gingivalis (amoebic) * Trichomonas tenax Other * Calculus * Clinical attachment loss * Edentulism * Fremitus * Furcation defect * Gingival enlargement * Gingival pocket * Gingival recession * Gingivitis * Horizontal bony defect * Linear gingival erythema * Occlusal trauma * Periodontal pocket * Periodontal disease * Periodontitis * Plaque * Vertical bony defect Treatment and prevention * Periodontal examination * Ante's law * Brushing * Bleeding on probing * Chlorhexidine gluconate * Flossing * Hydrogen peroxide * Mouthwash * Oral hygiene * Tetracycline * Triclosan * Host modulatory therapy Treatment Conventional therapy * Debridement * Scaling and root planing * Full mouth disinfection * Full mouth ultrasonic debridement Surgery * Apically positioned flap * Bone graft * Coronally positioned flap * Crown lengthening * Free gingival graft * Gingival grafting * Gingivectomy * Guided bone regeneration * Guided tissue regeneration * Enamel matrix derivative * Implant placement * Lateral pedicle graft * Open flap debridement * Pocket reduction surgery * Socket preservation * Sinus lift * Subepithelial connective tissue graft * Tools * Curette * Membrane * Probe * Scaler Important personalities * Tomas Albrektsson * Frank Beube * Per-Ingvar Brånemark * Robert Gottsegen * Gary Greenstein * Jan Lindhe * Brian Mealey * Preston D. Miller * Willoughby D. Miller * Carl E. Misch * John Mankey Riggs * Jay Seibert * Jørgen Slots * Paul Roscoe Stillman * Dennis P. Tarnow * Hom-Lay Wang * James Leon Williams * W. J. Younger Other specialties * Endodontology * Orthodontology * Prosthodontology * v * t * e Dentistry Specialties * Endodontics * Oral and maxillofacial pathology * Oral and maxillofacial radiology * Oral and maxillofacial surgery * Orthodontics and dentofacial orthopedics * Pediatric dentistry * Periodontics * Prosthodontics * Dental public health * Cosmetic dentistry * Dental implantology * Geriatric dentistry * Restorative dentistry * Forensic odontology * Dental traumatology * Holistic dentistry Dental surgery * Dental extraction * Tooth filling * Root canal therapy * Root end surgery * Scaling and root planing * Teeth cleaning * Dental bonding * Tooth polishing * Tooth bleaching * Socket preservation * Dental implant Organisations * American Association of Orthodontists * British Dental Association * British Dental Health Foundation * British Orthodontic Society * Canadian Association of Orthodontists * Dental Technologists Association * General Dental Council * Indian Dental Association * National Health Service See also * Index of oral health and dental articles * Outline of dentistry and oral health * Dental fear * Dental instruments * Dental material * History of dental treatments * Infant oral mutilation * Mouth assessment * Oral hygiene [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Aggressive periodontitis	c0031106	1,108	wikipedia	https://en.wikipedia.org/wiki/Aggressive_periodontitis	2021-01-18T18:45:27	{"mesh": ["D010520"], "umls": ["C0031106"], "wikidata": ["Q4692285"]}
See GGTQTL2 (612366) on chromosome 12q24 for another locus associated with the plasma level of gamma glutamyltransferase. Mapping Bathum et al. (2001) found evidence for a substantial genetic influence on the plasma level of gamma glutamyltransferase (GGT, or GGT1; 612346). Heritability ranged from 35 to 61% among 290 same-sex Danish twin pairs. Among 1,134 men and 2,241 women recruited through the Australian Twin Registry, Whitfield et al. (2002) found a heritability estimate of 0.52 for plasma GGT levels. Yuan et al. (2008) performed a genomewide association study of plasma liver-enzyme levels in 3 populations (total n = 7,715) with replication in 3 additional cohorts (total n = 4,704). A locus associated with plasma level of GGT was identified on chromosome 22q11.23 within the GGT1 gene. Significant linkage was found with rs4820599 (p = 4.0 x 10(-11)), which the authors suggested may affect differential expression of the GGT1 gene. Chambers et al. (2011) carried out a genomewide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma. The strongest association for GGT was at 22q11.23 with rs2073398 with an effect of 12.3%, 95% CI 10.9-13.7, p = 1.1 x 10(-109). The genes of interest in the area are GGT1 and GGTLC2 (612339). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	GAMMA GLUTAMYLTRANSFERASE, PLASMA LEVEL OF, QUANTITATIVE TRAIT LOCUS 1	c2676495	1,109	omim	https://www.omim.org/entry/612365	2019-09-22T16:01:47	{"omim": ["612365"], "synonyms": ["Alternative titles", "GGTQTL1"]}
Deafness-vitiligo-achalasia syndrome is characterized by the association of deafness, short stature, vitiligo, muscle wasting, and achalasia. ## Epidemiology It has been described in a brother and his sister born to first-cousin parents. ## Genetic counseling It is likely to be transmitted as an autosomal recessive trait. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Deafness-vitiligo-achalasia syndrome	c1857339	1,110	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3239	2021-01-23T18:58:06	{"gard": ["1705"], "mesh": ["C565642"], "omim": ["221350"], "umls": ["C1857339"], "icd-10": ["Q87.8"], "synonyms": ["Hearing loss-vitiligo-achalasia syndrome"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-53 (DFNB53) is caused by homozygous mutation in the COL11A2 gene (120290) on chromosome 6p21. Clinical Features Chen et al. (2005) reported a consanguineous Iranian family with a prelingual, profound, nonprogressive, and nonsyndromic sensorineural hearing loss. Chakchouk et al. (2015) studied a large multigenerational consanguineous Tunisian family in which 2 sisters and their male cousin as well as a more distant male relative had a history of prelingual hearing loss. Pure tone audiometry in the 2 affected sisters showed bilateral profound sensorineural hearing loss. Chakchouk et al. (2015) also studied 2 affected Turkish sisters with prelingual-onset hearing loss, born of consanguineous parents, who also exhibited bilateral profound sensorineural deafness. Mapping Using genomewide linkage analysis in 11 members of a consanguineous Iranian family with nonsyndromic hearing loss, Chen et al. (2005) identified a 9.4-cM region flanked by D6S276 and D6S1610 on chromosome 6p21.3, which they designated DFNB53. In a large multigenerational consanguineous Tunisian family segregating autosomal recessive congenital hearing loss, Chakchouk et al. (2015) performed a genomewide microsatellite scan that demonstrated possible linkage at 6p21, with 3 of 4 affected individuals homozygous for marker D6S1610. Molecular Genetics In 5 affected members of 2 sibships of a consanguineous Iranian family with nonsyndromic hearing loss, Chen et al. (2005) identified homozygosity for a missense mutation in the COL11A2 gene (P621T; 120290.0010). The 4 parents and 1 sib were heterozygous for the mutation. In a large multigenerational consanguineous Tunisian family segregating autosomal recessive congenital profound sensorineural hearing loss, Chakchouk et al. (2015) performed whole-exome sequencing and identified a homozygous missense mutation in the COL11A2 gene (A37S; 120290.0014) that segregated with disease. Family members who were heterozygous carriers of A37S exhibited apparently progressive sensorineural hearing loss after age 30 years. Whole-exome sequencing in 2 affected sisters from a consanguineous Turkish family revealed homozygosity for a different missense mutation in COL11A2 (P888T; 120290.0015); their unaffected parents and an unaffected sister were heterozygous for the mutation. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, nonprogressive profound, prelingual MISCELLANEOUS \- Prelingual onset \- Some heterozygous carriers exhibit accelerated age-related hearing loss MOLECULAR BASIS \- Caused by mutation in the alpha-2 collagen XI polypeptide gene (COL11A2, 120290.0010 ) ▲ 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	DEAFNESS, AUTOSOMAL RECESSIVE 53	c1864746	1,111	omim	https://www.omim.org/entry/609706	2019-09-22T16:05:45	{"doid": ["0110509"], "mesh": ["C566453"], "omim": ["609706"], "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"]}
A number sign (#) is used with this entry because of evidence that Alagille syndrome-2 (ALGS2) is caused by heterozygous mutation in the NOTCH2 gene (600275) on chromosome 1p12. For a general phenotypic description and a discussion of genetic heterogeneity of Alagille syndrome, see ALGS1 (118450). Clinical Features Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems. McDaniell et al. (2006) identified 2 probands with mutation in the NOTCH2 gene who, in addition to meeting the diagnostic criteria for ALGS, had severe renal disease. The first proband had cholestatic liver disease, cardiac disease (peripheral pulmonic stenosis and a small atrial septal defect), characteristic facial features, and severe infantile renal disease (small kidneys with cysts bilaterally, renal tubular acidosis, and renal insufficiency). He died of cardiopulmonary arrest at age 2 years. His mother had valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant. The second proband had cholestatic liver disease, which led to liver transplant, cardiac disease (tetralogy of Fallot), and ocular findings (posterior embryotoxon). She demonstrated renal disease (tubular acidosis and dysplastic kidneys) and at age 8 years was awaiting a renal transplant. Her mother had a history of asymptomatic hematuria and proteinuria, having come to medical attention at age 26 years with a mildly elevated urine protein level, which increased steadily over the next 10 years. Hypertension was diagnosed at the age of 36 years. Abdominal ultrasound indicated normal-sized kidneys. No cardiovascular or gastrointestinal abnormalities were present. A dysmorphologist recognized facial features characteristic of ALGS. The proband's maternal grandmother had advanced chronic renal insufficiency first noted at age 59 years. Her renal insufficiency worsened until age 65 years, when she began peritoneal dialysis. An ultrasound of the kidneys showed a right atrophic kidney, which was thought to be congenital. Cardiac evaluation was negative for a murmur, and there was no history of liver disease. Adult-onset diabetes, diagnosed just before dialysis was begun, was well controlled with diet alone. McDaniell et al. (2006) remarked that renal manifestations, noted in only 40 to 70% of patients with a clinical diagnosis of ALGS, were present in all affected individuals. There is evidence from mouse studies that functional NOTCH2 is required for normal kidney development, because mice homozygous for a hypomorphic Notch2 mutation died perinatally secondary to defects in glomerular development (McCright et al., 2001). McDaniell et al. (2006) concluded that ALGS caused by NOTCH2 mutations may have a phenotypic profile different from that of ALGS caused by JAG1 (601920) mutations. Molecular Genetics About 94% of patients with ALGS had been found to have mutations in the gene encoding the Notch signaling pathway ligand JAG1. McDaniell et al. (2006) screened 11 JAG1 mutation-negative probands with ALGS for alterations in the gene encoding the NOTCH2 receptor and found mutations (600275.0001, 600275.0002) in 2 families. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Pointed chin \- Broad forehead Eyes \- Posterior embryotoxon Nose \- Long nose \- Bulbous tip CARDIOVASCULAR Heart \- Atrial septal defect \- Pulmonic stenosis \- Tetralogy of Fallot Vascular \- Hypertension ABDOMEN Liver \- Cholestatic liver disease GENITOURINARY Kidneys \- Small kidneys \- Cystic kidneys \- Renal tubular acidosis \- Renal insufficiency \- Proteinuria \- Hematuria MISCELLANEOUS \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the Notch receptor 2 gene (NOTCH2, 600275.0001 ) ▲ 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	ALAGILLE SYNDROME 2	c0085280	1,112	omim	https://www.omim.org/entry/610205	2019-09-22T16:04:57	{"doid": ["9245"], "mesh": ["D016738"], "omim": ["610205"], "orphanet": ["52", "261629"], "genereviews": ["NBK1273"]}
A number sign (#) is used with this entry because Bowen-Conradi syndrome (BWCNS) is caused by homozygous mutation in the EMG1 gene (611531) on chromosome 12p13. Clinical Features Among the offspring of second-cousin Hutterite parents, Bowen and Conradi (1976) described 2 males with a distinctive syndrome: prominent 'proud' nose, micrognathia, fifth finger clinodactyly, 'rocker-bottom' feet, and death in the first months of life. No autopsy information was available. Hunter et al. (1979) reported on 5 additional Hutterite cases. Low birth weight, microcephaly, and mild joint restriction were additional nonspecific features. The causative mutation appears to be widely distributed among the 3 North American sects (leuts) of Hutterites. Lowry et al. (2003) ascertained 39 cases of Bowen-Conradi syndrome, born during the 33-year period from 1968 to 2000, and personally examined almost all. The patients belonged to 29 nuclear families and were ascertained in all 3 leuts: 14 in Dariusleut, 12 in Schmiedeleut, and 3 in Lehrerleut. Innes and Lowry (2002) cited 3 reports of possible Bowen-Conradi syndrome in non-Hutterite children. Lemire (2002) noted 2 non-Hutterite cases of this disorder. The first was reported by Le Marec et al. (1981) as an autosomal recessive phenocopy of trisomy 18 in a Turkish patient (case 13) and was subsequently identified as Bowen-Conradi syndrome. Another was reported by Gupta and Phadke (2001) in an Indian infant. Lemire (2002) suggested that Bowen-Conradi syndrome be considered in any infant with features compatible with the diagnosis, regardless of ethnicity. Mapping By linkage and haplotype analysis in 11 Canadian Hutterite families (8 Schmiedeleut and 3 Dariusleut), Lamont et al. (2005) mapped the Bowen-Conradi syndrome locus to a 3.5-cM segment on chromosome 12p13.3, bounded by VWF (613160) and D12S397. Molecular Genetics Using DNA samples from 11 Canadian Hutterite families with Bowen-Conradi syndrome, Armistead et al. (2009) analyzed 35 candidate genes within the 1.9-Mbp interval mapped by Lamont et al., 2005 and identified homozygosity for a missense mutation in the EMG1 gene (611531.0001) that segregated completely with disease. The mutation, which destroys an EcoRV site in the most highly conserved region of the protein, was not found in 414 non-Hutterite alleles. Nomenclature At the urging of Lowry (2004), the preferred title is listed as Bowen-Conradi syndrome. This title, as he pointed out, gives appropriate recognition to the first authors, indicates that the disorder occurs in non-Hutterites, and avoids a feeling of stigmatization on the part of the Hutterites. Limbs \- Fifth finger clinodactyly \- Rocker-bottom feet Inheritance \- Autosomal recessive Mandible \- Micrognathia Joints \- Mild restriction Cranium \- Microcephaly Growth \- Lethal in months \- Low birth weight Nose \- Prominent nose ▲ 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	BOWEN-CONRADI SYNDROME	c1859405	1,113	omim	https://www.omim.org/entry/211180	2019-09-22T16:30:21	{"doid": ["0050684"], "mesh": ["C537081"], "omim": ["211180"], "orphanet": ["1270"], "synonyms": ["Alternative titles", "BOWEN HUTTERITE SYNDROME, FORMERLY"]}
A rare respiratory malformation characterized by a hamartomatous mass of non-functioning lung tissue of variable extent and with variable degrees of cystic or adenomatoid change. Clinical presentation, prognosis, and presence of associated abnormalities depend on the subtype of the lesion. Based on histopathological findings, five subtypes (types 0 to 4) can be differentiated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Congenital pulmonary airway malformation	c0010668	1,114	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2444	2021-01-23T18:43:13	{"mesh": ["D015615"], "umls": ["C0010668", "C0158641"], "icd-10": ["Q33.0"], "synonyms": ["CCAM", "CPAM", "Congenital cystic adenomatoid malformation of the lung", "Congenital cystic adenomatous malformation of the lung", "Congenital cystic disease of the lung"]}
For the condition characterized by comorbidity of a specific set of impairments to executive functioning, see Dysexecutive syndrome. In psychology and neuroscience, executive dysfunction, or executive function deficit, is a disruption to the efficacy of the executive functions, which is a group of cognitive processes that regulate, control, and manage other cognitive processes.[1] Executive dysfunction can refer to both neurocognitive deficits and behavioural symptoms. It is implicated in numerous psychopathologies and mental disorders, as well as short-term and long-term changes in non-clinical executive control. Executive dysfunction is not the same as dysexecutive syndrome, which is a common pattern of dysfunction in executive functions, such as deficiencies in planning, abstract thinking, flexibility and behavioural control.[2][3] This group of symptoms, usually resulting from brain damage, tend to occur together.[4][5] ## Contents * 1 Overview * 2 Cause * 2.1 Neurophysiology * 2.2 Genetics * 3 Testing and measurement * 3.1 Clock drawing test * 3.2 Stroop task * 3.3 Wisconsin card sorting test * 3.4 Trail-making test * 4 In clinical populations * 4.1 Schizophrenia * 4.2 Attention deficit hyperactivity disorder * 4.3 Autism spectrum disorder * 4.4 Bipolar disorder * 4.5 Parkinson's disease * 4.6 Treatment * 4.6.1 Psychosocial treatment * 4.6.2 Cognitive-behavioral therapy and group rehabilitation * 4.6.3 Treatment for patients with acquired brain injury * 4.7 Developmental context * 4.8 Evolutionary perspective * 5 Comorbidity * 6 Socio-cultural implications * 6.1 Education * 6.2 Criminal behaviour * 7 See also * 8 References ## Overview[edit] Executive functioning is a theoretical construct representing a domain of cognitive processes that regulate, control, and manage other cognitive processes. Executive functioning is not a unitary concept; it is a broad description of the set of processes involved in certain areas of cognitive and behavioural control.[1] Executive processes are integral to higher brain function, particularly in the areas of goal formation, planning, goal-directed action, self-monitoring, attention, response inhibition, and coordination of complex cognition and motor control for effective performance.[6] Deficits of the executive functions are observed in all populations to varying degrees, but severe executive dysfunction can have devastating effects on cognition and behaviour in both individual and social contexts. Executive dysfunction does occur to a minor degree in all individuals on both short-term and long-term scales. In non-clinical populations, the activation of executive processes appears to inhibit further activation of the same processes, suggesting a mechanism for normal fluctuations in executive control.[7] Decline in executive functioning is also associated with both normal and clinical aging.[8] In aging populations, the decline of memory processes appears to affect executive functions, which also points to the general role of memory in executive functioning.[9] Executive dysfunction appears to consistently involve disruptions in task-oriented behavior, which requires executive control in the inhibition of habitual responses and goal activation.[10] Such executive control is responsible for adjusting behaviour to reconcile environmental changes with goals for effective behaviour.[11] Impairments in set shifting ability are a notable feature of executive dysfunction; set shifting is the cognitive ability to dynamically change focus between points of fixation based on changing goals and environmental stimuli.[12] This offers a parsimonious explanation for the common occurrence of impulsive, hyperactive, disorganized, and aggressive behaviour in clinical patients with executive dysfunction. Executive dysfunction, particularly in working memory capacity, may also lead to varying degrees of emotional dysregulation, which can manifest as chronic depression, anxiety, or hyperemotionality.[13] Russell Barkley proposed a hybrid model of the role of behavioural disinhibition in the presentation of ADHD, which has served as the basis for much research of both ADHD and broader implications of the executive system.[14] Other common and distinctive symptoms of executive dysfunction include utilization behaviour, which is compulsive manipulation/use of nearby objects due simply to their presence and accessibility (rather than a functional reason); and imitation behaviour, a tendency to rely on imitation as a primary means of social interaction.[15] Research also suggests that executive set shifting is a co-mediator with episodic memory of feeling-of-knowing (FOK) accuracy, such that executive dysfunction may reduce FOK accuracy.[16] There is some evidence suggesting that executive dysfunction may produce beneficial effects as well as maladaptive ones. Abraham et al.[17] demonstrate that creative thinking in schizophrenia is mediated by executive dysfunction, and they establish a firm etiology for creativity in psychoticism, pinpointing a cognitive preference for broader top-down associative thinking versus goal-oriented thinking, which closely resembles aspects of ADHD. It is postulated that elements of psychosis are present in both ADHD and schizophrenia/schizotypy due to dopamine overlap.[18] ## Cause[edit] The cause of executive dysfunction is heterogeneous,[19] as many neurocognitive processes are involved in the executive system and each may be compromised by a range of genetic and environmental factors. Learning and development of long-term memory play a role in the severity of executive dysfunction through dynamic interaction with neurological characteristics. Studies in cognitive neuroscience suggest that executive functions are widely distributed throughout the brain, though a few areas have been isolated as primary contributors. Executive dysfunction is studied extensively in clinical neuropsychology as well, allowing correlations to be drawn between such dysexecutive symptoms and their neurological correlates. Executive processes are closely integrated with memory retrieval capabilities for overall cognitive control; in particular, goal/task-information is stored in both short-term and long-term memory, and effective performance requires effective storage and retrieval of this information.[11] Executive dysfunction characterizes many of the symptoms observed in numerous clinical populations. In the case of acquired brain injury and neurodegenerative diseases there is a clear neurological etiology producing dysexecutive symptoms. Conversely, syndromes and disorders are defined and diagnosed based on their symptomatology rather than etiology. Thus, while Parkinson's disease, a neurodegenerative condition, causes executive dysfunction, a disorder such as attention-deficit/hyperactivity disorder is a classification given to a set of subjectively-determined symptoms implicating executive dysfunction – current models indicate that such clinical symptoms are caused by executive dysfunction.[14][19] ### Neurophysiology[edit] As previously mentioned, executive functioning is not a unitary concept.[1] Many studies have been conducted in an attempt to pinpoint the exact regions of the brain that lead to executive dysfunction, producing a vast amount of often conflicting information indicating wide and inconsistent distribution of such functions. A common assumption is that disrupted executive control processes are associated with pathology in prefrontal brain regions.[20] This is supported to some extent by the primary literature, which shows both pre-frontal activation and communication between the pre-frontal cortex and other areas associated with executive functions such as the basal ganglia and cerebellum.[19][21] In most cases of executive dysfunction, deficits are attributed to either frontal lobe damage or dysfunction, or to disruption in fronto-subcortical connectivity.[1] Neuroimaging with PET and fMRI has confirmed the relationship between executive function and functional frontal pathology.[1] Neuroimaging studies have also suggested that some constituent functions are not discretely localized in prefrontal regions.[22] Functional imaging studies using different tests of executive function have implicated the dorsolateral prefrontal cortex to be the primary site of cortical activation during these tasks.[23] In addition, PET studies of patients with Parkinson's disease have suggested that tests of executive function are associated with abnormal function in the globus pallidus[1] and appear to be the genuine result of basal ganglia damage.[1] With substantial cognitive load, fMRI signals indicate a common network of frontal, parietal and occipital cortices, thalamus, and the cerebellum.[24] This observation suggests that executive function is mediated by dynamic and flexible networks that are characterized using functional integration and effective connectivity analyses.[1] The complete circuit underlying executive function includes both a direct and an indirect circuit.[23] The neural circuit responsible for executive functioning is, in fact, located primarily in the frontal lobe.[23] This main circuit originates in the dorsolateral prefrontal cortex/orbitofrontal cortex and then projects through the striatum and thalamus to return to the prefrontal cortex.[23] Not surprisingly, plaques and tangles in the frontal cortex can cause disruption in functions as well as damage to the connections between prefrontal cortex and the hippocampus.[20] Another important point is in the finding that structural MRI images link the severity of white matter lesions to deficits in cognition.[25] The emerging view suggests that cognitive processes materialize from networks that span multiple cortical sites with closely collaborative and over-lapping functions.[22] A challenge for future research will be to map the multiple brain regions that might combine with each other in a vast number of ways, depending on the task requirements.[22] ### Genetics[edit] Certain genes have been identified with a clear correlation to executive dysfunction and related psychopathologies. According to Friedman et al. (2008),[26] the heritability of executive functions is among the highest of any psychological trait. The dopamine receptor D4 gene (DRD4) with 7'-repeating polymorphism (7R) has been repeatedly shown to correlate strongly with impulsive response style on psychological tests of executive dysfunction, particularly in clinical ADHD.[27] The catechol-o-methyl transferase gene (COMT) codes for an enzyme that degrades catecholamine neurotransmitters (DA and NE), and its Val158Met polymorphism is linked with the modulation of task-oriented cognition and behavior (including set shifting[28]) and the experience of reward, which are major aspects of executive functioning. COMT is also linked to methylphenidate (stimulant medication) response in children with ADHD.[29] Both the DRD4/7R and COMT/Val158Met polymorphisms are also correlated with executive dysfunction in schizophrenia and schizotypal behaviour.[30] ## Testing and measurement[edit] There are several measures that can be employed to assess the executive functioning capabilities of an individual. Although a trained non-professional working outside of an institutionalized setting can legally and competently perform many of these measures, a trained professional administering the test in a standardized setting will yield the most accurate results.[31] ### Clock drawing test[edit] The Clock drawing test (CDT) is a brief cognitive task that can be used by physicians who suspect neurological dysfunction based on history and physical examination. It is relatively easy to train non-professional staff to administer a CDT. Therefore, this is a test that can easily be administered in educational and geriatric settings and can be utilized as a precursory measure to indicate the likelihood of further/future deficits.[32] Also, generational, educational and cultural differences are not perceived as impacting the utility of the CDT.[33] The procedure of the CDT begins with the instruction to the participant to draw a clock reading a specific time (generally 11:10). After the task is complete, the test administrator draws a clock with the hands set at the same specific time. Then the patient is asked to copy the image.[34] Errors in clock drawing are classified according to the following categories: omissions, perseverations, rotations, misplacements, distortions, substitutions and additions.[32] Memory, concentration, initiation, energy, mental clarity and indecision are all measures that are scored during this activity.[35] Those with deficits in executive functioning will often make errors on the first clock but not the second.[32] In other words, they will be unable to generate their own example, but will show proficiency in the copying task. ### Stroop task[edit] The cognitive mechanism involved in the Stroop task is referred to as directed attention. The Stroop task requires the participant to engage in and allows assessment of processes such as attention management, speed and accuracy of reading words and colours and of inhibition of competing stimuli.[36] The stimulus is a colour word that is printed in a different colour than what the written word reads. For example, the word "red" is written in a blue font. One must verbally classify the colour that the word is displayed/printed in, while ignoring the information provided by the written word. In the aforementioned example, this would require the participant to say "blue" when presented with the stimulus. Although the majority of people will show some slowing when given incompatible text versus font colour, this is more severe in individuals with deficits in inhibition. The Stroop task takes advantage of the fact that most humans are so proficient at reading colour words that it is extremely difficult to ignore this information, and instead acknowledge, recognize and say the colour the word is printed in.[37] The Stroop task is an assessment of attentional vitality and flexibility.[36] More modern variations of the Stroop task tend to be more difficult and often try to limit the sensitivity of the test.[38] ### Wisconsin card sorting test[edit] The Wisconsin Card Sorting Test (WCST) is used to determine an individual's competence in abstract reasoning, and the ability to change problem-solving strategies when needed.[36] These abilities are primarily determined by the frontal lobes and basal ganglia, which are crucial components of executive functioning;[39] making the WCST a good measure for this purpose.[citation needed] The WCST utilizes a deck of 128 cards that contains four stimulus cards.[36] The figures on the cards differ with respect to color, quantity, and shape. The participants are then given a pile of additional cards and are asked to match each one to one of the previous cards. Typically, children between ages 9 and 11 are able to show the cognitive flexibility that is needed for this test.[40] ### Trail-making test[edit] Another prominent test of executive dysfunction is known as the Trail-making test. This test is composed of two main parts (Part A & Part B). Part B differs from Part A specifically in that it assesses more complex factors of motor control and perception.[41] Part B of the Trail-making test consists of multiple circles containing letters (A-L) and numbers (1-12). The participant's objective for this test is to connect the circles in order, alternating between number and letter (e.g. 1-A-2-B) from start to finish.[42] The participant is required not to lift their pencil from the page. The task is also timed as a means of assessing speed of processing.[43] Set-switching tasks in Part B have low motor and perceptual selection demands, and therefore provide a clearer index of executive function.[41] Throughout this task, some of the executive function skills that are being measured include impulsivity, visual attention and motor speed.[43] ## In clinical populations[edit] The executive system's broad range of functions relies on, and is instrumental in, a broad range of neurocognitive processes. Clinical presentation of severe executive dysfunction that is unrelated to a specific disease or disorder is classified as a dysexecutive syndrome, and often appears following damage to the frontal lobes of the cerebral cortex.[44] As a result, Executive dysfunction is implicated etiologically and/or co-morbidly in many psychiatric illnesses, which often show the same symptoms as the dysexecutive syndrome. It has been assessed and researched extensively in relation to cognitive developmental disorders, psychotic disorders, affective disorders, and conduct disorders, as well as neurodegenerative diseases and acquired brain injury (ABI). Environmental dependency syndrome is a dysexecutive syndrome marked by significant behavioural dependence on environmental cues and is marked by excessive imitation and utilization behaviour.[45] It has been observed in patients with a variety of etiologies including ABI, exposure to phendimetrazine tartrate,[46] stroke, and various frontal lobe lesions.[45] ### Schizophrenia[edit] Schizophrenia is commonly described as a mental disorder in which a person becomes detached from reality because of disruptions in the pattern of thinking and perception.[47] Although the etiology is not completely understood, it is closely related to dopaminergic activity and is strongly associated with both neurocognitive and genetic elements of executive dysfunction.[30] Individuals with schizophrenia may demonstrate amnesia for portions of their episodic memory. Observed damage to explicit, consciously accessed, memory is generally attributed to the fragmented thoughts that characterize the disorder.[47] These fragmented thoughts are suggested to produce a similarly fragmented organization in memory during encoding and storage, making retrieval more difficult. However, implicit memory is generally preserved in patients with schizophrenia. Patients with schizophrenia demonstrate spared performance on measures of visual and verbal attention and concentration, as well as on immediate digit span recall, suggesting that observed deficits cannot be attributed to deficits in attention or short-term memory.[48] However, impaired performance was measured on psychometric measures assumed to assess higher order executive function. Working memory and multi-tasking impairments typically characterize the disorder.[17] Persons with schizophrenia also tend to demonstrate deficits in response inhibition and cognitive flexibility.[49] Patients often demonstrate noticeable deficits in the central executive component of working memory as conceptualized by Baddeley and Hitch. However, performance on tasks associated with the phonological loop and visuospatial sketchpad are typically less affected.[47][50] More specifically, patients with schizophrenia show impairment to the central executive component of working memory, specific to tasks in which the visuospatial system is required for central executive control.[48] The phonological system appears to be more generally spared overall. ### Attention deficit hyperactivity disorder[edit] A triad of core symptoms – inattention, hyperactivity, and impulsivity – characterize attention deficit hyperactivity disorder (ADHD). Individuals with ADHD often experience problems with organization, discipline, and setting priorities, and these difficulties often persist from childhood through adulthood.[51] In both children and adults with ADHD, an underlying executive dysfunction involving the prefrontal regions and other interconnected subcortical structures has been found.[51] As a result, people with ADHD commonly perform more poorly than matched controls on interference control, mental flexibility and verbal fluency.[14][51][52] Also, a more central impairment in self-regulation is noted in cases of ADHD.[14] However, some research has suggested the possibility that the severity of executive dysfunction in individuals with ADHD declines with age as they learn to compensate for the aforementioned deficits.[51] Thus, a decrease in executive dysfunction in adults with ADHD as compared to children with ADHD is thought reflective of compensatory strategies employed on behalf of the adults (e.g. using schedules to organize tasks) rather than neurological differences. Although ADHD has typically been conceptualized in a categorical diagnostic paradigm, it has also been proposed that this disorder should be considered within a more dimensional behavioural model that links executive functions to observed deficits.[52] Proponents argue that classic conceptions of ADHD falsely localize the problem at perception (input) rather than focusing on the inner processes involved in producing appropriate behaviour (output).[52] Moreover, others have theorized that the appropriate development of inhibition (something that is seen to be lacking in individuals with ADHD) is essential for the normal performance of other neuropsychological abilities such as working memory, and emotional self-regulation.[14] Thus, within this model, deficits in inhibition are conceptualized to be developmental and the result of atypically operating executive systems. ### Autism spectrum disorder[edit] Autism is diagnosed based on the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activities and interests. It is a disorder that is defined according to behaviour as no specific biological markers are known.[47] Due to the variability in severity and impairment in functioning exhibited by autistic people, the disorder is typically conceptualized as existing along a continuum (or spectrum) of severity. Autistic individuals commonly show impairment in three main areas of executive functioning:[53][54][55][56] * Fluency. Fluency refers to the ability to generate novel ideas and responses. Although adult populations are largely underrepresented in this area of research, findings have suggested that autistic children generate fewer novel words and ideas and produce less complex responses than matched controls. * Planning. Planning refers to a complex, dynamic process, wherein a sequence of planned actions must be developed, monitored, re-evaluated and updated. Autistic persons demonstrate impairment on tasks requiring planning abilities relative to typically functioning controls, with this impairment maintained over time. As might be suspected, in the case of autism comorbid with learning disability, an additive deficit is observed in many cases. * Flexibility. Poor mental flexibility, as demonstrated in autistic individuals, is characterized by perseverative, stereotyped behaviour, and deficits in both the regulation and modulation of motor acts. Some research has suggested that autistic individuals experience a sort of 'stuck-in-set' perseveration that is specific to the disorder, rather than a more global perseveration tendency. These deficits have been exhibited in cross-cultural samples and have been shown to persist over time. Although there has been some debate, inhibition is generally no longer considered to be an executive function deficit in autistic people.[53][56] Autistic individuals have demonstrated differential performance on various tests of inhibition, with results being taken to indicate a general difficulty in the inhibition of a habitual response.[56] However, performance on the Stroop task, for example, has been unimpaired relative to matched controls. An alternative explanation has suggested that executive function tests that demonstrate a clear rationale are passed by autistic individuals.[56] In this light, it is the design of the measures of inhibition that have been implicated in the observation of impaired performance rather than inhibition being a core deficit. In general, autistic individuals show relatively spared performance on tasks that do not require mentalization.[47] These include: use of desire and emotion words, sequencing behavioural pictures, and the recognition of basic facial emotional expressions. In contrast, autistic individuals typically demonstrated impaired performance on tasks that do require mentalizing.[47] These include: false beliefs, use of belief and idea words, sequencing mentalistic pictures, and recognizing complex emotions such as admiring or scheming. ### Bipolar disorder[edit] Bipolar disorder is a mood disorder that is characterized by both highs (mania) and lows (depression) in mood. These changes in mood sometimes alternate rapidly (changes within days or weeks) and sometimes not so rapidly (within weeks or months).[55] Current research provides strong evidence of cognitive impairments in individuals with bipolar disorder, particularly in executive function and verbal learning.[57] Moreover, these cognitive deficits appear to be consistent cross-culturally,[57] indicating that these impairments are characteristic of the disorder and not attributable to differences in cultural values, norms, or practice. Functional neuroimaging studies have implicated abnormalities in the dorsolateral prefrontal cortex and the anterior cingulate cortex as being volumetrically different in individuals with bipolar disorder.[57] Individuals affected by bipolar disorder exhibit deficits in strategic thinking, inhibitory control, working memory, attention, and initiation that are independent of affective state.[55][58] In contrast to the more generalized cognitive impairment demonstrated in persons with schizophrenia, for example, deficits in bipolar disorder are typically less severe and more restricted. It has been suggested that a "stable dys-regulation of prefrontal function or the subcortical-frontal circuitry [of the brain] may underlie the cognitive disturbances of bipolar disorder".[59] Executive dysfunction in bipolar disorder is suggested to be associated particularly with the manic state, and is largely accounted for in terms of the formal thought disorder that is a feature of mania.[59] It is important to note, however, that patients with bipolar disorder with a history of psychosis demonstrated greater impairment on measures of executive functioning and spatial working memory compared with bipolar patients without a history of psychosis[58] suggesting that psychotic symptoms are correlated with executive dysfunction. ### Parkinson's disease[edit] Parkinson's disease (PD) primarily involves damage to subcortical brain structures and is usually associated with movement difficulties, in addition to problems with memory and thought processes.[47] Persons affected by PD often demonstrate difficulties in working memory, a component of executive functioning. Cognitive deficits found in early PD process appear to involve primarily the fronto-executive functions.[60] Moreover, studies of the role of dopamine in the cognition of PD patients have suggested that PD patients with inadequate dopamine supplementation are more impaired in their performance on measures of executive functioning.[61] This suggests that dopamine may contribute to executive control processes. Increased distractibility, problems in set formation and maintaining and shifting attentional sets, deficits in executive functions such as self-directed planning, problems solving, and working memory have been reported in PD patients.[60] In terms of working memory specifically, persons with PD show deficits in the areas of: a) spatial working memory; b) central executive aspects of working memory; c) loss of episodic memories; d) locating events in time.[47][60][61] Spatial working memory. PD patients often demonstrate difficulty in updating changes in spatial information and often become disoriented. They do not keep track of spatial contextual information in the same way that a typical person would do almost automatically. Similarly, they often have trouble remembering the locations of objects that they have recently seen, and thus also have trouble with encoding this information into long-term memory. Central executive aspects. PD is often characterized by a difficulty in regulating and controlling one's stream of thought, and how memories are utilized in guiding future behaviour. Also, persons affected by PD often demonstrate perseverative behaviours such as continuing to pursue a goal after it is completed, or an inability to adopt a new strategy that may be more appropriate in achieving a goal. However, some research from 2007 suggests that PD patients may actually be less persistent in pursuing goals than typical persons and may abandon tasks sooner when they encounter problems of a higher level of difficulty.[60] Loss of episodic memories. The loss of episodic memories in PD patients typically demonstrates a temporal gradient wherein older memories are generally more preserved than newer memories. Also, while forgetting event content is less compromised in Parkinson's than in Alzheimer's, the opposite is true for event data memories. Locating events in time. PD patients often demonstrate deficits in their ability to sequence information, or date events. Part of the problems is hypothesized to be due to a more fundamental difficulty in coordinating or planning retrieval strategies, rather than failure at the level of encoding or storing information in memory. This deficit is also likely to be due to an underlying difficulty in properly retrieving script information. PD patients often exhibit signs of irrelevant intrusions, incorrect ordering of events, and omission of minor components in their script retrieval, leading to disorganized and inappropriate application of script information. ### Treatment[edit] #### Psychosocial treatment[edit] Since 1997 there has been experimental and clinical practice of psychosocial treatment for adults with executive dysfunction, and particularly attention-deficit/hyperactivity disorder (ADHD). Psychosocial treatment addresses the many facets of executive difficulties, and as the name suggests, covers academic, occupational and social deficits. Psychosocial treatment facilitates marked improvements in major symptoms of executive dysfunction such as time management, organization and self-esteem.[62] #### Cognitive-behavioral therapy and group rehabilitation[edit] Cognitive-behavioural therapy (CBT) is a frequently suggested treatment for executive dysfunction, but has shown limited effectiveness. However, a study of CBT in a group rehabilitation setting showed a significant increase in positive treatment outcome compared with individual therapy. Patients' self-reported symptoms on 16 different ADHD/executive-related items were reduced following the treatment period.[63] #### Treatment for patients with acquired brain injury[edit] The use of auditory stimuli has been examined in the treatment of dysexecutive syndrome. The presentation of auditory stimuli causes an interruption in current activity, which appears to aid in preventing "goal neglect" by increasing the patients' ability to monitor time and focus on goals. Given such stimuli, subjects no longer performed below their age group average IQ.[64] Patients with acquired brain injury have also been exposed to goal management training (GMT). GMT skills are associated with paper-and-pencil tasks that are suitable for patients having difficulty setting goals. From these studies there has been support for the effectiveness of GMT and the treatment of executive dysfunction due to ABI.[65] ### Developmental context[edit] An understanding of how executive dysfunction shapes development has implications how we conceptualize executive functions and their role in shaping the individual. Disorders affecting children such as ADHD, along with oppositional defiant disorder, conduct disorder, high functioning autism, and Tourette's syndrome have all been suggested to involve executive functioning deficits.[66] The main focus of current research has been on working memory, planning, set shifting, inhibition, and fluency. This research suggests that differences exist between typically functioning, matched controls, and clinical groups, on measures of executive functioning.[66] Some research has suggested a link between a child's abilities to gain information about the world around them and having the ability to override emotions in order to behave appropriately.[67] One study required children to perform a task from a series of psychological tests, with their performance used as a measure of executive function.[67] The tests included assessments of: executive functions (self-regulation, monitoring, attention, flexibility in thinking), language, sensorimotor, visuospatial, and learning, in addition to social perception. The findings suggested that the development of theory of mind in younger children is linked to executive control abilities with development impaired in individuals who exhibit signs of executive dysfunction.[67] Both ADHD and obesity are complicated disorders and each produces a large impact on an individual's social well being.[68] This being both a physical and psychological disorder has reinforced that obese individuals with ADHD need more treatment time (with associated costs), and are at a higher risk of developing physical and emotional complications.[68] The cognitive ability to develop a comprehensive self-construct and the ability to demonstrate capable emotion regulation is a core deficit observed in people with ADHD and is linked to deficits in executive function.[68] Overall, low executive functioning seen in individuals with ADHD has been correlated with tendencies to overeat, as well as with emotional eating.[68] This particular interest in the relationship between ADHD and obesity is rarely clinically assessed and may deserve more attention in future research. It has been made known that young children with behavioral problems show poor verbal ability and executive functions.[69] The exact distinction between parenting style and the importance of family structure on child development is still somewhat unclear. However, in infancy and early childhood, parenting is among the most critical external influences on child reactivity.[70] In Mahoney's study of maternal communication, results indicated that the way mothers interacted with their children accounted for almost 25% of variability in children's rate of development.[71] Every child is unique, making parenting an emotional challenge that should be most closely related to the child's level of emotional self-regulation (persistence, frustration and compliance).[70] A promising approach that is currently being investigated amid intellectually disabled children and their parents is responsive teaching. Responsive teaching is an early intervention curriculum designed to address the cognitive, language, and social needs of young children with developmental problems.[72] Based on the principle of "active learning",[72] responsive teaching is a method that is currently being applauded as adaptable for individual caregivers, children and their combined needs[71] The effect of parenting styles on the development of children is an important area of research that seems to be forever ongoing and altering. There is no doubt that there is a prominent link between parental interaction and child development but the best child-rearing technique continues to vary amongst experts. ### Evolutionary perspective[edit] The prefrontal lobe controls two related executive functioning domains. The first is mediation of abilities involved in planning, problem solving, and understanding information, as well as engaging in working memory processes and controlled attention. In this sense, the prefrontal lobe is involved with dealing with basic, everyday situations, especially those involving metacognitive functions.[73] The second domain involves the ability to fulfill biological needs through the coordination of cognition and emotions which are both associated with the frontal and prefrontal areas.[73] From an evolutionary perspective, it has been hypothesized that the executive system may have evolved to serve several adaptive purposes.[74] The prefrontal lobe in humans has been associated both with metacognitive executive functions and emotional executive functions.[73] Theory and evidence suggest that the frontal lobes in other primates also mediate and regulate emotion, but do not demonstrate the metacognitive abilities that are demonstrated in humans.[73] This uniqueness of the executive system to humans implies that there was also something unique about the environment of ancestral humans, which gave rise to the need for executive functions as adaptations to that environment.[74] Some examples of possible adaptive problems that would have been solved by the evolution of an executive system are: social exchange, imitation and observational learning, enhanced pedagogical understanding, tool construction and use, and effective communication.[74] In a similar vein, some have argued that the unique metacognitive capabilities demonstrated by humans have arisen out of the development of a sophisticated language (symbolization) systems and culture.[73] Moreover, in a developmental context, it has been proposed that each executive function capability originated as a form of public behaviour directed at the external environment, but then became self-directed, and then finally, became private to the individual, over the course of the development of self-regulation.[74] These shifts in function illustrate the evolutionarily salient strategy of maximizing longer-term social consequences over near-term ones, through the development of an internal control of behaviour.[74] ## Comorbidity[edit] Flexibility problems are more likely to be related to anxiety,[75] and metacognition problems are more likely to be related to depression.[76] ## Socio-cultural implications[edit] ### Education[edit] In the classroom environment, children with executive dysfunction typically demonstrate skill deficits that can be categorized into two broad domains: a) self-regulatory skills; and b) goal-oriented skills.[77] The table below is an adaptation of McDougall's[77] summary and provides an overview of specific executive function deficits that are commonly observed in a classroom environment. It also offers examples of how these deficits are likely to manifest in behaviour. Self-regulatory skills Often exhibit deficits in... Manifestations in the classroom Perception. Awareness of something happening in the environment Doesn't "see" what is happening; Doesn't "hear" instructions Modulation. Awareness of the amount of effort needed to perform a task (successfully) Commission of errors at easy levels and success at harder levels; Indication that student thinks the task is "easy" then cannot do it correctly; Performance improves once the student realized that the task is more difficult than originally thought Sustained attention. Ability to focus on a task or situation despite distractions, fatigue or boredom Initiates the task, but doesn't continue to work steadily; Easily distracted; Fatigues easily; Complains task is too long or too boring Flexibility. Ability to change focus, adapt to changing conditions or revise plans in the face of obstacles, new information or mistakes (can also be considered as "adaptability") Slow to stop one activity and begin another after being instructed to do so; Tendency to stay with one plan or strategy even after it is shown to be ineffective; Rigid adherence to routines; Refusal to consider new information Working memory. Ability to hold information in memory while performing complex tasks with information Forgets instructions (especially if multi-step); Frequently asks for information to be repeated; Forgets books at home or at school; Can't do mental arithmetic; Difficulty making connections with previously learned information; Difficulty with reading comprehension Response inhibition. Capacity to think before acting (deficits are often observed as "impulsivity") Seems to act without thinking; Frequently interrupts; Talks out in class; Often out of seat/away from desk; Rough play gets out of control; Doesn't consider consequences of actions Emotional regulation. Ability to modulate emotional responses Temper outbursts; Cries easily; Very easily frustrated; Very quick to anger; Acts silly Goal-oriented skills Often exhibit deficits in... Manifestations in the classroom Planning. Ability to list steps needed to reach a goal or complete a task Doesn't know where to start when given large assignments; Easily overwhelmed by task demands; Difficulty developing a plan for long-term projects; Problem-solving strategies are very limited and haphazard; Starts working before adequately considering the demands of a task; Difficulty listing steps required to complete a task Organization. Ability to arrange information or materials according to a system Disorganized desk, binder, notebooks, etc.; Loses books, papers, assignments, etc.; Doesn't write down important information; Difficulty retrieving information when needed Time management. Ability to comprehend how much time is available, or to estimate how long it will take to complete a task, and keep track of how much time has passed relative to the amount of the task completed Very little work accomplished during a specified period of time; Wasting time, then rushing to complete a task at the last minute; Often late to class/assignments are often late; Difficulty estimating how long it takes to do a task; Limited awareness of the passage of time Self-monitoring. Ability to stand back and evaluate how you are doing (can also be thought of as "metacognitive" abilities) Makes "careless" errors; Does not check work before handing it in; Does not stop to evaluate how things are going in the middle of a task or activity; Thinks a task was well done, when in fact it was done poorly; Thinks a task was poorly done, when in fact it was done well Teachers play a crucial role in the implementation of strategies aimed at improving academic success and classroom functioning in individuals with executive dysfunction. In a classroom environment, the goal of intervention should ultimately be to apply external control, as needed (e.g. adapt the environment to suit the child, provide adult support) in an attempt to modify problem behaviours or supplement skill deficits.[78] Ultimately, executive function difficulties should not be attributed to negative personality traits or characteristics (e.g. laziness, lack of motivation, apathy, and stubbornness) as these attributions are neither useful nor accurate. Several factors should be considered in the development of intervention strategies. These include, but are not limited to: developmental level of the child, comorbid disabilities, environmental changes, motivating factors, and coaching strategies.[77][78] It is also recommended that strategies should take a proactive approach in managing behaviour or skill deficits (when possible), rather than adopt a reactive approach.[77] For example, an awareness of where a student may have difficulty throughout the course of the day can aid the teacher in planning to avoid these situations or in planning to accommodate the needs of the student. People with executive dysfunction have a slower cognitive processing speed and thus often take longer to complete tasks than people who demonstrate typical executive function capabilities. This can be frustrating for the individual and can serve to impede academic progress. Disorders affecting children such as ADHD, along with oppositional defiant disorder, conduct disorder, high functioning autism and Tourette's syndrome have all been suggested to involve executive functioning deficits.[56] The main focus of current research has been on working memory, planning, set shifting, inhibition, and fluency. This research suggests that differences exist between typically functioning, matched controls and clinical groups, on measures of executive functioning.[56] Moreover, some people with ADHD report experiencing frequent feelings of drowsiness.[79] This can hinder their attention for lectures, readings, and completing assignments. Individuals with this disorder have also been found to require more stimuli for information processing in reading and writing.[56] Slow processing may manifest in behavior as signaling a lack of motivation on behalf of the learner. However, slow processing is reflective of an impairment of the ability to coordinate and integrate multiple skills and information sources.[79] The main concern with individuals with autism regarding learning is in the imitation of skills.[56] This can be a barrier in many aspects such as learning about others intentions, mental states, speech, language, and general social skills.[56] Individuals with autism tend to be dependent on the routines that they have already mastered, and have difficulty with initiating new non-routine tasks. Although an estimated 25–40% of people with autism also have a learning disability, many will demonstrate an impressive rote memory and memory for factual knowledge.[56] As such, repetition is the primary and most successful method for instruction when teaching people with autism.[79] Being attentive and focused for people with Tourette's syndrome is a difficult process. People affected by this disorder tend to be easily distracted and act very impulsively.[80] That is why it is very important to have a quiet setting with few distractions for the ultimate learning environment. Focusing is particularly difficult for those who are affected by Tourette's syndrome comorbid with other disorders such as ADHD or obsessive-compulsive disorder, it makes focusing very difficult.[80] Also, these individuals can be found to repeat words or phrases consistently either immediately after they are learned or after a delayed period of time.[80] ### Criminal behaviour[edit] Prefrontal dysfunction has been found as a marker for persistent, criminal behavior.[81] The prefrontal cortex is involved with mental functions including; affective range of emotions, forethought, and self-control.[81] Moreover, there is a scarcity of mental control displayed by individuals with a dysfunction in this area over their behavior, reduced flexibility and self-control and their difficulty to conceive behavioral consequences, which may conclude in unstable (or criminal) behavior.[81][82] In a 2008 study conducted by Barbosa & Monteiro, it was discovered that the recurrent criminals that were considered in this study suffered from executive dysfunction.[81] In view of the fact that abnormalities in executive function can limit how people respond to rehabilitation and re-socialization programs[81] these findings of the recurrent criminals are justified. Statistically significant relations have been discerned between anti-social behavior and executive function deficits.[83] These findings relate to the emotional instability that is connected with executive function as a detrimental symptom that can also be linked towards criminal behavior. Conversely, it is unclear as to the specificity of anti-social behavior to executive function deficits as opposed to other generalized neuropsychological deficits.[83] The uncontrollable deficiency of executive function has an increased expectancy for aggressive behavior that can result in a criminal deed.[84][85] Orbitofrontal injury also hinders the ability to be risk avoidant, make social judgments, and may cause reflexive aggression.[84] A common retort to these findings is that the higher incidence of cerebral lesions among the criminal population may be due to the peril associated with a life of crime.[81] Along with this reasoning, it would be assumed that some other personality trait is responsible for the disregard of social acceptability and reduction in social aptitude. Furthermore, some think the dysfunction cannot be entirely to blame.[84] There are interacting environmental factors that also have an influence on the likelihood of criminal action. This theory proposes that individuals with this deficit are less able to control impulses or foresee the consequences of actions that seem attractive at the time (see above) and are also typically provoked by environmental factors. One must recognize that the frustrations of life, combined with a limited ability to control life events, can easily cause aggression and/or other criminal activities. ## See also[edit] * Autonoetic consciousness ## References[edit] 1. ^ a b c d e f g h Elliott, Rebecca (March 2003). "Executive functions and their disorders". British Medical Bulletin. 65 (1): 49–59. doi:10.1093/bmb/65.1.49. PMID 12697616. 2. ^ Wilson, Barbara A.; Evans, Jonathan J.; Emslie, Hazel; Alderman, Nick; Burgess, Paul (May 1998). "The Development of an Ecologically Valid Test for Assessing Patients with a Dysexecutive Syndrome". Neuropsychological Rehabilitation. 8 (3): 213–228. doi:10.1080/713755570. 3. ^ Baddeley, Alan; Wilson, Barbara (April 1988). "Frontal amnesia and the dysexecutive syndrome". Brain and Cognition. 7 (2): 212–230. doi:10.1016/0278-2626(88)90031-0. PMID 3377900. S2CID 26954876. 4. ^ Halligan, P.W., Kischka, U., & Marshall, J.C. (2004). Handbook of clinical neuropsychology. Oxford University Press.[page needed] 5. ^ Stuss, Donald T; Alexander, Michael P (3 April 2007). "Is there a dysexecutive syndrome?". Philosophical Transactions of the Royal Society B: Biological Sciences. 666 (1481): 901–915. doi:10.1098/rstb.2007.2096. PMC 2430005. PMID 17412679. 6. ^ Jurado, María Beatriz; Rosselli, Mónica (5 September 2007). "The Elusive Nature of Executive Functions: A Review of our Current Understanding". Neuropsychology Review. 17 (3): 213–233. doi:10.1007/s11065-007-9040-z. PMID 17786559. S2CID 207222990. 7. ^ Schmeichel, Brandon J. (2007). "Attention control, memory updating, and emotion regulation temporarily reduce the capacity for executive control". Journal of Experimental Psychology: General. 136 (2): 241–255. doi:10.1037/0096-3445.136.2.241. PMID 17500649. 8. ^ Zelazo, Philip David; Craik, Fergus I.M; Booth, Laura (February 2004). "Executive function across the life span". Acta Psychologica. 115 (2–3): 167–183. doi:10.1016/j.actpsy.2003.12.005. PMID 14962399. 9. ^ Bisiacchi, Patrizia S.; Borella, Erika; Bergamaschi, Susanna; Carretti, Barbara; Mondini, Sara (14 July 2008). "Interplay between memory and executive functions in normal and pathological aging". Journal of Clinical and Experimental Neuropsychology. 30 (6): 723–733. doi:10.1080/13803390701689587. PMID 18608665. S2CID 20708594. 10. ^ Nieuwenhuis, Sander; Broerse, Annelies; Nielen, Marjan M.A.; Jong, Ritske de (November 2004). "A goal activation approach to the study of executive function: An application to antisaccade tasks". Brain and Cognition. 56 (2): 198–214. doi:10.1016/j.bandc.2003.12.002. PMID 15518936. S2CID 1876331. 11. ^ a b Verbruggen, Frederick; Logan, Gordon D. (2008). "Long-term aftereffects of response inhibition: Memory retrieval, task goals, and cognitive control". Journal of Experimental Psychology: Human Perception and Performance. 34 (5): 1229–1235. doi:10.1037/0096-1523.34.5.1229. PMID 18823207. 12. ^ Avila, César; Barrós, Alfonso; Ortet, Generós; Antònia Parcet, Maria; Ibañez, M. Ignacio (November 2003). "Set‐shifting and sensitivity to reward: A possible dopamine mechanism for explaining disinhibitory disorders". Cognition & Emotion. 17 (6): 951–959. doi:10.1080/02699930341000031. S2CID 143887153. 13. ^ Schmeichel, Brandon J.; Volokhov, Rachael N.; Demaree, Heath A. (2008). "Working memory capacity and the self-regulation of emotional expression and experience". Journal of Personality and Social Psychology. 95 (6): 1526–1540. doi:10.1037/a0013345. PMID 19025300. 14. ^ a b c d e Barkley, Russell A. (January 1997). "Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD". Psychological Bulletin. 121 (1): 65–94. doi:10.1037/0033-2909.121.1.65. PMID 9000892. 15. ^ Hoffmann, MW; Bill, PL (7 March 1992). "The environmental dependency syndrome, imitation behaviour and utilisation behaviour as presenting symptoms of bilateral frontal lobe infarction due to moyamoya disease". South African Medical Journal. 81 (5): 271–3. PMID 1542821. 16. ^ Perrotin, Audrey; Tournelle, Lydia; Isingrini, Michel (June 2008). "Executive functioning and memory as potential mediators of the episodic feeling-of-knowing accuracy". Brain and Cognition. 67 (1): 76–87. doi:10.1016/j.bandc.2007.11.006. PMID 18206284. S2CID 25826386. 17. ^ a b Abraham, Anna; Windmann, Sabine; McKenna, Peter; Güntürkün, Onur (May 2007). "Creative thinking in schizophrenia: The role of executive dysfunction and symptom severity". Cognitive Neuropsychiatry. 12 (3): 235–258. doi:10.1080/13546800601046714. PMID 17453904. S2CID 5739810. 18. ^ Keshavan, Matcheri S.; Sujata, Mandayam; Mehra, Akhil; Montrose, Debra M.; Sweeney, John A. (January 2003). "Psychosis proneness and ADHD in young relatives of schizophrenia patients". Schizophrenia Research. 59 (1): 85–92. doi:10.1016/S0920-9964(01)00400-5. PMID 12413647. S2CID 2437970. 19. ^ a b c Nigg JT (2006). What causes ADHD?: Understanding what goes wrong and why. New York, NY: Guilford Press. ISBN 1-59385-267-3, ISBN 978-1-59385-267-2.[page needed] 20. ^ a b Glosser, Guila; Gallo, Jennifer L.; Clark, Christopher M.; Grossman, Murray (2002). "Memory encoding and retrieval in frontotemporal dementia and Alzheimer's disease". Neuropsychology. 16 (2): 190–196. doi:10.1037/0894-4105.16.2.190. PMID 11949711. 21. ^ Berquin, P. C.; Giedd, J. N.; Jacobsen, L. K.; Hamburger, S. D.; Krain, A. L.; Rapoport, J. L.; Castellanos, F. X. (1 April 1998). "Cerebellum in attention-deficit hyperactivity disorder: A morphometric MRI study". Neurology. 50 (4): 1087–1093. doi:10.1212/WNL.50.4.1087. PMID 9566399. S2CID 24771696. 22. ^ a b c Carpenter, P (1 April 2000). "Working memory and executive function: evidence from neuroimaging". Current Opinion in Neurobiology. 10 (2): 195–199. doi:10.1016/S0959-4388(00)00074-X. PMID 10753796. S2CID 109197. 23. ^ a b c d Ottowitz, William E.; Tondo, Leonardo; Dougherty, Darin D.; Savage, Cary R. (January 2002). "The Neural Network Basis for Abnormalities of Attention and Executive Function in Major Depressive Disorder: Implications for Application of the Medical Disease Model to Psychiatric Disorders". Harvard Review of Psychiatry. 10 (2): 86–99. doi:10.1080/10673220216210. PMID 11897749. 24. ^ Tomasi, D.; Chang, L.; Caparelli, E.C.; Ernst, T. (February 2007). "Different activation patterns for working memory load and visual attention load". Brain Research. 1132 (1): 158–165. doi:10.1016/j.brainres.2006.11.030. PMC 1831676. PMID 17169343. 25. ^ Buckner, Randy L. (September 2004). "Memory and Executive Function in Aging and AD". Neuron. 44 (1): 195–208. doi:10.1016/j.neuron.2004.09.006. PMID 15450170. S2CID 11679646. 26. ^ Friedman, Naomi P.; Miyake, Akira; Young, Susan E.; DeFries, John C.; Corley, Robin P.; Hewitt, John K. (May 2008). "Individual differences in executive functions are almost entirely genetic in origin". Journal of Experimental Psychology: General. 137 (2): 201–225. doi:10.1037/0096-3445.137.2.201. PMC 2762790. PMID 18473654. 27. ^ Langley, Kate; Marshall, Lucy; van den Bree, Marianne; Thomas, Hollie; Owen, Michael; O’Donovan, Michael; Thapar, Anita (January 2004). "Association of the Dopamine D4 Receptor Gene 7-Repeat Allele With Neuropsychological Test Performance of Children With ADHD". American Journal of Psychiatry. 161 (1): 133–138. doi:10.1176/appi.ajp.161.1.133. PMID 14702261. 28. ^ Tunbridge, E. M. (9 June 2004). "Catechol-O-Methyltransferase Inhibition Improves Set-Shifting Performance and Elevates Stimulated Dopamine Release in the Rat Prefrontal Cortex". Journal of Neuroscience. 24 (23): 5331–5335. doi:10.1523/JNEUROSCI.1124-04.2004. PMC 6729311. PMID 15190105. 29. ^ Sengupta, Sarojini; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Bellingham, Johanne; Polotskaia, Anna; Stepanian, Marina Ter; Goto, Yukiori; Grace, Anthony A.; Joober, Ridha (December 2008). "COMT Val 108/158 Met Polymorphism and the Modulation of Task-Oriented Behavior in Children with ADHD". Neuropsychopharmacology. 33 (13): 3069–3077. doi:10.1038/npp.2008.85. PMC 2885152. PMID 18580877. 30. ^ a b Alfimova, M. V.; Golimbet, V. E.; Gritsenko, I. K.; Lezheiko, T. V.; Abramova, L. I.; Strel’tsova, M. A.; Khlopina, I. V.; Ebstein, R. (September 2007). "Interaction of dopamine system genes and cognitive functions in patients with schizophrenia and their relatives and in healthy subjects from the general population". Neuroscience and Behavioral Physiology. 37 (7): 643–650. doi:10.1007/s11055-007-0064-x. PMID 17763983. S2CID 23033415. 31. ^ Monchi, Oury; Petrides, Michael; Petre, Valentina; Worsley, Keith; Dagher, Alain (1 October 2001). "Wisconsin Card Sorting Revisited: Distinct Neural Circuits Participating in Different Stages of the Task Identified by Event-Related Functional Magnetic Resonance Imaging". The Journal of Neuroscience. 21 (19): 7733–7741. doi:10.1523/JNEUROSCI.21-19-07733.2001. PMID 11567063. 32. ^ a b c Shulman, Kenneth I (June 2000). "Clock-drawing: is it the ideal cognitive screening test?". International Journal of Geriatric Psychiatry. 15 (6): 548–561. doi:10.1002/1099-1166(200006)15:6<548::AID-GPS242>3.0.CO;2-U. PMID 10861923. 33. ^ Hamilton, Joanne M.; Salmon, David P.; Galasko, Douglas; Raman, Rema; Emond, Jenn; Hansen, Lawrence A.; Masliah, Eliezer; Thal, Leon J. (2008). "Visuospatial deficits predict rate of cognitive decline in autopsy-verified dementia with Lewy bodies". Neuropsychology. 22 (6): 729–737. doi:10.1037/a0012949. PMC 2587484. PMID 18999346. 34. ^ Woo, Benjamin K. P.; Rice, Valerie A.; Legendre, Susan A.; Salmon, David P.; Jeste, Dilip V.; Sewell, Daniel D. (8 November 2004). "The Clock Drawing Test as a Measure of Executive Dysfunction in Elderly Depressed Patients". Journal of Geriatric Psychiatry and Neurology. 17 (4): 190–194. doi:10.1177/0891988704269820. PMID 15533989. S2CID 35863654. 35. ^ Tranel, Daniel; Rudrauf, David; Vianna, Eduardo P. M.; Damasio, Hanna (2008). "Does the Clock Drawing Test have focal neuroanatomical correlates?". Neuropsychology. 22 (5): 553–562. doi:10.1037/0894-4105.22.5.553. PMC 2834527. PMID 18763875. 36. ^ a b c d Seidman, Larry J.; Biederman, Joseph; Monuteaux, Michael C.; Weber, Wendy; Faraone, Stephen V. (May 2000). "Neuropsychological functioning in nonreferred siblings of children with attention deficit/hyperactivity disorder". Journal of Abnormal Psychology. 109 (2): 252–265. doi:10.1037/0021-843X.109.2.252. PMID 10895563. 37. ^ MacLeod, Colin M. (1991). "Half a century of research on the Stroop effect: An integrative review". Psychological Bulletin. 109 (2): 163–203. doi:10.1037/0033-2909.109.2.163. PMID 2034749. 38. ^ de Young, Raymond (2009). "Stroop task: A test of capacity to direct attention". 39. ^ Volz, Hans-Peter; Gaser, Christian; Häger, Frank; Rzanny, Reinhardt; Mentzel, Hans-Joachim; Kreitschmann-Andermahr, Ilonka; Kaiser, Werner Alois; Sauer, Heirich (October 1997). "Brain activation during cognitive stimulation with the Wisconsin Card Sorting Test — a functional MRI study on healthy volunteers and schizophrenics". Psychiatry Research: Neuroimaging. 75 (3): 145–157. doi:10.1016/S0925-4927(97)00053-X. PMID 9437772. S2CID 38891642. 40. ^ Chelune, Gordon J.; Baer, Ruth A. (4 January 2008). "Developmental norms for the wisconsin card sorting test". Journal of Clinical and Experimental Neuropsychology. 8 (3): 219–228. doi:10.1080/01688638608401314. PMID 3722348. 41. ^ a b Arbuthnott, Katherine; Frank, Janis (9 August 2010). "Trail Making Test, Part B as a Measure of Executive Control: Validation Using a Set-Switching Paradigm". Journal of Clinical and Experimental Neuropsychology. 22 (4): 518–528. doi:10.1076/1380-3395(200008)22:4;1-0;FT518. PMID 10923061. 42. ^ Gaudino, Elizabeth A.; Geisler, Mark W.; Squires, Nancy K. (August 1995). "Construct validity in the trail making test: What makes part B harder?". Journal of Clinical and Experimental Neuropsychology. 17 (4): 529–535. doi:10.1080/01688639508405143. PMID 7593473. 43. ^ a b Conn, Harold O. (June 1977). "Trailmaking and number-connection tests in the assessment of mental state in portal systemic encephalopathy". The American Journal of Digestive Diseases. 22 (6): 541–550. doi:10.1007/BF01072510. PMID 868833. S2CID 1668584. 44. ^ Chan, Raymond C. K. (August 2001). "Dysexecutive symptoms among a non-clinical sample: A study with the use of the Dysexecutive Questionnaire". British Journal of Psychology. 92 (3): 551–565. doi:10.1348/000712601162338. 45. ^ a b Lhermitte, F. (April 1986). "Human autonomy and the frontal lobes. Part II: Patient behavior in complex and social situations: The ?environmental dependency syndrome?". Annals of Neurology. 19 (4): 335–343. doi:10.1002/ana.410190405. PMID 3707085. S2CID 46441945. 46. ^ Hoffmann, Michael (2007). "Transient Environmental Dependency Syndrome due to Phendimetrazine Tartrate". European Neurology. 58 (1): 49–50. doi:10.1159/000102167. PMID 17483586. 47. ^ a b c d e f g h Ward, Jamie (2006). The Student's Guide to Cognitive Neuroscience. Psychology Press. ISBN 978-1-84169-535-8.[page needed] 48. ^ a b Oram, Joanne; Geffen, Gina M.; Geffen, Laurie B.; Kavanagh, David J.; McGrath, John J. (June 2005). "Executive control of working memory in schizophrenia". Psychiatry Research. 135 (2): 81–90. doi:10.1016/j.psychres.2005.03.002. PMID 15923044. S2CID 33009576. 49. ^ Thoma, Patrizia; Daum, Irene (May 2008). "Working memory and multi-tasking in paranoid schizophrenia with and without comorbid substance use disorder". Addiction. 103 (5): 774–786. doi:10.1111/j.1360-0443.2008.02156.x. PMID 18412756. 50. ^ Radvansky, GA (2006). Human Memory. United States of America: Allyn and Bacon.[page needed] 51. ^ a b c d Marchetta, Natalie D. J.; Hurks, Petra P. M.; Krabbendam, Lydia; Jolles, Jelle (2008). "Interference control, working memory, concept shifting, and verbal fluency in adults with attention-deficit/hyperactivity disorder (ADHD)" (PDF). Neuropsychology. 22 (1): 74–84. doi:10.1037/0894-4105.22.1.74. PMID 18211157. 52. ^ a b c Rosenman, Stephen (25 June 2016). "Reconsidering the Attention Deficit Paradigm". Australasian Psychiatry. 14 (2): 127–132. doi:10.1080/j.1440-1665.2006.02269.x. PMID 16734638. S2CID 208501945. 53. ^ a b Barnard, Louise; Muldoon, Kevin; Hasan, Reem; O'Brien, Gregory; Stewart, Mary (March 2008). "Profiling executive dysfunction in adults with autism and comorbid learning disability" (PDF). Autism. 12 (2): 125–141. doi:10.1177/1362361307088486. PMID 18308763. S2CID 17394248. 54. ^ Gilotty, Lisa; Kenworthy, Lauren; Sirian, Lisa; Black, David O.; Wagner, Ann E. (9 August 2010). "Adaptive Skills and Executive Function in Autism Spectrum Disorders". Child Neuropsychology. 8 (4): 241–248. doi:10.1076/chin.8.4.241.13504. PMID 12759821. S2CID 9714808. 55. ^ a b c Firestone, Philip; Dozois, David J. A. (2006). Abnormal Psychology: Perspectives (3rd ed.). Pearson Education Canada. ISBN 978-0-13-129837-8.[page needed] 56. ^ a b c d e f g h i j Hill, Elisabeth L. (January 2004). "Executive dysfunction in autism" (PDF). Trends in Cognitive Sciences. 8 (1): 26–32. doi:10.1016/j.tics.2003.11.003. PMID 14697400. S2CID 7338050. 57. ^ a b c Robinson, Lucy J.; Thompson, Jill M.; Gallagher, Peter; Goswami, Utpal; Young, Allan H.; Ferrier, I. Nicol; Moore, P. Brian (July 2006). "A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder". Journal of Affective Disorders. 93 (1–3): 105–115. doi:10.1016/j.jad.2006.02.016. PMID 16677713. 58. ^ a b Glahn, David C.; Bearden, Carrie E.; Barguil, Marcela; Barrett, Jennifer; Reichenberg, Abraham; Bowden, Charles L.; Soares, Jair C.; Velligan, Dawn I. (October 2007). "The Neurocognitive Signature of Psychotic Bipolar Disorder". Biological Psychiatry. 62 (8): 910–916. doi:10.1016/j.biopsych.2007.02.001. PMID 17543288. S2CID 36603785. 59. ^ a b Dixon, T; Kravariti, E; Frith, C; Murray, RM; McGuire, PK (July 2004). "Effect of symptoms on executive function in bipolar illness". Psychological Medicine. 34 (5): 811–21. doi:10.1017/s0033291703001570. PMID 15500302. 60. ^ a b c d Schneider, J. S. (23 February 2007). "Behavioral persistence deficit in Parkinson's disease patients". European Journal of Neurology. 14 (3): 300–304. doi:10.1111/j.1468-1331.2006.01647.x. PMID 17355551. S2CID 1211986. 61. ^ a b Grossman, Murray; Lee, Christine; Morris, Jennifer; Stern, Matthew B.; Hurtig, Howard I. (March 2002). "Assessing Resource Demands during Sentence Processing in Parkinson's Disease". Brain and Language. 80 (3): 603–616. doi:10.1006/brln.2001.2630. PMID 11896660. S2CID 34141712. 62. ^ Ramsay, J. Russell; Rostain, Anthony L. (2007). "Psychosocial treatments for attention-deficit/hyperactivity disorder in adults: Current evidence and future directions". Professional Psychology: Research and Practice. 38 (4): 338–346. doi:10.1037/0735-7028.38.4.338. 63. ^ Virta, Maarit; Vedenpää, Anita; Grönroos, Nina; Chydenius, Esa; Partinen, Markku; Vataja, Risto; Kaski, Markus; Iivanainen, Matti (11 January 2008). "Adults With ADHD Benefit From Cognitive—Behaviorally Oriented Group Rehabilitation". Journal of Attention Disorders. 12 (3): 218–226. doi:10.1177/1087054707311657. PMID 18192618. S2CID 19844131. 64. ^ Manly, Tom; Hawkins, Kari; Evans, Jon; Woldt, Karina; Robertson, Ian H (January 2002). "Rehabilitation of executive function: facilitation of effective goal management on complex tasks using periodic auditory alerts". Neuropsychologia. 40 (3): 271–281. doi:10.1016/S0028-3932(01)00094-X. PMID 11684160. S2CID 42175257. 65. ^ Levine, Brian; Robertson, Ian H.; Clare, Linda; Carter, Gina; Hong, Julia; Wilson, Barbara A.; Duncan, John; Stuss, Donald T. (1 March 2000). "Rehabilitation of executive functioning: An experimental–clinical validation of Goal Management Training". Journal of the International Neuropsychological Society. 6 (3): 299–312. doi:10.1017/s1355617700633052. PMID 10824502. 66. ^ a b Sergeant, Joseph A; Geurts, Hilde; Oosterlaan, Jaap (March 2002). "How specific is a deficit of executive functioning for Attention-Deficit/Hyperactivity Disorder?". Behavioural Brain Research. 130 (1–2): 3–28. doi:10.1016/S0166-4328(01)00430-2. PMID 11864714. S2CID 35062995. 67. ^ a b c Perner, Josef; Kain, Winfried; Barchfeld, Petra (June 2002). "Executive control and higher-order theory of mind in children at risk of ADHD". Infant and Child Development. 11 (2): 141–158. doi:10.1002/icd.302. 68. ^ a b c d Dempsey, Anita; Dyehouse, Janice (24 July 2008). "The Relationship Between Executive Function, AD/HD, and Obesity". Western Journal of Nursing Research. 30 (8): 1026–1027. doi:10.1177/0193945908323636. S2CID 56522437. 69. ^ Hughes, Claire; Ensor, Rosie (May 2006). "Behavioural problems in 2-year-olds: links with individual differences in theory of mind, executive function and harsh parenting". Journal of Child Psychology and Psychiatry. 47 (5): 488–497. doi:10.1111/j.1469-7610.2005.01519.x. PMID 16671932. 70. ^ a b Dennis, Tracy (2006). "Emotional self-regulation in preschoolers: The interplay of child approach reactivity, parenting, and control capacities". Developmental Psychology. 42 (1): 84–97. doi:10.1037/0012-1649.42.1.84. PMID 16420120. 71. ^ a b Mahoney, G (January 1988). "Maternal communication style with mentally retarded children". American Journal of Mental Retardation. 92 (4): 352–9. PMID 3342137. 72. ^ a b Mahoney, Gerald; Perales, Frida; Wiggers, Bridgette; Bob Herman, Bob (2006). "Responsive Teaching: Early intervention for children with Down syndrome and other disabilities". Down Syndrome Research and Practice. 11 (1): 18–28. doi:10.3104/perspectives.311. PMID 17048806. 73. ^ a b c d e Ardila, Alfredo (October 2008). "On the evolutionary origins of executive functions". Brain and Cognition. 68 (1): 92–99. doi:10.1016/j.bandc.2008.03.003. PMID 18397818. S2CID 16391054. 74. ^ a b c d e Barkley, Russell A. (2001). "The Executive Functions and Self-Regulation: An Evolutionary Neuropsychological Perspective". Neuropsychology Review. 11 (1): 1–29. doi:10.1023/A:1009085417776. PMID 11392560. S2CID 5367406. 75. ^ Hollocks, Matthew J.; Jones, Catherine R.G.; Pickles, Andrew; Baird, Gillian; Happé, Francesca; Charman, Tony; Simonoff, Emily (April 2014). "The Association Between Social Cognition and Executive Functioning and Symptoms of Anxiety and Depression in Adolescents With Autism Spectrum Disorders". Autism Research. 7 (2): 216–228. doi:10.1002/aur.1361. PMID 24737743. S2CID 5499308. 76. ^ Wallace, Gregory L.; Kenworthy, Lauren; Pugliese, Cara E.; Popal, Haroon S.; White, Emily I.; Brodsky, Emily; Martin, Alex (2016). "Real-World Executive Functions in Adults with Autism Spectrum Disorder: Profiles of Impairment and Associations with Adaptive Functioning and Co-morbid Anxiety and Depression". Journal of Autism and Developmental Disorders. 46 (3): 1071–1083. doi:10.1007/s10803-015-2655-7. PMC 5111802. PMID 26572659. 77. ^ a b c d McDougall A (2001). Executive functions: Practical strategies for supporting students. Psychological Services, DDSB. Symposium conducted at DDSB, Ontario, Canada.[verification needed] 78. ^ a b Lerner, Janet W.; Kline, Frank (2006). Learning Disabilities and Related Disorders: Characteristics and Teaching Strategies (10th ed.). Houghton Mifflin. ISBN 978-0-618-47402-8.[page needed] 79. ^ a b c Brown, Thomas E (February 2008). "Describing Six Aspects of a Complex Syndrome" (PDF). CHADD. 80. ^ a b c Gaffney, Gary R. (2005). "Tourette Syndrome". University of Iowa Hospital and Clinics. Archived from the original on 29 March 2009. 81. ^ a b c d e f Barbosa, Manuel Fernando Santos; Monteiro, Luis Manuel Coelho (10 April 2014). "Recurrent Criminal Behavior and Executive Dysfunction". The Spanish Journal of Psychology. 11 (1): 259–265. doi:10.1017/s1138741600004297. PMID 18630666. 82. ^ Ogilvie, James M.; Stewart, Anna L.; Chan, Raymond C. K.; Shum, David H. K. (1 November 2011). "Neuropsychological Measures of Executive Function and Antisocial Behavior: A Meta-Analysis". Criminology. 49 (4): 1063–1107. doi:10.1111/j.1745-9125.2011.00252.x. hdl:10072/42010. 83. ^ a b Morgan, Alex B.; Lilienfeld, Scott O. (January 2000). "A meta-analytic review of the relation between antisocial behavior and neuropsychological measures of executive function". Clinical Psychology Review. 20 (1): 113–136. doi:10.1016/s0272-7358(98)00096-8. PMID 10660831. 84. ^ a b c Brower, MC; Price, BH (December 2001). "Neuropsychiatry of frontal lobe dysfunction in violent and criminal behaviour: a critical review". Journal of Neurology, Neurosurgery, and Psychiatry. 71 (6): 720–6. doi:10.1136/jnnp.71.6.720. PMC 1737651. PMID 11723190. 85. ^ Meijers, J.; Harte, J. M.; Meynen, G.; Cuijpers, P. (8 February 2017). "Differences in executive functioning between violent and non-violent offenders". Psychological Medicine. 47 (10): 1784–1793. doi:10.1017/S0033291717000241. PMID 28173890. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Executive dysfunction	c2748208	1,115	wikipedia	https://en.wikipedia.org/wiki/Executive_dysfunction	2021-01-18T18:44:10	{"umls": ["C2748208"], "wikidata": ["Q5419936"]}
Fascial hernias in the form of nodules appear in the skin where the deep and superficial veins meet going through the fascia, most frequently occurring on the lower extremities, becoming prominent when the underlying muscles contract.[1]:610 ## See also[edit] * Skin lesion ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Fascial hernia	c1695781	1,116	wikipedia	https://en.wikipedia.org/wiki/Fascial_hernia	2021-01-18T19:03:31	{"umls": ["C1695781"], "wikidata": ["Q5436636"]}
Grisel's syndrome SpecialtyRheumatology Grisel’s syndrome is a non-traumatic subluxation of the atlanto-axial joint caused by inflammation of the adjacent tissues. This is a rare disease that usually affects children. Progressive throat and neck pain and neck stiffness can be followed by neurologic symptoms such as pain or numbness radiating to arms (radiculopathies). In extreme cases, the condition can lead to quadriplegia and even death from acute respiratory failure. The condition often follows soft tissue inflammation in the neck such as in cases of upper respiratory tract infections, peritonsillar or retropharyngeal abscesses. Post-operative inflammation after certain procedures such as adenoidectomy can also lead to this condition in susceptible individuals such as those with Down syndrome. ## Contents * 1 Pathophysiology * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Pathophysiology[edit] Pathophysiology of this disease consists of relaxation of the transverse ligament of the atlanto-axial joint. ## Diagnosis[edit] Diagnosis can be established using plain film x-rays as well as CT scan of the neck/cervical spine. Children with Down syndrome have inherently lax ligaments making them susceptible to this condition. In select cases, these children may require pre-operative imaging to assess the risk for complications after procedures such as adenoidectomy. ## Treatment[edit] Treatment includes anti-inflammatory medications and immobilization of the neck in addition to treatment of the offending infectious cause (if any) with appropriate antibiotics. Early treatment is crucial to prevent long-term sequelae. Surgical fusion may be required for residual instability of the joint. ## References[edit] * Grisel P. Enucléation de l’atlas et torticollis naso-pharyngien Presse Med 1930;38:50–4. * Mathern GW, Batzdorf U. Grisel's syndrome: Cervical spine clinical, pathologic, and neurologic manifestations. Clin Orthop Relat Res. 1989 Jul;(244):131-46. * C Bocciolini, D Dall’Olio, E Cunsolo, PP Cavazzuti, and P Laudadio, Grisel’s syndrome: a rare complication following adenoidectomy, Acta Otorhinolaryngol Ital. 2005 August; 25(4): 245–249. ## External links[edit] Classification D * ICD-9-CM: 723.5 * DiseasesDB: 32750 External resources * eMedicine: orthoped/503 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Grisel's syndrome	c0263885	1,117	wikipedia	https://en.wikipedia.org/wiki/Grisel%27s_syndrome	2021-01-18T18:28:01	{"umls": ["C0263885"], "icd-9": ["723.5"], "wikidata": ["Q3508650"]}
Traumatic alopecia SpecialtyDermatology Traumatic alopecia is a cutaneous condition that results from the forceful pulling out of the scalp hair.[1] ## See also[edit] * Traction alopecia * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1388. 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	Traumatic alopecia	c0002182	1,118	wikipedia	https://en.wikipedia.org/wiki/Traumatic_alopecia	2021-01-18T18:49:56	{"umls": ["C0002182"], "wikidata": ["Q7835819"]}
A number sign (#) is used with this entry because X-linked dystonia-parkinsonism (XDP) is caused by an SVA (short interspersed nuclear element, variable number of tandem repeats, and Alu composite) retrotransposon insertion in an intron of the TATA-binding protein-associated factor-1 gene (TAF1; 313650) on chromosome Xq13. XDP is a homogeneous disorder introduced by a founder effect in the Filipino population. In the local Filipino dialect, XDP is referred to as 'lubag,' meaning 'twisted' (Nolte et al., 2003; Evidente et al., 2004). Clinical Features Lee et al. (1976) identified an unusually high frequency of torsion dystonia in Panay, the sixth largest of the islands of the Philippines. Of 28 Filipino cases, 23 came from that island and 19 from the province of Capiz. All cases were in males. Six sets of affected brothers and 2 families with 2-generation involvement consistent with X-linked recessive inheritance were observed. The mean age of onset was 31 years. Spasmodic eye blinking was the first symptom in 4 patients. Kupke et al. (1990) conducted a more extensive investigation in Panay. Twenty-one pedigrees were documented in which several members were affected. Among 120 sons of carrier mothers, 64 (52%) were affected. One affected female was reported. The average age of onset was 38.6 years (range, 12-56 years), which is similar to that in the adult-onset autosomal dominant form. However, the X-linked form tended to generalize in most patients within 7 years of onset. Frequently, parkinsonian symptoms may accompany or precede dystonia in these patients (Fahn and Moskowitz, 1988). It subsequently became certain that the X-linked parkinsonism reported by Johnston and McKusick (1963) in a Filipino kindred, previously cataloged as a distinct entity, was in fact the X-linked torsion dystonia-parkinsonism syndrome. The proband in the study of Johnston and McKusick (1963) belonged to the family that had been studied by Fahn and Moskowitz (1988). Wilhelmsen et al. (1991) referred to this disorder by the name 'lubag,' a term used by the families when intermittent twisting movements were present. The families also used the term 'wa-eg' when sustained twisting postures occurred, and 'sud-sud,' an onomatopoeic term derived from the sound of sandals slapping the pavement. Muller et al. (1990) studied the natural history of the disorder in 42 affected individuals from 21 Filipino families. The mean age of onset was 34.8 +/- 8.1 (S.D.) years. First manifestations were noted in the head and neck in 39%, in the lower limbs in 33%, in the upper limbs in 24%, and in the trunk in 9%. At least one 'parkinsonian symptom' (bradykinesia, rigidity, loss of postural reflexes, and 'fine' resting tremor) was found in 36% of the cases. Within families, some affected males had parkinsonian symptoms but others did not. See 304700 for discussion of the dystonia-deafness syndrome. Evidente et al. (2004) found that 9 (53%) of 17 women from 5 unrelated XDP families who carried the DSC3 change or the XDP haplotype were symptomatic or had abnormal neurologic examinations. Of 8 symptomatic women, 7 were heterozygous and 1 was homozygous for the DSC3 change. Average age at onset for the women was 52 years (range, 26 to 75 years), with onset of parkinsonism or tremor in 4 patients, chorea in 3, and dystonia in 1. The features were generally mild, with only 1 woman treated with levodopa. Evidente et al. (2004) suggested that extreme X-inactivation likely underlies the disease in a subset of women carriers. Pathogenesis Nolte et al. (2003) considered several possibilities for the pathogenesis of XDP. The presence of INGX (300452) and of the CIS4 homolog on the opposite strand of DYT3 might indicate regulation of these 2 genes by at least some transcripts of DYT3. Transcript 3 covers portions of INGX and therefore could be involved in its regulation by antisense RNA, and all 4 transcripts partially overlap with the CIS4 homolog. Given that all 4 transcripts include DSC3 containing exon 4, potentially all transcripts could cause XDP by interfering with the function of the CIS4 homolog, provided it is not a pseudogene. An example of potential antisense regulation by disease gene is SCA8 (603680), the gene implicated in spinocerebellar ataxia-8 (608768). In that case, portions of the SCA8 gene might be a natural antisense RNA, because the SCA8 chain partially overlaps with the Kelch-like 1 (KLHL1; 605332) gene that is encoded by the opposite strand. Yet another possibility of the molecular pathologic mechanism of DSC3 action is a missense mutation in variant 4. This transcript potentially encodes a small polypeptide of 51 amino acids, and the base change would result in an exchange of an arginine for a cysteine. Goto et al. (2005) performed postmortem examination of the basal ganglia in 7 male patients with XDP, of whom 5 manifested dystonia and 2 had advanced stage parkinsonism. Immunostaining for the neurochemical marker calcineurin (114105) and the matrix marker calbindin (114050) showed that the 5 patients with dystonia had patchy areas of preserved neurons in the striosome and relative sparing of the matrix compartment, whereas the parkinsonian patients had severe depletion of the striosomal pathway with involvement of the matrix-based pathway as well. Goto et al. (2005) postulated that in earlier stages of XDP, severe loss of striosomal GABAergic projection neurons may lead to disinhibition of nigral dopaminergic neurons, resulting in a hyperkinetic dystonia disorder. At the later stage, when parkinsonism predominates, there may be greater involvement of the matrix compartment, leading to reduction of matrix-based projections and resulting in an 'extranigral form' of parkinsonism. Mapping Kupke et al. (1990) mapped the gene for X-linked torsion dystonia to Xq21 by linkage to DNA and other markers in that region. They found a maximum lod score of 3.06 at theta = 0.0 for linkage with DXYS2, which maps to Xq21.3. Kupke et al. (1992) determined by linkage analysis that the DYT3 locus lies in a 9-cM interval between DXS159 and DXS72 (Xq12-q21.1). In 19 kindreds, significant linkage disequilibrium was found with PGK1 (311800) and 4 DNA markers located in the region Xq12-q21.1. Using 4 dinucleotide tandem repeat (DNTR) sequences from Xq13-derived YACs, Graeber et al. (1992) narrowed the localization of DYT3 to a region in Xq13 and identified flanking markers. The assignment to this region was further supported by highly significant allelic association between DYT3 and the 4 DNTR loci located in a region defined by PGK1 and DXS56. Muller et al. (1994) concluded that the DYT3 locus is within Xq12-q13.1, flanked by DXS106 proximally and DXS559 distally. The distance between these 2 markers was estimated to be approximately 3.0 Mb. Haberhausen et al. (1995) narrowed the DYT3 locus to a smaller region defined by DXS7117 and DXS7119 within a 1.8-Mb YAC contig. The location was supported by application of a newly developed likelihood method for the analysis of linkage disequilibrium. Through association studies with short tandem repeat polymorphisms (STRPs) from the critical linkage region, Nemeth et al. (1999) facilitated assignment of DYT3 to an interval of approximately 400 kb. Extensive sequence analyses of both coding and noncoding regions of these genes in patients with X-linked dystonia-parkinsonism did not reveal a mutation, suggesting that XDP is caused by either a small structural rearrangement, a mutation in a regulatory element of a known gene, or a mutation in a hitherto unknown gene. Molecular Genetics Nolte et al. (2001) excluded the transcribed portion of the ACRC gene (300369) as the site of mutation in X-linked dystonia-parkinsonism. They noted that the transcribed portion of several other genes had been excluded and suggested that XDP is most likely caused by mutation in a regulatory region of a gene within the critical interval or by a structural rearrangement. Nolte et al. (2003) sequenced 260 kb of the critical interval in an XDP patient. Comparison to the published sequence of the interval revealed 2 SNPs that were polymorphic in patients only, 2 SNPs that were also polymorphic in controls, and 5 disease-specific single-nucleotide changes (DSC1, 2, 3, 10, and 12). The detection of only 4 SNPs within the 260 kb of the X chromosome sequence indicated that this region of the genome is of unusually low heterozygosity. The disease-specific changes were found in all XDP patients (N = 46) but in none of 178 unaffected male and female Filipino controls (208 X chromosomes) without a family history of XDP. In addition to the XDP-specific single-nucleotide changes, a 48-bp deletion was detected exclusively in patients. Only 1 disease-specific single-nucleotide change, referred to as DSC3, was located in a region of unique DNA not related to an annotated gene. DSC3 is a C-to-T transition at base 797 in exon 4 of a GenBank sequence (AJ549245.1). Extensive RT-PCR analysis of RNA isolated from patient and control lymphoblastoid cells and from human cordate nucleus by using primers from sequences surrounding DSC3 identified a transcribed fragment of 782 bp that is encoded by 2 exons separated by an intron of 987 bp. DSC3 is located in one of these exons. The novel transcript was given the gene name DYT3 in accordance with the Hugo nomenclature recommendation. The exon carrying DSC3 was found to be located in a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of 3 different transcription start sites that encode 4 different transcripts. Two of these transcripts include distal portions of the TAF1 gene and are alternatively spliced. Three exons overlap with INGX and with a homolog of CIS4 (605118), both of which are encoded by the opposite strand. The exon containing DSC3 is used by all alternative transcripts, making a pathogenic role of DSC3 in XDP likely. In a search for the causative gene responsible for X-linked dystonia-parkinsonism, Makino et al. (2007) performed genomic sequencing analysis of the critical mapping region of the DYT3 locus on Xq13.1, followed by expression analysis of brain tissues from XDP individuals. They found a disease-specific SVA retrotransposon insertion in intron 32 of the TAF1 gene (313650.0001), which encodes the largest component of the TFIID complex. Studies of XDP postmortem brain showed significantly decreased expression levels of TAF1 and of the dopamine receptor D2 gene (DRD2; 126450). Makino et al. (2007) also identified an abnormal pattern of DNA methylation in the retrotransposon in the genome from the patient's caudate, which could account for decreased expression of TAF1. The findings suggested that reduced expression of 1 or more neuron-specific isoforms of TAF1 is responsible for XDP. INHERITANCE \- X-linked recessive HEAD & NECK Eyes \- Spasmodic eye blinking NEUROLOGIC Central Nervous System \- Torsion dystonia \- Myoclonus \- Chorea \- Focal tremor \- Chorea-ballism \- Parkinsonism, levodopa-responsive (occurs at later stages, may replace dystonia symptoms) MISCELLANEOUS \- Onset in fourth decade \- Described predominantly in families from the Philippines \- Symptoms begin focally, later segmental or generalized \- Women may be mildly affected \- Associated with a disease-specific sequence change, referred to as 'DSC3,' within an open-reading frame (ORF) of a 'multiple transcript system' known as DYT3 MOLECULAR BASIS \- Caused by an SVA retrotransposon insertion in an intron of the TATA-binding protein-associated factor-1 gene (TAF1, 313650.0001 ) ▲ 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	DYSTONIA 3, TORSION, X-LINKED	c1839130	1,119	omim	https://www.omim.org/entry/314250	2019-09-22T16:17:17	{"doid": ["0090057"], "mesh": ["C564048"], "omim": ["314250"], "orphanet": ["53351"], "synonyms": ["Alternative titles", "DYSTONIA-PARKINSONISM, X-LINKED", "TORSION DYSTONIA-PARKINSONISM, FILIPINO TYPE"], "genereviews": ["NBK1489"]}
A rare histiocytic tumor characterized by a malignant proliferation of cells showing morphological and immunophenotypic features of mature tissue histiocytes. Most cases occur in extranodal sites, most commonly the intestinal tract, skin, and soft tissue. Patients may present with a solitary mass, lymphadenopathy, a skin rash or numerous tumors on the trunk and extremities, lytic bone lesions, hepatosplenomegaly with pancytopenia, intestinal obstruction, and/or systemic symptoms. The neoplasm is aggressive with typically poor therapy response. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Histiocytic sarcoma	c0334663	1,120	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86896	2021-01-23T17:36:47	{"mesh": ["D054747"], "umls": ["C0334663"], "icd-10": ["C96.8"]}
A heart muscle disease that consists in progressive dystrophy of primarily the right ventricular myocardium with fibro-fatty replacement and ventricular dilation, and that is clinically characterized by ventricular arrhythmias and a risk of sudden cardiac death. ## Epidemiology Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a reported prevalence of 1/2,500 to 1/5,000. ## Clinical description ARVC has a variable clinical picture. ARVC can be asymptomatic, or present, usually during adolescence, with ventricular arrhythmias with palpitations, chest pain, dizziness, fatigue, or syncope. All patients are at risk of sudden death, particularly during exertion. Although predominantly a disease of the right ventricle, ARVC may also involve the left ventricle (ARVC left dominant form) or both (ARVC biventricular form), the latter leading in later stages to progressive biventricular failure. ARVC can be associated with palmoplantar keratoderma and woolly hair, the so-called cardio cutaneous syndromes (Naxos disease and Carvajal syndromes, see these terms). ## Etiology ARVC results from a fibro-fatty replacement of myocardium. It is believed to be a disease of desmosomes with impaired cell-to-cell contact and signaling Mutations have been observed in genes encoding for proteins of the cardiac desmosomes (JUP; DSP; PKP2; DSG2; and DSC2). However, in a minority of patients, mutations in non-desmosomal genes (TGFβ3; TMEM43/LUMA; DES; CTNNA3; PLN; LMNA; TTN) have also been detected. Variable penetrance is found, suggesting a role for additional genetic or environmental modifiers. Compound/digenic heterozygosity is identified in up to 25% of mutation carriers and seems an additional risk factor. Recent investigations point to a role of the canonical Wnt signaling pathway in the pathogenesis of ARVC. ## Diagnostic methods Diagnosis is based on a scoring system taking into account right ventricle structural and functional abnormalities (dilatation, akinesia, dyskinesia, aneurysms) detected by echocardiography, MRI and angiography; electrocardiographic features (inverted T waves in right precordial leads, epsilon waves and late potentials by signal averaged ECG (SAECG), left bundle branch block ventricular tachycardia, >500 ventricular extrasystoles per 24 h); tissue characterization at endomyocardial biopsy (fibro-fatty replacement of myocardium); and family history. Contrast enhanced MRI substantially enhances the diagnostic sensitivity, particularly in left ventricle variants, while electroanatomic mapping is superior in detecting early RV involvement. ## Differential diagnosis Differential diagnosis includes idiopathic RV outflow tract tachycardia, myocarditis, sarcoidosis and congenital heart diseases (see these terms). ## Antenatal diagnosis Although prenatal diagnosis through amniocentesis is feasible, it is subject to ethical and legal considerations. ## Genetic counseling In more than half of the patients, the disease is familial, primarily autosomal dominant with variable penetrance and polymorphic expressivity. Naxos disease and Carvajal syndrome show an autosomal recessive mode of inheritance. The success rate of genotyping depends on several factors (such as cohort location and ethnicity) and hence requires specialized counseling. ## Management and treatment Risk stratification remains largely empiric and therapeutic interventions include antiarrhythmic drugs like beta-blockers, sotalol and amiodarone, catheter ablation, implantable cardioverter-defibrillator. In refractory congestive heart failure or untreatable ventricular arrhythmias, heart transplantation can be also considered. Since effort is a trigger for disease progression and arrhythmias, competitive sport and moderate to high intense physical activity should be avoided. ## Prognosis The disease progression is variable. Risk factors for sudden death include a history of aborted sudden death, syncope, young age, decreased left ventricular function, and marked decrease in right ventricular function. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Arrhythmogenic right ventricular cardiomyopathy	c0349788	1,121	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=247	2021-01-23T17:18:23	{"gard": ["5847"], "mesh": ["D019571"], "umls": ["C0349788"], "icd-10": ["I42.8"], "synonyms": ["ARVC", "ARVD", "Arrhythmogenic right ventricular dysplasia"]}
Autosomal dominant tubulointerstitial kidney disease due to UMOD mutations (ADTKD–UMOD) is an inherited disorder that causes a gradual loss of kidney function that eventually leads to the need for kidney transplantation or dialysis between the ages of 30 and 70. Patients with ADTKD-UMOD have high blood levels of uric acid before kidney failure develops, and some affected individuals may develop gout. Gout is a form of arthritis (inflammation) that occurs often in the big toe, ankle, knee, or other joints. ADTKD-UMOD is caused by a mistake (mutation) in the UMOD gene, which leads to the build-up of the altered uromodulin protein in the tubules of the kidney, leading to slow loss of kidney function. ADTKD-UMOD is inherited in a dominant pattern in families. It is diagnosed based on the symptoms, laboratory testing, family history and genetic testing. Many of the symptoms of ADTKD-UMOD can be treated with medication. For patients whose kidney function worsens to end-stage kidney disease, kidney transplant and dialysis can be used. The long-term outlook for people with ADTKD-UMOD is good, though patients may require dialysis or kidney transplantation between the ages of 30 and 70. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal dominant tubulointerstitial kidney disease due to UMOD mutations	c1859040	1,122	gard	https://rarediseases.info.nih.gov/diseases/10679/autosomal-dominant-tubulointerstitial-kidney-disease-due-to-umod-mutations	2021-01-18T18:01:56	{"mesh": ["C548033"], "omim": ["162000"], "umls": ["C1859040"], "orphanet": ["88950"], "synonyms": ["ADTKD-UMOD", "Autosomal dominant medullary cystic kidney disease type 2 (former)", "UMOD-related ADTKD", "Autosomal dominant medullary cystic kidney disease type 2", "MCKD2", "UMOD-related autosomal dominant tubulointerstitial kidney disease", "Familial juvenile hyperuricemic nephropathy type 1", "Medullary cystic kidney disease 2 (former)", "Familial Juvenile Hyperuricemic Nephropathy 1", "UMOD-Associated Kidney Disease", "Autosomal Dominant Tubulointerstitial Kidney Disease, UMOD-Related", "Uromodulin kidney disease", "Uromodulin-associated kidney disease", "ADTKD due to UMOD mutations"]}
The first HIV/AIDS case in Malaysia made its debut in 1986. Since then, HIV/AIDS has become one of the country's most serious health and development challenges.[1] As of 2019, the Ministry of Health estimated that there were 87,581 people living with HIV (PLHIV) in Malaysia. However, only 77,903 are aware of their status.[2] Malaysia is ranked seventh highest in adult prevalence of HIV/AIDS in Asia after Thailand, Papua New Guinea, Burma, Cambodia, Vietnam and Indonesia with a 0.45% prevalence rate.[3] According to the United Nations, Malaysia is one of the ten countries which together accounted for over 95% of all new HIV infections in the region of Asia-Pacific in 2016.[4] In 2015, Malaysia recorded the rate of 10.9 new cases per 100,000 of the population, which is below the target set by World Health Organization.[5] ## Contents * 1 Prevalence * 1.1 Means of Transmission * 1.2 Incidence & Mortality Rate * 2 At-risk group * 3 Laws and regulations * 3.1 Mandatory pre-marital HIV test * 4 Treatment * 5 Local support * 6 External sources * 7 References * 8 External links ## Prevalence[edit] Total Number of new HIV infections and AIDS death for each year between 1986 and 2010, by gender Number of new infections and percentage of new infections per State population in 2006,2007 and 2008 Malaysian HIV/AIDS cases have been reported since 1986 by the Ministry of Health. Since then, the national surveillance system had reported a cumulative of 105,189 HIV cases, 21,384 AIDS and 17,096 deaths related to HIV/AIDS giving total reported PLHIV of 88,093 cases or 96% of estimated PLHIV.[6] Males still make up the majority of HIV cases (89%), but the number of women with positive status of HIV has been increasing. This is shown by the decreasing trend of male:female ratio of 10:1 in 2002 to 4:1 in 2014.[7] 42% of HIV transmission by age group occurred in 30–39 bracket.[7] Between January to June 2014, 1,676 cases of HIV and 598 cases of AIDS with 402 deaths were recorded.[8] Out of this new infection, 79.7% are men. Reported New HIV Infections in Malaysia by Ethnic Groups (2016)[9] Percentage % Malay 57.5 Chinese 20.9 Indian 6.9 Foreigner 1.8 Others 12.9 ### Means of Transmission[edit] In 2013, heterosexuals transmission recorded the highest (51%), followed by Injecting Drug User (22%) and Homo/Bisexual transmission (22%). The scenario shifted gradually whereby in 2016, the means of transmission of new HIV cases were highest among Homo/Bisexual (46%), followed by Heterosexual (39%), Injecting Drug User (11%), Others (4%) and Mother-to-Child (1%).[9] In October 2018, Malaysia becomes the first country in the Western Pacific region to eliminate mother-to-child transmission of both HIV and syphilis, officially validated by the World Health Organization (WHO). [10] HIV Transmission by Risk Factor in 2016 (% of 3,397 new infections)[9] Homosexual/Bisexual (46%) Heterosexual (39%) Injecting Drug User (PWID) (11%) Others (4%) Mother-to-Child (1%) HIV Transmission by Age Group in 2016 (% of 3,397 new infections)[9] 20–29 (40%) 30–39 (31%) 40–49 (16%) > 50 (9%) 13–19 (3%) < 13 (1%) ### Incidence & Mortality Rate[edit] Incidence & Mortality Rate, 2016 (per 100,000 population)[11] Disease Incidence Rate Mortality Rate HIV 10.73 0.53 AIDS 3.86 2.34 ## At-risk group[edit] The HIV epidemic in Malaysia is concentrated in these key populations;[7] Sex workers Sex worker accounts for 0.6% of total reported cases thus far. However, the number of cases reported among sex workers are grossly under reported.[1] In 2014, Integrated Bio-Behavioral Surveillance (IBBS) in female sex workers shows an increase of sex workers living with HIV to 7.3% from 4.2% in 2012.[6] Transgender An IBBS done in 2009 found HIV prevalence among the group at 9.3%, and was decreased to 4.8% in 2012.[6] However, in 2014, the IBBS shows an increase of HIV prevalence to 5.6%.[6] Injecting Drug Users At the beginning of the epidemic, injecting drug user (PWID) accounted for 70–80% of all new reported cases. This has started to decline since 2004. In 2011, PWID accounts for 39% of new reported cases.[1] In 2014, 16.3% of the PWID are reported living with HIV.[6] Men who have sex with men (MSM) IBBS conducted in 2012 shows 7.1% of MSMs is living with HIV. In 2014, the figure has increased to 8.9%.[6] ## Laws and regulations[edit] In 2001, the Department of Occupational Safety and Health developed a non-compulsory ‘Code of Practice on Prevention and Management of HIV and AIDS’ which supports the creation of a non-judgemental and non-discriminatory work environment. [12] During the 2011 Nineteenth ASEAN Summit, Malaysia together with other ASEAN nations, adopted the "ASEAN Declaration of Commitment: Getting To Zero New HIV Infections, Zero Discrimination, Zero AIDS-Related Deaths, Bali, Indonesia, 17 November 2011" to reaffirm their commitment in working towards realizing an ASEAN community with Zero HIV Infections, Zero Discrimination and Zero AIDS-related Deaths.[13] On 13 October 2017, the then-Ministry of Human Resources Minister, Datuk Seri Dr Richard Riot Jaem announced that the government wants to draft a new regulation in an effort to eliminate discrimination against people living with HIV or AIDS at the workplace. The ministry plans to legislate the HIV and AIDS in Workplace Policy by 2020. [14] In October 2018, it is reported that the Malaysian AIDS Council (MAC) is currently working with the Ministry of Human Resources on a policy to ensure that people with HIV/AIDS including those receiving treatment are not discriminated when it comes to employment. [15] ### Mandatory pre-marital HIV test[edit] Mandatory pre-marital HIV screening for Muslim couples was made mandatory by the Religious Department of State Government in 9 states, beginning in November 2001 in Johor, followed by Perak, Perlis, Kelantan, Terengganu, Kedah, Pahang, Selangor, and possibly Melaka. Beginning January 2009, Muslim couples in the entire country are required to submit to premarital HIV testing.[16] In 2018, the Ministry of Women, Family and Community Development mulls to make HIV testing mandatory for non-Muslim couples seeking marriage as well.[17] The proposal is strongly opposed by NGOs such as the Malaysian AIDS Council and the Sarawak AIDS Concern Society (SACS) citing the stance of World Health Organization (WHO) and UNAIDS that do not support compulsory screening of individuals for HIV.[18] ## Treatment[edit] The first line of highly active antiretroviral therapy is provided for free in Malaysia by the Ministry of Health since 2006.[19] However, only 28% of HIV/AIDS patients seek consistent treatment as the awareness among patients to get treatment was still low because they were ashamed to seek treatment and did not know about the various types of treatment provided by the government to help them fight the disease.[20] The government hopes the figure will reach 90% in line with the National Strategic Plan Ending AIDS 2016–2030.[20] In September 2018, "HIV Connect", a self–paced, online learning platform that is designed for primary care physicians and other healthcare practitioners in Malaysia was launched. The online learning platform is a joint effort between the Malaysian AIDS Foundation (MAF) and the Malaysian Society for HIV Medicine (MASHM) to educate doctors regarding care and management of HIV/AIDS patients. [21] ## Local support[edit] The Malaysian AIDS Council * Malaysian AIDS Council (MAC) is a Malaysian non-profit organisation with a mission to represent, mobilise and strengthen non-governmental organisations and communities who were working with HIV/AIDS issues. * PT Foundation (formerly known as Pink Triangle) is a community-based organisation "providing HIV/AIDS education, prevention, care and support programs, sexuality awareness and empowerment programs for vulnerable communities in Malaysia". The communities include MSM (men who have sex with men), transgender, sex workers, drug users, and people living with HIV. * Kuala Lumpur AIDS Support Services Society (KLASS) [1] * APCASO – Asia Pacific Council of AIDS Service Organizations [2] * Tenaganita is a human rights organisation dedicated in assisting, building, advocating and protecting migrants, refugees, women and children from exploitation, abuse, discrimination, slavery and human trafficking.[3] * Persatuan Pengasih Malaysia (PENGASIH) * Community AIDS Service Penang (CASP) [4] * Federation of Reproductive Health Associations, Malaysia (FRHAM) [5] * Islamic Medical Association of Malaysia (PPIM) * Sarawak AIDS Concern Society (SACS) [6] * Women and Health Association of Kuala Lumpur (WAKE) * Persatuan Perantaraan Pesakit-Pesakit Kelantan (SAHABAT)[7] * Pertubuhan Advokasi Masyarakat Terpinggir[8], a non-governmental organisation for marginalised communities. ## External sources[edit] * Data Hub Satellite Page of Malaysia – a joint web platform between UNAIDS and the Ministry of Health of Malaysia. * National Strategic Plan for Ending AIDS 2016–2030 ## References[edit] 1. ^ a b c "The Global AIDS Response Progress Report 2014" (PDF). UN Aids. Archived from the original (PDF) on 10 September 2015. Retrieved 12 November 2015. 2. ^ "Living a full life despite AIDS". The Sun Daily. Retrieved 5 December 2020. 3. ^ "Country Comparison :: HIV/AIDS – Adult Prevalence Rate". Central Intelligence Agency. Retrieved 9 July 2016. 4. ^ "UN report: Malaysia among top 10 Asian nations affected by HIV". The Star Online. Retrieved 29 December 2017. 5. ^ "Malaysia optimistic of meeting WHO target in fight against HIV/AIDS". Astro Awani. Retrieved 31 March 2017. 6. ^ a b c d e f "The Global AIDS Response Progress Report Malaysia 2015" (PDF). UN Aids. Retrieved 14 April 2015. 7. ^ a b c "Annual Report 2014" (PDF). Malaysia Aids Council, Malaysia Aids Foundation. Retrieved 29 September 2014. 8. ^ "HIV/AIDS claim 16,742 lives in Malaysia since 1986". Astro Awani. Retrieved 29 September 2014. 9. ^ a b c d "Snapshot of HIV & AIDS in Malaysia 2016" (PDF). Malaysia Aids Council. Retrieved 6 March 2019. 10. ^ Caitlin Mahon (2 November 2018). "Malaysia eliminates HIV transmission from mother-to-child". Avert. Retrieved 21 November 2018. 11. ^ "Health Facts 2017" (PDF). Ministry of Health. Retrieved 29 December 2017. 12. ^ "Govt to draft new rules to curb workplace discrimination against people with HIV, AIDS". Malay Mail. Retrieved 15 October 2017. 13. ^ "Nineteenth ASEAN Summit, Bali, Indonesia, 14–19 November 2011". ASEAN. Retrieved 17 November 2017. 14. ^ "New regulation to eliminate discrimination against people with HIV and at workplace soon (Updated)". The Sun Daily. Retrieved 15 October 2017. 15. ^ "No more discrimination of those with HIV/AIDS in employment: MAC". The Sun Daily. 16 October 2018. Retrieved 1 November 2018. 16. ^ "Mandatory Premarital HIV Testing" (PDF). Open Society Institute. Retrieved 15 January 2019. 17. ^ "Govt seeks to make HIV testing mandatory for non-Muslim couples seeking marriage as well". New Straits Times. 17 December 2018. Retrieved 15 January 2019. 18. ^ "NGO opposes mandatory HIV screening for non-Muslim couples". The Star. 21 December 2018. Retrieved 15 January 2019. 19. ^ "Guidelines for the Management of Adult HIV Infection with Antiretroviral Therapy" (PDF). Ministry of Health. Retrieved 15 April 2016. 20. ^ a b "Only 28% of HIV/AIDS patients seek consistent treatment: Dr Hilmi". The Sun Daily. Retrieved 15 April 2016. 21. ^ "HIV Connect for Primary Care Physicians and Healthcare Practitioners". The Malaysian Medical Gazette. 21 September 2018. Retrieved 1 November 2018. ## External links[edit] * Malaysian AIDS Council * HIV Connect * v * t * e HIV/AIDS in Asia Sovereign states * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor (Timor-Leste) * Egypt * Georgia * India * Indonesia * Iran * Iraq * Israel * Japan * Jordan * Kazakhstan * North Korea * South Korea * Kuwait * Kyrgyzstan * Laos * Lebanon * Malaysia * Maldives * Mongolia * Myanmar * Nepal * Oman * Pakistan * Philippines * Qatar * Russia * Saudi Arabia * Singapore * Sri Lanka * Syria * Tajikistan * Thailand * Turkey * Turkmenistan * United Arab Emirates * Uzbekistan * Vietnam * Yemen States with limited recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * South Africa * Uganda * Zambia * Zimbabwe North America * Canada * Mexico * El Salvador * Guatemala * Honduras * Nicaragua United States * New York City Caribbean * Haiti * Jamaica * Dominican Republic South America * Bolivia * Brazil * Colombia * Guyana * Peru Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Cambodia * China (PRC) (Yunnan) * East Timor * India * Indonesia * Iran * Iraq * Japan * Jordan * North Korea * Laos * Malaysia * Myanmar (Burma) * Nepal * Pakistan * Philippines * Saudi Arabia * Sri Lanka * Taiwan (ROC) * Thailand * United Arab Emirates * Turkey * Vietnam Europe * United Kingdom * Russia * Ukraine Oceania * Australia * New Zealand * Papua New Guinea * List of countries by HIV/AIDS adult prevalence rate * List of HIV/AIDS cases and deaths registered by region [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	HIV/AIDS in Malaysia	None	1,123	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_Malaysia	2021-01-18T18:42:18	{"wikidata": ["Q5629859"]}
Hennekam syndrome is an inherited disorder resulting from malformation of the lymphatic system, which is part of both the circulatory system and immune system. The lymphatic system consists of a network of vessels that transport lymph fluid and immune cells throughout the body. The characteristic signs and symptoms of Hennekam syndrome are lymphatic vessels that are abnormally expanded (lymphangiectasia), particularly the vessels that transport lymph fluid to and from the intestines; puffiness or swelling caused by a buildup of fluid (lymphedema); and unusual facial features. Lymphangiectasia often impedes the flow of lymph fluid and can cause the affected vessels to break open (rupture). In the intestines, ruptured vessels can lead to accumulation of lymph fluid, which interferes with the absorption of nutrients, fats, and proteins. Accumulation of lymph fluid in the abdomen can cause swelling (chylous ascites). Lymphangiectasia can also affect the kidneys, thyroid gland, the outer covering of the lungs (the pleura), the membrane covering the heart (pericardium), or the skin. The lymphedema in Hennekam syndrome is often noticeable at birth and usually affects the face and limbs. Severely affected infants may have extensive swelling caused by fluid accumulation before birth (hydrops fetalis). The lymphedema usually affects one side of the body more severely than the other (asymmetric) and slowly worsens over time. Facial features of people with Hennekam syndrome may include a flattened appearance to the middle of the face and the bridge of the nose, puffy eyelids, widely spaced eyes (hypertelorism), small ears, and a small mouth with overgrowth of the gums (gingival hypertrophy). Affected individuals may also have an unusually small head (microcephaly) and premature fusion of the skull bones (craniosynostosis). Individuals with Hennekam syndrome often have intellectual disability that ranges from mild to severe, although most are on the mild end of the range and some have normal intellect. Many individuals with Hennekam syndrome have growth delay, respiratory problems, permanently bent fingers and toes (camptodactyly), or fusion of the skin between the fingers and toes (cutaneous syndactyly). Abnormalities found in a few individuals with Hennekam syndrome include a moderate to severe shortage of red blood cells (anemia) resulting from an inadequate amount (deficiency) of iron in the bloodstream, multiple spleens (polysplenia), misplaced kidneys, genital anomalies, a soft out-pouching around the belly-button (umbilical hernia), heart abnormalities, hearing loss, excessive body hair growth (hirsutism), a narrow upper chest that may have a sunken appearance (pectus excavatum), an abnormal side-to-side curvature of the spine (scoliosis), and inward- and upward-turning feet (clubfeet). The signs and symptoms of Hennekam syndrome vary widely among affected individuals, even those within the same family. Life expectancy depends on the severity of the condition and can vary from death in childhood to survival into adulthood. ## Frequency At least 50 cases of Hennekam syndrome have been reported worldwide. ## Causes Mutations in the CCBE1 or FAT4 gene can cause Hennekam syndrome. The CCBE1 gene provides instructions for making a protein that is found in the lattice of proteins and other molecules outside the cell (extracellular matrix). The CCBE1 protein is involved in the maturation (differentiation) and movement (migration) of immature cells called lymphangioblasts that will eventually form the lining (epithelium) of lymphatic vessels. The function of the protein produced from the FAT4 gene is largely unknown. Research shows that the FAT4 protein may be involved in determining the position of various components within cells (cell polarity). CCBE1 gene mutations that cause Hennekam syndrome change the three-dimensional shape of the protein and severely decrease its function. The abnormal protein cannot play its role in the formation of the lymphatic vessel epithelium. The resulting malformation of lymphatic vessels leads to lymphangiectasia, lymphedema, and other features of Hennekam syndrome. Since the lymphatic system extends throughout the body, a disruption to the vessels can affect almost any organ. Altered lymphatic development before birth may change the balance of fluids and impair normal development, contributing to many of the other signs of Hennekam syndrome such as unusual facial features. FAT4 gene mutations that cause Hennekam syndrome result in a FAT4 protein with decreased function. Reduced FAT4 protein activity seems to impair normal development of the lymphatic system, but the mechanism is unknown. Together, mutations in the CCBE1 and FAT4 genes are responsible for approximately half of all Hennekam syndrome cases. The cause of the remaining cases is unknown. ### Learn more about the genes associated with Hennekam syndrome * CCBE1 * FAT4 ## 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	Hennekam syndrome	c4012050	1,124	medlineplus	https://medlineplus.gov/genetics/condition/hennekam-syndrome/	2021-01-27T08:25:43	{"gard": ["3318"], "mesh": ["C537255"], "omim": ["235510", "616006"], "synonyms": []}
A rare skeletal dysplasia characterized by short stature, prominent abnormalities in hands and feet, and a characteristic facial appearance (described as happy''). ## Epidemiology Fewer than 30 cases have been reported to date. ## Clinical description The characteristic facial appearance (''happy'' face) consists in a shortened nose, full cheeks, hypertelorism, long flat philtrum, and a thin upper lip. Additional clinical features include progressive cardiac valvular thickening often leading to an early death, contractions of the gastrocnemius muscle and Achilles tendon leading to tip toe walking, tracheal stenosis, bronchopulmonary insufficiency, and liver enlargement. Radiological manifestations include delayed bone age, cone-shaped epiphyses, shortened long tubular bones and ovoid vertebral bodies. ## Etiology Mutations have been found in the ADAMTSL2 and FBN1 genes which appear to induce microfibrillar network disorganization and enhanced TGF-beta signaling. FBN1 encodes fibrillin-1 and ADAMTSL2 (Disintegrin And Metalloproteinase with Thrombospondin repeats- like 2) encodes a glycoprotein of unknown function. ## Genetic counseling Transmission is autosomal recessive in the cases with ADAMTSL2 gene mutations and autosomal dominant in the cases with FBN1 mutations. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Geleophysic dysplasia	c3489726	1,125	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2623	2021-01-23T18:54:36	{"gard": ["2449"], "mesh": ["C537677", "C535662"], "omim": ["231050", "614185", "617809"], "umls": ["C3489726"], "icd-10": ["Q87.1"], "synonyms": ["Geleophysic dwarfism"]}
See also: Pseudomembranous colitis Antibiotic-associated diarrhea Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotics. Microbiotal alteration changes carbohydrate metabolism with decreased short-chain fatty acid absorption and an osmotic diarrhea as a result. Another consequence of antibiotic therapy leading to diarrhea is overgrowth of potentially pathogenic organisms such as Clostridium difficile. It is defined as frequent loose and watery stools with no other complications.[1] ## Cause[edit] Clostridium difficile, also known more commonly as C. diff, accounts for 10 to 20% of antibiotic-associated diarrhea cases, because the antibiotics administered for the treatment of certain disease processes such as inflammatory colitis also inadvertently kill a large portion of the gut flora, the normal flora that is usually present within the bowel. With this lower level of "healthy" bacteria present, the overgrowth of C. diff is then responsible "for elaborating the enterotoxin".[1] ## Treatment[edit] Meta-analyses have concluded that probiotics may protect against antibiotic-associated diarrhea in both children and adults.[2][3] Evidence is insufficient, however, regarding an effect on rates of C. difficile colitis.[4] Efficacy of probiotic AAD prevention is dependent on the probiotic strain(s) used and on the dosage.[5][6] Up to a 50% reduction of AAD occurrences has been found.[7] No side effects have been reported. Caution is advised when using probiotics in immunocompromised individuals or those who have a compromised intestinal barrier because of the risk of an infection caused by the probiotic supplements. ## References[edit] 1. ^ a b Allan B. Wolfson, ed. (2005). Harwood-Nuss' Clinical Practice of Emergency Medicine (4th ed.). p. 400. ISBN 0-7817-5125-X. 2. ^ Hempel, S; Newberry, SJ; Maher, AR; Wang, Z; Miles, JN; Shanman, R; Johnsen, B; Shekelle, PG (May 9, 2012). "Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis". JAMA: The Journal of the American Medical Association. 307 (18): 1959–69. doi:10.1001/jama.2012.3507. PMID 22570464. 3. ^ Guo Q, Goldenberg JZ, Humphrey C, El Dib R, Johnston BC (2019). "Probiotics for the prevention of pediatric antibiotic-associated diarrhea". Cochrane Database Syst Rev. 4: CD004827. doi:10.1002/14651858.CD004827.pub5. PMC 6490796. PMID 31039287.CS1 maint: multiple names: authors list (link) 4. ^ Pillai, A; Nelson, R (January 23, 2008). "Probiotics for treatment of Clostridium difficile-associated colitis in adults". Cochrane Database of Systematic Reviews (1): CD004611. doi:10.1002/14651858.CD004611.pub2. PMID 18254055. 5. ^ Doron, S. I.; Hibberd, P. L.; Gorbach, S. L. (2008). "Probiotics for Prevention of Antibiotic-associated Diarrhea". Journal of Clinical Gastroenterology. 42: S58–S63. doi:10.1097/MCG.0b013e3181618ab7. PMID 18542041. 6. ^ Surawicz, C. M. (2008). "Role of Probiotics in Antibiotic-associated Diarrhea, Clostridium difficile-associated Diarrhea, and Recurrent Clostridium difficile-associated Diarrhea". Journal of Clinical Gastroenterology. 42: S64–S70. doi:10.1097/MCG.0b013e3181646d09. PMID 18545161. 7. ^ Sazawal, S; Hiremath, G; Dhingra, U; Malik, P; Deb, S; Black, RE (June 2006). "Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials". The Lancet Infectious Diseases. 6 (6): 374–82. doi:10.1016/S1473-3099(06)70495-9. PMID 16728323. * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Symptoms and signs relating to the human digestive system or abdomen Gastrointestinal tract * Nausea * Vomiting * Heartburn * Aerophagia * Pagophagia * Dysphagia * oropharyngeal * esophageal * Odynophagia * Bad breath * Xerostomia * Hypersalivation * Burping * Wet burp * Goodsall's rule * Chilaiditi syndrome * Dance's sign * Aaron's sign * Arapov's sign * Markle sign * McBurney's point * Sherren's triangle * Radiologic signs: Hampton's line * Klemm's sign Accessory * liver: Councilman body * Mallory body * biliary: Boas' sign * Courvoisier's law * Charcot's cholangitis triad/Reynolds' pentad * cholecystitis (Murphy's sign * Lépine's sign * Mirizzi's syndrome) * Nardi test Defecation * Flatulence * Fecal incontinence * Encopresis * Fecal occult blood * Rectal tenesmus * Constipation * Obstructed defecation * Diarrhea * Rectal discharge * Psoas sign * Obturator sign * Rovsing's sign * Hamburger sign * Heel tap sign * Aure-Rozanova's sign * Dunphy sign * Alder's sign * Lockwood's sign * Rosenstein's sign Abdomen Pain * Abdominal pain * Acute abdomen * Colic * Baby colic * Abdominal guarding * Blumberg sign Distension * Abdominal distension * Bloating * Ascites * Tympanites * Shifting dullness * Ascites * Fluid wave test Masses * Abdominal mass * Hepatosplenomegaly * Hepatomegaly * Splenomegaly Other * Jaundice * Mallet-Guy sign * Puddle sign * Ballance's sign * Aortic insufficiency * Castell's sign * Kehr's sign * Cullen's sign * Grey Turner's sign Hernia * Howship–Romberg sign * Hannington-Kiff sign Other * Cupola sign * Fothergill's sign * Carnett's sign * Sister Mary Joseph nodule [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Antibiotic-associated diarrhea	c0578159	1,126	wikipedia	https://en.wikipedia.org/wiki/Antibiotic-associated_diarrhea	2021-01-18T18:33:00	{"umls": ["C0578159"], "wikidata": ["Q574891"]}
## Summary The purpose of this overview is to increase clinician awareness of the genetic basis of dilated cardiomyopathy (DCM) and the benefits of early diagnosis and management to individuals with genetic DCM. The following are the goals of this overview. ### Goal 1. Define DCM. ### Goal 2. Identify the categories of DCM. ### Goal 3. Provide the evaluation strategy of a proband with nonsyndromic DCM. ### Goal 4. Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome. ## Diagnosis ## Clinical Characteristics ## Differential Diagnosis ## 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	Dilated Cardiomyopathy Overview	None	1,127	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1309/	2021-01-18T21:30:11	{"synonyms": []}
Frontal fibrosing alopecia (FFA) is a rare variant of lichen planopilaris (see this term) characterized by symmetrical, progressive, band-like anterior hair loss of the scalp. ## Epidemiology Prevalence is unknown. It most commonly affects postmenopausal women, although it has also been reported in men and premenopausal women. ## Clinical description Progressive recession of the frontal and temporal hairline is observed. Approximately half of all cases of FFA also have eyebrow loss; less often there is hair loss in other parts of the body. It is only very rarely associated with classic lichen planus lesions elsewhere. Histopathologically, perifollicular lymphocytic infiltrate and follicular hyperkeratosis are observed at the edge of the affected area, while the rest of the lesion appears pale with loss of the follicular ostia. It is histologically indistinguishable from other forms of lichen planopilaris. ## Etiology It was suggested that the disease could have a hormonal origin, but to date the precise etiology remains unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Frontal fibrosing alopecia	c1274700	1,128	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254492	2021-01-23T18:26:05	{"gard": ["10886"], "umls": ["C1274700"], "icd-10": ["L66.1"], "synonyms": ["FFA"]}
Median arcuate ligament syndrome Other namesCeliac artery compression syndrome Celiac axis syndrome Celiac trunk compression syndrome Dunbar syndrome Median arcuate ligament syndrome results from compression of the celiac artery by the median arcuate ligament. The median arcuate ligament is a fibrous arch formed by the left and right diaphragmatic crura, visible here on the underside of the diaphragm. SpecialtyGastroenterology, Vascular Surgery SymptomsEpigastric pain, anorexia, Weight loss ComplicationsGastroparesis Aneurysm of the superior and inferior pancreaticoduodenal arteries Usual onset20 to 40 years of age CausesCompression of the celiac artery from the median arcuate ligament Risk factorsFemale gender TreatmentSurgery In medicine, the median arcuate ligament syndrome (MALS, also known as celiac artery compression syndrome, celiac axis syndrome, celiac trunk compression syndrome or Dunbar syndrome) is a rare[1] condition characterized by abdominal pain attributed to compression of the celiac artery and the celiac ganglia by the median arcuate ligament.[2] The abdominal pain may be related to meals, may be accompanied by weight loss, and may be associated with an abdominal bruit heard by a clinician. The diagnosis of MALS is one of exclusion, as many healthy patients demonstrate some degree of celiac artery compression in the absence of symptoms. Consequently, a diagnosis of MALS is typically only entertained after more common conditions have been ruled out. Once suspected, screening for MALS can be done with ultrasonography and confirmed with computed tomography (CT) or magnetic resonance (MR) angiography. Treatment is generally surgical, the mainstay being open or laparascopic division, or separation, of the median arcuate ligament combined with removal of the celiac ganglia. The majority of patients benefit from surgical intervention. Poorer responses to treatment tend to occur in patients of older age, those with a psychiatric condition or who use alcohol, have abdominal pain unrelated to meals, or who have not experienced weight loss. ## Contents * 1 Signs and symptoms * 2 Anatomy and pathogenesis * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 History * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Patients with MALS reportedly experience abdominal pain, particularly in the epigastrium, which may be associated with eating and which may result in anorexia and weight loss. The pain can be in the left or right side, but usually where the ribs meet.[2] Other signs are persistent nausea, lassitude (especially after a heavy meal) and exercise intolerance. Diarrhea is a common symptom, some experience constipation. While some experience vomiting, not everyone does. Exercise or certain postures can aggravate the symptoms. Occasionally, physical examination reveals an abdominal bruit in the mid-epigastrium.[2] Complications of MALS result from chronic compression of the celiac artery. They include gastroparesis[3] and aneurysm of the superior and inferior pancreaticoduodenal arteries.[4] ## Anatomy and pathogenesis[edit] Side views (sagittal plane) of the descending aorta and two of its branches, the celiac trunk and superior mesenteric artery, demonstrate normal and MALS anatomy. Left The median arcuate ligament is normally several millimeters to centimeters superior to the origin of the celiac artery. Right In MALS, the ligament is anterior, rather than superior, to the celiac artery, resulting in compression of the vessel and a characteristic hook-shaped contour. The median arcuate ligament is a ligament formed at the base of the diaphragm where the left and right diaphragmatic crura join near the 12th thoracic vertebra. This fibrous arch forms the anterior aspect of the aortic hiatus, through which the aorta, thoracic duct, and azygos vein pass. The median arcuate ligament usually comes into contact with the aorta above the branch point of the celiac artery. However, in up to one quarter of normal individuals, the median arcuate ligament passes in front of the celiac artery, compressing the celiac artery and nearby structures such as the celiac ganglia.[2] In some of these individuals, this compression is pathologic and leads to the median arcuate ligament syndrome.[2] Several theories attempt to explain the origin of pain caused by compression of the celiac artery.[5] One proposes that compression of the celiac artery causes ischemia, or decreased blood flow, to abdominal organs, leading to pain. Another hypothesizes that there is compression not only of the celiac artery but also of the celiac ganglia, and that pain results from compression of the latter. ## Diagnosis[edit] Median arcuate ligament syndrome is a diagnosis of exclusion.[2][5] That is, the diagnosis of MALS is generally considered only after patients have undergone an extensive evaluation of their gastrointestinal tract including upper endoscopy, colonoscopy, and evaluation for gallbladder disease and gastroesophageal reflux disease (GERD).[5] The diagnosis of MALS relies on a combination of clinical features and findings on medical imaging.[2] Clinical features include those signs and symptoms mentioned above; classically, MALS involves a triad of abdominal pain after eating, weight loss, and an abdominal bruit, although the classic triad is found in only a minority of individuals that carry a MALS diagnosis.[5] Diagnostic imaging for MALS is divided into screening and confirmatory tests.[5] A reasonable screening test for patients with suspected MALS is duplex ultrasonography to measure blood flow through the celiac artery.[5][6] Peak systolic velocities greater than 200 cm/s are suggestive of celiac artery stenosis associated with MALS.[5] CT angiographic findings in MALS[2] 1. Focal narrowing of proximal celiac artery with poststenotic dilatation 2. Indentation on superior aspect of celiac artery 3. Hook-shaped contour of celiac artery Further evaluation and confirmation can be obtained via angiography to investigate the anatomy of the celiac artery.[5] Historically, conventional angiography was used, although this has been largely replaced by less invasive techniques such as computed tomography (CT) and magnetic resonance (MR) angiography.[2][5] Because it provides better visualization of intra-abdominal structures, CT angiography is preferred to MR angiography in this setting.[5] The findings of focal narrowing of the proximal celiac artery with poststenotic dilatation, indentation on the superior aspect of the celiac artery, and a hook-shaped contour of the celiac artery support a diagnosis of MALS.[2] These imaging features are exaggerated on expiration, even in normal asymptomatic individuals without the syndrome.[2] Proximal celiac artery stenosis with poststenotic dilatation can be seen in other conditions affecting the celiac artery.[2] The hook-shaped contour of the celiac artery is characteristic of the anatomy in MALS and helps distinguish it from other causes of celiac artery stenosis such as atherosclerosis.[2] This hooked contour is not entirely specific for MALS however, given that 10–24% of normal asymptomatic individuals have this anatomy.[2] ## Treatment[edit] Decompression of the celiac artery is the general approach to treatment of MALS.[5] The mainstay of treatment involves an open or laparoscopic surgery approaches to divide, or separate, the median arcuate ligament to relieve the compression of the celiac artery.[5] This is combined with removal of the celiac ganglia and evaluation of blood flow through the celiac artery, for example by intraoperative duplex ultrasound. If blood flow is poor, celiac artery revascularization is usually attempted; methods of revascularization include aortoceliac bypass, patch angioplasty, and others.[5] In recent, a laparoscopic approach used to achieve celiac artery decompression;[7] however, should the celiac artery require revascularization, the procedure would require conversion to an open approach.[5] Endovascular methods such as percutaneous transluminal angioplasty (PTA) have been used in patients who have failed open and/or laparoscopic intervention.[5] PTA alone, without decompression of the celiac artery, may not be of benefit.[5][8] ## Prognosis[edit] There are few studies of the long-term outcomes of patients treated for MALS.[5] According to Duncan,[5] the largest and more relevant late outcomes data come from a study of 51 patients who underwent open surgical treatment for MALS, 44 of whom were available for long-term follow-up at an average of nine years following therapy.[9] The investigators reported that among patients who underwent celiac artery decompression and revascularization, 75% remained asymptomatic at follow-up. In this study, predictors of favorable outcome included: * Age from 40 to 60 years * Lack of psychiatric condition or alcohol use * Abdominal pain that was worse after meals * Weight loss greater than 20 lb (9.1 kg) ## Epidemiology[edit] It is estimated that in 10–24% of normal, asymptomatic individuals the median arcuate ligament crosses in front of (anterior to) the celiac artery, causing some degree of compression.[2][10] Approximately 1% of these individuals exhibit severe compression associated with symptoms of MALS.[2] The syndrome most commonly affects individuals between 20 and 40 years old, and is more common in women, particularly thin women.[2] ## History[edit] Celiac artery compression was first observed by Benjamin Lipshutz in 1917.[11] MALS was first described by Pekka-Tapani Harjola in 1963[12] and subsequently by J. David Dunbar and Samuel Marable in 1965.[13] It has also been called Harjola-Marable syndrome and Marable syndrome.[11] ## See also[edit] * Nutcracker syndrome * Superior mesenteric artery syndrome ## References[edit] 1. ^ "Rare Disease Database: Median Arcuate Ligament Syndrome". rarediseases.org. Retrieved 22 January 2019. 2. ^ a b c d e f g h i j k l m n o p q Horton KM, Talamini MA, Fishman EK (2005). "Median arcuate ligament syndrome: evaluation with CT angiography". Radiographics. 25 (5): 1177–82. doi:10.1148/rg.255055001. PMID 16160104. 3. ^ Balaban DH, Chen J, Lin Z, Tribble CG, McCallum RW (March 1997). "Median arcuate ligament syndrome: a possible cause of idiopathic gastroparesis". Am. J. Gastroenterol. 92 (3): 519–23. PMID 9068484. 4. ^ Manghat NE, Mitchell G, Hay CS, Wells IP (September 2008). "The median arcuate ligament syndrome revisited by CT angiography and the use of ECG gating—a single centre case series and literature review". Br J Radiol. 81 (969): 735–42. doi:10.1259/bjr/43571095. PMID 18541631. 5. ^ a b c d e f g h i j k l m n o p q r Duncan AA (April 2008). "Median arcuate ligament syndrome". Curr Treat Options Cardiovasc Med. 10 (2): 112–6. doi:10.1007/s11936-008-0012-2. PMID 18325313. Archived from the original on December 4, 2012. 6. ^ Sproat IA, Pozniak MA, Kennell TW (November 1993). "US case of the day. Median arcuate ligament syndrome (celiac artery compression syndrome)". Radiographics. 13 (6): 1400–2. doi:10.1148/radiographics.13.6.8290734. PMID 8290734. 7. ^ Carbonell AM, Kercher KW, Heniford BT, Matthews BD (May 2005). "Multimedia article. Laparoscopic management of median arcuate ligament syndrome". Surg Endosc. 19 (5): 729. doi:10.1007/s00464-004-6010-x. PMID 15965588. 8. ^ Matsumoto AH, Tegtmeyer CJ, Fitzcharles EK, et al. (1995). "Percutaneous transluminal angioplasty of visceral arterial stenoses: results and long-term clinical follow-up". J Vasc Interv Radiol. 6 (2): 165–74. doi:10.1016/S1051-0443(95)71087-9. PMID 7787348. 9. ^ Reilly LM, Ammar AD, Stoney RJ, Ehrenfeld WK (January 1985). "Late results following operative repair for celiac artery compression syndrome". J. Vasc. Surg. 2 (1): 79–91. doi:10.1067/mva.1985.avs0020079. PMID 3965762. 10. ^ Lindner HH, Kemprud E (November 1971). "A clinicoanatomical study of the arcuate ligament of the diaphragm". Arch Surg. 103 (5): 600–5. doi:10.1001/archsurg.1971.01350110102016. PMID 5117015. 11. ^ a b synd/4106 at Who Named It? 12. ^ Harjola PT (1963). "A rare obstruction of the coeliac artery. Report of a case". Ann Chir Gynaecol Fenn. 52: 547–50. PMID 14083857. 13. ^ Dunbar JD, Molnar W, Beman FF, Marable SA (November 1965). "Compression of the celiac trunk and abdominal angina" (PDF). Am J Roentgenol Radium Ther Nucl Med. 95 (3): 731–44. PMID 5844938.[permanent dead link] ## External links[edit] Classification D * ICD-10: I77.4 * ICD-9-CM: 447.4 * MeSH: D000074742 * SNOMED CT: 9250002 External resources * eMedicine: article/188618 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Median arcuate ligament syndrome	c1861783	1,129	wikipedia	https://en.wikipedia.org/wiki/Median_arcuate_ligament_syndrome	2021-01-18T18:41:30	{"gard": ["12308"], "mesh": ["D000074742"], "umls": ["C1861783"], "orphanet": ["293208"], "wikidata": ["Q2456424"]}
A number sign (#) is used with this entry because familial infantile convulsions with paroxysmal choreoathetosis (ICCA) is caused by heterozygous mutation in the PRRT2 gene (614386) on chromosome 16p11. Description Benign familial infantile convulsions (BFIC; see 601764) is an autosomal dominant disorder characterized by afebrile seizures occurring between 3 and 12 months of age. Paroxysmal choreoathetosis is a disorder of involuntary movements characterized by attacks that occur spontaneously or are induced by a variety of stimuli. The ICCA syndrome shares overlapping clinical features with benign familial infantile seizures-2 (BFIS2; 605751) and episodic kinesigenic dyskinesia-1 (EKD1; 128200), which are allelic disorders. See also rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (608105), which maps to 16p. Clinical Features Szepetowski et al. (1997) studied 4 families from northwestern France in which benign infantile convulsions was inherited as an autosomal dominant trait together with variably expressed paroxysmal choreoathetosis. The authors suggested that the strong association of the 2 disorders in the same families defined a distinct neurologic syndrome. Partial seizures started with a psychomotor arrest and a deviation of the head and eyes to one side, often with secondary generalization. The seizures responded well to medication and remitted by age 12 months. Paroxysmal choreoathetotic movements were of the dystonic type and occurred at rest or in response to exertion or anxiety. Both seizures and movements occurred in clusters. Interictal EEGs were normal, and all patients showed normal psychomotor development. Swoboda et al. (2000) reported 44 individuals from 11 families with infantile convulsions (62% of patients), PKC (86%), or both (50%). Infantile convulsions were common, occurring in 9 of 11 families, and were characterized by onset between 3 and 18 months of age, eye deviation, staring, altered consciousness, apnea, and tonic stiffening. Remission occurred within 3 years. Age at onset for PKC was 6 to 28 years. Episodes were provoked by anxiety or exertion. EEG studies were normal in all patients except one. Mapping Szepetowski et al. (1997) performed linkage analysis in families with this disorder and found strong evidence of linkage in the pericentromeric region of chromosome 16, with a maximum 2-point lod score for D16S3133 of 6.76 at a recombination fraction of 0.0. Critical recombinants narrowed the region of interest to a 10-cM interval around the centromere, 16p12-q12. In a Chinese family, Lee et al. (1998) confirmed that the autosomal dominant trait of benign infantile convulsions and paroxysmal choreoathetosis of the dystonic form, the ICCA syndrome, is linked to the 16p12-q12 region. Some patients in this family also exhibited recurrence of epileptic seizures at a much later age. By analyzing 11 unrelated families with infantile convulsions, PKC, or both, Swoboda et al. (2000) defined a 26-cM candidate region between markers D16S3131 and D16S3396 on chromosome 16q (maximum lod score of 6.63 at D16S3131). In conjunction with previous data, the critical region was narrowed to a 3.2-cM region spanning the centromere. Molecular Genetics Using a combination of exome sequencing and linkage analysis in 2 large Han Chinese families with EKD1 (128200), Wang et al. (2011) identified 2 different heterozygous truncating mutations in the PRRT2 gene (649dupC; 614386.0001 and 614386.0009, respectively) that completely segregated with the phenotype in each family. Two patients in each family also had infantile convulsion and choreoathetosis syndrome, indicating intrafamilial variability. In 5 (83%) of 6 families with ICCA, Heron et al. (2012) identified 1 of 3 different heterozygous mutations in the PRRT2 gene. Three families had the common 649insC mutation (614386.0001), and 2 additional families each had a private mutation (614386.0004 and 614386.0005). Heterozygous PRRT2 mutations were also found in 14 (82%) of 17 families with benign familial infantile seizures-2 (BFIS2; 605751). The 649insC mutation was the most common mutation, found in 12 families with BFIS2. The families with this mutation were of different ethnic origin, including Australasian of western European heritage, Swedish, and Israeli Sephardic-Jewish, and there was no evidence of a common haplotype among these families, indicating a mutation hotspot. These findings demonstrated that mutations in PRRT2 cause both epilepsy and a movement disorder, with obvious pleiotropy in age of expression. The mutations were identified by linkage analysis, confirming linkage to chromosome 16p, followed by sequence-capture array of coding and promoter sequences within the candidate region. Lee et al. (2012) also identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0007 and 614386.0008) in affected members of families with ICCA. The mutations were identified by whole-genome sequencing of 6 well-characterized families. The findings were confirmed by the identification of PRRT2 mutations in 24 of 25 additional families with the disorder. The 649insC mutation was the most common mutation. Sanger sequencing of a third cohort of 78 probands with a less clear clinical diagnosis found that 10 patients with familial disease and 17 with sporadic disease had the common 649insC mutation; 1 additional patient had a different truncating PRRT2 mutation. None of the pathogenic alleles were found in over 2,500 control chromosomes. There was intrafamilial variability of the phenotype. In vitro functional expression assays showed that the mutant truncating proteins were not expressed and did not exert dominant-negative effect on the wildtype protein, suggesting haploinsufficiency as the pathologic mechanism. Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutation hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures, partial, afebrile \- Secondary generalization may occur \- Seizures, generalized, afebrile \- Seizures occur in clusters \- Seizures often begin with head and eye deviation \- Choreoathetosis, paroxysmal \- Dystonia, paroxysmal \- Involuntary movements may be precipitated by exertion or anxiety \- Normal psychomotor development \- Normal interictal EEG MISCELLANEOUS \- Average onset of seizures 6 months (range 3-12) \- Seizures easily controlled by medications \- Spontaneous resolution of seizures by 12 months of age \- Onset of choreoathetosis in childhood or young adult (6-23 years) MOLECULAR BASIS \- Caused by mutation in the proline-rich transmembrane protein 2 gene (PRRT2, 614386.0001 ). ▲ 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	CONVULSIONS, FAMILIAL INFANTILE, WITH PAROXYSMAL CHOREOATHETOSIS	c1865926	1,130	omim	https://www.omim.org/entry/602066	2019-09-22T16:14:03	{"mesh": ["C535522"], "omim": ["602066"], "orphanet": ["31709"], "synonyms": ["Alternative titles", "INFANTILE CONVULSIONS AND PAROXYSMAL CHOREOATHETOSIS, FAMILIAL", "ICCA SYNDROME", "PAROXYSMAL KINESIGENIC DYSKINESIA WITH INFANTILE CONVULSIONS"], "genereviews": ["NBK475803"]}
Abortion in Nevada is legal. 62% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases. Legislation by 2007 required informed consent. Attempts were successfully made to pass abortion legislation in May 2019, being pushed through a largely Democratic controlled state legislature. The number of abortion clinics in Nevada has decline over the years, with 25 in 1982, seventeen in 1992 and thirteen in 2014. There were 8,132 legal abortions in 2014, and 7,116 in 2015. State funding could be used to fund abortions in case of risk of life to the mother, rape or incest but no such funding was used in 2010. There are active abortion rights and anti-abortion rights activists in the state. ## Contents * 1 Terminology * 2 Context * 3 History * 3.1 Legislative history * 3.2 Judicial history * 3.3 Clinic history * 4 Statistics * 5 Abortion financing * 6 Abortion rights views and activities * 6.1 Protests * 6.2 Views * 7 Anti-abortion views and activities * 7.1 Views * 7.2 Violence * 8 Footnotes * 9 References ## Terminology[edit] Main article: Abortion See also: Definitions of abortion The abortion debate most commonly relates to the "induced abortion" of an embryo or fetus at some point in a pregnancy, which is also how the term is used in a legal sense.[note 1] Some also use the term "elective abortion", which is used in relation to a claim to an unrestricted right of a woman to an abortion, whether or not she chooses to have one. The term elective abortion or voluntary abortion describes the interruption of pregnancy before viability at the request of the woman, but not for medical reasons.[1] Anti-abortion advocates tend to use terms such as "unborn baby", "unborn child", or "pre-born child",[2][3] and see the medical terms "embryo", "zygote", and "fetus" as dehumanizing.[4][5] Both "pro-choice" and "pro-life" are examples of terms labeled as political framing: they are terms which purposely try to define their philosophies in the best possible light, while by definition attempting to describe their opposition in the worst possible light. "Pro-choice" implies that the alternative viewpoint is "anti-choice", while "pro-life" implies the alternative viewpoint is "pro-death" or "anti-life".[6] The Associated Press encourages journalists to use the terms "abortion rights" and "anti-abortion".[7] ## Context[edit] See also: Abortion in the United States Free birth control correlates to teenage girls having a fewer pregnancies and fewer abortions. A 2014 New England Journal of Medicine study found such a link. At the same time, a 2011 study by Center for Reproductive Rights and Ibis Reproductive Health also found that states with more abortion restrictions have higher rates of maternal death, higher rates of uninsured pregnant women, higher rates of infant and child deaths, higher rates of teen drug and alcohol abuse, and lower rates of cancer screening.[8] According to a 2017 report from the Center for Reproductive Rights and Ibis Reproductive Health, states that tried to pass additional constraints on a women's ability to access legal abortions had fewer policies supporting women's health, maternal health and children's health. These states also tended to resist expanding Medicaid, family leave, medical leave, and sex education in public schools.[9] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[9] Poor women in the United States had problems paying for menstrual pads and tampons in 2018 and 2019. Almost two-thirds of American women could not pay for them. These were not available through the federal Women, Infants, and Children Program (WIC).[10] Lack of menstrual supplies has an economic impact on poor women. A study in St. Louis found that 36% had to miss days of work because they lacked adequate menstrual hygiene supplies during their period. This was on top of the fact that many had other menstrual issues including bleeding, cramps and other menstrual induced health issues.[10] Connecticut, Florida, Illinois, Maryland, Massachusetts, Minnesota, New Jersey, New York, Nevada, and Pennsylvania all had exemptions for essential hygiene products like tampons and menstrual pads as of November 2018.[11][12][13][14] ## History[edit] ### Legislative history[edit] The state was one of 10 states in 2007 to have a customary informed consent provision for abortions.[15] In August 2018, the state had a law to protect the right to have an abortion.[16] As of May 14, 2019, the state prohibited abortions after the fetus was viable, generally some point between week 24 and 28. This period uses a standard defined by the US Supreme Court in 1973 with the Roe v. Wade ruling.[17] Florida, Nevada, and New York had laws prohibiting abortions after 24-weeks.[18][19] This law was still in place as of mid-May 2019.[20][19] The law also required that abortions be done by licensed physicians. In situations where abortions take place after 24 weeks, the law said that the procedure needed to take place at a licensed hospital.[19][21] SB 179, which would decriminalize medicated abortions, was scheduled to be voted on in late May 2019.[19] It passed the House 27–13, with only one Democrat voting against it.[22] Other revisions under the new law in May 2019 included abortion providers not longer needing to tell women of the "emotional implications" of having an abortion.[23] Trust Nevada Women Act, SB 179, was signed into law by Democratic Governor Steve Sisolak on May 31, 2019. In signing the bill, he said, "Nevada has a long history of trusting the women of our state to make their own reproductive health care decisions and protecting the right to reproductive freedom." The new law made several changes to existing abortion laws in the state, including decriminalizing the performing of abortion procedures, and removing informed consent laws that said doctors needed to tel women of the "emotional implications" in having an abortion and what she should do after the procedure to avoid post-op complications; the latter was changed to require doctors to tell women getting abortions about "describe the nature and consequences of the procedure." The law also meant doctors no longer had to collect data about women related to their marital status and age. In addition, Senate Bill 94 allocated $6 million to be spent statewide for grants to family planning organizations.[24][23] ### Judicial history[edit] The US Supreme Court's decision in 1973's Roe v. Wade ruling meant the state could no longer regulate abortion in the first trimester.[25] ### Clinic history[edit] Number of abortion clinics in Nevada by year. See also: Abortion clinic Between 1982 and 1992, the number of abortion clinics in the state decreased by eight, going from 25 in 1982 to seventeen in 1992.[26] In 2014, the state had thirteen facilities that provided abortions, of which 8 were abortion clinics.[27][28] In 2014, 88% of the counties in the state did not have an abortion clinic. That year, 9% of women in the state aged 15 – 44 lived in a county without an abortion clinic.[16] In 2017, there were three Planned Parenthood clinics in a state with a population of 668,173 women aged 15 – 49 of which two offered abortion services.[29] ## Statistics[edit] In 1990, 149,000 women in the state faced the risk of an unintended pregnancy.[26] Between 2011 and 2014, the state saw a decrease of 6% in the number of abortions performed in the state.[28] In 2014, 62% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases.[30] In 2017, the state had an infant mortality rate of 5.8 deaths per 1,000 live births.[9] Number of reported abortions, abortion rate and percentage change in rate by geographic region and state in 1992, 1995 and 1996[31] Census division and state Number Rate % change 1992–1996 1992 1995 1996 1992 1995 1996 US Total 1,528,930 1,363,690 1,365,730 25.9 22.9 22.9 –12 Mountain 69,600 63,390 67,020 21 17.9 18.6 –12 Arizona 20,600 18,120 19,310 24.1 19.1 19.8 –18 Colorado 19,880 15,690 18,310 23.6 18 20.9 –12 Idaho 1,710 1,500 1,600 7.2 5.8 6.1 –15 Montana 3,300 3,010 2,900 18.2 16.2 15.6 –14 Nevada 13,300 15,600 15,450 44.2 46.7 44.6 1 New Mexico 6,410 5,450 5,470 17.7 14.4 14.4 –19 Utah 3,940 3,740 3,700 9.3 8.1 7.8 –16 Wyoming 460 280 280 4.3 2.7 2.7 –37 Number, rate, and ratio of reported abortions, by reporting area of residence and occurrence and by percentage of abortions obtained by out-of-state residents, US CDC estimates Location Residence Occurrence % obtained by out-of-state residents Year Ref No. Rate^ Ratio^^ No. Rate^ Ratio^^ Nevada 13,300 44.2 1992 [31] Nevada 15,600 46.7 1995 [31] Nevada 15,450 44.6 199 [31] Nevada 7,870 13.9 219 8,132 14.4 227 3.9 2014 [32] Nevada 6,760 11.8 186 7,116 12.4 196 5.5 2015 [33] Nevada 6,873 11.9 190 7,284 12.6 201 5.9 2016 [34] ^number of abortions per 1,000 women aged 15–44; ^^number of abortions per 1,000 live births ## Abortion financing[edit] In 2010, the state had zero publicly funded abortions.[35] The law as of May 1, 2018 said that potential danger to the life of the mother, pregnancy as a result of rape or incest were the only reasons that state funding could be used by women seeking abortions.[28] SB 94 was passed in June 2019 in the final days of the legislative session. US$6 million was allocated as part of the bill to fund reproductive assistance measures in the state through family planning grants. Money could be used by eligible organizations for a wide variety of uses including immunizations, birth control, emergency contraception, and male sterilization surgery. It did not cover abortions. This money was intended to assist low income women and women living in largely rural areas.[36] ## Abortion rights views and activities[edit] ### Protests[edit] Women from the state participated in marches supporting abortion rights as part of a #StoptheBans movement in May 2019.[37] Abortion rights protesters were at the Nevada Capitol Building with signs to support the passage of SB 179, including pink signs that said "protect safe, legal abortion." [38] ### Views[edit] Women in Film Executive Director Kirsten Schaffer said of Georgia and other states similar restrictive abortion bans passed in early 2019, "A woman's right to make choices about her own body is fundamental to her personal and professional well-being. [...] We support people who make the choice not to take their production to Georgia or take a job in Georgia because of the draconian anti-choice law. To that end, we've compiled a list of pro-choice states that offer meaningful tax rebates and production incentives, and encourage everyone to explore these alternatives: California, Colorado, Hawaii, Illinois, Maine, Nevada, New Jersey, New Mexico, New York, Washington."[39] Legislation co-sponsor Democratic Senator Yvanna Cancela said of the SB 94's passage, "When the rest of the country may feel hopeless, may feel bleak, they should look to Nevada as the shining beacon that we are for women's rights."[38] ## Anti-abortion views and activities[edit] ### Views[edit] Following the passage of the May 2019 legislation SB 94, Republican . Assemblywoman Alexis Hansen said, "This bill is a slippery slope that (will) leave women and children less informed and more susceptible to exploitation."[38] ### Violence[edit] Rachelle "Shelley" Shannon attempted to set fires at abortion clinics in Oregon, California, Idaho and Nevada during the late 1980s and early 1990s and eventually plead guilty for these cases of arson. In 1993, she would be found guilty of attempted murder of Dr. George Tiller in 1993 at his Wichita, Kansas clinic.[40] ## Footnotes[edit] 1. ^ According to the Supreme Court's decision in Roe v. Wade: > (a) For the stage prior to approximately the end of the first trimester, the abortion decision and its effectuation must be left to the medical judgement of the pregnant woman's attending physician. (b) For the stage subsequent to approximately the end of the first trimester, the State, in promoting its interest in the health of the mother, may, if it chooses, regulate the abortion procedure in ways that are reasonably related to maternal health. (c) For the stage subsequent to viability, the State in promoting its interest in the potentiality of human life may, if it chooses, regulate, and even proscribe, abortion except where it is necessary, in appropriate medical judgement, for the preservation of the life or health of the mother. Likewise, Black's Law Dictionary defines abortion as "knowing destruction" or "intentional expulsion or removal". ## References[edit] 1. ^ Watson, Katie (20 Dec 2019). "Why We Should Stop Using the Term "Elective Abortion"". AMA Journal of Ethics. 20: E1175-1180. doi:10.1001/amajethics.2018.1175. PMID 30585581. Retrieved 17 May 2019. 2. ^ Chamberlain, Pam; Hardisty, Jean (2007). "The Importance of the Political 'Framing' of Abortion". The Public Eye Magazine. 14 (1). 3. ^ "The Roberts Court Takes on Abortion". New York Times. November 5, 2006. Retrieved January 18, 2008. 4. ^ Brennan 'Dehumanizing the vulnerable' 2000 5. ^ Getek, Kathryn; Cunningham, Mark (February 1996). "A Sheep in Wolf's Clothing – Language and the Abortion Debate". Princeton Progressive Review. 6. ^ "Example of "anti-life" terminology" (PDF). Archived from the original (PDF) on 2011-07-27. Retrieved 2011-11-16. 7. ^ Goldstein, Norm, ed. The Associated Press Stylebook. Philadelphia: Basic Books, 2007. 8. ^ Castillo, Stephanie (2014-10-03). "States With More Abortion Restrictions Hurt Women's Health, Increase Risk For Maternal Death". Medical Daily. Retrieved 2019-05-27. 9. ^ a b c "States pushing abortion bans have highest infant mortality rates". NBC News. Retrieved 2019-05-25. 10. ^ a b Mundell, E.J. (January 16, 2019). "Two-Thirds of Poor U.S. Women Can't Afford Menstrual Pads, Tampons: Study". US News & World Report. Retrieved May 26, 2019. 11. ^ Larimer, Sarah (January 8, 2016). "The 'tampon tax,' explained". The Washington Post. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 12. ^ Bowerman, Mary (July 25, 2016). "The 'tampon tax' and what it means for you". USA Today. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 13. ^ Hillin, Taryn. "These are the U.S. states that tax women for having periods". Splinter. Retrieved 2017-12-15. 14. ^ "Election Results 2018: Nevada Ballot Questions 1-6". KNTV. Retrieved 2018-11-07. 15. ^ "State Policy On Informed Consent for Abortion" (PDF). Guttmacher Policy Review. Fall 2007. Retrieved May 22, 2019. 16. ^ a b businessinsider (2018-08-04). "This is what could happen if Roe v. Wade fell". Business Insider (in Spanish). Retrieved 2019-05-24. 17. ^ Lai, K. K. Rebecca (2019-05-15). "Abortion Bans: 8 States Have Passed Bills to Limit the Procedure This Year". The New York Times. ISSN 0362-4331. Retrieved 2019-05-24. 18. ^ "Abortion Laws". Findlaw. Retrieved 2019-05-23. 19. ^ a b c d "Are there any states working to protect abortion rights?". Well+Good. 2019-05-17. Retrieved 2019-05-25. 20. ^ Tavernise, Sabrina (2019-05-15). "'The Time Is Now': States Are Rushing to Restrict Abortion, or to Protect It". The New York Times. ISSN 0362-4331. Retrieved 2019-05-24. 21. ^ "NRS: Chapter 442 - Maternal and Child Health; Abortion". www.leg.state.nv.us. Retrieved 2019-05-25. 22. ^ "Text-Only NPR.org : Nevada Law Removing Abortion Restrictions Passes State Assembly". text.npr.org. Retrieved 2019-05-28. 23. ^ a b Kelly, Caroline. "Nevada passes bill to no longer require doctors to tell women the 'emotional implications' of an abortion". CNN. Retrieved 2019-05-28. 24. ^ Veronica Stracqualursi and Chris Boyette. "Illinois and Nevada approve abortion rights bills that remove long-standing criminal penalties". CNN. Retrieved 2019-06-02. 25. ^ Buell, Samuel (1991-01-01). "Criminal Abortion Revisited". New York University Law Review. 66: 1774–1831. 26. ^ a b Arndorfer, Elizabeth; Michael, Jodi; Moskowitz, Laura; Grant, Juli A.; Siebel, Liza (December 1998). A State-By-State Review of Abortion and Reproductive Rights. Diane Publishing. ISBN 9780788174810. 27. ^ Gould, Rebecca Harrington, Skye. "The number of abortion clinics in the US has plunged in the last decade — here's how many are in each state". Business Insider. Retrieved 2019-05-23. 28. ^ a b c "State Facts About Abortion: Nevada". Guttmacher Institute. 2016-01-26. Retrieved 2019-05-28. 29. ^ "Here's Where Women Have Less Access to Planned Parenthood". Retrieved 2019-05-23. 30. ^ "Views about abortion by state - Religion in America: U.S. Religious Data, Demographics and Statistics". Pew Research Center. Retrieved 2019-05-23. 31. ^ a b c d "Abortion Incidence and Services in the United States, 1995-1996". Guttmacher Institute. 2005-06-15. Retrieved 2019-06-02. 32. ^ Jatlaoui, Tara C. (2017). "Abortion Surveillance — United States, 2014". MMWR. Surveillance Summaries. 66 (24): 1–48. doi:10.15585/mmwr.ss6624a1. ISSN 1546-0738. PMID 29166366. 33. ^ Jatlaoui, Tara C. (2018). "Abortion Surveillance — United States, 2015". MMWR. Surveillance Summaries. 67 (13): 1–45. doi:10.15585/mmwr.ss6713a1. ISSN 1546-0738. PMC 6289084. PMID 30462632. 34. ^ Jatlaoui, Tara C. (2019). "Abortion Surveillance — United States, 2016". MMWR. Surveillance Summaries. 68. doi:10.15585/mmwr.ss6811a1. ISSN 1546-0738. 35. ^ "Guttmacher Data Center". data.guttmacher.org. Retrieved 2019-05-24. 36. ^ Benavidez, Gabriella. "Gov. Sisolak to sign bills to decriminalize abortion, fund family planning services". FOX5 Las Vegas. Retrieved 2019-06-06. 37. ^ Bacon, John. "Abortion rights supporters' voices thunder at #StopTheBans rallies across the nation". USA Today. Retrieved 2019-05-25. 38. ^ a b c Tarinelli, Ryan. "Nevada lawmakers close to repealing tough abortion rules". chicagotribune.com. Retrieved 2019-06-06. 39. ^ Low, Matt Donnelly,Gene Maddaus,Elaine; Donnelly, Matt; Maddaus, Gene; Low, Elaine (2019-05-28). "Netflix the Only Hollywood Studio to Speak Out in Attack Against Abortion Rights (Exclusive)". Variety. Retrieved 2019-06-02. 40. ^ Jacobson, Mireille; Royer, Heather (December 2010). "Aftershocks: The Impact of Clinic Violence on Abortion Services". American Economic Journal: Applied Economics. 3: 189–223. doi:10.1257/app.3.1.189. Abortion in the United States by state States * Alabama * Alaska * Arizona * Arkansas * California * Colorado * Connecticut * Delaware * Florida * Georgia * Hawaii * Idaho * Illinois * Indiana * Iowa * Kansas * Kentucky * Louisiana * Maine * Maryland * Massachusetts * Michigan * Minnesota * Mississippi * Missouri * Montana * Nebraska * Nevada * New Hampshire * New Jersey * New Mexico * New York * North Carolina * North Dakota * Ohio * Oklahoma * Oregon * Pennsylvania * Rhode Island * South Carolina * South Dakota * Tennessee * Texas * Utah * Vermont * Virginia * Washington * West Virginia * Wisconsin * Wyoming Federal district Washington, D.C. Insular areas * American Samoa * Guam * Northern Mariana Islands * Puerto Rico * U.S. Virgin Islands [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Abortion in Nevada	None	1,131	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Nevada	2021-01-18T18:54:48	{"wikidata": ["Q64876938"]}
An extremely rare, major congenital malformation consisting of an absence of the nose ranging from hyporrhinia (absence of external nasal structures) to total arrhinia (absence of external nose, nasal airways, olfactory bulbs, or olfactory nerve) often causing respiratory distress and requiring surgical correction. Arrhinia can be bilateral or unilateral (hemiarrhinia). Associated anomalies include ocular features (hypertelorism, microphthalmia, eyelid coloboma), facial clefts, midline defects and microtia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Isolated arrhinia	c0265740	1,132	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1134	2021-01-23T17:27:42	{"gard": ["364"], "mesh": ["C537438"], "umls": ["C0265740"], "icd-10": ["Q30.1"], "synonyms": ["Isolated nose agenesis"]}
For a phenotypic description and a discussion of genetic heterogeneity of chronic lymphocytic leukemia (CLL), see 151400. Clinical Features Lynch et al. (2002) described a family in which the father and all 4 of his children had CLL. All of the children were male, and 2 were identical twins. CLL was diagnosed at the age of 77 in the father, at the ages of 56 and 54 in the identical twins, and at the ages of 47 and 39 in the other brothers. Mapping Raval et al. (2007) followed up the family studied by Lynch et al. (2002) and identified additional family members, both affected and unaffected. Genomewide linkage analysis identified a region on chromosome 9 between markers D9S175 and D9S1776 with a nonparametric linkage score of 0.96. High resolution genotyping identified a common haplotype of 707 kb in all affected family members for whom samples were available. The segment of the presumed haplotype included 3 known genes, including DAPK1 (600831), and 11 predicted genes. Based on epigenetic data indicating frequent loss of DAPK1 expression in CLL, Raval et al. (2007) hypothesized that DAPK1 might be the predisposing gene mutated in this family. Molecular Genetics In the CLL allele of affected family members, Raval et al. (2007) identified an A-to-G transition -6531 upstream of the DAPK1 gene promoter on chromosome 9q34 that was not identified in 383 control samples. Screening of 263 additional CLL cases identified one CLL case with the -6531A-G single-nucleotide polymorphism (SNP). Experiments using luciferase reporter constructs, semiquantitative PCR, and transfection with small interfering RNA (siRNA) demonstrated that DAPK1 expression is downregulated by HOXB7 and suggested that the -6531A-G SNP increases the affinity of HOXB7 binding, resulting in stronger repression of DAPK1 from the CLL allele. Bisulfite sequencing of peripheral blood mononuclear cell DNA from affected and unaffected family members for 2 promoter regions showed that both regions were highly methylated in affected family members. Raval et al. (2007) concluded that loss or reduced expression of DAPK1 underlies heritable predisposition to CLL and the majority of sporadic CLL. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	LEUKEMIA, CHRONIC LYMPHOCYTIC, SUSCEPTIBILITY TO, 3	c0855095	1,133	omim	https://www.omim.org/entry/612557	2019-09-22T16:01:14	{"doid": ["1040"], "omim": ["612557"], "orphanet": ["67038"], "synonyms": ["Alternative titles", "CLLS3"]}
Zlotogora-Ogur syndrome is an ectodermal dysplasia syndrome characterized by hair, skin and teeth anomalies, facial dysmophism with cleft lip and palate, cutaneous syndactyly and, in some cases, intellectual disability. ## Epidemiology The prevalence is unknown but to date, less than 50 cases have been described in the literature. The disorder is frequent on Margarita Island due to a founder effect. ## Clinical description Zlotogora-Ogur syndrome is a congenital disorder characterized by sparse and twisted hair (pili torti) and absent or sparse eyebrows, hypohidrosis, dry skin, palmoplantar keratoderma, abnormal teeth (delayed eruption, microdontia/hypodontia, and anodontia in adults), facial dysmophism (protruding and malformed ears, micrognathia, bilateral cleft lip and palate), cutaneous syndactyly (fingers and toes) and transverse crease on the palms. Onychodystrophy may be present. Additional features including intellectual disability, deafness, hypoplastic lacrimal puncta, nipple anomalies, genitourinary abnormalities (hypoplastic scrotum and presence of the testes in the inguinal canal), and lumbar lordosis may be observed. Zlotogora-Ogur syndrome and Margarita Island ectodermal dysplasia are the same entity. ## Etiology Zlotogora-Ogur syndrome is caused by mutations in the gene PVRL1 (11q23-q24) which encodes nectin-1, the principal receptor used by alpha-herpesviruses to mediate entry into human cells. Although the mechanism underlying the physiopathology of Zlotogora-Ogur syndrome is still unknown, it has been proposed that nectin-1 is a cell-cell adhesion molecule that is preferentially expressed in keratinocytes and that mutations in PVRL1 may abrogate NAP (nectin, afadin, ponsin)-dependent cell-cell adhesion. ## Genetic counseling Transmission is autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Cleft lip/palate-ectodermal dysplasia syndrome	c2931488	1,134	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3253	2021-01-23T17:33:12	{"gard": ["375"], "mesh": ["C536726"], "omim": ["225060"], "umls": ["C2931488"], "synonyms": ["CLPED1", "Cleft lip/palate-syndactyly-pili torti syndrome", "Syndactyly-ectodermal dysplasia-cleft/lip palate", "Zlotogora-Zilberman-Tenenbaum syndrome"]}
A number sign (#) is used with this entry because of evidence that anauxetic dysplasia-2 (ANXD2) is caused by homozygous or compound heterozygous mutation in the POP1 gene (602486) on chromosome 8q22. Description Anauxetic dysplasia is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability. Vertebrae are ovoid with concave dorsal surfaces in the lumbar region and show delayed bone maturation. Femoral heads and necks are hypoplastic, as are the iliac bodies. Long bones show irregular mineralization of the metaphyses. The first and fifth metacarpals are short and wide with small, late-ossifying epiphyses and bullet-shaped middle phalanges (summary by Barraza-Garcia et al., 2017). For a discussion of genetic heterogeneity of anauxetic dysplasia, see ANXD1 (607095). Clinical Features Glazov et al. (2011) studied 2 sisters with severe growth retardation of prenatal onset, a bone dysplasia affecting the epiphyses and metaphyses of the long bones, particularly in the lower limbs, and abnormalities of the spine including irregularly shaped vertebral bodies and marked cervical spine instability. X-rays at 13 months of age showed shortening of the tubular bones of the hand, with metaphyseal irregularities. The pubic bones were thin, and the iliac bodies were hypoplastic with slanting acetabular roofs. The capital femoral epiphyses were unossified and the femoral necks were hypoplastic and in varus position. The vertebral bodies were ovoid with dorsal wedging. There were metaphyseal irregularities at the knee and ankle, and the metaphyses of the distal tibiae were delta-shaped. Glazov et al. (2011) noted similarities to anauxetic dysplasia in the clinical and radiographic features of the affected sisters. Elalaoui et al. (2016) described a 5-year-old Moroccan boy with severe short stature who also exhibited thoracolumbar kyphoscoliosis and lumbosacral hyperlordosis, as well as facial dysmorphism involving midface hypoplasia and macroglossia. He had ligamentous laxity, with hypermobility of the hands and feet. Radiographs showed mild modification of vertebral bodies, hypoplastic ilia, small proximal femoral epiphyses, and metaphyseal dysplasia of the hip, knee, and wrist. Brachydactyly was striking, and middle and proximal phalanges were short, broad, and delta-shaped. These findings, together with unpublished photographs of the proband, were believed to be consistent with a diagnosis of anauxetic dysplasia. Barraza-Garcia et al. (2017) studied a 4.6-year old Moroccan girl and a 7-year-old Senegalese boy with skeletal dysplasia. The girl had short stature with short limbs at birth, and physical examination at 4.6 years of age showed relative macrocephaly, short neck, broad chest, hyperlordosis, brachydactyly, cubitus valgus with difficulties on extension, and prominent heels. Radiographic analysis showed mild irregularity of the vertebral endplates with posterior scalloping of the lower lumbar vertebral bodies, delayed ossification, hypoplastic femoral necks in valgus position, slightly widened iliac angle, irregular metaphyses of distal femur and proximal and distal tibiae, irregular metaphyses and cone-shaped epiphyses of all proximal and middle phalanges, and bullet-shaped middle phalanges. Examination of the boy at age 6 years showed sparse and apparently hypopigmented hair, hypodontia, and cubitus valgus with flexion contractures of the elbows. His hands were smaller when compared to the limbs, with pointed fingers and small, dysplastic nails. He had hip flexion deformity, kyphosis, and prominent heels. Radiologic analysis at 7 years of age showed bilateral coxa vara with short, broad, and bowed femora, flared metaphyses with irregular margins, and cupped distal tibial metaphyses. There was a chevron deformity of distal femoral epiphyses with premature fusion of the growth plates. He exhibited thoracolumbar scoliosis, tall vertebral bodies, posterior scalloping of lower thoracic and lumbar vertebral bodies, and relatively broad ribs. A clinical diagnosis of cartilage-hair hypoplasia (CHH; 250250) and/or ANXD was suspected, based on his extreme short stature, lumbar hyperlordosis and kyphoscoliosis, severe long-bone shortening with irregular metaphyses and deformed epiphyses, and brachydactyly with delayed carpal ossification. Psychomotor development was normal in the girl, but the boy showed cognitive developmental delay. Molecular Genetics In 2 sisters with anauxetic dysplasia, who were negative for mutation in the RMRP gene (157660), Glazov et al. (2011) performed exome sequencing and identified compound heterozygosity for a nonsense mutation (R513X; 602486.0001) and a missense mutation (G583E; 602486.0002) in the POP1 gene. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 186 controls or in public variant databases. In a 5-year-old Moroccan boy with anauxetic dysplasia, who was negative for mutation in the RMRP gene, Elalaoui et al. (2016) sequenced exons 11 and 13 of the POP1 gene looking for the previously reported R513X and G583E mutations. Neither of those mutations was found; however, they identified homozygosity for a different missense mutation in POP1 (P582S; 602486.0003), for which the proband's first-cousin unaffected parents were heterozygous. The variant was not found in 146 controls or in public variant databases, including dbSNP (build 131). In a 4.6-year-old Moroccan girl with severe short stature and relatively mild skeletal dysplasia, Barraza-Garcia et al. (2017) performed targeted next-generation sequencing and identified compound heterozygosity for mutations in the POP1 gene: the previously reported P582S variant and a 1-bp deletion (602486.0004). Her unaffected parents were each heterozygous for 1 of the mutations, which were not found in population databases. In a 7-year-old Senegalese boy with suspected ANXD, direct sequencing of POP1 revealed homozygosity for a missense mutation (D511Y; 602486.0005), found in heterozygosity in his unaffected parents, who were not of known consanguinity but originated from the same village. Barraza-Garcia et al. (2017) stated that these 2 patients exhibited the phenotypic extremes in the clinical presentation of POP1-associated dysplasia. INHERITANCE \- Autosomal recessive GROWTH Height \- Extreme short stature Other \- Growth retardation, prenatal onset HEAD & NECK Head \- Relative macrocephaly (in some patients) Face \- Midface hypoplasia Mouth \- Macroglossia (rare) Teeth \- Hypodontia (rare) Neck \- Short neck (rare) CHEST External Features \- Broad chest \- Prominent thorax SKELETAL \- Delayed bone age Spine \- Cervical spine instability (in some patients) \- Thoracolumbar kyphoscoliosis \- Lumbosacral hyperlordosis \- Ovoid vertebral bodies \- Dorsal wedging of vertebrae \- Posterior scalloping of lower thoracic and lumbar vertebral bodies Pelvis \- Hypoplastic iliac bodies \- Slanting or flaring acetabulae \- Coxa vara \- Coxa valga (in some patients) Limbs \- Hypoplastic femoral head \- Hypoplastic femoral neck \- Irregular metaphyseal mineralization \- Metaphyseal dysplasia of hip, knee, and wrist \- Delta-shaped or cupped metaphysis of distal tibia \- Cubitus valgus \- Flexion contracture of elbow \- Bowing of femur \- Bowing of ulna Hands \- Brachydactyly \- Metaphyseal irregularities of tubular bones \- Short broad bullet-shaped proximal and middle phalanges \- Cone-shaped epiphyses of proximal and middle phalanges \- Short and wide first and fifth metacarpals \- Small and late-ossifying epiphyses of first and fifth metacarpals Feet \- Prominent heels (in some patients) SKIN, NAILS, & HAIR Nails \- Small nails (rare) \- Dysplastic nails (rare) Hair \- Sparse hair (rare) \- Hypopigmented hair (rare) NEUROLOGIC Central Nervous System \- Mild intellectual disability (in some patients) MOLECULAR BASIS \- Caused by mutation in the POP1 homolog, ribonuclease P/MRP subunit gene (POP1, 602486.0001 ) ▲ 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	ANAUXETIC DYSPLASIA 2	c1846796	1,135	omim	https://www.omim.org/entry/617396	2019-09-22T15:45:54	{"mesh": ["C538256"], "omim": ["617396"], "orphanet": ["93347"]}
Intravascular papillary endothelial hyperplasia Other namesMasson's hemangio-endotheliome vegetant intravasculaire,[1] Masson's lesion,[1] Masson's pseudoangiosarcoma,[1] Masson's tumor,[1] and Papillary endothelial hyperplasia[1] SpecialtyOncology, rheumatology Intravascular papillary endothelial hyperplasia is a rare, benign tumor. It may mimic an angiosarcoma, with lesions that are red or purplish 5-mm to 5-cm papules and deep nodules on the head, neck, or upper extremities.[1][2]:592 ## Contents * 1 Pathology * 1.1 Histopathology Images * 2 See also * 3 References * 4 External links ## Pathology[edit] ### Histopathology Images[edit] * * * * * ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ a b c d e f 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; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. ## External links[edit] Classification D * ICD-10: D21 (ILDS D21.M20) * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Intravascular papillary endothelial hyperplasia	c0343083	1,136	wikipedia	https://en.wikipedia.org/wiki/Intravascular_papillary_endothelial_hyperplasia	2021-01-18T18:41:34	{"gard": ["10733"], "umls": ["C0343083"], "icd-10": ["D21"], "wikidata": ["Q6058576"]}
Neurocutaneous melanosis (NCM) is a rare, non-inherited condition of the central nervous system. It is characterized by melanocytic nevi in both the skin and the brain. Two-thirds of people with NCM have giant congenital melanocytic nevi, and the remaining one-third have numerous lesions but no giant lesions. The typical cutaneous lesions are present at birth. Neurological features typically present in the first or second year. Intracranial hypertension is the most common presentation, along with seizures, decreased alertness, and cranial nerve dysfunction.The underlying cause, while not completely understood, is believed to be a primary defect in the neural crest. Management depends on the symptoms present, and may include close observation, shunting to reduce intracranial pressure. The prognosis of patients with symptomatic neurocutaneous melanosis is generally poor, even in the absence of malignancy. Chemotherapy has been ineffective in the few patients in whom it has been tried. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neurocutaneous melanosis	c0544862	1,137	gard	https://rarediseases.info.nih.gov/diseases/7186/neurocutaneous-melanosis	2021-01-18T17:58:45	{"mesh": ["C537387"], "omim": ["249400"], "umls": ["C0544862"], "orphanet": ["2481"], "synonyms": ["Melanosis, neurocutaneous", "Neurocutaneous melanosis syndrome"]}
RAB18 deficiency causes two conditions with similar signs and symptoms that primarily affect the eyes, brain, and reproductive system. These two conditions, called Warburg micro syndrome and Martsolf syndrome, were once thought to be distinct disorders but are now considered to be part of the same disease spectrum because of their similar features and shared genetic cause. Warburg micro syndrome is the more severe condition. Individuals with this condition have several eye problems from birth, including clouding of the lenses of the eyes (cataracts), abnormally small eyes (microphthalmia), and small corneas (microcornea). The lens is a structure at the front of the eye that helps focus light, and the cornea is the outer covering of the eye. In addition, the pupils of the eyes may be abnormally small (constricted), and they may not enlarge (dilate) in low light. Individuals with Warburg micro syndrome also have degeneration of the nerves that carry visual information from the eyes to the brain (optic atrophy). The eye problems impair vision in affected individuals. People with Warburg micro syndrome have severe intellectual disability and other neurological features due to problems with growth and development of the brain. Affected individuals have delayed development and may never be able to sit, stand, walk, or speak. They usually have weak muscle tone (hypotonia) in infancy. By early childhood, they develop muscle stiffness (spasticity) and joint deformities (contractures) that restrict movement in the legs. The muscle problems worsen (progress) to include the arms and lead to paralysis of all four limbs (spastic quadriplegia). Eventually, breathing may be impaired. The brain abnormalities can contribute to vision problems (cortical visual impairment). Individuals with Warburg micro syndrome may also have recurrent seizures (epilepsy). Some people with Warburg micro syndrome have reduced production of the hormones that direct sexual development (hypogonadotropic hypogonadism). The shortage of these hormones impairs normal development of reproductive organs. Affected males may have a small penis (micropenis) or undescended testes (cryptorchidism). Affected females may have underdeveloped internal genital folds (labia minora) or a small clitoris or vaginal opening (introitus). Martsolf syndrome affects the same body systems as Warburg micro syndrome but is usually less severe. Individuals with Martsolf syndrome have cataracts, microphthalmia, and small pupils. They have milder optic atrophy and cortical visual impairment than people with Warburg micro syndrome. Intellectual disability is mild to moderate in people with Martsolf syndrome. While language and motor skills, such as sitting and walking, are delayed, affected individuals usually acquire them. Hypotonia is common in infants with Martsolf syndrome, although spasticity worsens more slowly than in individuals with Warburg micro syndrome, and it usually affects only the legs and feet. Hypogonadotropic hypogonadism can also occur in individuals with Martsolf syndrome. Neither Warburg micro syndrome nor Martsolf syndrome affect the life expectancy of affected individuals. ## Frequency RAB18 deficiency is rare; its exact prevalence is unknown. Warburg micro syndrome is more common than Martsolf syndrome. ## Causes RAB18 deficiency is caused by mutations in the RAB3GAP1, RAB3GAP2, RAB18, or TBC1D20 gene. RAB3GAP1 gene mutations are the most common cause of Warburg micro syndrome, although mutations in any of the genes can result in this condition. Mutations that cause Warburg micro syndrome completely eliminate the production or function of the protein produced from the gene. Martsolf syndrome is caused by mutations in the RAB3GAP2 gene or rarely the RAB3GAP1 gene. Mutations that result in Martsolf syndrome reduce but do not eliminate protein function. The RAB18 gene provides instructions for making the RAB18 protein. The RAB3GAP1, RAB3GAP2, and TBC1D20 genes provide instructions for making proteins that regulate the activity of this protein. The RAB3GAP1 and RAB3GAP2 proteins interact to form a complex that turns on RAB18. In contrast, the TBC1D20 protein turns off RAB18. When turned on, RAB18 regulates the movement of substances between compartments in cells and the storage and release of fats (lipids) by structures called lipid droplets. The protein also appears to play a role in a process called autophagy, which helps clear unneeded materials from cells. Mutations in the RAB18, RAB3GAP1, RAB3GAP2, or TBC1D20 gene are thought to disrupt RAB18 function. However, it is unclear why an absence or shortage (deficiency) of normal RAB18 activity leads to eye problems, brain abnormalities, and other features of Warburg micro syndrome or Martsolf syndrome. ### Learn more about the genes associated with RAB18 deficiency * RAB18 * RAB3GAP1 * RAB3GAP2 * TBC1D20 ## Inheritance Pattern RAB18 deficiency 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	RAB18 deficiency	c0796037	1,138	medlineplus	https://medlineplus.gov/genetics/condition/rab18-deficiency/	2021-01-27T08:24:45	{"gard": ["3406", "5534"], "mesh": ["C536028"], "omim": ["212720", "600118", "614225", "614222", "615663"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that isolated congenital digital clubbing can be caused by homozygous mutation in the 15-hydroxyprostaglandin dehydrogenase gene (HPGD; 601688) on chromosome 4q34. Description Digital clubbing is characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx (Myers and Farquhar, 2001). Clinical Features Weber (1919) reported 2 unrelated families and 1 unrelated individual with isolated clubbing of the digits. One family involved 2 otherwise healthy 25-year-old twin brothers who had clubbing of all digits in both hands; the toes were not affected. Their 30-year-old brother was said to have the same changes of the fingers, but their mother did not; their father was deceased. The proband of the second family was an otherwise healthy 25-year-old Irishman who had bilateral 'incurved nails' with clubbing of the fingers and toes 'ever since he could remember.' His father, 3 of his brothers, and 1 of his sisters were also said to have the condition. In addition, the author examined a 46-year-old man with psoriasis who had 'typical clubbing' of all his fingers, but not his toes, 'ever since he could remember;' no cause was found for the clubbing. Horsfall (1936) described 20 affected individuals from 3 unrelated multigenerational families with clubbing of the fingers, 10 of whom also had clubbing of the toes; all reported that the abnormality had been present from birth and remained fixed in degree with no progression or regression. The author examined 10 affected individuals, but found no organic lesion sufficient to account for the clubbing. The clubbing was uniformly in the form of a distal digital 'drumstick' or 'club-like enlargement' that was symmetric and bilateral, with the most extensive clubbing in the thumbs and great toes. In 2 affected females who were examined, not all digits were affected: both had bilateral involvement of the thumbs but sparing of the other fingers, and one had involvement only of the second and fourth toes, whereas in the other only the great toes were affected. X-rays of the hands and feet of the 3 probands revealed that the clubbing was apparently due to an increase in the soft tissues; there was also slight broadening of the tips of the terminal phalanges in 2 probands, but this was deemed insufficient to account for the clubbing, and the third proband had no bony changes. The author stated that there were no qualitative differences between the clubbing seen in these families and the clubbed fingers associated with pulmonary tuberculosis, lung abscess, bronchiectasis, and congenital heart disease, except for occasional cyanosis present in the latter group. Horsfall (1936) concluded that congenital clubbing is an inherited disorder that does not appear to be sex-linked. Fischer et al. (1964) reviewed both disease-associated and isolated congenital acropachy (clubbing) and reported 2 unrelated families with inherited clubbing. The first family involved white 21-year-old twin brothers who had symmetric clubbing of all fingers and the first and second toes, with the nail plate forming an angle of almost 180 degrees with the phalanx in affected digits. Physical examination was otherwise normal, and x-rays of the chest, hands, wrists, ankles, and feet were normal. The twins' paternal uncle also had symmetric clubbing of the fingers and toes, and their father and paternal grandmother were said to have marked clubbing of the fingers and toes. The proband of the second family was a 19-year-old black male who presented for evaluation of enlarged terminal digits of his hands and feet, particularly the thumbs and great toes, which he said had begun to enlarge 8 years previously at about the onset of puberty. He was healthy and examination was otherwise normal. Investigation of his family revealed that 11 of 24 paternal relatives and 6 of 12 maternal relatives were also affected; none had significant cardiopulmonary, hepatic, or gastrointestinal disease. The clubbing was generally first noted during puberty and progressed through adolescence and the early twenties and then stabilized; it never regressed. Of 7 prepubertal children examined, 4 had definite evidence of minimal clubbing. The clubbing in the maternal and paternal relatives, though prominent, was not as marked as in the proband, suggesting that he might be homozygous for the condition. In both families, the pattern of segregation suggested sex-limited autosomal dominant inheritance, with low penetrance for females. McKusick (1966) noted that familial clubbing might be more frequent in blacks than in whites, and that there was some uncertainty as to whether it was distinct from pachydermoperiostosis (167100). However, he stated that 'a particularly striking example of clubbing in a black father and 2 sons without accompanying features of pachydermoperiostosis leaves no doubt in my mind of the reality of this entity.' Diagnosis Myers and Farquhar (2001) analyzed 16 published reports of digital clubbing in which quantitative or qualitative assessment was described. The authors stated that clubbing, which is almost always painless, is caused by proliferation of connective tissue between the nail matrix and the distal phalanx, resulting in a nail-bed thickness of greater than 2.0 mm and a lower density of nail-bed connective tissue. On palpation of the base of the nail bed, there is 'sponginess' and the nail can appear to be 'floating' within the soft tissue. Myers and Farquhar (2001) recommended the use of the profile angle and phalangeal depth ratio as quantitative indices in identifying clubbing, and stated that when those values exceed 180 degrees and 1.0, respectively, clinical judgment must be exercised in determining the extent of further evaluation for underlying disease. Mapping Tariq et al. (2009) performed linkage analysis in a 6-generation consanguineous Pakistani family with isolated congenital clubbing, in which 11 affected members (4 males and 7 females) had bilateral symmetric clubbing in all fingernails and toenails with no associated abnormalities. Genomewide mapping revealed that all affected individuals were homozygous at marker D4S2368 on chromosome 4q32.3, where a maximum 2-point lod score of 2.98 (theta = 0.0) was obtained; a maximum multipoint lod score of 3.62 was achieved at several markers along the disease interval. Recombination events defined a 12.27-Mbp (13.25-cM) critical interval flanked by markers D4S2952 and D4S415. Molecular Genetics In a 6-generation consanguineous Pakistani family with isolated congenital clubbing mapping to chromosome 4q32.3, Tariq et al. (2009) sequenced 10 candidate genes and identified homozygosity for a missense mutation in the HPGD gene (S193P; 601688.0004) in affected individuals. Obligate carriers were heterozygous for the mutation, which was not found in 300 ethnically matched chromosomes. INHERITANCE \- Autosomal recessive SKELETAL Hands \- Digital clubbing \- Acropachy Feet \- Digital clubbing (in some patients) SKIN, NAILS, & HAIR Nails \- Incurved nails MOLECULAR BASIS \- Caused by mutation in the hydroxyprostaglandin dehydrogenase 15-(NAD) gene (HPGD, 119900.0004 ) ▲ 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	DIGITAL CLUBBING, ISOLATED CONGENITAL	c0345408	1,139	omim	https://www.omim.org/entry/119900	2019-09-22T16:43:08	{"mesh": ["D010004"], "omim": ["119900"], "orphanet": ["217059"], "synonyms": ["Alternative titles", "CLUBBING OF DIGITS", "ACROPACHY, HEREDITARY"]}
Factor VII deficiency is a rare bleeding disorder. The age of onset and severity varies from person to person. While severe cases may become apparent in infancy, very mild cases may never cause any bleeding problems. Signs and symptoms may include nosebleeds; easy bruising; bleeding gums; excessive or prolonged bleeding after injury or surgery; and heavy or prolonged menstrual bleeding in women. Some people with factor VII deficiency may have bleeding in the joints or blood in the urine. In very severe cases, factor VII deficiency can be life-threatening, causing bleeding inside the skull or digestive tract. Factor VII deficiency may be inherited or acquired. The inherited from is caused by mutations in the F7 gene and inheritance is autosomal recessive. The acquired form is not inherited and may be caused by liver disease, blood cell disorders, certain drugs, or vitamin K deficiency. Treatment for bleeding may include intravenous infusions of normal plasma, concentrated factor VII, or genetically-made (recombinant) factor VII. Those with acquired factor VII deficiency due to vitamin K deficiency may take vitamin K by mouth, injection, or infusion. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Factor VII deficiency	c0015503	1,140	gard	https://rarediseases.info.nih.gov/diseases/2238/factor-vii-deficiency	2021-01-18T18:00:36	{"mesh": ["D005168"], "omim": ["227500"], "umls": ["C0015503"], "orphanet": ["327"], "synonyms": ["Factor 7 deficiency", "F7 deficiency", "Hypoproconvertinemia", "Congenital proconvertin deficiency"]}
Cerebrospinal fluid (CSF) otorrhea is the leakage of cerebrospinal fluid (CSF) though the ear. It is a rare but very serious condition that requires rapid intervention. Symptoms include leak of clear fluid through the ear, inflammation of the membranes that cover the brain (meningitis), hearing loss, and seizures. The cause of a spinal fluid leak through the ear is a defect of the bone and meningeal layers covering the brain that separate the subarachnoid space of the brain from the middle ear and mastoid bone (located just behind the ear). The leaks occur after a surgery in the base of the skull, temporal bone fractures, congenital defects of the inner ear, trauma, or they may be spontaneous. Treatment depends on the cause and may include antibiotics, compression dressing and surgery. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Cerebrospinal fluid leak	c0023182	1,141	gard	https://rarediseases.info.nih.gov/diseases/10166/cerebrospinal-fluid-leak	2021-01-18T18:01:32	{"mesh": ["D065634"], "synonyms": ["CSF leak", "CSF rhinorrhea", "CSF otorrhea", "Spinal CSF leak"]}
A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 1A (DA1A) and type 2B4 (DA2B4) are caused by heterozygous mutation in the TPM2 gene (190990) on chromosome 9p13. Heterozygous mutation in the TPM2 gene can also cause nemaline myopathy-4 (NEM4; 609285), which shows similar features and may be identical to DA1A. Description In general, the distal arthrogryposes are a group of disorders characterized by contractures mainly involving the distal parts of the limbs. The hands have a characteristic position with medially overlapping fingers, clenched fists, ulnar deviation of fingers, and camptodactyly, and the feet have deformities. Contractures at other joints are variable; there are no associated visceral anomalies, and intelligence is normal. Bamshad et al. (1996) revised the classification by Hall et al. (1982) of the common mendelian arthrogryposis syndromes. The various phenotypic forms of distal arthrogryposis are classified hierarchically according to the proportion of features they share with one another and are designated DA1 through DA10 (summary by Bamshad et al., 2009). The prototypic distal arthrogryposis is type 1 (DA1), which is characterized largely by camptodactyly and clubfoot. Hypoplasia and/or absence of some interphalangeal creases is common. The shoulders and hips are less frequently affected. While the pattern of affected joints is consistent, the degree to which the joints are affected is highly variable, with equinovarus deformities ranging from mild to severe and hand involvement ranging from isolated hypoplasia of the distal interphalangeal crease of the fifth digit to severely clenched fists and ulnar deviation of the wrist (summary by Bamshad et al., 1996). Classically, DA was defined as being without overt neurologic or muscle disease (Lin et al., 1977 and Hall et al., 1982), although more recent evidence suggests that DA1A results from muscle dysfunction (Robinson et al., 2007; Mokbel et al., 2013; Davidson et al., 2013) (summary by Bamshad et al., 2009). The congenital contractures in distal arthrogryposis type 2B (Sheldon-Hall syndrome; see 601680) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by Bamshad et al., 2009). A review of patients diagnosed with DA1 or DA2B by Beck et al. (2013) found that the same mutation caused DA1 in some famlies and DA2B in others. There were no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. The authors suggested that DA1 and DA2B might represent phenotypic extremes of the same disorder. ### Genetic Heterogeneity of Distal Arthrogryposes Other forms of distal arthrogryposis include DA1B (614335), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; DA2A (Freeman-Sheldon syndrome, 193700), caused by mutation in the MYH3 gene (160720) on chromosome 17p13; DA2B1 (601680), caused by mutation in the TNNI2 gene (191043) on 11p15; DA2B2 (618435), caused by mutation in the TNNT3 gene (600692) on chromosome 11p15; DA2B3 (618436), caused by mutation in the MYH3 gene (160720) on chromosome 17p13; DA3 (Gordon syndrome, 114300) and DA5 (108145), caused by mutation in the PIEZO2 gene (613629) on chromosome 18p11; DA4 (609128), which has not been mapped; DA5D (615065), caused by mutation in the ECEL1 gene (605896) on chromosome 2q36; DA6 (108200); DA7 (158300), caused by mutation in the MYH8 gene (160741) on chromosome 17p13.1; DA9 (121050), caused by mutation in the FBN2 gene (612570) on chromosome 5q23; and DA10 (187370), which maps to chromosome 2q. Distal arthrogryposis-8 (DA8) has been reclassified as contractures, pterygia, and variable skeletal fusions syndrome-1A (CPSKF1A; 178110). See 277720 for discussion of a possible autosomal recessive form of DA2A. See 208155 for a description of Illum syndrome, which includes 'whistling face,' central nervous system dysfunction, and calcium deposition in central nervous system and muscle. There are other forms of arthrogryposis multiplex congenita (AMC), including a lethal congenital form (see LCCS1, 253310). Clinical Features ### Distal Arthrogryposis, Type 1A1 Bamshad et al. (1994) reported a large multigenerational family from Utah (family F) with distal arthrogryposis. One or more diagnostic features were present in all affected individuals. In the upper extremities, these features included ulnar deviation, camptodactyly, absent flexion creases, and overriding fingers. In the lower extremities, these features included metatarsus varus, talipes equinovarus, vertical talus, and a calcaneovalgus deformity. There was intrafamilial variability, and some patients also had hip dislocation. Bamshad et al. (1996) provided follow-up of family F. There were 15 affected family members showing marked variability in phenotypic expression. The most consistent features were overlapping fingers at birth, abnormal digital flexion creases, and foot deformities, including talipes equinovarus and vertical talus. The clinical severity varied from limited range of motion at the shoulders and small calves without foot deformities in 1 family member, to overlapping fingers, camptodactyly, abnormal flexion creases, ulnar deviation, bilateral talipes equinovarus, and bilateral dislocated hips in another family member. Five individuals had a small mouth and mild limitation in opening of the mouth. All affected family members had normal intelligence. Muscle weakness and/or atrophy were not mentioned. Bamshad et al. (1996) suggested that the findings in this family expanded the phenotypic range in DA1. ### Distal Arthrogryposis, Type 2B4 Tajsharghi et al. (2007) reported a mother and daughter, aged 65 and 28 years, with a form of distal arthrogryposis most consistent with type 2B. Both had presented with distal joint contractures at birth. At the time of examination, both complained of muscle weakness in proximal and distal muscles, most prominent in the hands and feet. Other notable features in both patients included hearing impairment, high-arched palate, short neck, short stature, contractures in proximal joints, smooth palms, and scoliosis. Neither had cardiac involvement. Muscle biopsies showed type 1 fiber predominance but no other major abnormalities. Ko et al. (2013) reported a Korean mother and daughter with distal arthrogryposis type 2B4. The proband was an infant who at birth showed camptodactyly, overlapping fingers, and adducted thumbs. She had a calcaneovalgus deformity with congenital vertical talus in the right foot and an equinovarus deformity in the left foot. She also displayed subtle facial dysmorphism, including a triangular face, downslanting palpebral fissures, and a small mouth. She had feeding difficulties and died at several months of age, presumably from aspiration pneumonia. The proband's 25-year-old mother had multiple congenital contractures of the distal limbs, camptodactyly with ulnar deviation of all fingers, and bilateral talocalcaneal coalition, with left clubfoot. She also had mild bilateral knee contractures. Facial features included a triangular face with downslanting palpebral fissures, low-set ears with attached earlobes, small mouth, high-arched palate, receding chin, prominent nasolabial folds, broad and long nasal bridge and root, and long philtrum. She had a short neck and sloping shoulders. She also had mild bilateral sensorineural hearing impairment. Electromyography revealed generalized myopathy with relative sparing of the slow-twitch muscle fibers. Mroczek et al. (2017) reported a female infant with congenital distal arthrogryposis, dysmorphic facial features, and myopathy. She required mechanical ventilation at birth and showed neither suck nor swallowing reflex. Dysmorphic features included hypertelorism, prominent eyes, hypertrichosis of the sacroiliac region, contractures of wrists, knees, fingers and toes, and bilateral clubfoot. She had persistent hypotonia. A muscle biopsy at age 7 months showed muscle fiber-type disproportion, with selective smallness of type 1 fibers. At age 13 months, she had contractures in the small joints of the hands and feet (with overlapping fingers and toes) as well as in the knee and at the hip joints, and she had reduced flexion of the wrist and elbow joint. She had an elongated face with bitemporal narrow forehead, low frontal hairline, short nose with depressed nasal bridge, underdeveloped nasolabial fold, and open mouth. She also had bilateral sensorineural hearing loss. She died suddenly at age 2 years and 8 months. Li et al. (2018) reported 5 affected members of a 4-generation Chinese family (family 1) segregating distal arthrogryposis type 2B of varying severity. The proband was a 59-year-old man with bilateral and symmetric congenital contractures of the distal limbs, including severe ulnar deviation, camptodactyly, adducted thumbs, and overlapping fingers. He also had short stature and minor facial anomalies, including a triangular face, downslanting palpebral fissures, and a small mouth. His 2 affected daughters had finger contractures, camptodactyly, and clubfeet. One daughter was pregnant, and ultrasound of her fetus indicated extended wrists, clenched fists, and bilateral clubfeet. Diagnosis ### Prenatal Diagnosis Baty et al. (1988) reported the prenatal diagnosis of distal arthrogryposis type I by ultrasound at 18 weeks' gestation in a family with 2 other affected members (mother and sister). The abnormality in the female infant was confirmed at birth. The diagnosis was based on the fact that the wrist remained extended and the fingers 'fisted' throughout a period of ultrasonic observation. Prenatal diagnosis in other forms of multiple joint contractures was reviewed. Inheritance The transmission pattern of DA1 in the family reported by Bamshad et al. (1994) was consistent with autosomal dominant inheritance. Mapping Using short tandem repeat (STR) polymorphisms in a genomewide search, Bamshad et al. (1994) mapped the DA1 gene to the pericentromeric region of chromosome 9 in a large kindred with distal arthrogryposis. Linkage analysis generated a lod score of 5.90 at theta = 0.0 with the marker GS-4. Analysis of an additional family demonstrated no linkage to the same locus, indicating probable locus heterogeneity. By 2-point linkage analysis in a Chinese family segregating DA2B, Li et al. (2018) found linkage of the disorder to chromosome 9p13, near the TPM2 gene. Molecular Genetics ### Distal Arthrogryposis, Type 1A In affected members of a large multigenerational family with DA1A (family K5), originally reported as family F by Bamshad et al. (1994) and linked to the pericentromeric region of chromosome 9, Sung et al. (2003) identified a heterozygous missense mutation in the TPM2 gene (R91G; 190990.0001). The findings indicated that this form of distal arthrogryposis has a myopathic origin, specifically in the contractile apparatus of fast-twitch myofibers. Functional studies of the variant and studies of patient cells were not performed. TPM2 mutations were not found in 13 additional probands with a similar disorder. ### Distal Arthrogryposis, Type 2B4 In a mother and daughter with a form of distal arthrogryposis most consistent with type 2B, Tajsharghi et al. (2007) identified a heterozygous mutation in the TPM2 gene (R133W; 190990.0004). In a Korean mother and daughter with distal arthrogryposis type 2B4, Ko et al. (2013) identified the same R133W mutation in the TPM2 gene that had been identified in an affected mother and daughter by Tajsharghi et al. (2007). In a female infant, born to unrelated parents, with congenital distal arthrogryposis, dysmorphic facial features, and myopathy, Mroczek et al. (2017) identified a de novo heterozygous splice site mutation in the TPM2 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the parents or in 100 healthy controls. In affected members of a Chinese family (family 1) segregating DA2B4, Li et al. (2018) identified heterozygosity for a missense mutation (Q103R; 190990.0010) in the TPM2 gene. The mutation was identified by linkage analysis and Sanger sequencing. Pathogenesis In in vitro studies, Robinson et al. (2007) demonstrated that the TPM2 R91G mutation (190990.0001) resulted in a gain of function with increased ATPase activity in actin-activated myosin ATPase assays, reflecting increased calcium sensitivity and consistent with increased contractility. Robinson et al. (2007) concluded that the mutation would cause increased tension in developing muscles, thus resulting in contractures and limb deformities via an active process rather than a passive process. These findings implicated disturbed muscle function as the pathogenic mechanism underlying DA1A. History Arthrogryposis is a highly heterogeneous category (Hall et al., 1977). The classic form of peripheral AMC, called amyoplasia by Hall et al. (1977), is always sporadic. Lacassie et al. (1977) and Sack (1978) reported a man who was born with limited flexion of all joints of the upper limbs and neck and with absent flexion creases of the fingers. Talipes equinovarus was corrected by bilateral triple arthrodeses and later Achilles tendon extensions. As an adult he was short with scoliosis and 4 symmetric dimples over the posterior ilia. Gaze, especially upward, was generally limited, and the muscles below the knees were atrophic. Intelligence was normal. His 2-year-old daughter showed the same findings. Muscle biopsy was normal. Daentl et al. (1974) described a father and his 2 daughters who had congenital contracture and deformity of the fingers, inguinal hernia, clubfoot, hip dislocation, small mandible, limitation of motion in the shoulders, elbows, wrist, knees and ankles, short neck, and elevated serum creatine phosphokinase. The authors reviewed familial forms of arthrogryposis and arthrogryposis-like disorders. McCormack et al. (1980) reported affected father, son and daughter. See digitotalar dysmorphism (126050). Hall et al. (1983) recognized a specific congenital contracture (arthrogryposis) syndrome in 135 of 350 patients with various kinds of congenital contractures. Always sporadic, this is the disorder that is usually meant when the term arthrogryposis multiplex congenita is used. Amyoplasia is the designation chosen by Hall et al. (1983) because absence of limb muscles, which are replaced by fibrous and fatty tissue, is the finding. At birth, characteristic positioning includes internal rotation at the shoulders, extension at the elbows, and flexion at the wrists. Severe equinovarus deformity of the feet is usually present. The face is typically round with a frontal midline capillary hemangioma and slightly small jaw. Intelligence is normal. About 63% had involvement of 4 limbs (usually symmetrically), 24% mainly of the lower limbs, and 13% mainly of the upper limbs. All cases are sporadic. Identical twins are always discordantly affected. Hall et al. (1983) found among 135 patients 11 who were the discordantly affected member of a pair of identical twins. As 8% of the total, this incidence seems to be a remarkable and probably biologically significant excess. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Face \- Retrognathia, mild \- Prominent nasolabial folds Ears \- Low-set ears \- Attached earlobes \- Sensorineural hearing loss, mild (in some patients) Eyes \- Ptosis (in 1 patient) Mouth \- Small mouth \- Impaired mouth opening Neck \- Webbed neck SKELETAL Spine \- Scoliosis Pelvis \- Congenital hip dislocation \- Hip flexion contractures \- Decreased hip abduction Limbs \- Elbow flexion contractures \- Knee contractures Hands \- Tightly clenched hands (visible on ultrasound) \- Camptodactyly \- Overlapping fingers \- Adducted thumbs \- Ulnar deviation \- Wrist contractures \- Contractures of small joints \- Absent distal interphalangeal creases \- Single transverse palmar crease Feet \- Talipes equinovarus (clubfoot) \- Talocalcaneal coalition, bilateral \- Overlapping toes \- Contractures of small joints SKIN, NAILS, & HAIR Skin \- Smooth palms MUSCLE, SOFT TISSUES \- Hypotonia \- Congenital fiber type disproportion (in 1 patient) MISCELLANEOUS \- Marked intrafamilial and interfamilial phenotypic variability \- Patients are variably described as having DA1A or DA2B \- Most frequently affected joints are the hands and feet MOLECULAR BASIS \- Caused by mutations in the tropomyosin 2 gene (TPM2, 190990.0001 ) ▲ 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	ARTHROGRYPOSIS, DISTAL, TYPE 1A	c1852085	1,142	omim	https://www.omim.org/entry/108120	2019-09-22T16:44:46	{"doid": ["0050646"], "mesh": ["C565097"], "omim": ["108120"], "orphanet": ["1146"], "synonyms": ["Alternative titles", "ARTHROGRYPOSIS, DISTAL, TYPE 1", "ARTHROGRYPOSIS MULTIPLEX CONGENITA, DISTAL, TYPE I"]}
Aldolase A deficiency Other namesALDOA deficiency, Red cell aldolase deficiency,[1] or Glycogen storage disease type 12 (GSD XII)[2] Aldolase A deficiency has an autosomal recessive pattern of inheritance SpecialtyEndocrinology Aldolase A deficiency, is an autosomal recessive[3] metabolic disorder resulting in a deficiency of the enzyme aldolase A; the enzyme is found predominantly in red blood cells and muscle tissue. The deficiency may lead to hemolytic anaemia as well as myopathy associated with exercise intolerance and rhabdomyolysis in some cases. ## Contents * 1 Symptoms and signs * 1.1 Anemia * 1.2 Myopathy * 1.3 Other * 2 Causes * 3 Diagnosis * 4 Management * 5 History * 6 References * 7 External links ## Symptoms and signs[edit] The low incidence of this syndrome is often related to aldolase A's essential glycolytic role along with its exclusive expression in blood and skeletal muscle.[4] Early developmental reliance and constitutive function prevents severe mutation in successful embryos.[5] Infrequent documentation thus prevents clear generalisation of symptoms and causes. However five cases have been well described.[4] ALDOA deficiency is diagnosed through reduced aldoA enzymatic activity, however, both physiological response and fundamental causes vary.[citation needed] Ethnicity Mutation Consanguinity Primary Symptoms Canadian Jewish Unknown Yes Dysmorphic features, Hemolytic anemia, Elevated liver glycogen, Stunted growth and development Japanese Unknown Probable Hemolytic anemia, Neonatal hyperbilirubinemia, Hepatomegaly, Splenomegaly Japanese 386 A:G (Asp128Gly) Probable Hemolytic anemia, Hepatomegaly, Splenomegaly German 619 G:A (Glu206Lys) No Hemolytic anemia, Rhabdomyolysis, Hyperbilirubinemia, Stunted growth and development Sicilian 931 C:T (Arg303X),1037 G:A (Cys 338Tyr) No Hemolytic anemia, Pyropoikilocytosis, Hyperkalemia, Jaundice, Rhabdomyolysis, Frequent infection ### Anemia[edit] Blood-related pathology is seen in all patients. Typically diagnosed at birth, congenital nonspherocytic hemolytic anemia is characterised by premature destruction of red blood cells without apparent abnormality in shape. Erythrocyte dependency on anaerobic glycolysis for ATP homeostasis, causes perturbation of this pathway to result in disruption of cellular processes including electrostatic membrane gradients (typically maintained through transporters of high energetic demand) ultimately leading to membrane instability and lysis.[4] Pathway summary: heme degradation to bilirubin This shortened erythrocyte life-span and increased destruction links to hyperbilirubinemia which often presents as jaundice in the accumulation of bilirubin through excessive hemoglobin breakdown. Another side effect of cellular rupture both in the form of hemolysis and rabdomyolysis is excessive plasma concentrations of electrolytes such as potassium. This can lead to hyperkalemia, potentially of great cardiac concern.[citation needed] Glycolysis also produces 2,3-diphosphoglycerate required to modulate hemoglobin's affinity for oxygen (2,3-Bisphosphoglycerate synthesis). Thus dysregulation of glycolysis is also implicated in the functional distribution of oxygen possibly leading to organ hypoxia. A complex pattern for this metabolite is suggested with discrepancy in findings. One Japanese patient had elevated levels,[6] while the original Jewish Canadian boy had below average concentration.[7] Glucose metabolism also links intrinsically to the pentose phosphate pathway in the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) necessary for synthetic processes and reduced glutathione involved in protecting red cells against oxidant damage. In particular increased fructose-1,6-bisphosphate accumulation can have inhibitory effects on glucose-6-phosphate dehydrogenase, an essential enzyme of this pathway.[6] Lactate accumulation has also been noted in some patients, potentially linked to reciprocal stimulation of pyruvate kinase, a key enzyme in lactic acid fermentation.[8] ### Myopathy[edit] In non-contiguous patients an aggravated form of adolase-a deficiency has been seen to manifest in muscular deterioration. This is often recognized initially through signs of muscle weakness and exercise intolerance, suggesting rapid muscular fatigue and damage, likely directly related to ATP depletion. This breakdown of muscular fibers or, rhabdomyolysis, can lead to detectable blood creatine phosphate level elevation [9] and potentially exaggerated hyperkalemia.[4] ### Other[edit] Delayed growth and development was noted in some patients, although not fully explained, this may be generally associated with the physiological difficulties implicit in errors of energy metabolism. In particular neurological impairment was conjecturally linked with the predominant role of aldolase A in the brain during development. However, this was not substantiated with direct enzymatic kinetic study.[10] Elevated liver glycogen in one patent was rationalised through an accumulation of fructose-1,6-bisphosphate leading to impaired glucose metabolism and increased diversion of hexose sugars from peripheral tissues. Within the liver the aldolase C isoform is unaffected and therefore hepatic metabolism is assumed to be normally functioning and compensatory processes may be operating.[10] Compromised immunity has also been indicated, relating to the predominance or exclusivity of aldolase A in leukocytes. This was correlated with recurrent infection in the Sicilian case.[4] Focal disruption of vital energy metabolism has thus far prevented complete investigation of non-catalytic perturbation. However relation to membrane structural stability has been implicated in the concurrence of aldolase A deficiency and dominant (mild) hereditary elliptocytosis, speculatively also relating to ATP depletion.[4] ## Causes[edit] Characterised as a recessive disorder, symptomatic presentation requires the inheritance of aldolase A mutations from both parents. This conclusion is substantiated through the continuum type presentation witnessed, wherein heterozygous parents have intermediate enzyme activity. Structural instability has been indicated in four of the patients, with particular sensitivity to increased temperature according to direct enzymatic testing. This is exemplified in the early diagnosis of hereditary pyropoikilocytosis in the Sicilian girl. Deterioration with fever is likewise congruent.[4] However, this direct relation has been disputed due to the increased overall metabolism and oxygen consumption also accompanying such maladies.[11] Sequence analysis has been conducted for three of the patients each revealing a distinct alteration at regions of typically high conservation. The conversion of the 128th aspartic acid to glycine causes conformational change according to CD spectral analysis and thermal lability in mutagenic analysis.[3][12] Similarly the charge disruption created through the exchange of the negatively charged glutamic acid for positively charged lysine (at residue 209 of the E helix) disrupts interface interaction of the protein's subunits and therein destabilises its native tetrahedral configuration.[9] The final case is unique in its non-homozygosity. A comparable maternal missense mutation wherein tyrosine is replaced by cysteine alters the carboxy-terminus due to its proximity to a crucial hinge structure. However, the paternal nonsense mutation at arginine 303 truncates the peptide. It is notable that Arg303 is required for enzymatic activity.[4] The initial 1973 case is atypical, in that no indication of aldolase A structural abnormality was found in isoelectric focusing, heat stabilization, electrophoresis or enzyme kinetics. It was concluded that either disordered regulation or a basic defect creating more rapid tetrameric inactivation were the most probable causes.[10] ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2016) ## Management[edit] This section is empty. You can help by adding to it. (December 2016) ## History[edit] The first recorded case of Aldolase A deficiency was described in 1973 (Beutler et al.) of a Jewish Canadian boy of Romanian descent. As his parents were first cousins, the presentation of dysmorphic features is conjecturally linked to confounding homozygosity at additional recessive loci. Inborn errors of metabolism are not typically associated with malformation and subsequent cases have lacked such physical manifestations.[7] In particular this leads to a complication for clearly delineating the effects of enzymatic aldolase-A deficiency.[citation needed] The two familial male patients reported in 1981 (having been born in 1967 and 1979) were from a small Japanese island indicating a similar possibility of consanguinity. However, unlike in the primary instance parental aldolase activity was also partially reduced without significant physiological ailment.[6] The other two cases documented in 1996 [9] and 2004 [4] lacked evidence for contiguity and deviated from previous findings in demonstration of additional myopathic complaints. The former boy's parents' and brother's aldolase activity's were half that of normal control values.[9] The Sicilian girl's mother had benign hereditary ellipocytosis, a dominant condition resulting in elongated erythrocytes, which was passed on to her. However, her father's blood count and smear produced normal findings.[4] ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 611881 2. ^ Orphanet: Glycogen storage disease due to aldolase A deficiency 3. ^ a b Kishi H, Mukai T, Hirono A, Fujii H, Miwa S, Hori K (1987). "Human aldolase A deficiency associated with a hemolytic anemia: Thermolabile aldolase due to a single base mutation". Proc. Natl. Acad. Sci. 84 (23): 8623–7. Bibcode:1987PNAS...84.8623K. doi:10.1073/pnas.84.23.8623. PMC 299598. PMID 2825199. 4. ^ a b c d e f g h i j Yao DC, Tolan DR, Murray MF, Harris DJ, Darras BJ, Geva A (2004). "Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutation of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr)". Blood. 103 (6): 2401–3. doi:10.1182/blood-2003-09-3160. PMID 14615364. 5. ^ Esposito G, Vitgliano L, Cevenini A, Amelio T, Zagari A, Salvatore F (2005). "Unraveling the structural and functional features of an aldolase A mutant involved in the hemolytic anemia and severe rhabdomyolysis reported in a child". Blood. 105 (2): 105–6. doi:10.1182/blood-2004-09-3558. PMID 15632214. 6. ^ a b c Miwa S, Fujii H, Tani K, Takahashi K, Takegawa S, Fujinami N, Sakurai M, Kubo M, Tanimoto Y, Kato T, Matsumoto N (1989). "Two cases of red cell aldolase deficiency associated with hereditary hemolytic anemia in a Japanese family". Am. J. Hematol. 11 (4): 425–37. doi:10.1002/ajh.2830110412. PMID 7331996. S2CID 22397286. 7. ^ a b Lowry RB, Hanson JW (1977). ""Aldolase A" deficiency with syndrome of growth and developmental retardation, midfacial hypoplasia, hematomegaly, and consanguineous parents". Birth Defects Org. Artic Ser. 13 (3B): 222–8. PMID 890096. 8. ^ Caspi R, Altman T, Dale JM, Dreher K, Fulcher CA, Gilham F, Kaipa P, Karthikeyan AS, Kothari A, Krummenacker M, Latendresse M, Mueller LA, Paley S, Popescu L, Pujar A, Shearer AG, Zhang P, Karp PD (2010). "The MetaCyc database of metabolic pathways and enzymes and the Biocyc collection of pathway/genome databases". Nucleic Acids Research. 38 (Database issue): D473–9. doi:10.1093/nar/gkp875. PMC 2808959. PMID 19850718. 9. ^ a b c d Kreuder J, Borkhardt A, Repp R, Perkrun A, Gottsche B, Gottschalk U, Reichmann H, Schachenmayr W, Schiegel K, Lampert F (1996). "Brief Report: Inherited Metabolic Myopathy and Hemolysis Due to a Mutation in Aldolase A". The New England Journal of Medicine. 334 (17): 1100–4. doi:10.1056/nejm199604253341705. PMID 8598869. 10. ^ a b c Beutler E, Scott S, Bishop A, Margolis F, Mastsumoto F, Kuhl W (1973). "Red Cell Aldolase Deficiency and Hemolytic Anemia: A New Syndrome". Trans. Assoc. Am. Physicians. 86: 154–66. PMID 4788792. 11. ^ Koop A, Bistrian BR (1996). "Inherited metabolic myopathy and hemolysis due to a mutation in aldolase A". The New England Journal of Medicine. 335 (16): 1242–3. doi:10.1056/NEJM199610173351618. PMID 8999331. 12. ^ Takasaki Y, Takahashi I, Mukai T, Hori K (1990). "Human Aldolase A of a Hemolytic Anemia Patient with Asp-128→Gly Substitution: Characteristics of an Enzyme Generated in E. coli Transinfected with the Expression Plasmid pHAAD128G". J. Biochem. 108 (2): 153–7. doi:10.1093/oxfordjournals.jbchem.a123174. PMID 2229018. ## External links[edit] * Media related to Aldolase A deficiency at Wikimedia Commons Classification D * ICD-10: E74.1 * OMIM: 611881 * MeSH: C562718 * DiseasesDB: 29873 External resources * Orphanet: 57 * v * t * e Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders Including glycogen storage diseases (GSD) Sucrose, transport (extracellular) Disaccharide catabolism * Congenital alactasia * Sucrose intolerance Monosaccharide transport * Glucose-galactose malabsorption * Inborn errors of renal tubular transport (Renal glycosuria) * Fructose malabsorption Hexose → glucose Monosaccharide catabolism Fructose: * Essential fructosuria * Fructose intolerance Galactose / galactosemia: * GALK deficiency * GALT deficiency/GALE deficiency Glucose ⇄ glycogen Glycogenesis * GSD type 0 (glycogen synthase deficiency) * GSD type IV (Andersen's disease, branching enzyme deficiency) * Adult polyglucosan body disease (APBD) Glycogenolysis Extralysosomal: * GSD type III (Cori's disease, debranching enzyme deficiency) * GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency) * GSD type V (McArdle's disease, myophosphorylase deficiency) * GSD type IX (phosphorylase kinase deficiency) Lysosomal (LSD): * GSD type II (Pompe's disease, glucosidase deficiency) Glucose ⇄ CAC Glycolysis * MODY 2/HHF3 * GSD type VII (Tarui's disease, phosphofructokinase deficiency) * Triosephosphate isomerase deficiency * Pyruvate kinase deficiency Gluconeogenesis * PCD * Fructose bisphosphatase deficiency * GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency) Pentose phosphate pathway * Glucose-6-phosphate dehydrogenase deficiency * Transaldolase deficiency * 6-phosphogluconate dehydrogenase deficiency Other * Hyperoxaluria * Primary hyperoxaluria * Pentosuria * Aldolase A deficiency * v * t * e 2,3-Bisphosphoglycerate synthesis, a Metabolic Pathway Fructose 1,6-bisphosphate Fructose-bisphosphate aldolase Dihydroxyacetone phosphate Glyceraldehyde 3-phosphate Triosephosphate isomerase Glyceraldehyde 3-phosphate Glyceraldehyde-3-phosphate dehydrogenase 1,3-Bisphosphoglycerate NAD+ + Pi NADH + H+ + 2 2 Bisphosphoglycerate mutase 2,3-Bisphosphoglycerate 2 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Aldolase A deficiency	c0272066	1,143	wikipedia	https://en.wikipedia.org/wiki/Aldolase_A_deficiency	2021-01-18T18:36:35	{"gard": ["600"], "mesh": ["C562718"], "umls": ["C0272066"], "icd-10": ["E74.1"], "orphanet": ["57"], "wikidata": ["Q4713937"]}
Nasopharyngeal carcinoma Other namesNasopharyngeal cancer, nasopharynx cancer, NPC Micrograph showing a nasopharyngeal carcinoma positive for Epstein-Barr virus-encoded small RNAs (EBER). SpecialtyOncology Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess (fossa of Rosenmüller), accounting for 50% of cases. NPC occurs in children and adults. NPC differs significantly from other cancers of the head and neck in its occurrence, causes, clinical behavior, and treatment. It is vastly more common in certain regions of East Asia and Africa than elsewhere, with viral, dietary and genetic factors implicated in its causation.[1] It is most common in males. It is a squamous cell carcinoma of an undifferentiated type. Squamous epithelial cells are a flat type of cell found in the skin and the membranes that line some body cavities. Differentiation means how different the cancer cells are from normal cells. Undifferentiated cells are cells that do not have their mature features or functions ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Classification * 3.2 Staging * 4 Risk factors * 4.1 EBV * 4.2 Smoking * 5 Treatment * 5.1 Radiation therapy * 5.2 Chemotherapy * 6 Surgery * 7 Epidemiology * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] See also: Trotter's syndrome NPC may present as a lump or a mass on both sides towards the back of the neck. These lumps usually are not tender or painful but appear as a result of the metastatic spread of the cancer to the lymph nodes, thus causing the lymph nodes to swell. Lymph nodes are defined as glands that function as part of the immune system and can be found throughout the body.[2] Swelling of the lymph nodes in the neck is the initial presentation in many people, and the diagnosis of NPC is often made by lymph node biopsy. Signs of nasopharyngeal cancer may appear as headaches, a sore throat, and trouble hearing, breathing, or speaking.[3] Additional symptoms of NPC include facial pain or numbness, blurred or double vision, trouble opening the mouth, or recurring ear infections. If the ear infection does not present with an upper respiratory tract infection, then an examination should be done on the nasopharynx. This is due to the fact that, in adults, ear infections are less common than in children.[4] Signs and symptoms related to the primary tumor include trismus, pain, otitis media, nasal regurgitation due to paresis (loss of or impaired movement) of the soft palate, hearing loss and cranial nerve palsy (paralysis). Larger growths may produce nasal obstruction or bleeding and a "nasal twang". Metastatic spread may result in bone pain or organ dysfunction. Rarely, a paraneoplastic syndrome of osteoarthropathy (diseases of joints and bones) may occur with widespread disease.[citation needed] ## Causes[edit] NPC is caused by a combination of factors: viral, environmental influences, and heredity.[5] The viral influence is associated with infection with Epstein-Barr virus (EBV).[6][7] The Epstein-Barr virus is one of the most common viruses. 95% of all people in the U.S. are exposed to this virus by the time they are 30–40 years old. The World Health Organization does not have set preventative measures for this virus because it is so easily spread and is worldwide. Very rarely does Epstein-Barr virus lead to cancer, which suggests a variety of influencing factors. Other likely causes include genetic susceptibility, consumption of food (in particular salted fish)[8] containing carcinogenic volatile nitrosamines.[9] Various mutations that activate NF-κB signalling have been reported in almost half of NPC cases investigated.[10] The association between Epstein-Barr virus and nasopharyngeal carcinoma is unequivocal in World Health Organization (WHO) types II and III tumors but less well-established for WHO type I (WHO-I) NPC, where preliminary evaluation has suggested that human papillomavirus (HPV) may be associated.[11] EBV DNA was detectable in the blood plasma samples of 96% of patients with non-keratinizing NPC, compared with only 7% in controls.[7] The detection of nuclear antigen associated with Epstein-Barr virus (EBNA) and viral DNA in NPC type 2 and 3, has revealed that EBV can infect epithelial cells and is associated with their transformation. The cause of NPC (particularly the endemic form) seems to follow a multi-step process, in which EBV, ethnic background, and environmental carcinogens all seem to play an important role. More importantly, EBV DNA levels appear to correlate with treatment response and may predict disease recurrence, suggesting that they may be an independent indicator of prognosis. The mechanism by which EBV alters nasopharyngeal cells is being elucidated[12] to provide a rational therapeutic target.[12] It is also being investigated as to whether or not chronic sinusitis could be a potential cause of cancer of the nasopharynx. It is hypothesised that this may happen in a way similar to how chronic inflammatory conditions in other parts of the body, such as esophagitis sometimes leading to Barrett's esophagus because of conditions such as gastroesophageal reflux disease.[13] ## Diagnosis[edit] ### Classification[edit] The World Health Organization (WHO) has identified three subtypes of nasopharyngeal carcinoma: * type 1: squamous cell carcinoma, typically found in older adults * type 2: non-keratinizing carcinoma * type 3: undifferentiated carcinoma Type 3 is most commonly found among younger children and adolescents, with a few type 2 cases. Both type 2 and 3 have been found to be associated with elevated levels of Epstein-Barr virus titers, but not type 1. Additionally, type 2 and type 3 may be followed with an influx of inflammatory cells, including lymphocytes, plasma cells, and eosinophils, generating the term lymphoepithelioma.[14] Nasopharyngeal carcinoma, also known as nasopharyngeal cancer, is classified as a malignant neoplasm, or cancer, arising from the mucosal epithelium of the nasopharynx, most often within the lateral nasopharyngeal recess or fossa of Rosenmüller (a recess behind the entrance of the eustachian tube opening). The World Health Organization classifies nasopharyngeal carcinoma in three types, in order of frequency: Non-keratinizing squamous cell carcinoma; keratinizing squamous cell carcinoma; and basaloid squamous cell carcinoma.[15] The tumor must show evidence of squamous differentiation, with the non-keratinizing type (also known as lymphoepithelioma) the tumor most strongly associated with Epstein-Barr virus infection of the cancerous cells.[16] * Undifferentiated nasopharyngeal carcinoma—low power * Undifferentiated nasopharyngeal carcinoma—med. power * Undifferentiated nasopharyngeal carcinoma—high power * Undifferentiated nasopharyngeal carcinoma—high power ### Staging[edit] FDG-PET/CT scan of a patient with nasopharyngeal cancer. Transverse slice demonstrating FDG-positive primary site Staging of nasopharyngeal carcinoma is based on clinical and radiologic examination. Most patients present with Stage III or IV disease. Stage I is a small tumor confined to nasopharynx. Stage II is a tumor extending in the local area, or that with any evidence of limited neck (nodal) disease. Stage III is a large tumor with or without neck disease, or a tumor with bilateral neck disease. Stage IV is a large tumor involving intracranial or infratemporal regions, an extensive neck disease, and/or any distant metastasis. [17] * Stage T1 nasopharyngeal cancer * Stage T2 nasopharyngeal cancer * Stage T3 nasopharyngeal cancer * Stage T4 nasopharyngeal cancer ## Risk factors[edit] Nasopharyngeal carcinoma, classified was a squamous cell cancer, has not been linked to excessive use of tobacco. However there are certain risk factors that can predispose an individual to NPC if exposed to them. These risk factors include: having Chinese, or Asian, ancestry, exposure to Epstein- Barr virus (EBV), unknown factors that result in rare familial clusters, and heavy alcohol consumption. [18] ### EBV[edit] Epstein- Barr virus infects and persists in more than 90% of world population. Transmission of this virus occurs through saliva and is more commonly seen in developing countries where there are living areas are more packed together and less hygienic. Replication of this virus can occur in the oropharyngeal epithelial tissue and nasopharyngeal tissue. EBV primarily targets B lymphocytes. Patients diagnosed with NPC were found to shown elevated levels of the antibodies against the EBV antigen than in individuals not diagnosed with NPC.[19] ### Smoking[edit] Individuals that are exposed to cigarette smoking have an increased risk of developing NPC by 2- to 6-fold. Approximately two-thirds of patients with type 1 NPC was attributed to smoking in the United States. However the declining rates of smoking in the US can be associated with less prevalence of type 1 NPC. In southern China and North Africa, it has been suggested that high smoking rates come from wood fires in the country rather than cigarette smoking. [19] ## Treatment[edit] NPC can be treated by surgery, by chemotherapy, or by radiotherapy.[20] There are different forms of radiation therapy, including 3D conformal radiation therapy, intensity-modulated radiation therapy, particle beam therapy and brachytherapy, which are commonly used in the treatments of cancers of the head and neck. The expression of EBV latent proteins within undifferentiated nasopharyngeal carcinoma can be potentially exploited for immune-based therapies.[21] Generally, there are three different types or treatment methods that can be used for patients with nasopharyngeal carcinoma. These three treatments are radiation therapy, chemotherapy, and surgery. Although there are currently three treatment methods, there are clinical trials taking place that may develop more effective treatments for NPC. A clinical trial is research study that works to develop new treatment techniques or to gain more information about or improve current methods. If an effective treatment comes out of the clinical trial, then this method may become a new standard treatment method. During the course of, or following, treatment, tests may be done in order to determine if the treatment is working, or if treatment needs to be dropped or changed. Tests that are done after treatment to determine the condition of patient after completing treatment are called follow-up tests and tell the doctor if the patients condition has changed or if the cancer has come back. [22] ### Radiation therapy[edit] Radiation therapy uses high energy x-rays or other types of radiation aimed to prevent cancer cells from growing or kill them altogether. This kind of therapy can be administered to the patient externally or internally. With external radiation, a machine is used to send targeted radiation to the cancer site. A mesh mask is used on the patenting order to keep their head and neck still while the machine rotates to send out beams of radiation. In undergoing this kind of treatment, healthy cells may also be damaged during the process. Therefore, there are 2 other forms of radiation therapy that decreases the likelihood of damaging nearby healthy cells: intensity-modulated radiation therapy and stereotactic radiation therapy. Intensity-modulated radiation therapy (IMRT) uses 3D images of the size and shape fo the tumor to then direct thin beams of radiation at different intensities from multiple angles. In stereotactic radiation therapy, radiation is aimed directly at the tumor. in this therapy, the total amount of radiation is divided into smaller does that will be given over the course of several days.[citation needed] Using radiation therapy as a cancer treatment method depends on the type and stage of cancer, however, internal and external radiation therapies can be used to treat NPC. If external radiation therapies are being aimed at the thyroid, then this could effect the way the thyroid works. For that reason, blood tests are done before and after radiation to check thyroid hormone levels. [22] ### Chemotherapy[edit] Chemotherapy works as cancer treatment by using drugs that stop the growth of cancer cells, by either killing the cells or preventing them from dividing. This kind of therapy can be administered systemically or regionally. Systemic chemotherapy is when the chemotherapy is taken orally or is injected into a vein or muscle. In this method, the drug circulates through the blood system and can reach cancer cells throughout the body. Regional chemotherapy is when chemotherapy is administered directly into the cerebrospinal fluid, an organ, or a body cavity, for example, the abdomen. In this way, the drugs will mainly affect cancer cells in that area. However, the type of chemotherapy that is administered to the patient depends on the type and stage of the cancer. Additionally, chemotherapy can be used as an adjuvant therapy after radiation to lower the risk of recurrence in the patient. If given after radiation, chemotherapy can be used to kill any cancer cells that may have remained. [22] ## Surgery[edit] Surgery can be used as a method to determine whether there is cancer present or to remove cancer from the body. If the tumor does not respond to radiation therapy, then the patient may undergo an operation to have it removed. Cancers that may have spread to the lymph nodes may require the doctor to remove lymph nodes or other tissue in the neck.[22] ## Epidemiology[edit] As of 2010, NPC resulted in 65,000 deaths globally up from 45,000 in 1990.[23] NPC is uncommon in the United States and most other nations, representing less than 1 case per 100,000 in most populations.[6] but is extremely common in southern regions of China,[24] particularly in Guangdong, accounting for 18% of all cancers in China.[9] It is sometimes referred to as Cantonese cancer (廣東癌) because it occurs in about 25 cases per 100,000 people in this region, 25 times higher than the rest of the world.[9] It is also quite common in Taiwan.[9] This could be due to the Southeast Asian diet[9] or that Southern Chinese people such as the Cantonese and Taiwanese have Southeast Asian ancestry (such as the proto-Kra-Dai speaking peoples and proto-Austronesian peoples) via ancient intermarriages with Han Chinese from Northeast Asia which led to the transmission of a genetic risk for nasopharynx cancer.[25] While NPC is seen primarily in middle-aged persons in Asia, a high proportion of African cases appear in children. The cause of increased risk for NPC in these endemic regions is not clear.[16] In low-risk populations, such as in the United States, a bimodal peak is observed. The first peak occurs in late adolescence/early adulthood (ages 15–24 years), followed by a second peak later in life (ages 65–79 years).[citation needed] ## See also[edit] * Baseball player Babe Ruth died from NPC in 1948. * Endoscopic nasopharyngectomy * Lymphoepithelioma-like carcinoma ## References[edit] 1. ^ https://cebp.aacrjournals.org/content/15/10/1765.short 2. ^ "Signs and Symptoms of Nasopharyngeal Cancer". www.cancer.org. Retrieved 2020-04-27. 3. ^ "Nasopharyngeal Cancer Treatment (Adult) (PDQ®)–Patient Version - National Cancer Institute". www.cancer.gov. 2020-04-13. Retrieved 2020-04-27. 4. ^ "Signs and Symptoms of Nasopharyngeal Cancer". www.cancer.org. Retrieved 2020-04-27. 5. ^ Zhang, F.; Zhang, J. (1999). "Clinical hereditary characteristics in nasopharyngeal carcinoma through Ye-Liang's family cluster". Chinese Medical Journal. 112 (2): 185–7. PMID 11593591. 6. ^ a b "Initiative for Vaccine Research (IVR): Viral cancers". World Health Organization. Archived from the original on 1 April 2019. Retrieved 2 October 2012. 7. ^ a b Lo, Kwok-Wai; Chung, Grace Tin-Yun; To, Ka-Fai (2012). "Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches". Seminars in Cancer Biology. 22 (2): 79–86. doi:10.1016/j.semcancer.2011.12.011. PMID 22245473. 8. ^ Yu, M. C.; Ho, J. H.; Lai, S. H.; Henderson, B. E. (1986). "Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: Report of a case-control study in Hong Kong". Cancer Research. 46 (2): 956–61. PMID 3940655. 9. ^ a b c d e Chang, E. T.; Adami, H.-O. (2006). "The Enigmatic Epidemiology of Nasopharyngeal Carcinoma". Cancer Epidemiology, Biomarkers & Prevention. 15 (10): 1765–1777. doi:10.1158/1055-9965.EPI-06-0353. PMID 17035381. 10. ^ Li, Yvonne Y.; Chung, Grace T. Y.; Lui, Vivian W. Y.; To, Ka-Fai; Ma, Brigette B. Y.; Chow, Chit; Woo, John K, S.; Yip, Kevin Y.; Seo, Jeongsun; Hui, Edwin P.; Mak, Michael K. F.; Rusan, Maria; Chau, Nicole G.; Or, Yvonne Y. Y.; Law, Marcus H. N.; Law, Peggy P. Y.; Liu, Zoey W. Y.; Ngan, Hoi-Lam; Hau, Pok-Man; Verhoeft, Krista R.; Poon, Peony H. Y.; Yoo, Seong-Keun; Shin, Jong-Yeon; Lee, Sau-Dan; Lun, Samantha W. M.; Jia, Lin; Chan, Anthony W. H.; Chan, Jason Y. K.; Lai, Paul B. S.; et al. (2017). "Exome and genome sequencing of nasopharynx cancer identifies NF-κB pathway activating mutations". Nature Communications. 8: 14121. Bibcode:2017NatCo...814121L. doi:10.1038/ncomms14121. PMC 5253631. PMID 28098136. 11. ^ Lo, Emily J.; Bell, Diana; Woo, Jason S.; Li, Guojun; Hanna, Ehab Y.; El-Naggar, Adel K.; Sturgis, Erich M. (2010). "Human papillomavirus and WHO type I nasopharyngeal carcinoma". The Laryngoscope. 120 (10): 1990–1997. doi:10.1002/lary.21089. PMC 4212520. PMID 20824783. 12. ^ a b Lo, Angela Kwok-Fung; Lo, Kwok-Wai; Ko, Chun-Wai; Young, Lawrence S.; Dawson, Christopher W. (2013). "Inhibition of the LKB1-AMPK pathway by the Epstein-Barr virus-encoded LMP1 promotes proliferation and transformation of human nasopharyngeal epithelial cells". The Journal of Pathology. 230 (3): 336–346. doi:10.1002/path.4201. PMID 23592276. S2CID 10765689. 13. ^ Tsou, YA; Lin, CC; Tai, CJ; Tsai, MH; Tsai, TC; Chen, CM (1 July 2014). "Chronic rhinosinusitis and the risk of nasopharyngeal cancer in a Taiwanese health study". American Journal of Rhinology and Allergy. 28 (4): 168–72. doi:10.2500/ajra.2014.28.4083. PMID 25197911. S2CID 30791737. 14. ^ Brennan, Bernadette (2006-06-26). "Nasopharyngeal carcinoma". Orphanet Journal of Rare Diseases. 1: 23. doi:10.1186/1750-1172-1-23. ISSN 1750-1172. PMC 1559589. PMID 16800883. 15. ^ Petersson BF, Bell D, El-Mofty SK, et al. (2017-01-23). Nasopharyngeal carcinoma: Tumours of the Nasopharynx, in World Health Organization Classification of Head and Neck Tumours (4th ed.). pp. 65–70. ISBN 978-92-832-2438-9. 16. ^ a b Cote, Richard; Suster, Saul; Weiss, Lawrence (2002). Weidner, Noel (ed.). Modern Surgical Pathology. London: W B Saunders. ISBN 978-0-7216-7253-3.[page needed] 17. ^ AJCC Cancer Staging Manual (7th ed.). New York, NY: Springer. 2010. pp. 41–56. 18. ^ PDQ Adult Treatment Editorial Board (2002), "Nasopharyngeal Cancer Treatment (Adult) (PDQ®): Health Professional Version", PDQ Cancer Information Summaries, National Cancer Institute (US), PMID 26389193, retrieved 2020-04-28 19. ^ a b Chang, Ellen T.; Adami, Hans-Olov (2006-10-01). "The Enigmatic Epidemiology of Nasopharyngeal Carcinoma". Cancer Epidemiology and Prevention Biomarkers. 15 (10): 1765–1777. doi:10.1158/1055-9965.EPI-06-0353. ISSN 1055-9965. PMID 17035381. 20. ^ Brennan, Bernadette (2006). "Nasopharyngeal carcinoma". Orphanet Journal of Rare Diseases. 1: 23. doi:10.1186/1750-1172-1-23. PMC 1559589. PMID 16800883. 21. ^ Khanna, Rajiv; Moss, Denis; Gandhi, Maher (2005). "Technology Insight: Applications of emerging immunotherapeutic strategies for Epstein–Barr virus-associated malignancies". Nature Clinical Practice Oncology. 2 (3): 138–149. doi:10.1038/ncponc0107. PMID 16264907. S2CID 7615720. 22. ^ a b c d "Nasopharyngeal Cancer Treatment (Adult) (PDQ®)–Patient Version - National Cancer Institute". www.cancer.gov. 2020-04-13. Retrieved 2020-04-27. 23. ^ Lozano, Rafael; Naghavi, Mohsen; Foreman, Kyle; Lim, Stephen; Shibuya, Kenji; Aboyans, Victor; Abraham, Jerry; Adair, Timothy; Aggarwal, Rakesh; Ahn, Stephanie Y.; Almazroa, Mohammad A.; Alvarado, Miriam; Anderson, H Ross; Anderson, Laurie M.; Andrews, Kathryn G.; Atkinson, Charles; Baddour, Larry M.; Barker-Collo, Suzanne; Bartels, David H.; Bell, Michelle L.; Benjamin, Emelia J.; Bennett, Derrick; Bhalla, Kavi; Bikbov, Boris; Abdulhak, Aref Bin; Birbeck, Gretchen; Blyth, Fiona; Bolliger, Ian; Boufous, Soufiane; et al. (2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010". The Lancet. 380 (9859): 2095–2128. doi:10.1016/S0140-6736(12)61728-0. hdl:10536/DRO/DU:30050819. PMID 23245604. S2CID 1541253. 24. ^ Fang, Weiyi; Li, Xin; Jiang, Qingping; Liu, Zhen; Yang, Huiling; Wang, Shuang; Xie, Siming; Liu, Qiuzhen; Liu, Tengfei; Huang, Jing; Xie, Weibing; Li, Zuguo; Zhao, Yingdong; Wang, Ena; Marincola, Francesco M.; Yao, Kaitai (2008). "Transcriptional patterns, biomarkers and pathways characterizing nasopharyngeal carcinoma of Southern China". Journal of Translational Medicine. 6: 32. doi:10.1186/1479-5876-6-32. PMC 2443113. PMID 18570662. 25. ^ Wee, J. T.; Ha, T. C.; Loong, S. L.; Qian, C. N. (2010). "Is nasopharyngeal cancer really a "Cantonese cancer"?". Chinese Journal of Cancer. 29 (5): 517–26. doi:10.5732/cjc.009.10329. PMID 20426903. Archived from the original on 2019-04-01. Retrieved 2018-10-16. ## External links[edit] Classification D * ICD-10: C11 * ICD-9-CM: 147 * OMIM: 161550 * MeSH: D009303 * DiseasesDB: 8814 External resources * eMedicine: ped/1553 * Cancer Management Handbook: Head and Neck Tumors * Clinically reviewed nasopharyngeal cancer information for patients from Cancer Research UK * v * t * e Cancer involving the respiratory tract Upper RT Nasal cavity Esthesioneuroblastoma Nasopharynx Nasopharyngeal carcinoma Nasopharyngeal angiofibroma Larynx Laryngeal cancer Laryngeal papillomatosis Lower RT Trachea * Tracheal tumor Lung Non-small-cell lung carcinoma * Squamous-cell carcinoma * Adenocarcinoma (Mucinous cystadenocarcinoma) * Large-cell lung carcinoma * Rhabdoid carcinoma * Sarcomatoid carcinoma * Carcinoid * Salivary gland–like carcinoma * Adenosquamous carcinoma * Papillary adenocarcinoma * Giant-cell carcinoma Small-cell carcinoma * Combined small-cell carcinoma Non-carcinoma * Sarcoma * Lymphoma * Immature teratoma * Melanoma By location * Pancoast tumor * Solitary pulmonary nodule * Central lung * Peripheral lung * Bronchial leiomyoma Pleura * Mesothelioma * Malignant solitary fibrous tumor * v * t * e Tumors of lip, oral cavity and pharynx / head and neck cancer Oral cancer Salivary gland malignant epithelial tumors * Acinic cell carcinoma * Mucoepidermoid carcinoma * Adenoid cystic carcinoma * Salivary duct carcinoma * Epithelial-myoepithelial carcinoma * Polymorphous low-grade adenocarcinoma * Hyalinizing clear cell carcinoma benign epithelial tumors * Pleomorphic adenoma * Warthin's tumor ungrouped: * Oncocytoma Tongue * Leukoplakia * Rhabdomyoma * Oropharynx * v * t * e Infectious diseases – viral systemic diseases Oncovirus DNA virus HBV Hepatocellular carcinoma HPV Cervical cancer Anal cancer Penile cancer Vulvar cancer Vaginal cancer Oropharyngeal cancer KSHV Kaposi's sarcoma EBV Nasopharyngeal carcinoma Burkitt's lymphoma Hodgkin lymphoma Follicular dendritic cell sarcoma Extranodal NK/T-cell lymphoma, nasal type MCPyV Merkel-cell carcinoma RNA virus HCV Hepatocellular carcinoma Splenic marginal zone lymphoma HTLV-I Adult T-cell leukemia/lymphoma Immune disorders * HIV * AIDS Central nervous system Encephalitis/ meningitis DNA virus Human polyomavirus 2 Progressive multifocal leukoencephalopathy RNA virus MeV Subacute sclerosing panencephalitis LCV Lymphocytic choriomeningitis Arbovirus encephalitis Orthomyxoviridae (probable) Encephalitis lethargica RV Rabies Chandipura vesiculovirus Herpesviral meningitis Ramsay Hunt syndrome type 2 Myelitis * Poliovirus * Poliomyelitis * Post-polio syndrome * HTLV-I * Tropical spastic paraparesis Eye * Cytomegalovirus * Cytomegalovirus retinitis * HSV * Herpes of the eye Cardiovascular * CBV * Pericarditis * Myocarditis Respiratory system/ acute viral nasopharyngitis/ viral pneumonia DNA virus * Epstein–Barr virus * EBV infection/Infectious mononucleosis * Cytomegalovirus RNA virus * IV: Human coronavirus 229E/NL63/HKU1/OC43 * Common cold * MERS coronavirus * Middle East respiratory syndrome * SARS coronavirus * Severe acute respiratory syndrome * SARS coronavirus 2 * Coronavirus disease 2019 * V, Orthomyxoviridae: Influenza virus A/B/C/D * Influenza/Avian influenza * V, Paramyxoviridae: Human parainfluenza viruses * Parainfluenza * Human orthopneumovirus * hMPV Human digestive system Pharynx/Esophagus * MuV * Mumps * Cytomegalovirus * Cytomegalovirus esophagitis Gastroenteritis/ diarrhea DNA virus Adenovirus Adenovirus infection RNA virus Rotavirus Norovirus Astrovirus Coronavirus Hepatitis DNA virus HBV (B) RNA virus CBV HAV (A) HCV (C) HDV (D) HEV (E) HGV (G) Pancreatitis * CBV Urogenital * BK virus * MuV * Mumps [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Nasopharyngeal carcinoma	c2750548	1,144	wikipedia	https://en.wikipedia.org/wiki/Nasopharyngeal_carcinoma	2021-01-18T18:46:22	{"gard": ["7163"], "mesh": ["D000077274"], "umls": ["C2750548"], "orphanet": ["150"], "wikidata": ["Q1693598"]}
Medical condition in which gallstones cause acute pain Biliary colic Other namesGallstone attack, gallbladder attack Biliary colic is often related to a stone in the gallbladder SpecialtyGastroenterology Biliary colic, also known as symptomatic cholelithiasis, a gallbladder attack or gallstone attack, is when a colic (sudden pain) occurs due to a gallstone temporarily blocking the cystic duct.[1] Typically, the pain is in the right upper part of the abdomen.[2] Pain usually lasts from 15 minutes to a few hours.[1] Often, it occurs after eating a heavy meal, or during the night.[1] Repeated attacks are common.[3] Gallstone formation occurs from the precipitation of crystals that aggregate to form stones. The most common form is cholesterol gallstones.[4] Other forms include calcium, bilirubin, pigment, and mixed gallstones.[4] Other conditions that produce similar symptoms include appendicitis, stomach ulcers, pancreatitis, and gastroesophageal reflux disease.[1] Treatment for gallbladder attacks is typically surgery to remove the gallbladder.[1] This can be either done through small incisions or through a single larger incision.[1] Open surgery through a larger incision is associated with more complications than surgery through small incisions.[5] Surgery is typically done under general anesthesia.[1] In those who are unable to have surgery, medication to try to dissolve the stones or shock wave lithotripsy may be tried.[1] As of 2017,[update] it is not clear whether surgery is indicated for everyone with biliary colic.[5] In the developed world, 10 to 15% of adults have gallstones.[3] Of those with gallstones, biliary colic occurs in 1 to 4% each year.[3] Nearly 30% of people have further problems related to gallstones in the year following an attack.[3] About 15% of people with biliary colic eventually develop inflammation of the gallbladder if not treated.[3] Other complications include inflammation of the pancreas.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Risk factors * 3 Diagnosis * 4 Management * 4.1 Medications * 4.2 Surgery * 5 Complications * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Pain is the most common presenting symptom. It is usually described as sharp right upper quadrant pain that radiates to the right shoulder, or less commonly, behind the breastbone.[6] Nausea and vomiting can be associated with biliary colic. Individuals may also present with pain that is induced following a fatty meal and the symptom of indigestion. The pain often lasts longer than 30 minutes, up to a few hours.[6] Patients usually have normal vital signs with biliary colic, whereas patients with cholecystitis are usually febrile and more ill appearing. Lab studies that should be ordered include a complete blood count, liver function tests and lipase. In biliary colic, lab findings are usually within normal limits. Alanine aminotransferase and aspartate transaminase are usually suggestive of liver disease whereas elevation of bilirubin and alkaline phosphatase suggests common bile duct obstruction.[7] Pancreatitis should be considered if the lipase value is elevated; gallstone disease is the major cause of pancreatitis. ## Causes[edit] Biliary pain is most frequently caused by obstruction of the common bile duct or the cystic duct by a gallstone. However, the presence of gallstones is a frequent incidental finding and does not always necessitate treatment, in the absence of identifiable disease. Furthermore, biliary pain may be associated with functional disorders of the biliary tract, so called acalculous biliary pain (pain without stones), and can even be found in patients post-cholecystectomy (removal of the gallbladder), possibly as a consequence of dysfunction of the biliary tree and the sphincter of Oddi. Acute episodes of biliary pain may be induced or exacerbated by certain foods, most commonly those high in fat.[8] ### Risk factors[edit] Cholesterol gallstone formation risk factors include age, female sex, family history, race,[6][9] pregnancy, parity, obesity, hormonal birth control, diabetes mellitus, cirrhosis, prolonged fasting, rapid weight loss, total parenteral nutrition, ileal disease and impaired gallbladder emptying.[10] Patients that have gallstones and biliary colic are at increased risk for complications, including cholecystitis.[11] Complications from gallstone disease is 0.3% per year and therefore prophylactic cholecystectomy are rarely indicated unless part of a special population that includes porcelain gallbladder, individuals eligible for organ transplant, diabetics and those with sickle cell anemia.[6] ## Diagnosis[edit] Diagnosis is guided by the person's presenting symptoms and laboratory findings. The gold standard imaging modality for the presence of gallstones is ultrasound of the right upper quadrant. There are many reasons for this choice, including no exposure to radiation, low cost, and availability in city, urban, and rural hospitals. Gallstones are detected with a specificity and sensitivity of greater than 95% with ultrasound.[12][page needed] Further signs on ultrasound may suggest cholecystitis or choledocholithiasis.[13] Computed Tomography (CT) is not indicated when investigating for gallbladder disease as 60% of stones are not radiopaque.[13] CT should only be utilized if other intra-abdominal pathology exists or the diagnosis is uncertain.[14] Endoscopic retrograde cholangiopancreatography (ERCP) should be used only if lab tests suggest the existence of a gallstone in the bile duct.[13] ERCP is then both diagnostic and therapeutic. ## Management[edit] ### Medications[edit] Initial management includes the relief of symptoms and correcting electrolyte and fluid imbalance that may occur with vomiting.[7] Antiemetics, such as dimenhydrinate, are used to treat the nausea.[7] Pain may be treated with anti-inflammatories, NSAIDs such as ketorolac or diclofenac.[15] Opioids, such as morphine, less commonly may be used.[16] NSAIDs are more or less equivalent to opioids.[17] Hyoscine butylbromide, an antispasmodic, is also indicated in biliary colic.[18] In biliary colic, the risk of infection is minimal and therefore antibiotics are not required.[19] Presence of infection indicates cholecystitis.[19] ### Surgery[edit] It is unclear whether those experiencing a gallstone attack should receive surgical treatment or not.[5] The scientific basis to assess whether surgery outperformed other treatment was insufficient and better studies were needed as of a SBU report in 2017.[5] Treatment of biliary colic is dictated by the underlying cause.[citation needed] The presence of gallstones, usually visualized by ultrasound, generally necessitates a surgical treatment (removal of the gall bladder, typically via laparoscopy).[citation needed] Removal of the gallbladder with surgery, known as a cholecystectomy, is the definitive surgical treatment for biliary colic.[citation needed] A 2013 Cochrane review found tentative evidence to suggest that early gallbladder removal may be better than delayed removal.[20] Early laparoscopic cholescystectomy happens within 72 hours of diagnosis.[13] In a Cochrane review that evaluated receiving early versus delayed surgery, they found that 23% of those who waited on average 4 months ended up in hospital for complications, compared to none with early intervention with surgery.[13][20] Early intervention has other advantages including reduced number of visits to the emergency department, fewer conversions to an open surgery, less operating time required, and reduced time in hospital post operatively.[13] The Swedish agency SBU estimated in 2017 that increasing acute phase surgeries could free multiple in-hospital days per patient and would additionally spare pain and suffering in wait of receiving an operation.[5] The report found that those with acute inflammation of the gallbladder can be surgically treated in the acute phase, within a few days of symptom debut, without increasing the risk for complications (compared to when the surgery is done later in an asymptomatic stage).[5] ## Complications[edit] The presence of gallstones can lead to inflammation of the gallbladder (cholecystitis) or the biliary tree (cholangitis) or acute inflammation of the pancreas (pancreatitis). Rarely, a gallstone can become impacted in the ileocecal valve that joins the caecum and the ileum, causing gallstone ileus (mechanical ileus).[6] Complications from delayed surgery include pancreatitis, empyema, and perforation of the gallbladder, cholecystitis, cholangitis, and obstructive jaundice.[13] Biliary pain in the absence of gallstones, known as postcholecystectomy syndrome, may severely affect the patient's quality of life, even in the absence of disease progression.[21] ## Epidemiology[edit] The annual risk of developing biliary colic is 2 to 3%.[6][11] ## References[edit] 1. ^ a b c d e f g h "Gallstones". NIDDK.NIH.gov. Washington DC: National Institute of Diabetes and Digestive and Kidney Diseases. November 2013. Archived from the original on 16 August 2016. Retrieved 27 July 2016. 2. ^ Internal Clinical Guidelines Team (October 2014). "Gallstone Disease: Diagnosis and Management of Cholelithiasis, Cholecystitis and Choledocholithiasis". NICE.org: 21. PMID 25473723. Clinical Guideline 188. Retrieved 24 June 2018. 3. ^ a b c d e f Ansaloni, L. (2016). "2016 WSES guidelines on acute calculous cholecystitis". World Journal of Emergency Surgery : WJES. 11: 25. doi:10.1186/s13017-016-0082-5. PMC 4908702. PMID 27307785. 4. ^ a b Sabiston, David C.; Townsend, Courtney M. (2012). Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. Philadelphia: Elsevier/Saunders. pp. 328–358. ISBN 978-1-4377-1560-6. 5. ^ a b c d e f "Surgery to treat gallstones and acute inflammation of the gallbladder". SBU.se. Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU). 2016-12-16. Retrieved 2017-06-01. 6. ^ a b c d e f Portincasa, P.; Moschetta, A.; Petruzzelli, M.; Palasciano, G.; Di Ciaula, A.; Pezzolla, A. (2006). "Gallstone disease: Symptoms and diagnosis of gallbladder stones". Best Practice & Research: Clinical Gastroenterology. 20 (6): 1017–1029. doi:10.1016/j.bpg.2006.05.005. PMID 17127185. 7. ^ a b c Rosen, Peter; Marx, John A. (2013). Rosen's Emergency Medicine: Concepts and Clinical Practice. Philadelphia: Elsevier/Saunders. pp. 1186–1206. ISBN 978-1-4557-0605-1. 8. ^ Rodriguez, Diana. "When Gallbladder Problems Lead to Biliary Colic". Everyday Health. 9. ^ Stinton, Laura M.; Shaffer, Eldon A. (15 April 2012). "Epidemiology of Gallbladder Disease: Cholelithiasis and Cancer". Gut and Liver. 6 (2): 172–187. doi:10.5009/gnl.2012.6.2.172. PMC 3343155. PMID 22570746. 10. ^ Walton, Thomas J.; Lobo, Dileep N. (2009). "Gallstones". Surgery. 27 (1): 19–24. doi:10.1016/j.mpsur.2008.12.001. 11. ^ a b Afdhal, Nezam H. (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier/Saunders. pp. 1011–1020. ISBN 978-1-4377-1604-7. 12. ^ Fischer, J. E., ed. (2007). Master of Surgery (5th ed.). Philadelphia: Lippincott Williams & Wilkins. 13. ^ a b c d e f g Duncan, C. B.; Riall, T. S. (Nov 2012). "Evidence-based current surgical practice: calculous gallbladder disease". Journal of Gastrointestinal Surgery. 16 (11): 2011–2025. doi:10.1007/s11605-012-2024-1. PMC 3496004. PMID 22986769. 14. ^ Shakespear, J. S.; Shaaban, A. M.; Rezvani, M. (2010). "CT findings of acute cholecystitis and its complications". American Journal of Roentgenology. 194 (6): 1523–1529. doi:10.2214/ajr.09.3640. PMID 20489092. 15. ^ Fraquelli, M.; Casazza, G.; Conte, D.; Colli, A. (9 September 2016). "Non-steroid anti-inflammatory drugs for biliary colic". The Cochrane Database of Systematic Reviews. 9: CD006390. doi:10.1002/14651858.CD006390.pub2. PMC 6457716. PMID 27610712. 16. ^ Rosen, Peter; Marx, John A. (2013). Rosen's Emergency Medicine: Concepts and Clinical Practice. Philadelphia: Elsevier/Saunders. pp. 223–233. ISBN 978-1-4557-0605-1. 17. ^ Colli, A.; Conte, D.; Valle, S. D.; Sciola, V.; Fraquelli, M. (June 2012). "Meta-analysis: nonsteroidal anti-inflammatory drugs in biliary colic". Alimentary Pharmacology & Therapeutics. 35 (12): 1370–1378. doi:10.1111/j.1365-2036.2012.05115.x. PMID 22540869. 18. ^ "Hyoscine butylbromide (Buscopan) injection: Risk of serious adverse effects in patients with underlying cardiac disease". Gov.uk. Retrieved 23 September 2017. 19. ^ a b Cecil, Russell L. (Russell La Fayette); Goldman, Lee; Schafer, Andrew I. (2012). Goldman's Cecil Medicine. Philadelphia: Elsevier/Saunders. pp. 1011–1021. ISBN 978-1-4377-1604-7. 20. ^ a b Gurusamy, K. S.; Koti, R.; Fusai, G.; Davidson, B. R. (2013). "Early versus delayed laparoscopic cholecystectomy for uncomplicated biliary colic". Cochrane Database Syst Rev. 6 (6): CD007196. doi:10.1002/14651858.CD007196.pub3. PMID 23813478. 21. ^ Postcholecystectomy Syndrome at eMedicine ## External links[edit] Classification D * ICD-10: K80.5 * ICD-9-CM: 574.20 * DiseasesDB: 2533 External resources * eMedicine: med/224 * Diagram of pain radiation * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Biliary colic	c0151824	1,145	wikipedia	https://en.wikipedia.org/wiki/Biliary_colic	2021-01-18T19:03:28	{"icd-9": ["574.20"], "icd-10": ["K80.5"], "wikidata": ["Q2727106"]}
Plexopathy is a disorder affecting a network of nerves, blood vessels, or lymph vessels.[1] The region of nerves it affects are at the brachial or lumbosacral plexus. Symptoms include pain, loss of motor control, and sensory deficits.[2] ## Contents * 1 Types * 2 Cause * 3 Diagnosis * 4 Treatment * 5 See also * 6 References ## Types[edit] There are two main types of plexopathy: brachial plexopathy and lumbosacral plexopathy. ## Cause[edit] They are usually caused from some sort of localized trauma such as a dislocated shoulder. The disorder can also be caused secondary to a compression, co-morbid vascular disease, infection, or may be idiopathic with an unknown cause.[2] Both plexopathies can also occur as a consequence of radiation therapy,[3] sometimes after 30 or more years have passed, in conditions known as Radiation-induced Brachial Plexopathy (RIBP)[4] and Radiation-induced Lumbosacral Plexopathy (RILP).[5] ## Diagnosis[edit] The first steps in the evaluation and later management of plexopathy would consist of gathering a medical history and conducting a physical examination by a healthcare clinician. Motor function defect patterns detected within either the upper or lower extremities help with diagnosis of the disorder.[2] X-rays of the cervical spine, chest, and shoulder are usually ordered if symptoms point to acute Brachial plexopathy. If the physical history reveals a history of diabetes, collagen vascular disease, or symptoms of infection, the physician may order a series of blood tests including a complete blood count (CBC) and a comprehensive metabolic panel (CMP).[2] Plexopathy symptoms often resemble spinal cord disorders.[6] A neurosurgical consultation is usually undertaken to ensure proper diagnosis, management, and treatment. Patients with chronic symptoms will likely be advised to follow up with outpatient care from either their health care provider or specialist.[2] ## Treatment[edit] Mild cases are usually treated by the administration of analgesia and muscle relaxers. Reduced and limited physical activity with repeated follow-ups with the health care provider are required for one diagnosed with plexopathy. Individuals with prolonged, chronic symptoms will require additional testing and treatment.[2] With brachial plexopathy, surgical decompression may be warranted if the pathophysiology of the disease is causing pressure on the affected nerves. In some cases of brachial plexopathy, no treatment is required and recovery happens on its own.[7] Treatment for lumbosacral plexopathy that is not caused by trauma, but instead from diabetic plexopathy, is directed at controlling the person's blood sugar level. By preventing the deterioration of the nerve fibers from hyperglycemia, patients may recover significant muscle strength.[8] For radiation-induced plexopathies, treatment options are limited to pain/symptom management and provision of assistive devices. ## See also[edit] * plexus * nerve plexus * radiculopathy ## References[edit] 1. ^ Plexopathy entry in the public domain NCI Dictionary of Cancer Terms 2. ^ a b c d e f Allan B. Wolfson, ed. (2005). Harwood-Nuss' Clinical Practice of Emergency Medicine (4th ed.). pp. 614–615. ISBN 0-7817-5125-X. 3. ^ "Radiation plexopathy - Introduction". www.medmerits.com. Retrieved 2016-03-03. 4. ^ "Radiation-Induced Brachial Plexopathy: Background, Pathophysiology, Epidemiology". Cite journal requires `\|journal=` (help) 5. ^ "Radiation-Induced Lumbosacral Plexopathy: Background, Pathophysiology, Epidemiology". Cite journal requires `\|journal=` (help) 6. ^ Dyck, PJ; Thomas, PK (1993). Peripheral Neuropathy (3rd ed.). Philadelphia: WB Sanders. 7. ^ "Brachial Plexopathy". Health Guide. The New York Times. 2009-12-09. Retrieved 10 December 2009. 8. ^ "Lumbosacral Plexopathies: Diagnosis and rehabilitation". BNET. CBS Interactive Inc. 1999. Retrieved 10 December 2009. This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms". * v * t * e Diseases relating to the peripheral nervous system Mononeuropathy Arm median nerve * Carpal tunnel syndrome * Ape hand deformity ulnar nerve * Ulnar nerve entrapment * Froment's sign * Ulnar tunnel syndrome * Ulnar claw radial nerve * Radial neuropathy * Wrist drop * Cheiralgia paresthetica long thoracic nerve * Winged scapula * Backpack palsy Leg lateral cutaneous nerve of thigh * Meralgia paraesthetica tibial nerve * Tarsal tunnel syndrome plantar nerve * Morton's neuroma superior gluteal nerve * Trendelenburg's sign sciatic nerve * Piriformis syndrome Cranial nerves * See Template:Cranial nerve disease Polyneuropathy and Polyradiculoneuropathy HMSN * Charcot–Marie–Tooth disease * Dejerine–Sottas disease * Refsum's disease * Hereditary spastic paraplegia * Hereditary neuropathy with liability to pressure palsy * Familial amyloid neuropathy Autoimmune and demyelinating disease * Guillain–Barré syndrome * Chronic inflammatory demyelinating polyneuropathy Radiculopathy and plexopathy * Brachial plexus injury * Thoracic outlet syndrome * Phantom limb Other * Alcoholic polyneuropathy Other General * Complex regional pain syndrome * Mononeuritis multiplex * Peripheral neuropathy * Neuralgia * Nerve compression syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Plexopathy	c1335437	1,146	wikipedia	https://en.wikipedia.org/wiki/Plexopathy	2021-01-18T18:53:05	{"umls": ["C1335437"], "wikidata": ["Q7204901"]}
A number sign (#) is used with this entry because of evidence that some cases of preaxial polydactyly type IV are caused by heterozygous mutation in the GLI3 gene (165240) on chromosome 7p14. Description Although both preaxial polydactyly and syndactyly are cardinal features of this malformation, it is classified as a form of polydactyly because syndactyly does not occur in the absence of polydactyly (McClintic, 1935), the opposite not being true. On the other hand, polysyndactyly is here classified as a type of syndactyly because polydactyly (of the third or fourth fingers and fifth toes) does not occur in the absence of syndactyly. The thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. The foot malformation is more constant and consists of duplication of part or all of the first or second toes and syndactyly affects all of the toes, especially the second and third. Clinical Features Thomsen (1927) described 10 affected females and 5 affected males in 5 generations. McClintic (1935) observed 15 affected in 5 generations, and Goodman (1965) 5 affected in 3 generations. Baraitser et al. (1983) pointed out that the digital changes of this disorder are identical to those of Greig syndrome (GCPS; 175700); that the facial features of Greig syndrome can be so mild as to be indistinguishable from the normal; and, therefore, that delineation of type IV preaxial polydactyly (uncomplicated polysyndactyly) as a distinct entity (Temtamy and McKusick, 1978) is not certain. Reynolds et al. (1984) reported 21 affected persons in 5 generations. Variability in expression without apparent sex influence and with complete penetrance was noted. The deformities were more severe in the feet than in the hands. Anteroposterior flatness of the thumbs was the only manifestation of the trait in the hands of several affected family members. X-rays of the thumbs in a pictured case showed dysplastic distal phalanges with a central hole--a most curious and perhaps specific finding of type IV preaxial polydactyly. It is possible that this is the same disorder as that called type I crossed polydactyly (CP1) by Ishikiriyama et al. (1991). Crossed polydactyly (CP) is defined as coexistence of preaxial and postaxial polydactyly with discrepancy in the axes of polydactyly between hands and feet. CP is divided into 2 types: in type I, postaxial polydactyly of the hands is combined with preaxial polydactyly of the feet; in type II, the opposite is found. CP is often associated with congenital malformation syndromes, while nonsyndromic CP is rare. McClintic (1935), Goodman (1965), and Giorgini et al. (1979) reported families with CP type I. Abnormal earlobes were present in the family reported by Goldberg and Pashayan (1976); see 186350. Most patients in these families showed not only preaxial polydactyly of the feet but also syndactyly of toes II-V. In the family studied by McClintic (1935), there were 6 fingers and 7 toes. Ishikiriyama et al. (1991) described a Japanese mother and son with CP type I. Unlike the affected members of the previously reported families, syndactyly of the toes was not present. Radhakrishna et al. (1999) described a large family from the Gujarat state in western India in which 22 affected individuals over 4 generations exhibited preaxial polydactyly type IV. Most had bilateral anomalies of the feet, although their hands were less severely affected, and some individuals had apparently normal hands. Foot polydactyly was the only abnormality in 12 of the 22 affected individuals. The anomaly ranged from duplication of the great toe ('double toes') to syndactyly of toes with postaxial polydactyly. Hand polydactyly was not observed without foot polydactyly. The more severely affected individuals with hand/foot polydactyly had bilateral duplication of the fifth fingers and nails and unilateral triplication of the fifth finger. There were no craniofacial signs, such as frontal bossing, macrocephaly, hypertelorism, or broad base of the nose, in any individuals with digital anomalies. Mapping In a large 4-generation family from the Gujarat state in western India segregating autosomal dominant preaxial polydactyly type IV, Radhakrishna et al. (1999) performed linkage analysis in a candidate region of chromosome 7p and obtained a maximum lod score of 3.91 for marker D7S521 (theta = 0.00). Using 2 microsatellite polymorphisms within the GLI3 gene, they obtained a Z(max) score of 5.51, suggesting GLI3 as a strong candidate gene for the phenotype in this family. Molecular Genetics In a large 4-generation family from the Gujarat state in western India with preaxial polydactyly type IV mapping to chromosome 7p, Radhakrishna et al. (1999) identified heterozygosity for a 1-bp insertion in the GLI3 gene (165240.0005) that segregated with disease. In a father and son with preaxial polydactyly type IV, Fujioka et al. (2005) identified heterozygosity for a nonsense mutation in the GLI3 gene (R290X; 165240.0014). The authors noted that the son also had syndactyly of the third and fourth fingers on his left hand, whereas his father had no abnormalities of his hands, indicating that phenotypic variation may be seen between cases of preaxial polydactyly with identical mutations in GLI3. Biesecker and Johnston (2005) raised the question of whether there was sufficient phenotypic evidence to rule out a diagnosis of GCPS in the father and son reported by Fujioka et al. (2005). Fujioka and Ariga (2005) noted that Baraitser et al. (1983) had reported that facial features of Greig syndrome can be so mild as to be indistinguishable from normal and had suggested that preaxial polydactyly type IV may be Greig syndrome. INHERITANCE \- Autosomal dominant SKELETAL Hands \- Duplicated thumb, mild \- Syndactyly of 3rd and 4th fingers \- Bilateral duplication of 5th fingers (in some patients) \- Unilateral triplication of 5th finger (in some patients) Feet \- Duplication of great toe, bilateral \- Variable syndactyly of toes MISCELLANEOUS \- Intrafamilial phenotypic variability \- Some patients have only foot involvement \- Hand polydactyly only seen in individuals with foot polydactyly MOLECULAR BASIS \- Caused by mutation in the GLI-Kruppel family member-3 gene (GLI3, 165240.0004 ) ▲ 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	POLYDACTYLY, PREAXIAL IV	c0265553	1,147	omim	https://www.omim.org/entry/174700	2019-09-22T16:36:02	{"doid": ["1148"], "mesh": ["D013576"], "omim": ["174700"], "orphanet": ["93338"], "synonyms": ["Alternative titles", "POLYSYNDACTYLY, UNCOMPLICATED"]}
Mucinous cystadenocarcinoma of the lung Other namesMucinous multilocular cyst carcinoma, Pseudomyxomatous pulmonary adenocarcinoma, Mucinous cystic tumor of low malignant potential[1] SpecialtyOncology Mucinous cystadenocarcinoma of the lung (MCACL) is a very rare malignant mucus-producing neoplasm arising from the uncontrolled growth of transformed epithelial cells originating in lung tissue. ## Contents * 1 Classification * 2 Histogenesis * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Incidence * 7 References * 8 External links ## Classification[edit] According to the most recent revision (2004) of the World Health Organization (WHO) histological classification system for lung tumors ("WHO2004"), currently the most widely recognized typing scheme for pulmonary neoplasia, MCACL is considered a distinctive variant of adenocarcinoma.[2] Informally, some experts have included these tumors as a distinct variant among a spectrum of mucus-producing adenocarcinomas, including — in order of increasing relative extent of cellular mucus production and extracellular mucus accumulation — solid adenocarcinoma, mucoepidermoid carcinoma, mucinous bronchioloalveolar carcinoma, signet ring cell adenocarcinoma, mucinous cystadenocarcinoma, and mucinous "colloid" adenocarcinoma.[3] ## Histogenesis[edit] MCACL has been noted in most cases to show areas of gradual transition wherein cells become more atypical and feature more pronounced characteristics of malignancy as one proceeds from the capsule, or outermost layers of the tumor, toward the center of the mass.[4] Some experts suggest that this tumor often develops after a slow progression from a relatively benign to a frankly malignant phenotype over a period of years to decades.[1] The putative cell of origin of this tumor is unknown. Electron microscopic studies in 3 cases[5][6] described intracytoplasmic mucin, convoluted oval nuclei, prominent nucleoli, homogeneous euchromatin with peripheral chromatin condensation, microvilli, junctional complexes, and primitive lumen formation. Their failure to identify lamellar bodies and large dense granules seemed to rule out origination from either Club cells or Type II pneumocytes.[1] In a review of 66 cystic pulmonary mucinous lesions, Gao and colleagues reported that p53 expression and a Ki-67 index exceeding 20% is characteristic of MCACL.[1] ## Diagnosis[edit] This particular variant of lung cancer is usually asymptomatic and is found after chest x-rays are taken for other reasons.[7] Hemoptysis is seen occasionally[7] and, in some cases, distal obstruction of bronchi by blood clots or mucus plugs produces cough and/or infection.[1] Lesions often enlarge and progress slowly, over many years.[8] The 1999 World Health Organization classification system defined MCACL as a cystic adenocarcinoma with copious mucin production that, histologically, resembles (the more common) mucus-producing cystadenocarcinomas originating in the ovary, breast and pancreas.[9] The 2004 revision of the WHO classification noted that the tumors tend to be well circumscribed by a partial fibrous tissue capsule with central cystic change and copious mucin pooling.[2] The thin, fibrous wall circumscribing the tumor is highly characteristic of this lesion.[4] It can sometimes occur within a pulmonary bronchocele, and this tumor entity should be kept in mind after identification of a bronchocele with suspicious or non-prototypical imaging characteristics.[10][11] Microscopically, the neoplastic epithelial cells tend to grow along the alveolar walls, in a fashion similar to the mucinous variant of bronchioloalveolar carcinoma, a more common form of adenocarcinoma.[2] Hemoptysis is seen occasionally.[7] Positron Emission Tomography (PET) scanning can be of assistance in diagnosing MCACL,[10] as these lesions show intense uptake, typically in the wall of the tumor.[7] CA 19-9 has been reported to be elevated in MCACL.[7] Differential diagnosis of MCACL includes secondary metastatic cystadenocarcinomatous lesions, particularly from the pancreas or ovary, mucoepidermoid carcinoma, and pulmonary mucinous bronchioloalveolar carcinoma.[4][1][12] The mouse monoclonal antibody 1D3, developed to detect a high molecular weight mucin found in a number of cystic malignancies of various organs, may be of use in differentiating primary mucinous cystadenocarcinoma of the lung from metastatic lung tumors due to mucinous cystic lesions of the uterus and pancreas, as well as those primary in the colon and stomach.[13] ## Treatment[edit] For treatment purposes, MCACL has been traditionally considered a non-small cell lung carcinoma (NSCLC). Complete radical surgical resection is the treatment of choice.[14] There is virtually no data regarding new molecular targets or targeted therapy in the literature to date. Iwasaki and co-workers failed to find mutations of the epidermal growth factor receptor (EGFR) or the cellular Kirsten rat sarcoma virus oncogene K-ras in one reported case.[citation needed] ## Prognosis[edit] MCACL has a much more favorable prognosis than most other forms of adenocarcinoma and most other NSCLC's.[10][14] Cases have been documented of continued growth of these lesions over a period of 10 years without symptoms or metastasis.[8] The overall mortality rate appears to be somewhere in the vicinity of 18% to 27%, depending on the criteria that are used to define this entity.[1] ## Incidence[edit] Accurate incidence statistics on MCACL are unavailable. It is a very rare tumor,[12] with only a few dozen cases reported in the literature to date.[1] In the few cases described in the literature to date, the male-to-female ratio is approximately unity, and right lung lesions occurred twice as commonly as left lung lesions. Approximately 2/3 of cases have been associated with tobacco smoking.[1] Cases have been reported in patients as young as 29.[8] ## References[edit] 1. ^ a b c d e f g h i Gao ZH, Urbanski SJ (July 2005). "The spectrum of pulmonary mucinous cystic neoplasia : a clinicopathologic and immunohistochemical study of ten cases and review of literature". Am. J. Clin. Pathol. 124 (1): 62–70. doi:10.1309/52XXR6E6U0J2JX0F. PMID 15923171. 2. ^ a b c Travis, William D; Brambilla, Elisabeth; Muller-Hermelink, H Konrad; et al., eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 978-92-832-2418-1. Archived from the original (PDF) on 23 August 2009. Retrieved 27 March 2010. 3. ^ Tsuta K; Ishii G; Nitadori J (May 2006). "Comparison of the immunophenotypes of signet-ring cell carcinoma, solid adenocarcinoma with mucin production, and mucinous bronchioloalveolar carcinoma of the lung characterized by the presence of cytoplasmic mucin". J. Pathol. 209 (1): 78–87. doi:10.1002/path.1947. PMID 16463270. S2CID 22202641. 4. ^ a b c Tangthangtham A, Chonmaitri I, Tungsagunwattana S, Charupatanapongse U (October 1998). "Mucinous cystadenocarcinoma of the lung". J Med Assoc Thai. 81 (10): 794–8. PMID 9803072. 5. ^ Kragel PJ, Devaney KO, Meth BM, Linnoila I, Frierson HF, Travis WD (October 1990). "Mucinous cystadenoma of the lung. A report of two cases with immunohistochemical and ultrastructural analysis". Arch. Pathol. Lab. Med. 114 (10): 1053–6. PMID 1699507. 6. ^ Dixon AY, Moran JF, Wesselius LJ, McGregor DH (July 1993). "Pulmonary mucinous cystic tumor. Case report with review of the literature". Am. J. Surg. Pathol. 17 (7): 722–8. doi:10.1097/00000478-199307000-00010. PMID 8317612. 7. ^ a b c d e Iwasaki T, Kawahara K, Nagano T, Nakagawa K (March 2007). "Pulmonary mucinous cystadenocarcinoma: an extremely rare tumor presenting as a cystic lesion of the lung". Gen Thorac Cardiovasc Surg. 55 (3): 143–6. doi:10.1007/s11748-006-0089-z. PMID 17447515. S2CID 33648202. 8. ^ a b c Sezer O; Hoffmeier A; Bettendorf O (April 2006). "Mucinous cystadenocarcinoma—an extremely rare tumor in a young patient". Thorac Cardiovasc Surg. 54 (3): 216–7. doi:10.1055/s-2005-872950. PMID 16639689. 9. ^ Travis, W.D.; Colby, T.V.; Corrin, B. (1999). Histological Typing of Lung and Pleural Tumors. International histological classification of tumours, no. 1 (3rd ed.). Berlin: Springer. ISBN 978-3-540-65219-9. 10. ^ a b c Raza SA, Alexakis C, Creagh M, Lawrence DR, Wood M (2009). "Primary pulmonary mucinous cystadenocarcinoma presenting as a complex bronchocele: a case report". J Med Case Rep. 3: 8581. doi:10.4076/1752-1947-3-8581. PMC 2737758. PMID 19830231. 11. ^ Butnor KJ, Sporn TA, Dodd LG (2001). "Fine needle aspiration cytology of mucinous cystadenocarcinoma of the lung: report of a case with radiographic and histologic correlation". Acta Cytol. 45 (5): 779–83. doi:10.1159/000328305. PMID 11575661. S2CID 3339868. 12. ^ a b Ishibashi H; Moriya T; Matsuda Y (November 2003). "Pulmonary mucinous cystadenocarcinoma: report of a case and review of the literature". Ann. Thorac. Surg. 76 (5): 1738–40. doi:10.1016/S0003-4975(03)00657-X. PMID 14602331. 13. ^ Gangopadhyay A, Bhattacharya M, Chatterjee SK, Barlow JJ, Tsukada Y (April 1985). "Immunoperoxidase localization of a high-molecular-weight mucin recognized by monoclonal antibody 1D3". Cancer Res. 45 (4): 1744–52. PMID 3884144. 14. ^ a b Gaeta M, Blandino A, Scribano E, Ascenti G, Minutoli F, Pandolfo I (1999). "Mucinous cystadenocarcinoma of the lung: CT-pathologic correlation in three cases". J Comput Assist Tomogr. 23 (4): 641–3. doi:10.1097/00004728-199907000-00028. PMID 10433300. ## External links[edit] * [1] World Health Organization Histological Typing of Lung and Pleural Tumors, 4th edition. * v * t * e Cancer involving the respiratory tract Upper RT Nasal cavity Esthesioneuroblastoma Nasopharynx Nasopharyngeal carcinoma Nasopharyngeal angiofibroma Larynx Laryngeal cancer Laryngeal papillomatosis Lower RT Trachea * Tracheal tumor Lung Non-small-cell lung carcinoma * Squamous-cell carcinoma * Adenocarcinoma (Mucinous cystadenocarcinoma) * Large-cell lung carcinoma * Rhabdoid carcinoma * Sarcomatoid carcinoma * Carcinoid * Salivary gland–like carcinoma * Adenosquamous carcinoma * Papillary adenocarcinoma * Giant-cell carcinoma Small-cell carcinoma * Combined small-cell carcinoma Non-carcinoma * Sarcoma * Lymphoma * Immature teratoma * Melanoma By location * Pancoast tumor * Solitary pulmonary nodule * Central lung * Peripheral lung * Bronchial leiomyoma Pleura * Mesothelioma * Malignant solitary fibrous tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Mucinous cystadenocarcinoma of the lung	None	1,148	wikipedia	https://en.wikipedia.org/wiki/Mucinous_cystadenocarcinoma_of_the_lung	2021-01-18T18:57:20	{"umls": ["C1711166"], "wikidata": ["Q17155516"]}
A rare inherited cancer-predisposing syndrome characterized by early-onset hepatocellular carcinoma, genomic instability, and progeroid features, such as short stature, low body weight, muscular atrophy, lipodystrophy, bilateral cataracts, and premature hair graying. Dysmorphic craniofacial features include triangular face, small, deep-set eyes, and micrognathia. Kyphoscoliosis, sloping shoulders, mild pectus excavatum, bilateral contractures of the elbows and fingers, bilateral clinodactyly, and pes planus 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	Progeroid features-hepatocellular carcinoma predisposition syndrome	c4015461	1,149	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=435953	2021-01-23T17:06:56	{"omim": ["616200"], "synonyms": ["Ruijs-Aalfs syndrome"]}
MBD25–related intellectual disability, or MBD25 haploinsufficiency, is a neurological and developmental disorder characterized by developmental delay, intellectual disability, speech problems, seizures, sleep troubles, and abnormal behaviors. Most children lack speech entirely or may only be able to use single words, short phrases, or short sentences. Seizures are present in about 80% and usually begin around age two years. Sleep troubles, present in about 80% of children, can cause daytime drowsiness. Abnormal behaviors can include autistic-like-behavior (80%) and self-injury and aggression (60%). The disorder is caused by mutations or deletions (loss) of the MBD5 gene located on chromosome 2. People who have deletions of chromosome 2q23.1 which only include the MBD5 gene have similar symptoms and features to people with mutations of the MBD5 gene. People with larger deletions may also have ataxia, eating disorders, growth delay, and small hands and feet. These extra features in people with larger deletions are believed to be due to the loss of other genes located near the MBD5 gene on chromosome 2. Inheritance is autosomal dominant. Treatment depends on the symptoms and features present in each person. For a comprehensive review of MBD25 Haploinsufficiency, you can visit GeneReviews. GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	MBD25–related intellectual disability	c1969562	1,150	gard	https://rarediseases.info.nih.gov/diseases/12852/mbd25-related-intellectual-disability	2021-01-18T17:59:12	{"mesh": ["C566947"], "omim": ["156200"], "synonyms": ["Autosomal dominant intellectual disability 1", "MBD5 Haploinsufficiency"]}
Sturge–Weber syndrome Other namesSturge–Weber–Krabbe disease CT scan of Sturge-Weber syndrome SpecialtyMedical genetics Sturge–Weber syndrome, sometimes referred to as encephalotrigeminal angiomatosis, is a rare congenital neurological and skin disorder. It is one of the phakomatoses and is often associated with port-wine stains of the face, glaucoma, seizures, intellectual disability, and ipsilateral leptomeningeal angioma (cerebral malformations and tumors). Sturge–Weber syndrome can be classified into three different types. Type 1 includes facial and leptomeningeal angiomas as well as the possibility of glaucoma or choroidal lesions. Normally, only one side of the brain is affected. This type is the most common. Type 2 involvement includes a facial angioma (port wine stain) with a possibility of glaucoma developing. There is no evidence of brain involvement. Symptoms can show at any time beyond the initial diagnosis of the facial angioma. The symptoms can include glaucoma, cerebral blood flow abnormalities and headaches. More research is needed on this type of Sturge–Weber syndrome. Type 3 has leptomeningeal angioma involvement exclusively. The facial angioma is absent and glaucoma rarely occurs. This type is only diagnosed via brain scan.[1] Sturge–Weber is an embryonal developmental anomaly resulting from errors in mesodermal and ectodermal development. Unlike other neurocutaneous disorders (phakomatoses), Sturge–Weber occurs sporadically (i.e., does not have a hereditary cause). It is caused by a mosaic, somatic activating mutation occurring in the GNAQ gene.[2] Radiological findings will show tram track calcifications on CT, bilaterally.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 Eponym * 8 Society and culture * 9 References * 10 Further reading * 11 External links ## Signs and symptoms[edit] Dilated bulbar vessels in Sturge–Weber syndrome Sturge–Weber syndrome is usually manifested at birth by a port-wine stain on the forehead and upper eyelid of one side of the face, or the whole face. The birthmark can vary in color from light pink to deep purple and is caused by an overabundance of capillaries around the ophthalmic branch of the trigeminal nerve, just under the surface of the face. There is also malformation of blood vessels in the pia mater overlying the brain on the same side of the head as the birthmark. This causes calcification of tissue and loss of nerve cells in the cerebral cortex.[citation needed] Neurological signs include seizures that begin in infancy and may worsen with age. Convulsions usually happen on the side of the body opposite the birthmark, and vary in severity. There may also be muscle weakness on the side of the body opposite the birthmark.[citation needed] Some children will have developmental delays and cognitive delays; about 50% will have glaucoma (optic neuropathy often associated with increased intraocular pressure), which can be present at birth or develop later. Glaucoma can be expressed as leukocoria, which should suggest further evaluation for retinoblastoma. Increased pressure within the eye can cause the eyeball to enlarge and bulge out of its socket (buphthalmos).[citation needed] Sturge–Weber syndrome rarely affects other body organs.[citation needed] Presentation[4] Seizures 75–90% Vascular headache 40–60% Developmental (cognitive) delay 50–70% Glaucoma 30–70% Hemianopsia 40–45% Hemiparesis 25–60% ## Cause[edit] The blood vessel formations associated with SWS start in the fetal stage. Around the sixth week of development, a network of nerves develops around the area that will become a baby's head. Normally, this network goes away in the ninth week of development. In babies with SWS due to mutation of gene GNAQ, this network of nerves doesn't go away. This reduces the amount of oxygen and blood flowing to the brain, which can affect brain tissue development.[citation needed] ## Diagnosis[edit] See also: List of radiographic findings associated with cutaneous conditions CT and MRI are most often used to identify intracranial abnormalities. When a child is born with a facial cutaneous vascular malformation covering a portion of the upper or the lower eyelids, imaging should be performed to screen for intracranial leptomeningeal angiomatosis. The haemangioma present on the surface of the brain is in the vast majority of cases on the same side as the birth mark and gradually results in calcification of the underlying brain and atrophy of the affected region.[5] ## Treatment[edit] Treatment for Sturge–Weber syndrome is symptomatic. Laser treatment may be used to lighten or remove the birthmark. Anticonvulsant medications may be used to control seizures. Doctors recommend early monitoring for glaucoma, and surgery may be performed on more serious cases. When one side of the brain is affected and anticonvulsants prove ineffective, the standard treatment is neurosurgery to remove or disconnect the affected part of the brain (hemispherectomy). Physical therapy should be considered for infants and children with muscle weakness. Educational therapy is often prescribed for those with intellectual disability or developmental delays, but there is no complete treatment for the delays. Brain surgery involving removing the portion of the brain that is affected by the disorder can be successful in controlling the seizures so that the patient has only a few seizures that are much less intense than pre-surgery. Surgeons may also opt to "switch-off" the affected side of the brain.[6] Latanoprost (Xalatan), a prostaglandin, may significantly reduce IOP (intraocular pressure) in patients with glaucoma associated with Sturge–Weber syndrome. Latanoprost is commercially formulated as an aqueous solution in a concentration of 0.005% preserved with 0.02% benzalkonium chloride (BAC). The recommended dosage of latanoprost is one drop daily in the evening, which permits better diurnal IOP control than does morning instillation. Its effect is independent of ethnicity, gender or age, and it has few to no side effects. Contraindications include a history of cystic macular edema (CME), epiretinal membrane formation, vitreous loss during cataract surgery, history of macular edema associated with branch retinal vein occlusion, history of anterior uveitis, and diabetes mellitus. It is also wise to advise patients that unilateral treatment can result in heterochromia or hypertrichosis that may become cosmetically objectionable.[citation needed] Complication[4] Treatment (1st choice) Treatment (2nd choice) Glaucoma Beta blocker drops Adrenergic drops Partial Epilepsy Carbamazepine Valproate, Topiramate Headache Ibuprofen Sumatriptan Strokelike Episodes Aspirin None Neurobehavior Methylphenidate Clonidine ## Prognosis[edit] Although it is possible for the birthmark and atrophy in the cerebral cortex to be present without symptoms, most infants will develop convulsive seizures during their first year of life. There is a greater likelihood of intellectual impairment when seizures are resistant to treatment. Studies do not support the widely held belief that seizure frequency early in life in patients who have SWS is a prognostic indicator.[4] ## Epidemiology[edit] It occurs in approximately 1 in 50,000 newborns.[4] ## Eponym[edit] It is named for William Allen Sturge and Frederick Parkes Weber.[7][8][9] ## Society and culture[edit] The Sturge-Weber Foundation's (The SWF) international mission is to improve the quality of life and care for people with Sturge–Weber syndrome and associated port wine birthmark conditions. It supports affected individuals and their families with education, advocacy, and research to promote effective management and awareness. The SWF was founded by Kirk and Karen Ball, who began searching for answers after their daughter was diagnosed with Sturge–Weber syndrome at birth. The SWF was incorporated in the US in 1987 as an International 501(c)(3) non-profit organization. In 1992, the mission was expanded to include individuals with capillary vascular birthmarks, Klippel Trenaunay (KT) and Port Wine Birthmarks.[citation needed] The Hemispherectomy Foundation was formed in 2008 to assist families with children who have Sturge–Weber syndrome and other conditions that require hemispherectomy.[10] The Brain Recovery Project was formed in 2011 to fund research and establish rehabilitation protocols to help children who have had hemispherectomy surgery reach their full potential.[citation needed] Sturge Weber UK (SWUK), formerly Sturge-Weber Foundation UK, is a volunteer-run registered charity formed in 1990. The charity exists to support those affected by Sturge Weber syndrome, promote research into the condition and raise awareness of the condition amongst both public and professionals. The charity was instrumental in setting up a specialist Sturge Weber clinic at Great Ormond Street Hospital.[11] Sturge Weber UK has created an annual Sturge Weber Awareness Day to coincide with William Allen Sturge's birth date on November 1. The Sturge Weber Awareness Day is a collaboration with international Sturge Weber support groups to raise public and professional awareness of Sturge Weber syndrome around the world.[citation needed] ## References[edit] 1. ^ "The Sturge-Weber Foundation : Home". 2. ^ Shirley, Matthew D.; Tang, Hao; Gallione, Carol J.; Baugher, Joseph D.; Frelin, Laurence P.; Cohen, Bernard; North, Paula E.; Marchuk, Douglas A.; Comi, Anne M.; Pevsner, Jonathan (8 May 2013). "Sturge–Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation in". New England Journal of Medicine. 368 (21): 1971–9. doi:10.1056/NEJMoa1213507. PMC 3749068. PMID 23656586. 3. ^ Zaki, Syed Ahmed; Vijay Lad (July 2011). "Sturge-Weber syndrome with bilateral facial nevus and early cerebral calcification". Journal of Pediatric Neurosciences. 6 (2): 114–5. doi:10.4103/1817-1745.92825 (inactive 2021-01-17). PMC 3296402. PMID 22408657.CS1 maint: DOI inactive as of January 2021 (link) 4. ^ a b c d Thomas-Sohl, Kristin A; Vaslow, Dale F; Maria, Bernard L (May 2004). "Sturge-Weber syndrome: A review". Pediatric Neurology. 30 (5): 303–310. doi:10.1016/j.pediatrneurol.2003.12.015. PMID 15165630. 5. ^ "Sturge-Weber syndrome: Radiopaedia.org". 6. ^ "Norfolk girl recovers after half of brain 'switched off'". BBC News. 2011-05-20. 7. ^ synd/1764 at Who Named It? 8. ^ Sturge WA (1879). "A case of partial epilepsy, apparently due to a lesion of one of the vasomotor centres of the brain". Transactions of the Clinical Society of London. 12: 162. 9. ^ Weber FP (1922). "Right-sided hemi-hypertrophy resulting from right-sided congenital spastic hemiplegia, with a morbid condition of the left side of the brain, revealed by radiograms". Journal of Neurology and Psychopathology. London. 3 (10): 134–9. doi:10.1136/jnnp.s1-3.10.134. PMC 1068054. PMID 21611493. 10. ^ "The Community News". Archived from the original on March 29, 2009. Retrieved 2009-02-25. 11. ^ "Search Results \| Great Ormond Street Hospital". ## Further reading[edit] Wikimedia Commons has media related to Sturge–Weber syndrome. * Greenwood M, Meechan JG (July 2003). "General medicine and surgery for dental practitioners Part 4: Neurological disorders". Br Dent J. 195 (1): 19–25. doi:10.1038/sj.bdj.4810275. PMID 12856021. " Fig. 2 A patient with Sturge Weber Syndrome" ## External links[edit] Classification D * ICD-10: Q85.8 * ICD-9-CM: 759.6 * OMIM: 185300 * MeSH: D013341 * DiseasesDB: 12572 External resources * MedlinePlus: 001426 * eMedicine: neuro/356 * Orphanet: 3205 * sturge_weber at NINDS * v * t * e Phakomatosis Angiomatosis * Sturge–Weber syndrome * Von Hippel–Lindau disease Hamartoma * Tuberous sclerosis * Hypothalamic hamartoma (Pallister–Hall syndrome) * Multiple hamartoma syndrome * Proteus syndrome * Cowden syndrome * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease Neurofibromatosis * Type I * Type II Other * Abdallat–Davis–Farrage syndrome * Ataxia telangiectasia * Incontinentia pigmenti * Peutz–Jeghers syndrome * Encephalocraniocutaneous lipomatosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Sturge–Weber syndrome	c0038505	1,151	wikipedia	https://en.wikipedia.org/wiki/Sturge%E2%80%93Weber_syndrome	2021-01-18T18:52:04	{"gard": ["7706"], "mesh": ["D013341"], "umls": ["C0038505"], "icd-9": ["759.6"], "icd-10": ["Q85.8"], "orphanet": ["3205"], "wikidata": ["Q1886238"]}
A number sign (#) is used with this entry because idiopathic basal ganglia calcification-4 (IBGC4) is caused by heterozygous mutation in the PDGFRB gene (173410) on chromosome 5q32. Description Idiopathic basal ganglia calcification-4 is an autosomal dominant condition characterized by the accumulation of calcium deposits in various brain regions, most commonly in the basal ganglia. About half of mutation carriers are asymptomatic, but some present later in life with parkinsonism and impaired cognitive function. Migraine or depression may occur in younger individuals (summary by Nicolas et al., 2013). For a detailed phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (213600). Clinical Features Nicolas et al. (2013) reported a large 3-generation French family in which multiple members had basal ganglia calcifications apparent on brain imaging. The proband was a woman in the oldest generation who presented at age 54 years with asymmetric parkinsonism with a good response to levodopa. Medical history revealed that she was diagnosed with bipolar disorder at age 20 years. At age 65 years, she showed cognitive impairment with dysexecutive syndrome and memory difficulties, which progressed to dementia. Brain CT showed strio-pallido-thalamo-dentate calcifications, with periventricular and juxtacortical hyperintensities on MRI. Brain imaging of 12 other relatives showed basal ganglia calcifications, although most were clinically asymptomatic. One patient had severe personality disorder, nystagmus, and suicide attempts, and died at age 34 years. The 6-year-old child of this patient had calcifications and attention deficit-hyperactivity disorder and migraine. Two others had migraine with aura. Six mutation carriers were asymptomatic, including 2 individuals in their sixties. An unrelated woman with the disorder presented at age 66 years with a cognitive dysexecutive disorder. Physical examination showed bradykinesia and pyramidal signs without rigidity. Brain imaging showed basal ganglia calcifications and periventricular and subcortical abnormalities on MRI. Inheritance The transmission pattern of IBGC4 in the family reported by Nicolas et al. (2013) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of a large 3-generation family with idiopathic basal ganglia calcification-4, Nicolas et al. (2013) identified a heterozygous mutation in the PDGFRB gene (L658P; 173410.0001). The mutation, which was identified by exome sequencing of 2 affected individuals and confirmed by Sanger sequencing, segregated with the disorder in this family and was not found in several large exome databases. Sequencing of the PDGRFB gene in 10 other affected families and 9 patients with apparently sporadic disease revealed 1 adult with a heterozygous mutation (173410.0002) and no family history. Nicolas et al. (2013) noted that animal models have shown a key role for Pdgfrb in the development of pericytes in vessels within the brain, and that pericytes have a key role in maintaining the integrity of the blood-brain barrier, which is hypothesized to be impaired in IBGC. In addition, the PDGFB-PDGFRB pathway appears to be involved in phosphate-induced calcifications in vascular smooth muscle cells by modulating expression of the phosphate transporter SLC20A1 (137570) (Villa-Bellosta et al., 2009); IBGC1 (213600) is caused by mutation in a related phosphate transporter SLC20A2 (158378). These findings suggest that cerebral phosphate homeostasis may play a role in vascular calcifications. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus (rare) NEUROLOGIC Central Nervous System \- Basal ganglia calcifications \- Parkinsonism (in some) \- Impaired executive function (in some patients) \- Dementia (in some patients) \- Migraine (in some patients) \- Subcortical atrophy (in some patients) \- Subcortical and periventricular white matter abnormalities seen on MRI (in some patients) Behavioral Psychiatric Manifestations \- Depression (in some patients) MISCELLANEOUS \- One large French family and 1 patient with sporadic occurrence have been reported (last curated January 2013) \- Most patients are asymptomatic \- Variable age of onset of symptoms MOLECULAR BASIS \- Caused by mutation in the platelet-derived growth factor receptor, beta polypeptide gene (PDGFRB, 173410.0001 ) ▲ 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	BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 4	c0393590	1,152	omim	https://www.omim.org/entry/615007	2019-09-22T15:53:29	{"doid": ["0060230"], "omim": ["615007"], "orphanet": ["1980"], "genereviews": ["NBK1421"]}
Lethal polymalformative syndrome, Boissel type is a rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by failure to thrive, severe developmental delay, severe postanatal microcephaly, frequent congenital cardiac defects and characteristic facial dysmorphysm (including coarse face with anteverted nostrils, thin vermillion, prominent alveolar ridge and retro- or micrognatia). Additional common features include neurologic abnormalities (hyper-/hypotonia, sensorineural deafness, hydrocephalus, cerebral atrophy, seizures), as well as brachydactyly, cutis marmorata and genital anomalies. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Lethal polymalformative syndrome, Boissel type	c2752001	1,153	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=210144	2021-01-23T17:58:03	{"mesh": ["C567856"], "omim": ["612938"], "umls": ["C2752001"], "icd-10": ["Q87.8"]}
Lateral pontine syndrome Pons SpecialtyNeurology A lateral pontine syndrome is a lesion which is similar to the lateral medullary syndrome, but because it occurs in the pons, it also involves the cranial nerve nuclei of the pons. ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Symptoms[edit] Damage to the following areas produces symptoms (from medial to lateral): Structure affected Effect Lateral spinothalamic tract Contralateral loss of pain and temperature from the trunk and extremities. Facial nucleus & facial Nerve (CN.VII) (1) Ipsilateral paralysis of the upper and lower face (lower motor neuron lesion). (2) Ipsilateral loss of lacrimation and reduced salivation. (3) Ipsilateral loss of taste from the anterior two-thirds of the tongue. (4) Loss of corneal reflex (efferent limb). Principal sensory trigeminal nucleus and tract Ipsilateral loss of all sensory modalities to the face (facial hemianesthesia) Vestibular Nuclei and intraaxial nerve fibers Nystagmus, nausea, vomiting, and vertigo Cochlear nuclei and intraaxial nerve fibers Hearing loss \- ipsilateral central deafness Middle & inferior cerebellar peduncle Ipsilateral limb and gait ataxia Descending sympathetic tract Ipsilateral Horner's syndrome (ptosis, miosis, & anhydrosis) ## Causes[edit] It can be caused by an interruption to the blood supply of the anterior inferior cerebellar artery or circumferential arteries.[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## References[edit] 1. ^ Campbell, William W. (2012). DeJong's The Neurologic Examination. Lippincott, Williams & Wilkins. p. 338. ISBN 9781469817521. ## External links[edit] Classification D * ICD-10: G46.3 * v * t * e Cerebrovascular diseases including stroke Ischaemic stroke Brain * Anterior cerebral artery syndrome * Middle cerebral artery syndrome * Posterior cerebral artery syndrome * Amaurosis fugax * Moyamoya disease * Dejerine–Roussy syndrome * Watershed stroke * Lacunar stroke Brain stem * Brainstem stroke syndrome * Medulla * Medial medullary syndrome * Lateral medullary syndrome * Pons * Medial pontine syndrome / Foville's * Lateral pontine syndrome / Millard-Gubler * Midbrain * Weber's syndrome * Benedikt syndrome * Claude's syndrome Cerebellum * Cerebellar stroke syndrome Extracranial arteries * Carotid artery stenosis * precerebral * Anterior spinal artery syndrome * Vertebrobasilar insufficiency * Subclavian steal syndrome Classification * Brain ischemia * Cerebral infarction * Classification * Transient ischemic attack * Total anterior circulation infarct * Partial anterior circulation infarct Other * CADASIL * Binswanger's disease * Transient global amnesia Haemorrhagic stroke Extra-axial * Epidural * Subdural * Subarachnoid Cerebral/Intra-axial * Intraventricular Brainstem * Duret haemorrhages General * Intracranial hemorrhage Aneurysm * Intracranial aneurysm * Charcot–Bouchard aneurysm Other * Cerebral vasculitis * Cerebral venous sinus thrombosis * v * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia This article about a medical condition affecting the nervous 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	Lateral pontine syndrome	None	1,154	wikipedia	https://en.wikipedia.org/wiki/Lateral_pontine_syndrome	2021-01-18T18:38:21	{"wikidata": ["Q17125280"]}
For the equine form of the disease, see Pituitary pars intermedia dysfunction. Cushing's disease Other namesCushing disease, tertiary or secondary hypercortisolism, tertiary or secondary hypercorticism, Itsenko-Cushing disease[1][2] SpecialtyEndocrinology Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (specifically pituitary basophilism) or due to excess production of hypothalamus CRH (corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism) that stimulates the synthesis of cortisol by the adrenal glands. Pituitary adenomas are responsible for 80% of endogenous Cushing's syndrome,[3] when excluding Cushing's syndrome from exogenously administered corticosteroids. This should not be confused with ectopic Cushing syndrome or exogenous steroid use.[4] ## Contents * 1 Signs and symptoms * 1.1 Common * 1.2 Less common * 2 Diagnosis * 2.1 ACTH blood test * 2.2 Dexamethasone suppression test * 2.3 ACTH stimulation test * 2.4 Imaging * 2.5 Inferior petrosal sinus sampling * 2.6 Urinary free cortisol test * 2.7 Late night (midnight) salivary cortisol test * 3 Treatment * 4 Epidemiology * 5 History * 6 References * 7 External links ## Signs and symptoms[edit] The symptoms of Cushing's disease are similar to those seen in other causes of Cushing's syndrome.[5] Patients with Cushing's disease usually present with one or more signs and symptoms secondary to the presence of excess cortisol or ACTH.[6] Although uncommon, some patients with Cushing's disease have large pituitary tumors (macroadenomas). In addition to the severe hormonal effects related to increased blood cortisol levels, the large tumor can compress adjacent structures.[citation needed] These tumors can compress the nerves that carry information from the eyes, causing a decrease in peripheral vision.[citation needed] Glaucoma and cataracts also may occur in Cushing's syndrome. In children, the two main symptoms are obesity and decreased linear growth.[7] The clinical diagnosis must be based on the presence of one or more of the symptoms listed below, because the syndrome itself has no true pathognomonic signs or symptoms.[citation needed] The most common symptoms seen in male patients are purple striae, muscle atrophy, osteoporosis, and kidney stones.[7] ### Common[edit] Common signs and symptoms of Cushing's disease include the following: * weight gain * high blood pressure[8] * poor short-term memory * irritability * excess hair growth (women)[3] * Impaired immunological function[8] * red, ruddy face * extra fat around neck, "Buffalo Hump" * moon face * fatigue * red stretch marks * poor concentration * irregular menstruation[7] ### Less common[edit] The less-common signs and symptoms of Cushing's disease include the following: * insomnia * recurrent infection * thin skin and stretch marks[8] * easy bruising * weak bones * acne * balding (women) * depression * hip and shoulder weakness * swelling of feet/legs * diabetes mellitus[8] * erectile dysfunction ## Diagnosis[edit] Diagnosis is made first by diagnosing Cushing's syndrome, which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients.[9] Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test (DST), and bilateral inferior petrosal sinus sampling (IPSS or BIPSS for bilateral IPSS). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis.[7] Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists.[7] ### ACTH blood test[edit] Once Cushing's syndrome has been diagnosed, the first step towards finding the cause is measuring plasma adrenocorticotropic hormone (ACTH) concentration. A concentration consistently below 1.1 pmol/L is classified as corticotropin-independent and does not lead to a diagnosis of Cushing's disease. In such cases, the next step is adrenal imaging with CT. If plasma corticotropin concentrations are consistently above 3.3 pmol/L, then corticotropin-dependent Cushing's syndrome is most likely. Any intermediate values need to be cautiously interpreted and a corticotropin-releasing hormone (CRH) test is advised in order to confirm corticotropin dependency. If corticotropin-dependent Cushing's syndrome is determined then the next step is to distinguish between Cushing's disease and ectopic corticotropin syndrome. This is done via a combination of techniques including CRH, high-dose DST, BIPSS, and pituitary MRI. ### Dexamethasone suppression test[edit] Two dexamethasone suppression tests (DSTs) are generally used, the overnight test and the 48 hour test.[7] For both tests, a plasma cortisol level above 50 nmol/L is indicative of Cushing's disease.[7] However, 3–8% of patients with Cushing's disease will test negative due to a retention of dexamethasone suppression abilities.[7] For non-Cushing or healthy patients, the false-positive rate is 30%.[7] The 48-h DST is advantageous since it is more specific and can be done by outpatients upon proper instruction.[7] In the high-dose 48-h DST, 2 mg of dexamethasone is given every 6 hours for 48 hours or a single dose of 8 mg is given.[7] This test is not needed if the 48-h low-dose DST has shown suppression of cortisol by over 30%.[7] These tests are based on the glucocorticoid sensitivity of pituitary adenomas compared to non-pituitary tumors.[7] ### ACTH stimulation test[edit] An ACTH stimulation test involving administration of corticotropin-releasing hormone (CRH) or another agent can differentiate this condition from ectopic ACTH secretion. In a patient with Cushing's disease, the tumor cells will be stimulated to release corticotropin and elevated plasma corticotropin levels will be detected.[7] This rarely occurs with ectopic corticotropin syndrome and thus is quite useful for distinguishing between the two conditions.[7] If ectopic, the plasma ACTH and cortisol levels should remain unchanged; if this is pituitary related, levels of both would rise. The CRH test uses recombinant human or bovine-sequence CRH, which is administered via a 100μg intravenous bolus dose. The sensitivity of the CRH test for detecting Cushing's disease is 93% when plasma levels are measured after fifteen and thirty minutes.[7] However, this test is used only as a last resort due to its high cost and complexity.[9] ### Imaging[edit] A CT or MRI of the pituitary may also show the ACTH-secreting tumor if present. However, in 40% of Cushing's disease patients MRI is unable to detect a tumor.[7] In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery. The average size of tumor, both those that were identified on MRI and those that were only discovered during surgery, was 6 mm.[10] ### Inferior petrosal sinus sampling[edit] IPSS (inferior petrosal sinus sampling) or BIPSS (bilateral IPSS) is a more accurate but invasive test used to differentiate pituitary from ectopic or adrenal Cushing's syndrome.[11] A corticotropin gradient sample via BIPSS is required to confirm diagnosis when pituitary MRI imaging and biochemical diagnostic tests have been inconclusive.[7] A basal central:peripheral ratio of over 2:1, or a ratio over 3:1 when CRH is administered, is indicative of Cushing’s disease.[7] This test has been the gold standard for distinguishing between Cushing's disease and ectopic corticotropin syndrome.[7] The BIPSS has a sensitivity and specificity of 94% for Cushing's disease but it is usually used as a last resort due to its invasiveness, rare but serious complications, and the expertise required to perform it.[9] ### Urinary free cortisol test[edit] Another diagnostic test used is the urinary free cortisol (UFC) test, which measures the excess cortisol excreted by the kidneys into the urine. Results of 4x higher cortisol levels than normal are likely to be Cushing's disease.[7][9] This test should be repeated three times in order to exclude any normally occurring periods of hypercortisolism.[9] The UFC test has a specificity of 81% and thus has a high rate of false-positives that are due to pseudo-Cushing states, sleep apnea, polycystic ovary syndrome, familial glucocorticoid resistance, and hyperthyroidism.[9] ### Late night (midnight) salivary cortisol test[edit] The late night or midnight salivary cortisol test has been gaining support due to its ease of collection and stability at room temperature, therefore it can be assigned to outpatients.[7] The test measures free circulating cortisol and has both a sensitivity and specificity of 95–98%.[7][9] This test is especially useful for diagnosing children.[7] ## Treatment[edit] The first-line treatment of Cushing's disease is surgical resection of ACTH-secreting pituitary adenoma; this surgery involves removal of the tumor via transsphenoidal surgery (TSS).[12] There are two possible options for access to the sphenoidal sinus, including of endonasal approach (through the nostril) or sublabial approach (through an incision under the upper lip); many factors such as the size of nostril, the size of the lesion, and the preferences of the surgeon cause the selection of one access route over the other.[13] Some tumors do not contain a discrete border between the tumor and pituitary gland; therefore, careful sectioning through the pituitary gland may be required to identify the location of the tumor.[14] The probability of successful resection is higher in patients where the tumor was identified at initial surgery in comparison to patients where no tumor was found initially; the overall remission rates in patients with microadenomas undergoing TSS are in range of 65%–90%, and the remission rate in patients with macroadenomas are lower than 65%.[14] Patients with persistent disease after initial surgery are treated with repeated pituitary surgery as soon as the active persistent disease is evident; however, reoperation has a lower success rate and increases the risk of pituitary insufficiency.[14] Pituitary radiation therapy is another option for treatment of postoperative persisting hypercortisolemia following unsuccessful transsphenoidal surgery.[15] External-beam pituitary RT is more effective treatment for pediatric CD in children with cure rates of 80–88%. Hypopituitarism specifically growth hormone deficiency has been reported as the only most common late morbidity of this treatment; GHD has been reported in 36% and 68% of the patients undergoing post-pituitary RT for Cushing's disease.[15] Bilateral adrenalectomy is another treatment that provides immediate reduction of cortisol level and control of hypercortisolism. However, it requires education of patients, because lifelong glucocorticoid and mineralocorticoid replacement therapy is needed for these patients. One of the major complications of this treatment is progression of Nelson's syndrome which is caused by enhance level of tumor growth and ACTH secretion post adrenalectomy in 8–29% of patients with CD.[16] During post surgical recovery, patients collect 24-hour urine sample and blood sample for detecting the level of cortisol with the purpose of cure test; level of cortisol near the detection limit assay, corresponds to cure. Hormonal replacement such as steroid is given to patients because of steroid withdrawal. After the completion of collecting urine and blood samples, patients are asked to switch to glucocorticoid such as prednisone to decrease symptoms associated with adrenal withdrawal. Mitotane is also used[17] A study of 3,525 cases of TSS for Cushing's disease in the nationally representative sample of US hospitals between 1993 and 2002 was conducted and revealed the following results: the in-hospital mortality rate was 0.7%; the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. The analyses of the study show that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were more likely to have an adverse outcome and prolonged hospital stay. Women were 0.3 times less likely to have adverse outcomes in comparison to men.[18] ## Epidemiology[edit] Cases of Cushing's disease are rare, and little epidemiological data is available on the disease. An 18-year study conducted on the population of Vizcaya, Spain reported a 0.004% prevalence of Cushing's disease.[19] The average incidence of newly diagnosed cases was 2.4 cases per million inhabitants per year. The disease is often diagnosed 3–6 years after the onset of illness.[19] Several studies have shown that Cushing's disease is more prevalent in women than men at a ratio of 3–6:1, respectively.[20][21] Moreover, most women affected were between the ages of 50 and 60 years. The prevalence of hypertension, and abnormalities in glucose metabolism are major predictors of mortality and morbidity in untreated cases of the disease.[19] The mortality rate of Cushing's disease was reported to be 10–11%,[19][22] with the majority of deaths due to vascular disease[8][19] Women aged 45–70 years have a significantly higher mortality rate than men.[19] Moreover, the disease shows a progressive increase with time. Reasons for the trend are unknown, but better diagnostic tools, and a higher incidence rate are two possible explanations.[19] ## History[edit] The disease associated with this increased secretion of cortisol was described by the American neurosurgeon Harvey Cushing in 1912, after he was presented with a unique case of the disease in 1910[23][24] a 23-year-old woman called Minnie G. whose symptoms included painful obesity, amenorrhea, hypertrichosis (abnormal hair growth), underdevelopment of secondary sexual characteristics, hydrocephalus and cerebral tension.[3] This combination of symptoms was not yet described by any medical disorder at the time.[3] However, Cushing was confident that Minnie's symptoms were due to dysfunction of the pituitary gland and resembled those associated with an adrenal tumor. Given this conviction, and his knowledge of the three anterior pituitary cell types, Cushing hypothesized that if acidophil hyperpituitarism (excess secretion from the acidophil cells) caused acromegaly, then an excess of basophil cells must be involved in another pituitary disorder that involves sexual dysfunction (amenorrhea in females and erectile dysfunction in males) and could explain Minnie's symptoms.[3] Experimental evidence and case reports by Cushing led to his publication in 1932 on pituitary basophilism as the cause of Cushing's disease. In this publication, the clinical symptoms of the disease, named after Cushing, were described.[25][26] Out of the 12 cases with hypercortisolism described in Cushing's monograph on the pituitary body, 67% died within a few years after symptom presentation, whereas Minnie G. survived for more than 40 years after symptom presentation, despite the fact that she did not receive any treatments for a pituitary tumor.[3] The prolonged survival made Minnie's case unique at the time. The reason behind this survival remains a mystery, since an autopsy of Minnie was refused after her death.[3] However, the most likely explanation, proposed by J. Aidan Carney and based on statistical evidence, was that the basophil adenoma Minnie might have harbored underwent partial infarction, leading to symptom regression.[3] The other hypothesis was that Minnie might have suffered from Primary Pigmented Nodular Adrenocortical Disease (PPNAD), which when associated with Cushing's syndrome (Carney complex) can infrequently cause spontaneous symptom regression of the latter.[3] In 1924, the Soviet neurologist Nikolai Itsenko reported two patients with pituitary adenoma. The resulting excessive adrenocorticotropic hormone secretion led to the production of large amounts of cortisol by the adrenal glands. Considering this impact, the name of Itsenko was added to the title in some East European and Asian countries, and the disease is called Itsenko-Kushing disease.[citation needed] ## References[edit] 1. ^ "Whonamedit – Nikolai Mikhailovich Itsenko". "Nikolai Mikhailovich Itsenko investigated neural infections, vegetative nervous system diseases and cerebral tumors. In 1926 he was the first one who described Itsenko-Cushing's disease, six years before Cushing." 2. ^ A.I. Gozhenko; I.P. Gurkalova; W. Zukow; Z. Kwasnik; B. Mroczkowska (2009). "Trematoda". Pathology: Medical Student's Library. Radomska Szkola Wyžsza uk. Zubrzyckiego. p. 280. ISBN 978-83-61047-18-6. 3. ^ a b c d e f g h i Lanzino, Giuseppe; Maartens, Niki F.; Laws, Edward R. (2002). "Cushing's case XLV: Minnie G.". Journal of Neurosurgery. 97 (1): 231–234. doi:10.3171/jns.2002.97.1.0231. PMID 12134925. 4. ^ https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001443/ 5. ^ "Cushing's Syndrome Information Page". Archived from the original on July 27, 2013. Retrieved August 26, 2013. 6. ^ Kirk, Lawrence F., Jr; Robert B. Hash; Harold P. Katner; Tom Jones (September 2000). "Cushing's Disease: Clinical Manifestations and Diagnostic Evaluation". American Family Physician. 62 (5): 1119–27, 1133–4. PMID 10997535. Retrieved August 26, 2013. 7. ^ a b c d e f g h i j k l m n o p q r s t u v w x Newell-Price, J.; Bertagna, X.; Grossman, A.B.; Nieman, L.K. (2006). "Cushing's syndrome". The Lancet. 367 (9522): 1605–1617. doi:10.1016/S0140-6736(06)68699-6. PMID 16698415. S2CID 36208358. Retrieved January 30, 2014. 8. ^ a b c d e Wilson, P.J.; Williams, J.R.; Smee, R.I. (2014). "Cushing's disease: A single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy". Journal of Clinical Neuroscience. 21 (1): 100–106. doi:10.1016/j.jocn.2013.04.007. PMID 24074805. S2CID 35091145. 9. ^ a b c d e f g Nieman, L.K.; Ilias, I. (2005). "Evaluation and treatment of Cushing's syndrome". The American Journal of Medicine. 118 (12): 1340–1346. doi:10.1016/j.amjmed.2005.01.059. PMID 16378774. Retrieved January 30, 2014. 10. ^ Jagannathan J.; et al. (2009). "Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease". Journal of Neurosurgery. 111 (3): 531–9. doi:10.3171/2008.8.JNS08339. PMC 2945523. PMID 19267526. 11. ^ Deipolyi, A; Karaosmanoglu, A; Habito, C; Brannan, S; Wicky, S; Hirsch, J; Oklu, R (February 23, 2011). "The role of bilateral inferior petrosal sinus sampling in the diagnostic evaluation of Cushing disease". Diagnostic and Interventional Radiology (Ankara, Turkey). 18 (1): 132–8. doi:10.4261/1305-3825.DIR.4279-11.0. PMID 21348009. S2CID 41885668. 12. ^ Ding D, Starke RM, Sheehan JP (May 2014). "Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy". J. Neurooncol. 117 (3): 445–57. doi:10.1007/s11060-013-1262-8. PMID 24122025. S2CID 9927830. 13. ^ Laws, Edward R (2010). Transsphenoidal Surgery. Elsevier Inc.[permanent dead link] 14. ^ a b c Biller BM, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JA, Boscaro M (2008). "Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 93 (7): 2454–2462. doi:10.1210/jc.2007-2734. PMC 3214276. PMID 18413427. 15. ^ a b Storr, HL; Plowman PN; Carroll PV; François I; Krassas GE; Afshar F; Besser GM; Grossman AB; Savage MO. (2003). "Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing's Disease: An Effective Second-Line Treatment". J Clin Endocrinol Metab. 88 (1): 34–37. doi:10.1210/jc.2002-021032. PMID 12519825. 16. ^ Gadelha, Mônica R.; Leonardo Vieira Neto (2014). "Efficacy of medical treatment in Cushing's disease: a systematic review". Clinical Endocrinology. 80 (1): 1–12. doi:10.1111/cen.12345. PMID 24118077. S2CID 21444684. 17. ^ Fairfield, Wesley P. (2003). "Cushing's Disease after Successful Transsphenoidal Surgery – What to Expect and How to Manage". Retrieved January 31, 2014. 18. ^ Patil, CG; Lad, SP; Harsh, GR; Laws ER, Jr; Boakye, M (2007). "National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002". Neurosurgical Focus. 23 (3): E7. doi:10.3171/foc.2007.23.3.9. PMID 17961019. S2CID 24097046. 19. ^ a b c d e f g Etxabe, J.; J. A. Vazquez (1994). "Morbidity and mortality in Cushing's disease: an epidemiological approach". Clinical Endocrinology. 40 (4): 479–484. doi:10.1111/j.1365-2265.1994.tb02486.x. PMID 8187313. S2CID 9409591. 20. ^ Boggan, J.E; Tyrell, J.B; Wilson C.B (1983). "Transsphenoidal microsurgical management of Cushing's disease: report of 100 cases". Journal of Neurosurgery. 59 (2): 195–200. doi:10.3171/jns.1983.59.2.0195. PMID 6306181. S2CID 23636688. 21. ^ Howlet, T.A; Perry L.; Doniach I.; Rees LH.; Besser G.M (1986). "Diagnosis and management of ACTHdependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production". Clinical Endocrinology. 24 (6): 699–713. doi:10.1111/j.1365-2265.1986.tb01667.x. PMID 3024870. S2CID 2569895. 22. ^ Lindholm, J.; Juul, S.; Jørgensen, J.O.L.; Astrup, J.; Bjerre, P.; Feldt-Rasmussen, U.; Hagen, C.; Jørgensen, J.; Kosteljanetz, M.; Kristensen, L.Ø.; Laurberg, P.; Schmidt, K.; Weeke, J (2001). "Incidence and late prognosis of Cushing's syndrome: A population-based study". Journal of Clinical Endocrinology and Metabolism. 86 (1): 117–123. doi:10.1210/jcem.86.1.7093. PMID 11231987. 23. ^ Cushing H: The Pituitary Body and its Disorders: Clinical States Produced by Disorders of the Hypophysis Cerebra. Philadelphia: JB Lippincott, 1912 24. ^ Laws ER, Ezzat S, Asa SL, Rio LM, Michel L, Knutzen R, eds. (2013). Pituitary Disorders: Diagnosis and Management. United Kingdom: Wiley-blackwell. p. xiv. ISBN 978-0-470-67201-3. 25. ^ Cushing, Harvey (1932). "The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)". Bulletin of the Johns Hopkins Hospital. 50: 137–95. Reprinted in Cushing H (April 1969). "The basophil adenomas of the pituitary body". Ann R Coll Surg Engl. 44 (4): 180–1. PMC 2387613. PMID 19310569. 26. ^ "Dr. Cushing Dead; Brain Surgeon, 70. A Pioneer Who Won Fame as Founder of New School of Neuro-Surgery. Discovered Malady Affecting Pituitary dre. Was Noted Teacher and author". The New York Times. October 8, 1939. Retrieved March 21, 2010. ## External links[edit] * The difference between Cushing's disease and other forms of Cushing's syndrome * Australian Pituitary Foundation * Cushing's Support & Research Foundation * "The burden of Cushing's disease (CD): clinical and health-related quality of life aspects" (RA Feelders, SJ Pulgar, A Kempel, and AM Pereira) Classification D * ICD-10: E24.0 * OMIM: 219090 * SNOMED CT: 190502001 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Cushing's disease	c0010481	1,155	wikipedia	https://en.wikipedia.org/wiki/Cushing%27s_disease	2021-01-18T18:40:47	{"mesh": ["D003480"], "icd-10": ["E24.0"], "orphanet": ["96253"], "wikidata": ["Q1947304"]}
Langer–Giedion syndrome Other namesDeletion 8q24.1, monosomy 8q24.1, trichorhinophalangeal syndrome type II (TRPS2), Langer-Giedion chromosome region (LGCR)[1][2] A person showing the typical features of Langer-Giedion syndrome SpecialtyMedical genetics Langer–Giedion syndrome (LGS) is a very uncommon autosomal dominant genetic disorder caused by a deletion of a small section of material on chromosome 8. It is named after the two doctors who undertook the main research into the condition in the 1960s. Diagnosis is usually made at birth or in early childhood. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] The features associated with this condition include: mild to moderate learning difficulties, short stature, unique facial features, small head and skeletal abnormalities including bony growths projecting from the surfaces of bones.[3] Typically, individuals with Langer–Giedion syndrome have fine scalp hair, ears that may be large or prominent, broad eyebrows, deep-set eyes, a bulbous nose, a long narrow upper lip and missing teeth.[citation needed] * The right foot of a person with Langer–Giedion syndrome showing the characteristic features * Hands of a person with Langer–Giedion syndrome showing the characteristic short fingers ## Cause[edit] The syndrome occurs when a small piece of chromosome 8's long arm, which contains a number of genes, is missing. The loss of these genes is responsible for some of the overall characteristics of Langer–Giedion syndrome.[citation needed] The missing portion of the chromosome is 8q23.2–q24.1.[2] This region includes the genes TRPS1 and EXT1.[citation needed] ## Diagnosis[edit] Diagnosis is based on clinical findings and can be confirmed by cytogenetic testing, when the deletion is in an average of 5 Mb (millions of base pairs). Nowadays, it is a common practice to run an aCGH (array chromosome hybridization genome) study on peripheral blood of the patient, in order to delineate the extent of the loss of the genomic area, and the deleted genes.[4] ## Treatment[edit] While no genetic syndrome is capable of being cured, treatments are available for some symptoms. External fixators have been used for limbic and facial reconstructions.[citation needed] ## See also[edit] * TRPS1 ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 150230 2. ^ a b McBrien, J.; Crolla, J. A.; Huang, S.; Kelleher, J.; Gleeson, J.; Lynch, S. A. (June 2008). "Further case of microdeletion of 8q24 with phenotype overlapping Langer–Giedion withoutTRPS1 deletion". American Journal of Medical Genetics Part A. 146A (12): 1587–1592. doi:10.1002/ajmg.a.32347. PMID 18478595. 3. ^ Devidayal; Marwaha RK (February 2006). "Langer-Giedion Syndrome" (PDF). Indian Pediatrics. 43 (2): 174–175. PMID 16528117. 4. ^ http://www.omim.org/entry/150230 ## External links[edit] Classification D * ICD-10: ICD-10: Q87.8 * OMIM: 150230 * MeSH: D015826 * DiseasesDB: 31949 External resources * Orphanet: 502 * Trichorhinophalangeal syndrome type 2 at NIH's Office of Rare Diseases * v * t * e Genetic disorders relating to deficiencies of transcription factor or coregulators (1) Basic domains 1.2 * Feingold syndrome * Saethre–Chotzen syndrome 1.3 * Tietz syndrome (2) Zinc finger DNA-binding domains 2.1 * (Intracellular receptor): Thyroid hormone resistance * Androgen insensitivity syndrome * PAIS * MAIS * CAIS * Kennedy's disease * PHA1AD pseudohypoaldosteronism * Estrogen insensitivity syndrome * X-linked adrenal hypoplasia congenita * MODY 1 * Familial partial lipodystrophy 3 * SF1 XY gonadal dysgenesis 2.2 * Barakat syndrome * Tricho–rhino–phalangeal syndrome 2.3 * Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome * Denys–Drash syndrome * Duane-radial ray syndrome * MODY 7 * MRX 89 * Townes–Brocks syndrome * Acrocallosal syndrome * Myotonic dystrophy 2 2.5 * Autoimmune polyendocrine syndrome type 1 (3) Helix-turn-helix domains 3.1 * ARX * Ohtahara syndrome * Lissencephaly X2 * MNX1 * Currarino syndrome * HOXD13 * SPD1 synpolydactyly * PDX1 * MODY 4 * LMX1B * Nail–patella syndrome * MSX1 * Tooth and nail syndrome * OFC5 * PITX2 * Axenfeld syndrome 1 * POU4F3 * DFNA15 * POU3F4 * DFNX2 * ZEB1 * Posterior polymorphous corneal dystrophy * Fuchs' dystrophy 3 * ZEB2 * Mowat–Wilson syndrome 3.2 * PAX2 * Papillorenal syndrome * PAX3 * Waardenburg syndrome 1&3 * PAX4 * MODY 9 * PAX6 * Gillespie syndrome * Coloboma of optic nerve * PAX8 * Congenital hypothyroidism 2 * PAX9 * STHAG3 3.3 * FOXC1 * Axenfeld syndrome 3 * Iridogoniodysgenesis, dominant type * FOXC2 * Lymphedema–distichiasis syndrome * FOXE1 * Bamforth–Lazarus syndrome * FOXE3 * Anterior segment mesenchymal dysgenesis * FOXF1 * ACD/MPV * FOXI1 * Enlarged vestibular aqueduct * FOXL2 * Premature ovarian failure 3 * FOXP3 * IPEX 3.5 * IRF6 * Van der Woude syndrome * Popliteal pterygium syndrome (4) β-Scaffold factors with minor groove contacts 4.2 * Hyperimmunoglobulin E syndrome 4.3 * Holt–Oram syndrome * Li–Fraumeni syndrome * Ulnar–mammary syndrome 4.7 * Campomelic dysplasia * MODY 3 * MODY 5 * SF1 * SRY XY gonadal dysgenesis * Premature ovarian failure 7 * SOX10 * Waardenburg syndrome 4c * Yemenite deaf-blind hypopigmentation syndrome 4.11 * Cleidocranial dysostosis (0) Other transcription factors 0.6 * Kabuki syndrome Ungrouped * TCF4 * Pitt–Hopkins syndrome * ZFP57 * TNDM1 * TP63 * Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8 Transcription coregulators Coactivator: * CREBBP * Rubinstein–Taybi syndrome Corepressor: * HR (Atrichia with papular lesions) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Langer–Giedion syndrome	c0023003	1,156	wikipedia	https://en.wikipedia.org/wiki/Langer%E2%80%93Giedion_syndrome	2021-01-18T18:30:25	{"gard": ["7801"], "mesh": ["D015826"], "umls": ["C2931237"], "icd-9": ["755.8"], "icd-10": ["Q87.8"], "orphanet": ["502"], "wikidata": ["Q3508795"]}
"CCVI" redirects here. For other uses, see CCVI (disambiguation). Chronic cerebrospinal venous insufficiency Veins of the neck. V.jugularis interna is proposed to be stenosed or have a malformed valve in CCSVI cases. SpecialtyCardiology Chronic cerebrospinal venous insufficiency (CCSVI or CCVI) is a term invented by Italian researcher Paolo Zamboni in 2008 to describe compromised flow of blood in the veins draining the central nervous system.[1][2] Zamboni hypothesized that it might play a role in the cause or development of multiple sclerosis (MS).[3][4] Zamboni also devised a surgical procedure which the media nicknamed a liberation procedure or liberation therapy, involving venoplasty or stenting of certain veins.[5] Zamboni's ideas about CCSVI are very controversial, with significantly more detractors than supporters, and any treatments based on his ideas are considered experimental.[6][7] There is no scientific evidence that CCSVI is related to MS, and there is no good evidence that the surgery helps MS patients. Zamboni's first published research was neither blinded nor did it have a comparison group.[5] Zamboni also did not disclose his financial ties to Esaote, the manufacturer of the ultrasound specifically used in CCSVI diagnosis.[8] The "liberation procedure" has been criticized for possibly resulting in serious complications and deaths, while its purported benefits have not been proven.[5][7] In 2012, the United States Food and Drug Administration states that it is not clear if CCSVI exists as a clinical entity and that these treatments may cause more harm.[9] In 2017 they emphasized that this use of balloon angioplasty is not an approved use.[10] In a 2017 study Zamboni et al. stated "Venous PTA cannot be recommended for patients with relapsing-remitting multiple sclerosis."[11] In 2018 a study in Neurology concluded "Our data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS."[12] Research on CCSVI was fast-tracked, but researchers have been unable to find a connection between CCSVI and MS.[13] This has raised serious objections to the hypothesis of CCSVI originating multiple sclerosis.[14] Additional research investigating the CCSVI hypothesis is underway.[15] A 2013 study found that CCSVI is equally rare in people with and without MS, while narrowing of the cervical veins is equally common.[16][17] ## Contents * 1 Hypothesis * 2 Pathophysiology * 2.1 Venous malformations * 2.2 Iron deposits * 2.3 Genetics * 3 Diagnosis * 4 Treatment * 4.1 All proposed treatments are experimental * 4.2 Procedures * 4.3 Adverse effects * 5 History * 6 Society and culture * 6.1 Conflict of interest * 6.2 Media * 6.3 Reception in Canada * 6.4 Organizations * 7 Research * 8 See also * 9 References * 10 Further reading * 11 External links ## Hypothesis[edit] Proposed consequences of CCSVI syndrome include intracranial hypoxia, delayed perfusion, reduced drainage of catabolites, increased transpulmonary pressure,[18] and iron deposits around the cerebral veins.[19][20] Multiple sclerosis has been proposed as a possible outcome of CCSVI. ## Pathophysiology[edit] Zamboni and colleagues claimed that in MS patients diagnosed with CCSVI, the azygos and IJV veins are stenotic (abnormally narrowed) in around 90% of cases. Zamboni theorized that malformed blood vessels cause increased deposition of iron in the brain, which in turn triggers autoimmunity and degeneration of the nerve's myelin sheath.[19][21] While the initial article on CCSVI claimed that abnormal venous function parameters were not seen in healthy people, others have noted that this is not the case.[21] In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did.[1][21] Such outstanding results have raised suspicions of a possible spectrum bias, which originates on a diagnostic test not being used under clinically significant conditions.[21] Further studies of the relationship between CCSVI and MS have had variable results,[13] with many failing to reproduce the association between MS and CCSVI.[22][23][24] Moreover, the greatest predictor of positive results is researchers' involvement in the administration of the "liberation procedure".[22][24] This effect goes to the extent that, when only fully independent studies are considered, no association at all is found.[24] The poor reproducibility across studies and diagnostic modalities has led some authors to conclude that CCVSI might be nothing more than a clinically irrelevant sonographic construct.[22] Already by 2010, there were "a growing number of papers that raise serious questions about its (CCSVI) validity",[14] although evidence had been "both for and against the controversial hypothesis".[25] It was agreed that it was urgent to perform appropriate epidemiological studies to define the possible relationship between CCSVI and MS, although existing data did not support CCSVI as the cause of MS.[13] ### Venous malformations[edit] Most of the venous problems in MS patients have been reported to be truncular venous malformations, including azygous stenosis, defective jugular valves and jugular vein aneurysms. Problems with the innominate vein and superior vena cava have also been reported to contribute to CCSVI.[26] A vascular component in MS had been cited previously.[27][28] Several characteristics of venous diseases make it difficult to include MS in this group.[14] In its current form, CCSVI cannot explain some of the epidemiological findings in MS. These include risk factors such as Epstein-Barr infection, parental ancestry, date of birth and geographic location.[14][29] MS is also more common in women, while venous diseases are more common in men. Venous pathology is commonly associated with hypertension, infarcts, edema and transient ischemia, and occurs more often with age, however these conditions are hardly ever seen in MS and the disease seldom appears after age 50. Finally, an organ-specific immune response is not seen in any other kind of venous disease.[14] ### Iron deposits[edit] Iron deposition as a cause of MS received support when a relationship between venous pressure and iron depositions in MS patients was found in a neuroimaging study, and criticism as other researchers found normal ferritin levels in the cerebrospinal fluid of MS patients.[13][30] Additionally iron deposition occurs in different neurological diseases such as Alzheimer's disease or Parkinson's disease that are not associated with CCSVI.[1][21] Evidence linking CCSVI and iron deposition is lacking, and dysregulation of iron metabolism in MS is more complex than simply iron accumulation in the brain tissue.[31] ### Genetics[edit] A small genetic study looked at fifteen MS patients who also had CCSVI. It found 234 specific copy number variations in the human leukocyte antigen focus. Of these, GRB2, HSPA1L and HSPA1A were found to be specifically connected to both MS and angiogenesis, TAF11 was connected to both MS and artery passage, and HLA-DQA2 was suggestive of having an implication for angiogenesis as it interacts with CD4.[32] A study in 268 MS patients and 155 controls reported more a frequency of CCSVI in the MS group that was more than twice as high as in the controls group and was also higher in the progressive MS group than in the non-progressive MS group. This study found no relationship between CCSVI and HLA DRB11501, a genetic variation that has been consistently linked to MS.[33] ## Diagnosis[edit] Computer-enhanced transcranial doppler. CCSVI was first described using specialized extracranial and transcranial doppler sonography.[1][21] Five ultrasound criteria of venous drainage have been proposed to be characteristic of the syndrome, although two are considered sufficient for diagnosis of CCSVI:[1][21][34] reflux in the internal jugular and vertebral veins, * reflux in the deep cerebral veins, * high-resolution B-mode ultrasound evidence of stenosis of the internal jugular vein, * absence of flow in the internal jugular or vertebral veins on Doppler ultrasound, and * reverted postural control of the main cerebral venous outflow pathways. It is still not clear whether magnetic resonance venography, venous angiography, or Doppler sonography should be considered the gold standard for the diagnosis of CCSVI.[13] Use of magnetic resonance venography for the diagnosis of CCSVI in MS patients has been proposed by some to have limited value, and should be used only in combination with other techniques.[35] Others have stated that magnetic resonance venography is a valid measure which has advantages over Doppler including the fact that results are more operator-independent.[36] Diagnostic criteria have been criticized. Both the number of criteria and the need of being positive for two of them as enough for diagnosis are arbitrary ideas.[36] Moreover, experienced groups in the use of ultrasound have not been able to show intracranial or extracranial reflux in MS patients or even healthy controls whereas the criterion of absence of flow and the criterion regarding stenosis are considered not valid since they are related to normal physiological processes and not pathology.[36] These problems in the criteria have led some researchers to consider the criteria inadequate and more generally the concept of CCSVI flawed.[36] ## Treatment[edit] ### All proposed treatments are experimental[edit] Treatment based on the idea of CCSVI is considered experimental.[6] Balloon dilatation of stenosed jugular vein in a MS patient. Stenosis prevents the balloon from inflating (in the middle) while pressure is low. Further trials are required to determine if the benefits, if any, of the procedure outweigh its risks.[21] Most experts, and medical and patients organizations, including the National Multiple Sclerosis Society of the USA or the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), recommend not using the proposed treatment outside clinical trials until its effectiveness is confirmed by controlled studies.[3][5][7][21][37][38] Moreover, the CIRSE has stated that treatment research should begin by a small, placebo-controlled, prospective randomised trial which should be monitored by an independent organization.[38] An exception has been the Society of Interventional Radiology in the US and Canada, which considered research on the effectiveness of CCSVI intervention to be inconclusive as of 2010.[39] In March 2013 a press release indicated that the first prospective, placebo-controlled study of balloon angioplasty for MS had not shown any benefit of the therapy. The study, a phase II clinical trial designed to evaluate safety and efficacy of endovascular treatment, enrolled initially 10 patients that received the treatment and 20 more afterwards that were either allocated to receive angioplasty or a placebo intervention.[40] Kuwait became the first country in the world where treatment of CCSVI, as of 2010, was explicitly allowed by the medical authorities and paid by the state health system.[41] As of 2010, the procedure was performed privately in 40 countries,[42] and, despite existing recommendations, as of 2013 it is believed that over 30,000 patients have undergone the procedure.[40] ### Procedures[edit] Balloon angioplasty and stenting have been proposed as treatment options for CCSVI in MS. The proposed treatment has been termed "liberation therapy" though the name has been criticized for suggesting unrealistic results.[14] Balloon angioplasty in a preliminary, uncontrolled, unblinded study by Zamboni improved symptoms in MS in a minority of treated people.[43] Although the procedure pushes the vein open temporarily, the effect does not persist,[21] supporters advise against using stents.[44] Venous percutaneous transluminal angioplasty (PTA) has proven to be safe but due to its ineffectiveness is not recommended.[15] ### Adverse effects[edit] While the procedure has been reported to be generally safe for MS patients,[13][40][45] severe complications related to the angioplasty and stenting that have been reported include intracranial hemorrhage, stent migration into a renal vein, thrombosis and nerve compression syndrome of cranial nerves XI and XII.[13][14][36] One death case appeared in the scientific literature, while 3 other deaths have been related to CCSVI treatment in the media.[36] Some United States hospitals have banned the surgical procedure outside clinical trials due to safety concerns until more evidence to support its use is available.[7][46] In May 2012 the U.S. Food and Drug Administration issued a safety communication on CCSVI, stating that MS patients undergoing angioplasty and/or stenting to treat CCSVI risk serious injuries or death. Furthermore, it also noted that the benefits of these experimental procedures have not been proven and that studies exploring a link between MS and CCSVI are inconclusive.[9] ## History[edit] Paolo Zamboni described CCSVI in 2008. Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins.[47] Later, in 1935, Tracy Putnam was able to produce similar lesions in dogs blocking their veins[48] The term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis.[1][21] Zamboni's results were criticized because his study was not blinded and his results needed to be verified by further studies.[1][21] Zamboni had become interested in CCSVI in 1999 when his wife was diagnosed with MS.[49] ## Society and culture[edit] ### Conflict of interest[edit] Paolo Zamboni has patents related to the highly sensitive ultrasound diagnostic systems manufactured by Esaote which, he proposes, should be used to diagnose CCSVI.[8] Moreover, Zamboni's research center has also received support in the form of equipment and technical assistance from this manufacturer.[8] These are potential conflicts of interest that he has never disclosed when publishing scientific articles, which would be against ethical practices of some countries such as the United States.[8] ### Media[edit] CCSVI has received a great deal of attention in all media, the scientific literature and on the Internet.[14] Moreover, the CCSVI case has been considered a good example of how new communication technologies and social media are modifying the traditional relationship between science, politics, medicine, and the general public.[49] In this sense they have played a key role in effectively promoting the theory.[49] Media coverage has been perceived by some as "hype", with exaggerated claims that have led to excessive expectations.[5][50] This has been partially attributed to some of the investigators of the theory.[5] Mainstream media initial approximations to Zamboni's theory were enthusiastic and emphasized Zamboni's effort to find a cure for his wife, along with the improvement of some patients after its alleged treatment.[49] Initial difficulty reproducing results connecting MS and CCSVI, combined with reports of secondary effects of the surgical procedure, led to a more cautious discourse proposing that more investigation in the relationship between CCSVI and MS was needed.[49] The first fatality related to CCSVI treatment was a pivotal development in this trend towards a less optimistic media view of the theory.[49] The Internet has been extensively used by patient groups to obtain and disseminate information on CCSVI. People with MS often read extensively about the CCSVI theory and its development on Internet sites,[51] and a search for "liberation procedure" in Google as of August 2010 yielded more than 2.5 million hits.[14] The Internet has also been used to advertise places where stenting for CCSVI is performed,[14] and to more generally disseminate all the information on CCSVI.[49] Social media have served patient groups in their attempt to pressure official bodies to make decisions favoring funding of clinical trials, or the public coverage of stenting and venoplasty as treatments of MS.[49] Likewise, social media have been accused of creating a division between CCSVI supporters and those who say it does not work.[49][50] Indeed, they have been repeatedly used by advocates of the CCSVI theory to attack those who were more critical or cautious, most commonly with accusations of being tainted due to commercial relationships with pharmaceutical companies.[49] Many patients who have had the surgical procedure report their improvements on social media websites such as structured patient databases and YouTube.[36][51] Such stories are only anecdotal evidence of efficacy, and do not constitute a scientific proof of the efficacy of the treatment since, for example, those who have had a positive result are more prone to post their cases than those who had little or no improvement,[51] and the reported improvements in patients' condition can be attributed to the placebo effect.[50][52][53] Patients' reasons for not publishing negative results may include embarrassment about the money spent in the procedure without effect and the negative reaction they expect from other people with MS.[50] Caution has been recommended regarding patients' self-reports found on the web.[50][51][52] Scientists and physicians transmitted their arguments regarding CCSVI inadequately, especially after the initial rising of the hypothesis. Their communication was characterized by an excessive hesitation and a lack of clear statements, as opposed to CCSVI proponents, who "won the communication battle, at least in the early rounds."[49] A positive effect of the important media coverage may be that it forces the world of medical research to be self-critical and give appropriate responses to the questions that globalization of the theory raises, especially among MS sufferers.[50] ### Reception in Canada[edit] While reasons are not completely clear, the CCSVI theory was received differently in Canada than other places. The public interest and number of media appearances were much greater than elsewhere, including Italy, and debate has been heated regarding funding.[25][49] As an example, by the end of 2009, a public petition to the country health authorities in support of the "liberation treatment" had received over 17,000 signatures.[49] The debate regarding funding in Canada has been considered to be specially informative as an example of extreme involvement of politics, due to public pressure, in decisions usually governed by scientific evidence.[49] In 2009, the Multiple Sclerosis Society of Canada committed to funding research on the connection between CCSVI and MS,[54] although later in 2010 it came under criticism for opposing clinical trials of CCSVI therapy.[55] The MS Society of Canada in September 2010 reserved one million dollars toward CCSVI research "when a therapeutic trial is warranted and approved."[56] At a political level there have been contradictory positions, with some provinces funding trials, others stating that since therapy is unproven they should wait,[57][58] and others urging for a pan-Canadian trial.[59] British Columbia, Alberta, and Newfoundland and Labrador funded observational studies in which patients who had already received the treatment were included. Over 2 million dollars were allocated to these studies.[49] The province of Saskatchewan was more aggressive and provided 2.2 million dollars for some of its residents to be included in a clinical trial.[49] The Canadian Institutes of Health Research (CIHR), the federal agency responsible for funding health research, recommended in 2010 against funding a pan-Canadian trial of liberation therapy because there was a lack of evidence on the safety or efficacy of the procedure. It suggested a scientific expert working group made up of the principal investigators for the seven MS Society-sponsored studies.[49][60] The health minister accepted the CIHR recommendation and said that Canada was not going to fund clinical trials.[61] The expert panel was created by the end of 2010 together between the CIHR and the MS Society of Canada.[49] It has been proposed that the creation of this expert panel was partly directed to cope with the high levels of social pressure the CCSVI theory had raised and at the same time try to maintain a scientific perspective in the funding and investigation of CCSVI.[49] The main task of the panel was to monitor the results of the ongoing studies in the relationship between CCSVI and MS and recommend the funding of a clinical trial in case that there was evidence of a true relationship between the two.[49] In 2011, the Canadian federal government announced that they would fund clinical trials of the procedure to widen the veins since CIHR considered that evidence of venous abnormalities in MS was enough for small treatment trials.[49][62] It has been proposed that the recommendation to fund phase I and II trials instead of a big study was a compromise between the high levels of social and political pressure and the low level of evidence on the theory.[49] Two qualitative studies have investigated the motives and experiences of Canadian patients traveling abroad to get the "liberation procedure".[63][64] One of the studies identified three factors contributing to patients going abroad seeking treatment: a loss of faith in the Canadian health system when it did not provide access to CCSVI treatment in Canada, hope in the new treatment as a solution for their worsening health, and trust in the MS community and the organizations, clinics and doctors facilitating or providing the desired operation.[63] Conversely, the other study concluded that sense of community and cooperation (from family, MS groups and the general population) was a key motivating factor.[64] Other motivating factors included media reports, perception of approval from their health providers, the apparent low risk of the operation, or accessibility of the hospital that offered the procedure directly or through a medical tourism company.[64] On the other hand, hesitating factors included the cost and effort required for the operation, the mistrust of foreign health systems, the underlying rationale for the operation, or advice against the procedure from trusted health providers.[64] In 2013, a case-control study found evidence against the involvement of chronic cerebrospinal venous abnormalities in MS.[65] Later in 2013 a study found that vein narrowing appears to be present equally in those with and without MS on ultrasound and catheter venography.[66] The results of the study were described as a "death knell" for Zamboni's theory.[67] Another study released by the University of British Columbia in 2017 was described as a "definitive debunking" of liberation therapy.[68] ### Organizations[edit] Several national and international organizations have been created to further the research and dissemination of the CCSVI theory, such as the International Society for Neurovascular Disease and the National CCSVI Society of Canada.[69] They are working together with already existing organizations like the International Union of Phlebology (Union internationale de phlébologie-UIP- in French, its original working language)[70] of which Zamboni is a member.[71] The UIP for example proposed that developmental abnormalities were the primary cause of CCSVI.[72] ## Research[edit] There were further studies aimed at clarifying if there is a relationship between MS and CCSVI. In particular, the US and Canadian MS societies launched seven such studies.[14][73] Recent reviewers have shown "no significant difference in prevalence of CCSVI in people with MS compared to people without MS".[36] In 2014 imaging criteria for venous abnormalities were published to help with research on this topic.[74] ## See also[edit] * Chronic venous insufficiency * Pathophysiology of multiple sclerosis * Vascular myelopathy ## References[edit] 1. ^ a b c d e f g Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall'Ara S, et al. (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". Journal of Neurology, Neurosurgery, and Psychiatry. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024. 2. ^ Al-Omari MH, Rousan LA (April 2010). "Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis". International Angiology. 29 (2): 115–20. PMID 20351667. 3. ^ a b Khan O, Filippi M, Freedman MS, Barkhof F, Dore-Duffy P, Lassmann H, et al. (March 2010). "Chronic cerebrospinal venous insufficiency and multiple sclerosis". Annals of Neurology. 67 (3): 286–90. CiteSeerX 10.1.1.606.8269. doi:10.1002/ana.22001. PMID 20373339. S2CID 16580847. "A chronic state of impaired venous drainage from the central nervous system, termed chronic cerebrospinal venous insufficiency (CCSVI), is claimed to be a pathologic phenomenon exclusively seen in multiple sclerosis (MS)." 4. ^ Lee AB, Laredo J, Neville R (April 2010). "Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency". International Angiology. 29 (2): 95–108. PMID 20351665. "A similar condition involving the head and neck venous system may cause chronic cerebro-spinal venous insufficiency (CCSVI) and may be involved in the development or exacerbation of multiple sclerosis." 5. ^ a b c d e f Qiu J (May 2010). "Venous abnormalities and multiple sclerosis: another breakthrough claim?". The Lancet. Neurology. 9 (5): 464–5. doi:10.1016/S1474-4422(10)70098-3. PMID 20398855. S2CID 206159378. 6. ^ a b Ferral, Hector; Lorenz, Jonathan M. (13 April 2018). Radcases Interventional Radiology. Thieme Medical Publishers. ISBN 978-1-62623-283-9. 7. ^ a b c d "Experimental multiple sclerosis vascular shunting procedure halted at Stanford". Annals of Neurology. 67 (1): A13-5. January 2010. doi:10.1002/ana.21969. PMID 20186848. S2CID 37071227. 8. ^ a b c d Stone K (March 2012). "Medical device conflict of interest in the CCSVI debate". Annals of Neurology. 71 (3): A6-8. doi:10.1002/ana.23560. PMID 22451214. S2CID 205343879. 9. ^ a b FDA (May 2012). "FDA Safety Communication: Chronic Cerebrospinal Venous Insufficiency Treatment in Multiple Sclerosis Patients". Retrieved 6 November 2013. 10. ^ "Safety Alerts for Human Medical Products - Balloon angioplasty devices to treat autonomic dysfunction: FDA Safety Communication - FDA concern over experimental procedures". www.fda.gov. Retrieved 9 March 2017. 11. ^ Zamboni P, Tesio L, Galimberti S, Massacesi L, Salvi F, D'Alessandro R, et al. (January 2018). "Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial". JAMA Neurology. 75 (1): 35–43. doi:10.1001/jamaneurol.2017.3825. PMC 5833494. PMID 29150995. 12. ^ Traboulsee AL, Machan L, Girard JM, Raymond J, Vosoughi R, Hardy BW, et al. (October 2018). "Safety and efficacy of venoplasty in MS: A randomized, double-blind, sham-controlled phase II trial". Neurology. 91 (18): e1660–e1668. doi:10.1212/WNL.0000000000006423. PMC 6207414. PMID 30266886. 13. ^ a b c d e f g Ghezzi A, Comi G, Federico A (February 2011). "Chronic cerebro-spinal venous insufficiency (CCSVI) and multiple sclerosis". Neurological Sciences. 32 (1): 17–21. doi:10.1007/s10072-010-0458-3. PMID 21161309. S2CID 27687609. 14. ^ a b c d e f g h i j k Dorne H, Zaidat OO, Fiorella D, Hirsch J, Prestigiacomo C, Albuquerque F, Tarr RW (December 2010). "Chronic cerebrospinal venous insufficiency and the doubtful promise of an endovascular treatment for multiple sclerosis". Journal of NeuroInterventional Surgery. 2 (4): 309–11. doi:10.1136/jnis.2010.003947. PMID 21990639. 15. ^ a b Jagannath VA, Pucci E, Asokan GV, Robak EW (May 2019). "Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in people with multiple sclerosis". The Cochrane Database of Systematic Reviews. 5: CD009903. doi:10.1002/14651858.CD009903.pub3. PMC 6543952. PMID 31150100. 16. ^ Traboulsee AL, Knox KB, Machan L, Zhao Y, Yee I, Rauscher A, et al. (January 2014). "Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study". Lancet. 383 (9912): 138–45. doi:10.1016/S0140-6736(13)61747-X. PMID 24119384. S2CID 25925875. 17. ^ Paul F, Wattjes MP (January 2014). "Chronic cerebrospinal venous insufficiency in multiple sclerosis: the final curtain". Lancet. 383 (9912): 106–8. doi:10.1016/S0140-6736(13)61912-1. PMID 24119383. S2CID 205970625. 18. ^ Franceschi C (April 2009). "The unsolved puzzle of multiple sclerosis and venous function". Journal of Neurology, Neurosurgery, and Psychiatry. 80 (4): 358. doi:10.1136/jnnp.2008.168179. PMID 19289474. S2CID 30645997. 19. ^ a b Singh AV, Zamboni P (December 2009). "Anomalous venous blood flow and iron deposition in multiple sclerosis". Journal of Cerebral Blood Flow and Metabolism. 29 (12): 1867–78. doi:10.1038/jcbfm.2009.180. PMID 19724286. 20. ^ Zamboni P (November 2006). "The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis". Journal of the Royal Society of Medicine. 99 (11): 589–93. doi:10.1258/jrsm.99.11.589. PMC 1633548. PMID 17082306. 21. ^ a b c d e f g h i j k l Khan O, Filippi M, Freedman MS, Barkhof F, Dore-Duffy P, Lassmann H, et al. (March 2010). "Chronic cerebrospinal venous insufficiency and multiple sclerosis". Annals of Neurology. 67 (3): 286–90. CiteSeerX 10.1.1.606.8269. doi:10.1002/ana.22001. PMID 20373339. S2CID 16580847. Archived from the original on 23 November 2010. 22. ^ a b c Tsivgoulis G, Faissner S, Voumvourakis K, Katsanos AH, Triantafyllou N, Grigoriadis N, et al. (January 2015). ""Liberation treatment" for chronic cerebrospinal venous insufficiency in multiple sclerosis: the truth will set you free". Brain and Behavior. 5 (1): 3–12. doi:10.1002/brb3.297. PMC 4321389. PMID 25722945. 23. ^ Jedynak W, Cieszanowski A (2014). "Is there any relation between chronic cerebrospinal venous insufficiency and multiple sclerosis? - a critical review". Polish Journal of Radiology. 79: 131–6. doi:10.12659/PJR.890379. PMC 4049975. PMID 24917892. 24. ^ a b c Tsivgoulis G, Sergentanis TN, Chan A, Voumvourakis K, Triantafyllou N, Psaltopoulou T, et al. (March 2014). "Chronic cerebrospinal venous insufficiency and multiple sclerosis: a comprehensive meta-analysis of case-control studies". Therapeutic Advances in Neurological Disorders. 7 (2): 114–36. doi:10.1177/1756285613499425. PMC 3932766. PMID 24587827. 25. ^ a b Jeffrey S (3 December 2009). "CCSVI in Focus at ECTRIMS: New Data but Still Little Clarity". Medscape. Retrieved 23 November 2010. 26. ^ Lee AB, Laredo J, Neville R (April 2010). "Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency" (PDF). International Angiology. 29 (2): 95–108. PMID 20351665. Archived from the original (PDF) on 4 July 2010. Retrieved 13 June 2010. 27. ^ Simka M (May 2009). "Blood brain barrier compromise with endothelial inflammation may lead to autoimmune loss of myelin during multiple sclerosis". Current Neurovascular Research. 6 (2): 132–9. CiteSeerX 10.1.1.537.4685. doi:10.2174/156720209788185605. PMID 19442163. 28. ^ Marrie RA, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T (March 2010). "Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis". Neurology. 74 (13): 1041–7. doi:10.1212/WNL.0b013e3181d6b125. PMC 2848107. PMID 20350978. 29. ^ Handel AE, Lincoln MR, Ramagopalan SV (August 2010). "Chronic cerebrospinal venous insufficiency and multiple sclerosis". Annals of Neurology. 68 (2): 270. doi:10.1002/ana.22067. PMID 20695021. S2CID 29625376. 30. ^ Primary studies during 2010 on neuroimaging, CCSVI, and MS: * Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, et al. (November 2010). "Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency". Neurology. 75 (18): 1617–22. doi:10.1212/WNL.0b013e3181fb449e. PMID 20881272. S2CID 22277005. * Haacke EM, Garbern J, Miao Y, Habib C, Liu M (April 2010). "Iron stores and cerebral veins in MS studied by susceptibility weighted imaging". International Angiology. 29 (2): 149–57. PMID 20351671. 31. ^ van Rensburg SJ, van Toorn R (November 2010). "The controversy of CCSVI and iron in multiple sclerosis: is ferritin the key?". Neurology. 75 (18): 1581–2. doi:10.1212/WNL.0b013e3181fb44f0. PMID 20881276. S2CID 139095367. 32. ^ Ferlini A, Bovolenta M, Neri M, Gualandi F, Balboni A, Yuryev A, et al. (April 2010). "Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis". BMC Medical Genetics. 11: 64. doi:10.1186/1471-2350-11-64. PMC 2880319. PMID 20426824. (primary source) 33. ^ Weinstock-Guttman B, Zivadinov R, Cutter G, Tamaño-Blanco M, Marr K, Badgett D, et al. (February 2011). Kleinschnitz C (ed.). "Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB11501 status in multiple sclerosis patients". PLOS ONE. 6 (2): e16802. Bibcode:2011PLoSO...616802W. doi:10.1371/journal.pone.0016802. PMC 3038867. PMID 21340025. (primary source) 34. ^ Simka M, Kostecki J, Zaniewski M, Majewski E, Hartel M (April 2010). "Extracranial Doppler sonographic criteria of chronic cerebrospinal venous insufficiency in the patients with multiple sclerosis". International Angiology. 29 (2): 109–14. PMID 20351666. 35. ^ Hojnacki D, Zamboni P, Lopez-Soriano A, Galleotti R, Menegatti E, Weinstock-Guttman B, et al. (April 2010). "Use of neck magnetic resonance venography, Doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls". International Angiology. 29 (2): 127–39. PMID 20351669. 36. ^ a b c d e f g h Valdueza JM, Doepp F, Schreiber SJ, van Oosten BW, Schmierer K, Paul F, Wattjes MP (May 2013). "What went wrong? The flawed concept of cerebrospinal venous insufficiency". Journal of Cerebral Blood Flow and Metabolism. 33 (5): 657–68. doi:10.1038/jcbfm.2013.31. PMC 3652697. PMID 23443168. 37. ^ Jeffrey S (3 December 2009). "Endovascular Treatment of Cerebrospinal Venous Insufficiency Safe, May Provide Benefit in MS". Medscape. Retrieved 27 January 2010. 38. ^ a b Reekers JA, Lee MJ, Belli AM, Barkhof F (February 2011). "Cardiovascular and Interventional Radiological Society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency". Cardiovascular and Interventional Radiology. 34 (1): 1–2. doi:10.1007/s00270-010-0050-5. PMC 2816826. PMID 21136256. 39. ^ Vedantham S, Benenati JF, Kundu S, Black CM, Murphy KJ, Cardella JF (September 2010). "Interventional endovascular management of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a position statement by the Society of Interventional Radiology, endorsed by the Canadian Interventional Radiology Association". Journal of Vascular and Interventional Radiology. 21 (9): 1335–7. doi:10.1016/j.jvir.2010.07.004. PMID 20800776. 40. ^ a b c Russell P (18 March 2013). Meredith S (ed.). "Study casts doubt on MS treatment". BootsWebMD. Archived from the original on 29 March 2013. Retrieved 21 March 2013. 41. ^ Favaro A (9 April 2010). "Kuwait to offer controversial MS treatment". CTV Winnipeg. Retrieved 4 October 2010. 42. ^ Melnychuk P (16 September 2010). "Seeking liberation". Bclocalnews.com. Archived from the original on 2 October 2010. Retrieved 4 October 2010. 43. ^ Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, et al. (December 2009). "A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency". Journal of Vascular Surgery. 50 (6): 1348–58.e1–3. doi:10.1016/j.jvs.2009.07.096. PMID 19958985. 44. ^ Laino C (17 June 2010). "New Theory on CCSVI and MS Needs Further Study, Experts Say". Neurology Today. Archived from the original on 8 June 2011. Retrieved 17 June 2010. 45. ^ Ludyga T, Kazibudzki M, Simka M, Hartel M, Swierad M, Piegza J, et al. (December 2010). "Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe?". Phlebology. 25 (6): 286–95. doi:10.1258/phleb.2010.010053. PMID 21107001. S2CID 25063737. 46. ^ Agrell S (29 April 2010). "Legal fears thwart doctor's bid for 'liberation' from MS pain". The Globe and Mail. Toronto. Retrieved 26 June 2010. 47. ^ Lassmann H (July 2005). "Multiple sclerosis pathology: evolution of pathogenetic concepts". Brain Pathology. 15 (3): 217–22. doi:10.1111/j.1750-3639.2005.tb00523.x. PMID 16196388. S2CID 8342303.[verification needed] 48. ^ Putnam T (1935). "Encephalitis and sclerotic plaques produced by venular obstruction". Arch Neurol Psychiatry. 33 (5): 929–940. doi:10.1001/archneurpsyc.1935.02250170015002. 49. ^ a b c d e f g h i j k l m n o p q r s t u v Pullman D, Zarzeczny A, Picard A (February 2013). "Media, politics and science policy: MS and evidence from the CCSVI Trenches". BMC Medical Ethics. 14: 6. doi:10.1186/1472-6939-14-6. PMC 3575396. PMID 23402260. 50. ^ a b c d e f Sinemma J (10 August 2010). "MS therapy divides even sufferers, as social media drives hype". Calgary Herald. Retrieved 19 October 2010.[permanent dead link] 51. ^ a b c d Locke T (12 October 2010). "CCSVI for MS in the UK". WebMD Health News. WebMD UK Limited and Boots UK Limited. Archived from the original on 8 July 2011. Retrieved 14 October 2010. 52. ^ a b "Information Sheet on Multiple Sclerosis (MS) and "Chronic Cerebrospinal Venous Insufficiency" (CCSVI)" (PDF). Alberta Health Services. 6 August 2010. Retrieved 20 October 2010. 53. ^ Cowan P (6 August 2010). "'Placebo effect' a concern with controversial MS treatment: Experts". Retrieved 20 October 2010.[permanent dead link] 54. ^ Picard A (23 November 2009). "MS group to fund research into 'liberation procedure'". The Globe and Mail. Toronto. Retrieved 5 September 2010. 55. ^ "MS Society's stand sparks resignation". The Telegram. 1 September 2010. Archived from the original on 8 September 2010. Retrieved 5 September 2010. 56. ^ "MS Society sets aside $1M in case CCSVI patient trial developed and approved". CBC News. 16 September 2010. Retrieved 18 September 2010.[dead link] 57. ^ Breakenridge R (4 August 2010). "Premiers jump the gun on MS treatment". Calgary Herald.[permanent dead link] 58. ^ "Premiers to debate MS treatment". CBC News. 2 August 2010. 59. ^ "MS therapy trial urged by Manitoba minister". CBC News. Canadian Press. 16 August 2010. 60. ^ "CIHR makes recommendations on Canadian MS research priorities". Canadian Institutes of Health Research. 31 August 2010. Archived from the original on 3 September 2010. Retrieved 9 December 2010. 61. ^ "Health minister rejects MS therapy trial". CBC News. 2 September 2010. 62. ^ Weeks C (29 June 2011). "Ottawa to fund clinical trials for controversial MS treatment". The Globe and Mail. Retrieved 3 April 2013. 63. ^ a b Snyder J, Adams K, Crooks VA, Whitehurst D, Vallee J (September 2014). ""I knew what was going to happen if I did nothing and so I was going to do something": faith, hope, and trust in the decisions of Canadians with multiple sclerosis to seek unproven interventions abroad". BMC Health Services Research. 14: 445. doi:10.1186/1472-6963-14-445. PMC 4263058. PMID 25265935. 64. ^ a b c d Ploughman M, Harris C, Hogan SH, Murray C, Murdoch M, Austin MW, Stefanelli M (2014). "Navigating the "liberation procedure": a qualitative study of motivating and hesitating factors among people with multiple sclerosis". Patient Preference and Adherence. 8: 1205–13. doi:10.2147/PPA.S65483. PMC 4164287. PMID 25228799. 65. ^ Rodger IW, Dilar D, Dwyer J, Bienenstock J, Coret A, Coret-Simon J, et al. (14 August 2013). "Evidence against the involvement of chronic cerebrospinal venous abnormalities in multiple sclerosis. A case-control study". PLOS ONE. 8 (8): e72495. Bibcode:2013PLoSO...872495R. doi:10.1371/journal.pone.0072495. PMC 3743778. PMID 23967312. 66. ^ Traboulsee AL, Knox KB, Machan L, Zhao Y, Yee I, Rauscher A, et al. (January 2014). "Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: a blinded, case-control study". Lancet. 383 (9912): 138–45. doi:10.1016/s0140-6736(13)61747-x. PMID 24119384. S2CID 25925875. 67. ^ Definitive imaging study finds no link between venous narrowing and multiple sclerosis, University of British Columbia, media release 8 October 2013. 68. ^ "'Scientific quackery': UBC study says it's debunked controversial MS procedure". CBC News. 8 March 2017. Retrieved 8 March 2017. 69. ^ "What's the Latest on CCSVI and MS? Discover New Research at the National CCSVI Society's Major Canadian CCSVI Forum". Reuters. 6 July 2011. 70. ^ "UIP self report". Archived from the original on 18 May 2013. Retrieved 9 April 2013. 71. ^ Favaro A (27 January 2010). "Italian group offers $4.5M to fund new MS research". CTV News. Archived from the original on 12 August 2010. Retrieved 29 September 2010. 72. ^ Lee BB, Bergan J, Gloviczki P, Laredo J, Loose DA, Mattassi R, et al. (December 2009). "Diagnosis and treatment of venous malformations. Consensus document of the International Union of Phlebology (IUP)-2009". International Angiology. 28 (6): 434–51. PMID 20087280. 73. ^ "CCSVI – current studies". mssociety.org.uk. Archived from the original on 23 February 2011. 74. ^ Zivadinov R, Bastianello S, Dake MD, Ferral H, Haacke EM, Haskal ZJ, et al. (November 2014). "Recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of chronic cerebrospinal venous insufficiency: a position statement of the International Society for Neurovascular Disease". Journal of Vascular and Interventional Radiology. 25 (11): 1785–94.e17. doi:10.1016/j.jvir.2014.07.024. PMID 25255703. ## Further reading[edit] Tullis P (26 October 2012). "A Controversial 'Cure' for M.S." The New York Times. Overview, interviews with proponents and critics. * Rhodes MA (10 January 2014). Haacke ME, Moore EA (eds.). CCSVI as the Cause of Multiple Sclerosis: The Science Behind the Controversial Theory. McFarland Health Topics. ISBN 978-0-7864-8628-1. ## External links[edit] Classification D * ICD-10: I87.8 * MeSH: D014689 * 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	Chronic cerebrospinal venous insufficiency controversy	None	1,157	wikipedia	https://en.wikipedia.org/wiki/Chronic_cerebrospinal_venous_insufficiency_controversy	2021-01-18T18:56:59	{"umls": ["CL529180"], "icd-10": ["I87.8"], "wikidata": ["Q1088054"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "HIV/AIDS in South African townships" – news · newspapers · books · scholar · JSTOR (January 2020) (Learn how and when to remove this template message) This article relies too much on references to primary sources. Please improve this by adding secondary or tertiary sources. (January 2020) (Learn how and when to remove this template message) 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: "HIV/AIDS in South African townships" – news · newspapers · books · scholar · JSTOR (January 2020) (Learn how and when to remove this template message) Some of this section's listed sources may not be reliable. Please help this article by looking for better, more reliable sources. Unreliable citations may be challenged or deleted. (January 2020) (Learn how and when to remove this template message) (Learn how and when to remove this template message) A street shop in Dukatole, one of South Africa's Black townships. South Africa's HIV/AIDS epidemic, which is among the most severe in the world, is concentrated in its townships, where many black South Africans live due to the lingering effects of the Group Areas Act. False traditional beliefs about HIV/AIDS, which contribute to the spread of the disease, persist in townships due to the lack of education and awareness programmes in these regions. Sexual violence and local attitudes toward HIV/AIDS have also amplified the epidemic. Although some education efforts and treatment and prevention programmes have succeeded in spreading awareness about HIV/AIDS in townships, the impact of the disease remains severe. ## Contents * 1 Prevalence * 2 Traditional beliefs about HIV/AIDS * 2.1 Stigma * 3 Spread of the disease * 3.1 Sexual violence * 4 AIDS orphans * 5 Education * 6 Treatment and prevention * 7 Attempts to address the epidemic * 7.1 National government * 7.2 NGOs * 7.2.1 Treatment Action Campaign * 8 See also * 9 References ## Prevalence[edit] Provinces of South Africa. In 2008, HIV/AIDS was most prevalent in the South African provinces of KwaZulu-Natal (15.8% HIV-positive), Mpumalanga (15.4% HIV-positive), Free State (12.6% HIV-positive), and North West (11.3% HIV-positive), while only 3.8% of the population was HIV-positive in Western Cape. A survey conducted in 2010 indicated that HIV/AIDS infection among pregnant women is highest in KwaZulu-Natal (39.5%), Mpumalanga (35.1%), Free State (30.6%), and Gauteng (30.4%). ## Traditional beliefs about HIV/AIDS[edit] South Africans in townships are more likely to hold false beliefs about HIV transmission and prevention because they are less likely to have received a formal education or be employed.[1] Many South Africans in townships are unaware of the primary modes of HIV/AIDS transmission: through unprotected sex with an HIV-positive individual, through contact with the blood of an HIV-positive individual, and through mother-to-child transmission from an HIV-positive mother to her baby during pregnancy.[2] Instead, the traditional beliefs of South Africans in townships have contributed to sexual violence in South Africa and stigmatized HIV-positive individuals, particularly women, thereby increasing the severity of the disease in the region. ### Stigma[edit] HIV/AIDS stigma is widespread in South Africa: a 2002 national survey revealed that 26% of respondents were unwilling to share a meal with a person living with AIDS, 18% were unwilling to sleep in the same room as with someone with AIDS, and 6% were unwilling to talk to a person with AIDS.[1] AIDS-related stigma is most severe among township residents in South Africa because they lack access to reliable information about the disease. Many South Africans in townships wrongly believe that HIV is transmitted through proximity to HIV-positive individuals, which leads them to claim that people with AIDS should be socially ostracized.[1] In addition, many traditional groups believe that ancestral spirits and supernatural forces punish those who have failed to lead moral lives by infecting them with HIV. According to a study published in 2004, South Africans who attributed HIV/AIDS to spirits and the supernatural were more likely to claim that people with HIV/AIDS were "dirty," "repulsive," "cursed," and "foolish" and should "have restrictions on their freedom," "be isolated," and "feel guilty and ashamed."[1] Women are particularly vulnerable to HIV/AIDS infection and stigma because they are often economically dependent on men and frequently lack access to education. Men who have the disease may avoid testing and remain anonymous, but women who undergo pre-natal testing are less likely to escape a diagnosis. Because women are often identified as HIV-positive before men, they are branded as the spreaders of the disease and may subsequently face physical abuse and abandonment.[3] A study conducted in 2010 indicated that the majority of girls in a Cape Town township correlated thinness with disease – in particular, HIV/AIDS. Because of this, women who are slender or experience weight loss also face discrimination. This form of stigma affects women living in townships most severely because rates of malnourishment are higher in townships than in other parts of South Africa.[4] ## Spread of the disease[edit] Multiple factors have contributed to the spread of HIV/AIDS in South African townships. Sexual violence in townships, which results partially from cultural norms regarding gender-based power dynamics and partially from psychological desperation, makes women particularly susceptible to HIV/AIDS. Female rates of HIV infection in South Africa are on average five times higher than male infection rates due to biological and social vulnerability.[3] ### Sexual violence[edit] Further information: Sexual violence in South Africa Although many township inhabitants are knowledgeable about HIV/AIDS prevention methods, rates of condom use are still strikingly low. Studies suggest that fear of sexual abuse, which results from unequal power dynamics between men and women in South African townships, is the primary explanation for low condom use rates. Women in Khutsong reported that their relationship would deteriorate if they insisted that their partner use a condom because such a request demonstrates a lack of trust and respect.[5] Ubuntu, an African philosophy that promotes a spirit of brotherhood between and among community members, explains why township adolescents knowingly spread the disease – they believe that the entire community should share their burden. As a result of this philosophy, HIV-positive fathers will sometimes rape their daughters to guarantee their loyalty and care when their parent's health begins to deteriorate. It is likely that the sense of peer group affiliation that developed among township adolescents during apartheid has contributed to the desire to share the frustration and hopelessness that accompany the disease.[6] ## AIDS orphans[edit] An AIDS orphan is defined as "any child under the age of 18 years who had lost one or both parents through an HIV-related illness."[7] Orphanhood is a severe consequence of the AIDS epidemic in South African townships: a 2006 study stated that there were 2.2 million AIDS-orphaned children in South Africa alone. AIDS orphans in an urban Cape Town township have been shown to have significant rates of depression, anxiety, post-traumatic stress, peer relationship difficulties, suicidal urges, delinquency, and homelessness. These rates are higher than those of both non-AIDS orphans and non-orphans in South African townships.[8] AIDS orphans are particularly vulnerable to poverty, malnutrition, stigma, exploitation, sickness, and sexual abuse, which lead to intense psychological trauma.[7] AIDS orphans are also less likely than non-AIDS orphans and non-orphans to attend and remain enrolled in school due to stigma and an increase in adult responsibilities such as care work and formal or informal employment.[9] ## Education[edit] There is currently no law requiring AIDS education in South African schools and government attempts to raise AIDS awareness have largely failed to reach South Africa's underserved townships, where the quality of education is poor.[10] However, there is a clear need for education programmes in South African townships – a survey in Khutsong demonstrated that 70% of the community's young men believed they were not vulnerable to infection.[5] A 1994 pilot study in an urban Cape Town township demonstrated the potential, but also the limitations, of AIDS education. The study compared AIDS knowledge in two schools, one of which underwent an intensive AIDS awareness programme and one of which did not. Before the programme, students in both schools were misinformed about HIV transmission – many wrongly believed that drinking from an unwashed cup and touching somebody with the disease could transmit the virus.[10] Few students knew that using condoms, having only one sexual partner, and attending clinics for information and tests can all help prevent HIV/AIDS. Before the implementation of the educational programme, students in both schools also expressed hostility toward HIV-positive individuals – very few indicated that they would welcome an HIV-positive student into their class. They were also likely to underestimate the prevalence and severity of the disease.[10] Following the completion of the AIDS awareness programme, the students who had participated were more knowledgeable about HIV transmission, prevention, and the course of the disease. However, hostility toward HIV-positive individuals decreased only slightly among the students after the programme and the students did not demonstrate any intention to increase their use of condoms.[10] ## Treatment and prevention[edit] Most of South Africa's current anti-HIV/AIDS efforts involve treatment rather than prevention. Although prevention programmes are considered more cost effective, the pervasiveness of the disease has made treatment facilities increasingly important. A 2005 study determined that the introduction of antiretroviral medication, mother-to-child transmission prevention programmes, and Médecins Sans Frontières, or Doctors Without Borders, clinics to Khayelitsha played a role in reducing the impact of the disease.[11] These programmes have started to confront the HIV/AIDS epidemic in Khayelitsha by making treatment more widely available and providing incentives for HIV testing. Despite these specific successes, treatment has played a limited role in South African townships due to their lack of infrastructure and trained professionals and the high cost of antiretroviral drugs.[11] HIV/AIDS prevention efforts such as school education, education in the workplace, and mass media campaigns have largely failed to significantly impact South African townships. For example, HIV voluntary counseling and testing programmes have improved HIV/AIDS awareness in Khayelitsha, but have for the most part failed to influence behavior.[12] On the other hand, specific HIV/AIDS prevention methods such as the Priorities for Local AIDS Control Efforts (PLACE) method have demonstrated a potential for success.[13] A 2003 study used the PLACE method to determine where in townships people meet new sexual partners in order to strategically focus prevention efforts in these locations. These locations included bars, taverns, bottle stores, nightclubs, streets, hotels, and local shebeens. The vast majority of these locations did not provide condoms or information about the transmission of HIV/AIDS. Most patrons visit these sites daily or weekly; therefore, the PLACE method suggests that prevention efforts such as education and social support could be successfully focused on these popular venues.[13] Churches in South African townships have largely failed to use their social and cultural influence to combat the HIV/AIDS epidemic. Many churches reject HIV-positive members because they are ignorant about the causes of AIDS, have traditional views on sexual morality, or believe that HIV/AIDS is well-deserved punishment for immoral behavior. In addition, many organizations such as the South African Church Leaders Association have only formally acknowledged the severity of the HIV/AIDS epidemic within the last decade.[11] Despite these large-scale failures, some township churches have become actively engaged in preventing the spread of HIV/AIDS in their communities. Archbishop Desmond Tutu of the Anglican Church in the Western Cape founded the Desmond Tutu HIV Foundation and speaks openly and progressively about the role of education in battling HIV/AIDS. St. Michael's Church in Khayelitsha has supported the efforts of the Millennium Development Goals by founding an HIV/AIDS clinic and orphanage known as Fikelela; this movement has spread to dozens of other Anglican churches in the region.[11] ## Attempts to address the epidemic[edit] HIV/AIDS was largely considered a peripheral problem by the South African government and NGOs before the disintegration of apartheid in 1994. However, since then, efforts have been made to address the epidemic with varying levels of success. South Africa's government leaders largely failed to acknowledge the severity of the AIDS epidemic until 2009, which prevented the implementation of successful policy. However, many NGOs have succeeded in targeting South Africa's vulnerable township populations. ### National government[edit] The effectiveness of government-based anti-HIV/AIDS programmes in South African townships was severely reduced by the AIDS denialism of President Thabo Mbeki, who was in office from 14 June 1999 until 24 September 2008, and Manto Tshabalala-Msimang, who served as Health Minister from 25 September 2008 through 10 May 2009. These South African leaders brought the issue of AIDS denialism to the forefront of South African politics by rejecting scientific evidence demonstrating the connection between HIV and AIDS and declaring antiretroviral therapy ineffective.[14] In 2000, President Mbeki invited nonconformist scientists such as Peter Duesberg and David Rasnick to a Presidential Advisory Panel on AIDS while excluding leading researchers from the convention. President Mbeki's denialism hindered progress in government HIV/AIDS policy by generating skepticism about HIV/AIDS among members of South Africa's Department of Health. This skepticism slowed the implementation of antiretroviral therapy programmes in many of South Africa's townships, particularly in Mpumalanga.[14] Despite President Mbeki's denialism, the South African government did make efforts to combat the nation's HIV/AIDS crisis while Mbeki was in office. The National AIDS Convention of South Africa (NACOSA) first met in 1992 to design a national AIDS plan to fight the emerging epidemic, which was endorsed by Nkosazana Dlamini-Zuma, South Africa's incoming Minister of Health. However, the plan was largely ineffective because it failed to acknowledge the government's lack of economic resources. The development of the controversial AIDS drug Virodene in South Africa in 1996 reintroduced enthusiasm about HIV/AIDS into the political sphere and led to the successful implementation of several small-scale projects by the national government.[15] The Khayelitsha District Management Team was established to focus on AIDS from an epidemiological angle and an AIDS programme coordinator was appointed to Khayelitsha to monitor the disease in the township. The government also financed a mother-to-child-transmission programme in Khayelitsha in 1999. However, stigmatization and the government's dismissal of new treatment options continued as Mbeki's denialism campaign intensified in the early 2000s. The government issued the HIV/AIDS/STD Strategic Plan for South Africa 2000-2005 at the urging of the United Nations, but the plan lacked concrete proposals and a timeline and largely neglected the potential of antiretroviral therapy.[15] Jacob Zuma, South Africa's president as of 9 May 2009, has expanded the national government's HIV/AIDS outreach programmes in an attempt to serve marginalized township populations and the country as a whole. On World AIDS Day on 1 December 2009, President Zuma announced his intention to reverse South Africa's health trends by increasing HIV treatment nationwide. He insisted that HIV-positive children under age one and pregnant women would receive increased attention and treatment in accordance with World Health Organization treatment guidelines.[16] However, the national government remains hindered by the high cost of medication and the nation's unpredictable funding, poor health systems, and widespread stigma, leaving many townships unaided.[17] ### NGOs[edit] NGOs have played a significant role in combating and raising awareness about the HIV/AIDS epidemic in South African townships. * The Red Cross Society has focused its HIV/AIDS care and awareness efforts in Khayelitsha and Nyanga through home-based initiatives and education programmes in schools.[13] * The Township AIDS Project (TAP) was established by medical professionals in 1989 in order to spread accurate information about HIV/AIDS to the poor in South Africa's townships.[18] * Médecins Sans Frontières, or Doctors Without Borders, established an HIV treatment programme in Khayelitsha in 1999 and has provided over 17,650 patients in the township with antiretroviral treatment since 2001.[19] * Population Services International established the Society for Family Health (SFH) in South Africa in 1992. The SFH's youth outreach programme, YouthAIDS, educates township populations across South Africa about HIV/AIDS transmission.[20] #### Treatment Action Campaign[edit] The Treatment Action Campaign (TAC) was launched in 1998 to "campaign for greater access to treatment for all South Africans, by raising public awareness and understanding about issues surrounding the availability, affordability and use of HIV treatments."[21] The TAC's goals are to "ensure access to affordable and quality treatment for people with HIV/AIDS, prevent and eliminate new HIV infections, improve the affordability and quality of healthcare access for all, and campaign against the view that AIDS is a death sentence."[21] The TAC has focused its efforts on urban populations in Gauteng and Western Cape, but is continuing to extend its reach to townships and rural areas in South Africa such as Lusikisiki.[21] The TAC is well-established in Mpumalanga and has contributed substantially to the HIV/AIDS campaign in KwaZulu-Natal, which was among the first provinces to provide antiretroviral drugs to HIV-positive pregnant women.[22] In August 2002, the TAC campaigned to have the local clinic in Nyanga open for five days per week rather than two.[23] The TAC distributes over 500,000 condoms in Khayelitsha every month, which helped reduce the incidence of sexually transmitted diseases in the township by 50% between 2004 and 2007.[24] Mortality statistics in Khayelitsha have also improved in recent years, which may be partially due to the TAC's outreach efforts.[25] ## See also[edit] * HIV/AIDS in South Africa * Sexual violence in South Africa ## References[edit] 1. ^ a b c d S.C., Kalichman, and Simbayi L. "Traditional Beliefs about the Cause of AIDS and AIDS-related Stigma in South Africa." AIDS Care 16.5 (2004): 572-80. Print. 2. ^ "HIV/AIDS Information." Modes of HIV Transmission. Web. 8 Apr. 2012. <http://www.hivaidscare.com/hivtransmission.php?acode=na>. 3. ^ a b "HIV and AIDS." UNICEF South Africa. UNICEF. Web. 30 Mar. 2012. <http://www.unicef.org/southafrica/hiv_aids_729.html>. 4. ^ Puoane, Thandi, Lungiswa Tsolekile, and Nelia Steyn. "Perceptions about Body Image and Sizes among Black African Girls Living in Cape Town." Ethnicity & Disease 20 (2010): 29-34. Print. 5. ^ a b MacPhail, Catherine, and Catherine Campbell. "‘I Think Condoms Are Good But, Aai, I Hate Those Things’: Condom Use among Adolescents and Young People in a Southern African Township." Social Science & Medicine 52.11 (2001): 1613-627. Print. 6. ^ Leclerc‐Madlala, Suzanne. "Infect One, Infect All: Zulu Youth Response to the Aids Epidemic in South Africa." Medical Anthropology 17.4 (1997): 363-80. Print. 7. ^ a b Van Rooyen, Dalena, Sharron Frood, and Esmeralda Ricks. "The Experiences of AIDS Orphans Living in a Township." Health SA Gesondheid 17.1 (2012). Print. 8. ^ Cluver, Lucie, Frances Gardner, and Don Operario. "Psychological Distress amongst AIDS-orphaned Children in Urban South Africa." Journal of Child Psychology and Psychiatry 48.8 (2007): 755-63. Print. 9. ^ Cluver, Lucie, Frances Gardner, and Don Operario. "Poverty and Psychological Health among AIDS-orphaned Children in Cape Town, South Africa." AIDS Care 21.6 (2009): 732-41. Print. 10. ^ a b c d Kuhn, L., M. Steinberg, and C. Mathews. "Participation of the School Community in AIDS Education: An Evaluation of a High School Programme in South Africa." AIDS Care 6.2 (1994): 161-71. Print. 11. ^ a b c d Levy, N. C. "From Treatment to Prevention: The Interplay Between HIV/AIDS Treatment Availability and HIV/AIDS Prevention Programming in Khayelitsha, South Africa." Journal of Urban Health 82.3 (2005): 498-509. Print. 12. ^ Venkatesh, Kartik K., Precious Madiba, Guy De Bruyn, Mark N. Lurie, Thomas J. Coates, and Glenda E. Gray. "Who Gets Tested for HIV in a South African Urban Township? Implications for Test and Treat and Gender-based Prevention Interventions." JAIDS: Journal of Acquired Immune Deficiency Syndromes 56.2 (2011): 151-65. Print. 13. ^ a b c Weir, Sharon, Charmaine Pailman, Xoli Mahlalela, Nicol Coetzee, Farshid Meidany, and Ties Boerma. "From People to Places: Focusing AIDS Prevention Efforts Where It Matters Most." Epidemiology & Social 17.6 (2003): 895-903. Print. 14. ^ a b Daniel, John, Adam Habib, and Roger Southall. State of the Nation: South Africa, 2003-2004. Cape Town, South Africa: HSRC, 2003. Print. 15. ^ a b Butler, A. "South Africa's HIV/AIDS Policy, 1994-2004: How Can It Be Explained?" African Affairs 104.417 (2005): 591-614. Print. 16. ^ Dugger, Celia. "Breaking With Past, South Africa Issues Broad AIDS Policy." New York Times. 1 Dec. 2009. Web. 14 Apr. 2012. <https://www.nytimes.com/2009/12/02/world/africa/02safrica.html>. 17. ^ Fleshman, Michael. "At Last, Signs of Progress on AIDS." UN News Center. United Nations. Web. 14 Apr. 2012. <http://www.un.org/en/africarenewal/vol23no4/progress-on-aids.html>. 18. ^ "Township AIDS Project (TAP)." Peacebuilding Portal. Web. 13 Apr. 2012. <http://www.peacebuildingportal.org/index.asp?pgid=9>. 19. ^ "South Africa." Médecins Sans Frontières. Web. 14 Apr. 2012. <http://www.doctorswithoutborders.org/publications/ar/report.cfm?id=5376>. 20. ^ "PSI." South Africa. Web. 14 Apr. 2012. <http://www.psi.org/south-africa>. 21. ^ a b c Friedman, S. "A Rewarding Engagement? The Treatment Action Campaign and the Politics of HIV/AIDS." Politics & Society 33.4 (2005): 511-65. Print. 22. ^ Mosoetsa, Sarah. "The Legacies of Apartheid and Implications of Economic Liberalisation: A Post-Apartheid Township." Crisis States Programme (2004): 1-16. Print. 23. ^ Robins, Steven, and Bettina Von Lieres. "Remaking Citizenship, Unmaking Marginalization: The Treatment Action Campaign in Post-Apartheid South Africa." Canadian Journal of African Studies 38.3 (2004): 575-86. Print. 24. ^ "Pope’s Comments on Condoms Are Wrong and Irresponsible." Pambazuka News. Web. 8 Apr. 2012. <http://www.pambazuka.org/en/category/comment/54977>. 25. ^ "Key HIV Statistics." Treatment Action Campaign. Web. 8 Apr. 2012. <http://www.tac.org.za/community/keystatistics>. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	HIV/AIDS in South African townships	None	1,158	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_South_African_townships	2021-01-18T18:34:37	{"wikidata": ["Q5629880"]}
Pyoderma gangrenosum (PG) is a primarily sterile inflammatory neutrophilic dermatosis characterized by recurrent cutaneous ulcerations with a mucopurulent or hemorrhagic exudate. ## Epidemiology The exact prevalence of PG is unknown. The incidence has been estimated to range between 1 and 3.3 in 330,000. The incidence peak occurs between the ages of 20 to 50 years, with women being more often affected than men. ## Clinical description Clinically, onset occurs with sterile pustules that rapidly progress and turn into very painful ulcers of variable depth and size, with undermined bluish or violaceous borders and surrounding erythema. The legs are most commonly affected but other parts of the skin and mucous membranes may also be involved. The clinical course can be mild or malignant, chronic or relapsing with significant morbidity. In many cases, PG is associated with an underlying disease, most commonly inflammatory bowel disease, rheumatic or hematological disease, or malignancy. ## Etiology The etiology has not yet been clearly determined. ## Diagnostic methods Diagnosis of PG is based on the history of the underlying disease, typical clinical presentation, histopathology, and exclusion of other diseases that would lead to a similar clinical picture. ## Management and treatment The treatment of PG is a challenge. Randomized, double-blind prospective multicenter trials for PG are not available. The best documented treatments are systemic corticosteroids and cyclosporin A. Combinations of steroids with cytotoxic drugs are used in resistant cases. The combinations of steroids with sulfa drugs or immunosuppressants are used as steroid sparing modalities. Rapid improvement of PG has been obtained by anti-tumor necrosis alpha therapy used in Crohn's disease. Skin transplants and the application of bioengineered skin is useful in selected cases, as a complementary therapy to the immunosuppressive treatment. Topical therapy with modern wound dressings is useful to minimize pain and the risk of secondary infections. ## Prognosis Despite recent advances in therapy, the prognosis of PG remains unpredictable. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pyoderma gangrenosum	c0085652	1,159	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=48104	2021-01-23T16:53:03	{"gard": ["7510"], "mesh": ["D017511"], "umls": ["C0085652"], "icd-10": ["L88"]}
Elastofibroma dorsi is a rare, acquired, dermis elastic tissue disorder characterized by a benign, slowly progressive, often bilateral, non-encapsulated lesion, usually presenting as an ill-defined mass under the inferior angle of the scapula (but other locations have been reported), which adheres to the deep layers and presents no local signs of inflammation. It is commonly asymptomatic and discovered inadvertently, but symptoms may include pain and discomfort or stiffness when using the shoulder. The presence of a firm mass masked by the scapula during retropulsion of the shoulder and becoming prominent when the shoulder is displaced toward the front is a frequent sign. Neuromuscular involvement of the upper limb may occur in rare cases. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Elastofibroma dorsi	c0334460	1,160	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228243	2021-01-23T18:51:26	{}
Yuan-Harel-Lupski (YUHAL) syndrome is a rare neurological condition that has a combination of features of two other disorders, Potocki-Lupski syndrome and type 1A Charcot-Marie-Tooth disease. The first signs and symptoms of YUHAL syndrome begin in infancy. Infants with YUHAL syndrome usually have weak muscle tone (hypotonia), which may lead to feeding problems. They typically do not grow and gain weight at the expected rate. Babies and children with YUHAL syndrome have delayed development, including delayed speech and language skills and motor skills such as walking. YUHAL syndrome is also associated with behavioral difficulties. Many affected individuals have sleep problems, including pauses in breathing during sleep (sleep apnea) or trouble falling asleep and staying asleep. Some people with YUHAL syndrome have subtle differences in facial features, including outside corners of the eyes that point downward (down-slanting palpebral fissures), a triangular face, and eyes that do not look in the same direction (strabismus). These signs and symptoms are similar to those of Potocki-Lupski syndrome. Other signs and symptoms of YUHAL syndrome begin in childhood and result from damage to peripheral nerves, which connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, and heat. Damage to peripheral nerves can lead to loss of sensation and wasting (atrophy) of muscles in the legs. Children with YUHAL syndrome often develop muscle weakness, particularly in the lower legs, which may lead to an unusual walking style (gait). Some affected individuals have foot abnormalities such as flat feet (pes planus), high arches (pes cavus), or an inward- and upward-turning foot (clubfoot). They may also experience reduced reflexes and a decreased sensitivity to touch, heat, and cold in the feet and lower legs. Similar features are seen in individuals with type 1A Charcot-Marie-Tooth disease, although they may appear earlier in people with YUHAL syndrome, often before age 5. Abnormal development of other tissues and organs, such as the heart or kidneys, can occur in YUHAL syndrome. ## Frequency The prevalence of YUHAL syndrome is unknown. More than 20 people with the condition have been described in the medical literature. ## Causes YUHAL syndrome results from an extra copy (duplication) of a small piece of chromosome 17 in each cell. The duplication occurs on the short (p) arm of the chromosome in a region designated 17p12-17p11.2. The duplicated segment ranges in size from approximately 3.2 million DNA building blocks (also written as 3.2 megabases or 3.2 Mb) to 19.7 Mb. The duplicated region always contains at least two genes, RAI1 and PMP22. Researchers believe that having an extra copy of both of these genes underlies the characteristic features of YUHAL syndrome. The RAI1 gene provides instructions for making a protein that helps regulate the activity (expression) of other genes. Although most of the genes regulated by the RAI1 protein have not been identified, the protein appears to play a role in many body processes, including the sleep-wake cycle and development of the brain and bones in the head and face (craniofacial bones). Research suggests that duplications involving this gene lead to higher-than-normal amounts of the RAI1 protein, which disrupts the expression of genes that influence brain and craniofacial development and the sleep-wake cycle. Excess RAI1 protein likely causes feeding and sleep problems, delayed development, behavioral difficulties, and facial differences in people with YUHAL syndrome. Duplications that involve the RAI1 gene but not the PMP22 gene cause Potocki-Lupski syndrome, which shares these features. The PMP22 gene provides instructions for making a protein that is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. It is thought that an extra copy of the PMP22 gene leads to overproduction of PMP22 protein. Too much PMP22 protein may overwhelm the cells' ability to process it correctly, leading to a buildup of unprocessed, nonfunctional protein. This buildup may impair the formation of myelin. A shortage of functional PMP22 protein leads to instability and loss of myelin (demyelination). Demyelination reduces the ability of the peripheral nerves to activate muscles used for movement or to relay information from sensory cells back to the brain. As a result, individuals with a duplication of the PMP22 gene develop muscle weakness and impaired sensitivity to touch, heat, and cold. Duplications that involve the PMP22 gene but not the RAI1 gene cause type 1A Charcot-Marie-Tooth disease, which is characterized by similar problems with muscle weakness and sensation. Researchers suspect that having an extra copy of additional genes in the duplicated region contribute to other features of the disorder, such as kidney abnormalities. ### Learn more about the genes and chromosome associated with Yuan-Harel-Lupski syndrome * PMP22 * RAI1 * chromosome 17 ## Inheritance Pattern YUHAL syndrome follows an autosomal dominant pattern of inheritance, which means one copy of the chromosome duplication in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) duplications that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Yuan-Harel-Lupski syndrome	c4225255	1,161	medlineplus	https://medlineplus.gov/genetics/condition/yuan-harel-lupski-syndrome/	2021-01-27T08:24:33	{"omim": ["616652"], "synonyms": []}
Not to be confused with sarcoma. Sarcoidosis Other namesSarcoïdosis, sarcoid, Besnier-Boeck-Schaumann disease[1] Chest X-ray showing the typical nodularity of sarcoidosis, predominantly in the bases of the lungs. Pronunciation * sar-koy-DO-sis SpecialtyRheumatology SymptomsDepends on the organ involved[2] Lungs: wheezing, cough, shortness of breath, chest pain[3] Skin: lumps, ulcers, discolored skin[3] Children: weight loss, bone pain, feeling tired[3] Usual onset20–50 year old women[4] DurationFew years to long term[2][5] CausesUnknown[2] Risk factorsFamily history[4] Diagnostic methodBased on symptoms and tissue biopsy[6] Differential diagnosisTuberculosis, lymphoma, infectious mononucleosis, pulmonary eosinophilia[7] TreatmentIbuprofen, prednisone, methotrexate[8][9] PrognosisMortality 1–7%[5] Frequency1.9 million with interstitial lung disease (2015)[10] Deaths122,000 with interstitial lung disease (2015)[11] Sarcoidosis is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata.[2] The disease usually begins in the lungs, skin, or lymph nodes.[2] Less commonly affected are the eyes, liver, heart, and brain.[2] Any organ, however, can be affected.[2] The signs and symptoms depend on the organ involved.[2] Often, no, or only mild, symptoms are seen.[2] When it affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur.[3] Some may have Löfgren syndrome with fever, large lymph nodes, arthritis, and a rash known as erythema nodosum.[2] The cause of sarcoidosis is unknown.[2] Some believe it may be due to an immune reaction to a trigger such as an infection or chemicals in those who are genetically predisposed.[12][13] Those with affected family members are at greater risk.[4] Diagnosis is partly based on signs and symptoms, which may be supported by biopsy.[6] Findings that make it likely include large lymph nodes at the root of the lung on both sides, high blood calcium with a normal parathyroid hormone level, or elevated levels of angiotensin-converting enzyme in the blood.[6] The diagnosis should only be made after excluding other possible causes of similar symptoms such as tuberculosis.[6] Sarcoidosis may resolve without any treatment within a few years.[2][5] However, some people may have long-term or severe disease.[5] Some symptoms may be improved with the use of anti-inflammatory drugs such as ibuprofen.[8] In cases where the condition causes significant health problems, steroids such as prednisone are indicated.[9] Medications such as methotrexate, chloroquine, or azathioprine may occasionally be used in an effort to decrease the side effects of steroids.[9] The risk of death is 1–7%.[5] The chance of the disease returning in someone who has had it previously is less than 5%.[2] In 2015, pulmonary sarcoidosis and interstitial lung disease affected 1.9 million people globally and they resulted in 122,000 deaths.[10][11] It is most common in Scandinavians, but occurs in all parts of the world.[14] In the United States, risk is greater among black people as opposed to white people.[14] It usually begins between the ages of 20 and 50.[4] It occurs more often in women than men.[4] Sarcoidosis was first described in 1877 by the English doctor Jonathan Hutchinson as a non-painful skin disease.[15] ## Contents * 1 Signs and symptoms * 1.1 Respiratory tract * 1.2 Skin * 1.3 Heart * 1.4 Eye * 1.5 Nervous system * 1.6 Endocrine and exocrine * 1.7 Gastrointestinal and genitourinary * 1.8 Blood * 1.9 Bone, joints, and muscles * 2 Cause * 2.1 Genetics * 2.2 Infectious agents * 2.3 Autoimmune * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 5 Treatment * 5.1 Antimetabolites * 5.2 Immunosuppressants * 5.3 Specific organ treatments * 5.4 Symptoms * 6 Prognosis * 7 Epidemiology * 8 History * 8.1 Etymology * 9 Society and culture * 10 Pregnancy * 11 References * 12 External links ## Signs and symptoms[edit] Signs and symptoms of sarcoidosis[16] Sarcoid affecting the skin Sarcoidosis is a systemic inflammatory disease that can affect any organ, although it can be asymptomatic and is discovered by accident in about 5% of cases.[17] Common symptoms, which tend to be vague, include fatigue (unrelieved by sleep; occurs in 66% of cases), lack of energy, weight loss, joint aches and pains (which occur in about 70% of cases),[18] arthritis (14–38% of cases), dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry, hacking cough, or skin lesions.[19][20][21][22] Less commonly, people may cough up blood.[19] The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum, granuloma annulare, or lupus pernio. Sarcoidosis and cancer may mimic one another, making the distinction difficult.[23] The combination of erythema nodosum, bilateral hilar lymphadenopathy, and joint pain is called Löfgren syndrome, which has a relatively good prognosis.[19] This form of the disease occurs significantly more often in Scandinavian patients than in those of non-Scandinavian origin.[24] ### Respiratory tract[edit] Localization to the lungs is by far the most common manifestation of sarcoidosis.[25] At least 90% of those affected experience lung involvement.[26] Overall, about 50% develop permanent pulmonary abnormalities, and 5 to 15% have progressive fibrosis of the lung parenchyma. Sarcoidosis of the lung is primarily an interstitial lung disease in which the inflammatory process involves the alveoli, small bronchi, and small blood vessels.[27] In acute and subacute cases, physical examination usually reveals dry crackles.[26] At least 5% of cases include pulmonary arterial hypertension.[26][28] The upper respiratory tract (including the larynx, pharynx, and sinuses) may be affected, which occurs in between 5 and 10% of cases.[29] The four stages of pulmonary involvement are based on radiological stage of the disease, which is helpful in prognosis:[30] * Stage I: bilateral hilar lymphadenopathy (BHL) alone * Stage II: BHL with pulmonary infiltrates * Stage III: pulmonary infiltrates without BHL * Stage IV: fibrosis Use of the Scadding scale only provides general information regarding the prognosis of the pulmonary disease over time. Caution is recommended, as it only shows a general relation with physiological markers of the disease and the variation is such that it has limited applicability in individual assessments, including treatment decisions.[12] ### Skin[edit] Main article: Skin manifestations of sarcoidosis Sarcoidosis involves the skin in between 9 and 37% of cases and is more common in African Americans than in European Americans.[26] The skin is the second-most commonly affected organ after the lungs.[31] The most common lesions are erythema nodosum, plaques, maculopapular eruptions, subcutaneous nodules, and lupus pernio.[31] Treatment is not required, since the lesions usually resolve spontaneously in 2–4 weeks. Although it may be disfiguring, cutaneous sarcoidosis rarely causes major problems.[26][32][33] Sarcoidosis of the scalp presents with diffuse or patchy hair loss.[34][35] ### Heart[edit] Histologically, sarcoidosis of the heart is an active granulomatous inflammation surrounded by reactive oedema. The distribution of affected areas is patchy with localised enlargement of heart muscles. This causes scarring and remodelling of the heart, which leads to dilatation of heart cavities and thinning of heart muscles. As the situation progresses, it leads to aneurysm of heart chambers. When the distribution is diffuse, there would be dilatation of both ventricles of the heart, causing heart failure and arrhythmia. When the conduction system in the intraventricular septum is affected, it would lead to heart block, ventricular tachycardia and ventricular arrhythmia, causing sudden death. Nevertheless, the involvement of pericardium and heart valves are uncommon.[36] The frequency of cardiac involvement varies and is significantly influenced by race; in Japan, more than 25% of those with sarcoidosis have symptomatic cardiac involvement, whereas in the US and Europe, only about 5% of cases present with cardiac involvement.[26] Autopsy studies in the US have revealed a frequency of cardiac involvement of about 20–30%, whereas autopsy studies in Japan have shown a frequency of 60%.[21] The presentation of cardiac sarcoidosis can range from asymptomatic conduction abnormalities to fatal ventricular arrhythmia.[37][38] Conduction abnormalities are the most common cardiac manifestations of sarcoidosis in humans and can include complete heart block.[39] Second to conduction abnormalities, in frequency, are ventricular arrhythmias, which occurs in about 23% of case with cardiac involvement.[39] Sudden cardiac death, either due to ventricular arrhythmias or complete heart block is a rare complication of cardiac sarcoidosis.[40][41] Cardiac sarcoidosis can cause fibrosis, granuloma formation, or the accumulation of fluid in the interstitium of the heart, or a combination of the former two.[42][43] Cardiac sarcoidosis may also cause congestive heart failure when granulomas cause myocardial fibrosis and scarring.[44] Congestive heart failure affects 25-75% of those with cardiac sarcoidosis. Pulmonary arterial hypertension occurs by two mechanisms in cardiac sarcoidosis: reduced left heart function due to granulomas weakening the heart muscle or from impaired blood flow.[45] ### Eye[edit] Eye involvement occurs in about 10–90% of cases.[21] Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness.[46] The most common ophthalmologic manifestation of sarcoidosis is uveitis.[21][47][48] The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever or Heerfordt syndrome (D86.8). Development of scleral nodule associated with sarcoidosis has been observed.[49] ### Nervous system[edit] Main article: Neurosarcoidosis Any of the components of the nervous system can be involved.[50] Sarcoidosis affecting the nervous system is known as neurosarcoidosis.[50] Cranial nerves are most commonly affected, accounting for about 5–30% of neurosarcoidosis cases, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis.[50][51][52] It occurs suddenly and is usually transient. The central nervous system involvement is present in 10–25% of sarcoidosis cases.[29] Other common manifestations of neurosarcoidosis include optic nerve dysfunction, papilledema, palate dysfunction, neuroendocrine changes, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic meningitis, and peripheral neuropathy.[26] Myelopathy, that is spinal cord involvement, occurs in about 16–43% of neurosarcoidosis cases and is often associated with the poorest prognosis of the neurosarcoidosis subtypes.[50] Whereas facial nerve palsies and acute meningitis due to sarcoidosis tend to have the most favourable prognosis,[50] another common finding in sarcoidosis with neurological involvement is autonomic or sensory small-fiber neuropathy.[53][54] Neuroendocrine sarcoidosis accounts for about 5–10% of neurosarcoidosis cases and can lead to diabetes insipidus, changes in menstrual cycle and hypothalamic dysfunction.[50][52] The latter can lead to changes in body temperature, mood, and prolactin (see the endocrine and exocrine section for details).[50] ### Endocrine and exocrine[edit] Prolactin is frequently increased in sarcoidosis, between 3 and 32% of cases have hyperprolactinemia[55] this frequently leads to amenorrhea, galactorrhea, or nonpuerperal mastitis in women. It also frequently causes an increase in 1,25-dihydroxy vitamin D, the active metabolite of vitamin D, which is usually hydroxylated within the kidney, but in sarcoidosis patients, hydroxylation of vitamin D can occur outside the kidneys, namely inside the immune cells found in the granulomas the condition produces. 1,25-dihydroxy vitamin D is the main cause for hypercalcemia in sarcoidosis and is overproduced by sarcoid granulomata. Gamma-interferon produced by activated lymphocytes and macrophages plays a major role in the synthesis of 1 alpha, 25(OH)2D3.[56] Hypercalciuria (excessive secretion of calcium in one's urine) and hypercalcemia (an excessively high amount of calcium in the blood) are seen in <10% of individuals and likely results from the increased 1,25-dihydroxy vitamin D production.[57] Thyroid dysfunction is seen in 4.2–4.6% of cases.[58][59] Parotid enlargement occurs in about 5–10% of cases.[18] Bilateral involvement is the rule. The gland is usually not tender, but firm and smooth. Dry mouth can occur; other exocrine glands are affected only rarely.[26] The eyes, their glands, or the parotid glands are affected in 20–50% of cases.[60] ### Gastrointestinal and genitourinary[edit] Symptomatic gastrointestinal (GI) involvement occurs in less than 1% of cases (if one excludes the liver), and most commonly the stomach is affected, although the small or large intestine may also be affected in a small portion of cases.[18][61] Studies at autopsy have revealed GI involvement in less than 10% of people.[52] These cases would likely mimic Crohn's disease, which is a more commonly intestine-affecting granulomatous disease.[18] About 1–3% of people have evidence of pancreatic involvement at autopsy.[52] Symptomatic kidney involvement occurs in just 0.7% of cases, although evidence of kidney involvement at autopsy has been reported in up to 22% of people and occurs exclusively in cases of chronic disease.[18][21][52] Symptomatic kidney involvement is usually nephrocalcinosis, although granulomatous interstitial nephritis that presents with reduced creatinine clearance and little proteinuria is a close second.[18][52] Less commonly, the epididymis, testicles, prostate, ovaries, fallopian tubes, uterus, or the vulva may be affected, the latter may cause vulva itchiness.[21][62][63] Testicular involvement has been reported in about 5% of people at autopsy.[52][63] In males, sarcoidosis may lead to infertility.[63] Around 70% of people have granulomas in their livers, although only in about 20–30% of cases, liver function test anomalies reflecting this fact are seen.[19][26] About 5–15% of sufferers exhibit hepatomegaly.[21] Only 5–30% of cases of liver involvement are symptomatic.[64] Usually, these changes reflect a cholestatic pattern and include raised levels of alkaline phosphatase (which is the most common liver function test anomaly seen in those with sarcoidosis), while bilirubin and aminotransferases are only mildly elevated. Jaundice is rare.[18][26] ### Blood[edit] Abnormal blood tests are frequent, accounting for over 50% of cases, but are not diagnostic.[26][29] Lymphopenia is the most common blood anomaly in sarcoidosis.[26] Anemia occurs in about 20% of people with sarcoidosis.[26] Leukopenia is less common and occurs in even fewer cases but is rarely severe.[26] Thrombocytopenia and hemolytic anemia are fairly rare.[18] In the absence of splenomegaly, leukopenia may reflect bone marrow involvement, but the most common mechanism is a redistribution of blood T cells to sites of disease.[65] Other nonspecific findings include monocytosis, occurring in the majority of sarcoidosis cases,[66] increased hepatic enzymes or alkaline phosphatase. People with sarcoidosis often have immunologic anomalies like allergies to test antigens such as Candida or purified protein derivative.[60] Polyclonal hypergammaglobulinemia is also a fairly common immunologic anomaly seen in sarcoidosis.[60] Lymphadenopathy (swollen glands) is common in sarcoidosis and occurs in 15% of cases.[22] Intrathoracic nodes are enlarged in 75 to 90% of all people; usually this involves the hilar nodes, but the paratracheal nodes are commonly involved. Peripheral lymphadenopathy is very common, particularly involving the cervical (the most common head and neck manifestation of the disease), axillary, epitrochlear, and inguinal nodes.[67] Approximately 75% of cases show microscopic involvement of the spleen, although only in about 5–10% of cases does splenomegaly appear.[18][60] ### Bone, joints, and muscles[edit] Sarcoidosis can be involved with the joints, bones, and muscles. This causes a wide variety of musculoskeletal complaints that act through different mechanisms.[68] About 5–15% of cases affect the bones, joints, or muscles.[29] Arthritic syndromes can be categorized as acute or chronic.[68] Sarcoidosis patients suffering acute arthritis often also have bilateral hilar lymphadenopathy and erythema nodosum. These three associated syndromes often occur together in Löfgren syndrome.[68] The arthritis symptoms of Löfgren syndrome occur most frequently in the ankles, followed by the knees, wrists, elbows, and metacarpophalangeal joints.[68] Usually, true arthritis is not present, but instead, periarthritis appears as a swelling in the soft tissue around the joints that can be seen by ultrasonographic methods.[68] These joint symptoms tend to precede or occur at the same time as erythema nodosum develops.[68] Even when erythema nodosum is absent, it is believed that the combination of hilar lymphadenopathy and ankle periarthritis can be considered as a variant of Löfgren syndrome.[68] Enthesitis also occurs in about one-third of patients with acute sarcoid arthritis, mainly affecting the Achilles tendon and heels.[68] Soft-tissue swelling of the ankles can be prominent, and biopsy of this soft tissue reveals no granulomas, but does show panniculitis similar to erythema nodosum.[68] Chronic sarcoid arthritis usually occurs in the setting of more diffuse organ involvement.[68] The ankles, knees, wrists, elbows, and hands may all be affected in the chronic form and often this presents itself in a polyarticular pattern.[68] Dactylitis similar to that seen in psoriatic arthritis, that is associated with pain, swelling, overlying skin erythema, and underlying bony changes may also occur.[68] Development of Jaccoud arthropathy (a nonerosive deformity) is very rarely seen.[68] Bone involvement in sarcoidosis has been reported in 1–13% of cases.[52] The most frequent sites of involvement are the hands and feet, whereas the spine is less commonly affected.[68] Half of the patients with bony lesions experience pain and stiffness, whereas the other half remain asymptomatic.[68] Periostitis is rarely seen in sarcoidosis and has been found to present itself at the femoral bone.[69][70] ## Cause[edit] The exact cause of sarcoidosis is not known.[2] The current working hypothesis is, in genetically susceptible individuals, sarcoidosis is caused through alteration to the immune response after exposure to an environmental, occupational, or infectious agent.[71] Some cases may be caused by treatment with tumor necrosis factor (TNF) inhibitors like etanercept.[72] ### Genetics[edit] The heritability of sarcoidosis varies according to ethnicity. About 20% of African Americans with sarcoidosis have a family member with the condition, whereas the same figure for European Americans is about 5%. Additionally, in African Americans, who seem to experience more severe and chronic disease, siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for developing the disease.[24] In Swedish individuals heritability was found to be 39%.[73] In this group, if a first-degree family member was affected, a person has a four-fold greater risk of being affected.[73] Investigations of genetic susceptibility yielded many candidate genes, but only few were confirmed by further investigations and no reliable genetic markers are known. Currently, the most interesting candidate gene is BTNL2; several HLA-DR risk alleles are also being investigated.[74][75] In persistent sarcoidosis, the HLA haplotype HLA-B7-DR15 is either cooperating in disease or another gene between these two loci is associated. In nonpersistent disease, a strong genetic association exists with HLA DR3-DQ2.[76][77] Cardiac sarcoid has been connected to tumor necrosis factor alpha (TNFA) variants.[78] ### Infectious agents[edit] Several infectious agents appear to be significantly associated with sarcoidosis, but none of the known associations is specific enough to suggest a direct causative role.[79] The major implicated infectious agents include: mycobacteria, fungi, borrelia, and rickettsia.[80] A meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, but they also detected a possible publication bias, so the results need further confirmation.[81][82] Mycobacterium tuberculosis catalase-peroxidase has been identified as a possible antigen catalyst of sarcoidosis.[83] The disease has also been reported by transmission via organ transplants.[84] A large epidemiological study found little evidence that infectious diseases spanning years before sarcoidosis diagnosis could confer measurable risks for sarcoidosis diagnosis in the future.[85] ### Autoimmune[edit] Association of autoimmune disorders has been frequently observed. The exact mechanism of this relation is not known, but some evidence supports the hypothesis that this is a consequence of Th1 lymphokine prevalence.[58][86] Tests of delayed cutaneous hypersensitivity have been used to measure progression.[87] ## Pathophysiology[edit] Granulomatous inflammation is characterized primarily by the accumulation of macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, Tumor necrosis factor alpha (TNF), Interferon gamma, Interleukin 2 (IL-2), IL-8, IL-10, IL-12, IL-18, IL-23 and transforming growth factor beta (TGF-β), indicative of a T helper cell-mediated immune response.[80][88] Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by increased macrophage and CD4 helper T-cell activation, resulting in accelerated inflammation, but immune response to antigen challenges such as tuberculin is suppressed. This paradoxic state of simultaneous hyper- and hypoactivity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer.[citation needed] The regulatory T-lymphocytes in the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.[89] Schaumann bodies seen in sarcoidosis are calcium and protein inclusions inside of Langhans giant cells as part of a granuloma. Sarcoidosis is characterized by the formation of non-caseous epithelioid cell granulomas in various organs and tissues.[90] While TNF is widely believed to play an important role in the formation of granulomas (this is further supported by the finding that in animal models of mycobacterial granuloma formation inhibition of either TNF or IFN-γ production inhibits granuloma formation), sarcoidosis can and does still develop in those being treated with TNF antagonists like etanercept.[91] B cells also likely play a role in the pathophysiology of sarcoidosis.[24] Serum levels of soluble human leukocyte antigen (HLA) class I antigens and angiotensin converting enzyme (ACE) are higher in people with sarcoidosis.[24] Likewise the ratio of CD4/CD8 T cells in bronchoalveolar lavage is usually higher in people with pulmonary sarcoidosis (usually >3.5), although it can be normal or even abnormally low in some cases.[24] Serum ACE levels have been found to usually correlate with total granuloma load.[80] Cases of sarcoidosis have also been reported as part of the immune reconstitution syndrome of HIV, that is, when people receive treatment for HIV, their immune system rebounds and the result is that it starts to attack the antigens of opportunistic infections caught prior to said rebound and the resulting immune response starts to damage healthy tissue.[88] * Sarcoidosis in a lymph node * Asteroid body in sarcoidosis * Micrograph showing pulmonary sarcoidosis with granulomas with asteroid bodies, H&E stain ## Diagnosis[edit] CT scan of the chest showing lymphadenopathy (arrows) in the mediastinum due to sarcoidosis Diagnosis of sarcoidosis is a matter of exclusion, as there is no specific test for the condition. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve a chest radiograph, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with fine-needle aspiration of mediastinal lymph nodes (EBUS FNA). Tissue from biopsy of lymph nodes is subjected to both flow cytometry to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain) to rule out microorganisms and fungi.[92][93][12][94] Serum markers of sarcoidosis, include: serum amyloid A, soluble interleukin-2 receptor, lysozyme, angiotensin converting enzyme, and the glycoprotein KL-6.[95] Angiotensin-converting enzyme blood levels are used in the monitoring of sarcoidosis.[95] A bronchoalveolar lavage can show an elevated (of at least 3.5) CD4/CD8 T cell ratio, which is indicative (but not proof) of pulmonary sarcoidosis.[24] In at least one study the induced sputum ratio of CD4/CD8 and level of TNF was correlated to those in the lavage fluid.[95] A sarcoidosis-like lung disease called granulomatous–lymphocytic interstitial lung disease can be seen in patients with common variable immunodeficiency (CVID) and therefore serum antibody levels should be measured to exclude CVID.[citation needed] Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodules, granulomatosis with polyangiitis, varicella infection, tuberculosis, and atypical infections, such as Mycobacterium avium complex, cytomegalovirus, and cryptococcus.[96] Sarcoidosis is confused most commonly with neoplastic diseases, such as lymphoma, or with disorders characterized also by a mononuclear cell granulomatous inflammatory process, such as the mycobacterial and fungal disorders.[26] Chest radiograph changes are divided into four stages:[97] 1. bihilar lymphadenopathy 2. bihilar lymphadenopathy and reticulonodular infiltrates 3. bilateral pulmonary infiltrates 4. fibrocystic sarcoidosis typically with upward hilar retraction, cystic and bullous changes Although people with stage 1 radiographs tend to have the acute or subacute, reversible form of the disease, those with stages 2 and 3 often have the chronic, progressive disease; these patterns do not represent consecutive "stages" of sarcoidosis. Thus, except for epidemiologic purposes, this categorization is mostly of historic interest.[26] In sarcoidosis presenting in the Caucasian population, hilar adenopathy and erythema nodosum are the most common initial symptoms. In this population, a biopsy of the gastrocnemius muscle is a useful tool in correctly diagnosing the person. The presence of a noncaseating epithelioid granuloma in a gastrocnemius specimen is definitive evidence of sarcoidosis, as other tuberculoid and fungal diseases extremely rarely present histologically in this muscle.[98] Cardiac magnetic resonance imaging (CMR) is one modality for diagnosing cardiac sarcoidosis. It has 78% specificity in diagnosing cardiac sarcoidosis.[36] Its T2-weighted imaging can detect acute inflammation. Meanwhile, late gadolinium contrast (LGE) can detect fibrosis or scar. Lesions at the subpericardium and midwall enhancement of basal spetum or inferolateral wall is strongly suggestive of sarcoidosis.[36] MRI can also follow up on the treatment efficacy of corticosteriods and prognosis of cardiac sarcoidosis.[99] PET scan is able to quantify disease activity which cannot be performed by CMR.[100] * Hilar adenopathy especially on the person's left (AP CXR) * Hilar adenopathy especially on the person's left (lateral CXR) * Hilar adenopathy especially on the person's left (coronal CT) * Hilar adenopathy especially on the person's left (transverse CT) ### Classification[edit] Sarcoidosis may be divided into the following types:[34] * Annular sarcoidosis * Erythrodermic sarcoidosis * Ichthyosiform sarcoidosis * Hypopigmented sarcoidosis * Löfgren syndrome * Lupus pernio * Morpheaform sarcoidosis * Mucosal sarcoidosis * Neurosarcoidosis * Papular sarcoid * Scar sarcoid * Subcutaneous sarcoidosis * Systemic sarcoidosis * Ulcerative sarcoidosis ## Treatment[edit] Treatments for sarcoidosis vary greatly depending on the patient.[101] At least half of patients require no systemic therapy.[102] Most people (>75%) only require symptomatic treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin.[103] For those presenting with lung symptoms, unless the respiratory impairment is devastating, active pulmonary sarcoidosis is observed usually without therapy for two to three months; if the inflammation does not subside spontaneously, therapy is instituted.[26] Major categories of drug interventions include glucocorticoids, antimetabolites, biologic agents especially monoclonal anti-tumor necrosis factor antibodies.[102] Investigational treatments include specific antibiotic combinations and mesenchymal stem cells.[102] If drug intervention is indicated, a step-wise approach is often used to explore alternatives in order of increasing side effects and to monitor potentially toxic effects.[102] Corticosteroids, most commonly prednisone or prednisolone, have been the standard treatment for many years.[18] In some people, this treatment can slow or reverse the course of the disease, but other people do not respond to steroid therapy. The use of corticosteroids in mild disease is controversial because in many cases the disease remits spontaneously.[104][105] ### Antimetabolites[edit] Antimetabolites, also categorized as steroid-sparing agents, such as azathioprine, methotrexate, mycophenolic acid, and leflunomide[106][107] are often used as alternatives to corticosteroids.[18][108] Of these, methotrexate is most widely used and studied.[108][109] Methotrexate is considered a first-line treatment in neurosarcoidosis, often in conjunction with corticosteroids.[50][108] Long-term treatment with methotrexate is associated with liver damage in about 10% of people and hence may be a significant concern in people with liver involvement and requires regular liver function test monitoring.[18] Methotrexate can also lead to pulmonary toxicity (lung damage), although this is fairly uncommon and more commonly it can confound the leukopenia caused by sarcoidosis.[18] Due to these safety concerns it is often recommended that methotrexate is combined with folic acid in order to prevent toxicity.[18] Azathioprine treatment can also lead to liver damage.[109] However, the risk of infection appears to be about 40% lower in those treated with methotrexate instead of azathioprine.[110] Leflunomide is being used as a replacement for methotrexate, possibly due to its purportedly lower rate of pulmonary toxicity.[109] Mycophenolic acid has been used successfully in uveal sarcoidosis,[111] neurosarcoidosis (especially CNS sarcoidosis; minimally effective in sarcoidosis myopathy),[112] and pulmonary sarcoidosis.[113][114] ### Immunosuppressants[edit] As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some success using immunosuppressants (like cyclophosphamide, cladribine,[115] chlorambucil, and cyclosporine), immunomodulatory (pentoxifylline and thalidomide), and anti-tumor necrosis factor treatment[116][117] (such as infliximab, etanercept, golimumab, and adalimumab).[17][118][119] In a clinical trial cyclosporine added to prednisone treatment failed to demonstrate any significant benefit over prednisone alone in people with pulmonary sarcoidosis, although there was evidence of increased toxicity from the addition of cyclosporine to the steroid treatment including infections, malignancies (cancers), hypertension, and kidney dysfunction.[109] Likewise chlorambucil and cyclophosphamide are seldom used in the treatment of sarcoidosis due to their high degree of toxicity, especially their potential for causing malignancies.[120] Infliximab has been used successfully to treat pulmonary sarcoidosis in clinical trials in a number of cases.[109] Etanercept, on the other hand, has failed to demonstrate any significant efficacy in people with uveal sarcoidosis in a couple of clinical trials.[109] Likewise golimumab has failed to show any benefit in those with pulmonary sarcoidosis.[109] One clinical trial of adalimumab found treatment response in about half of subjects, which is similar to that seen with infliximab, but as adalimumab has better tolerability profile it may be preferred over infliximab.[109] ### Specific organ treatments[edit] Ursodeoxycholic acid has been used successfully as a treatment for cases with liver involvement.[121] Thalidomide has also been tried successfully as a treatment for treatment-resistant lupus pernio in a clinical trial, which may stem from its anti-TNF activity, although it failed to exhibit any efficacy in a pulmonary sarcoidosis clinical trial.[88][118] Cutaneous disease may be successfully managed with antimalarials (such as chloroquine and hydroxychloroquine) and the tetracycline antibiotic, minocycline.[26][118] Antimalarials have also demonstrated efficacy in treating sarcoidosis-induced hypercalcemia and neurosarcoidosis.[18] Long-term use of antimalarials is limited, however, by their potential to cause irreversible blindness and hence the need for regular ophthalmologic screening.[120] This toxicity is usually less of a problem with hydroxychloroquine than with chloroquine, although hydroxychloroquine can disturb the glucose homeostasis.[120] Recently selective phosphodiesterase 4 (PDE4) inhibitors like apremilast (a thalidomide derivative), roflumilast, and the less subtype-selective PDE4 inhibitor, pentoxifylline, have been tried as a treatment for sarcoidosis, with successful results being obtained with apremilast in cutaneous sarcoidosis in a small open-label study.[122][123] Pentoxifylline has been used successfully to treat acute disease although its use is greatly limited by its gastrointestinal toxicity (mostly nausea, vomiting, and diarrhea).[107][109][120] Case reports have supported the efficacy of rituximab, an anti-CD20 monoclonal antibody and a clinical trial investigating atorvastatin as a treatment for sarcoidosis is under-way.[124][125] ACE inhibitors have been reported to cause remission in cutaneous sarcoidosis and improvement in pulmonary sarcoidosis, including improvement in pulmonary function, remodeling of lung parenchyma and prevention of pulmonary fibrosis in separate case series'.[126][127][128] Nicotine patches have been found to possess anti-inflammatory effects in sarcoidosis patients, although whether they had disease-modifying effects requires further investigation.[129] Antimycobacterial treatment (drugs that kill off mycobacteria, the causative agents behind tuberculosis and leprosy) has also proven itself effective in treating chronic cutaneous (that is, it affects the skin) sarcoidosis in one clinical trial.[130] Quercetin has also been tried as a treatment for pulmonary sarcoidosis with some early success in one small trial.[131] Because of its uncommon nature, the treatment of male reproductive tract sarcoidosis is controversial. Since the differential diagnosis includes testicular cancer, some recommend orchiectomy, even if evidence of sarcoidosis in other organs is present. In the newer approach, testicular, epididymal biopsy and resection of the largest lesion has been proposed.[63] ### Symptoms[edit] People with sarcoidosis may have a range of symptoms that do not correspond with objective physical evidence of disease but that still decrease quality of life.[132] Physical therapy, rehabilitation, and counseling can help avoid deconditioning,[132]:733 and improve social participation, psychological well-being, and activity levels. Key aspects are avoiding exercise intolerance and muscle weakness.[132]:734 Low or moderate-intensity physical training has been shown to improve fatigue, psychological health, and physical functioning in people sarcoidosis without adverse effects.[133][134] Inspiratory muscle training has also decreased severe fatigue perception in subjects with early stages of sarcoidosis, as well as improving functional and maximal exercise capacity and respiratory muscle strength.[135] The duration, frequency, and physical intensity of exercise needs to accommodate impairments such as joint pain, muscle pain, and fatigue.[132]:734[134][136] Neurostimulants such as methylphenidate and modafinil have shown some effectiveness as an adjunct for treatment of sarcoidosis fatigue.[132]:733[137] Treatments for symptomatic neuropathic pain in sarcoidosis patients is similar to that for other causes, and include antidepressants, anticonvulsants and prolonged-release opioids, however, only 30 to 60% of patients experience limited pain relief.[132]:733 ## Prognosis[edit] Gross pathology image showing sarcoidosis with honeycombing: Prominent honeycombing is present in the lower lobes accompanied by fibrosis and some honeycombing in the upper lungs. Honeycombing consists of cystically dilated airways separated by scar tissue resembling the honeycomb of bees. It is a nonspecific end stage of many types of interstitial lung disease. The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some cases, it can progress to pulmonary fibrosis and death. In benign cases, remission can occur in 24 to 36 months without treatment but regular follow ups are required. Some cases, however, may persist several decades.[18] Two-thirds of people with the condition achieve a remission within 10 years of the diagnosis.[138] When the heart is involved, the prognosis is generally less favourable, though corticosteroids appear effective in improving AV conduction.[139][140] The prognosis tends to be less favourable in African Americans than in white Americans.[24] In a Swedish population-based analysis, the majority of cases who did not have severe disease at diagnosis had comparable mortality to the general population.[141] The risk for premature death was markedly (2.3-fold) increased compared to the general population for a smaller group of cases with severe disease at diagnosis.[141] Serious infections, sometimes multiple during the course of disease, and heart failure might contribute to the higher risk of early death in some patients with sarcoidosis.[142][143] Some 1990s studies indicated that people with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer, lymphomas,[144] and cancer in other organs known to be affected in sarcoidosis.[145][146] In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma.[147] This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process.[148] Sarcoidosis can also follow cancer[149][150] or occur concurrently with cancer.[151][152] There have been reports of hairy cell leukemia,[153] acute myeloid leukemia,[154] and acute myeloblastic leukemia[155] associated with sarcoidosis. Sometimes, sarcoidosis, even untreated, can be complicated by opportunistic infections.[156][157] ## Epidemiology[edit] Sarcoidosis most commonly affects young adults of both sexes, although studies have reported more cases in females. Incidence is highest for individuals younger than 40 and peaks in the age-group from 20 to 29 years; a second peak is observed for women over 50.[18][139] Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5 per 100,000 in men and 19 per 100,000 in women. The disease is most common in Northern European countries and the highest annual incidence of 60 per 100,000 is found in Sweden and Iceland. In the United Kingdom the prevalence is 16 in 100,000.[158] In the United States, sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9 per 100,000, respectively.[159] Sarcoidosis is less commonly reported in South America, Spain, India, Canada, and the Philippines. There may be a higher susceptibility to sarcoidosis in those with celiac disease. An association between the two disorders has been suggested.[160] There also has been a seasonal clustering observed in sarcoidosis-affected individuals.[161] In Greece about 70% of diagnoses occur between March and May every year, in Spain about 50% of diagnoses occur between April and June, and in Japan it is mostly diagnosed during June and July.[161] The differing incidence across the world may be at least partially attributable to the lack of screening programs in certain regions of the world, and the overshadowing presence of other granulomatous diseases, such as tuberculosis, that may interfere with the diagnosis of sarcoidosis where they are prevalent.[139] There may also be differences in the severity of the disease between people of different ethnicities. Several studies suggest the presentation in people of African origin may be more severe and disseminated than for Caucasians, who are more likely to have asymptomatic disease.[65] Manifestation appears to be slightly different according to race and sex. Erythema nodosum is far more common in men than in women and in Caucasians than in other races. In Japanese people, ophthalmologic and cardiac involvement are more common than in other races.[18] It is more common in certain occupations, namely firefighters, educators, military personnel, those who work in industries where pesticides are used, law enforcement, and healthcare personnel.[162] In the year after the September 11 attacks, the rate of sarcoidosis incidence went up four-fold (to 86 cases per 100,000).[29][162] ## History[edit] It was first described in 1877 by Dr. Jonathan Hutchinson, a dermatologist as a condition causing red, raised rashes on the face, arms, and hands.[15] In 1889 the term Lupus pernio was coined by Dr. Ernest Besnier, another dermatologist.[163] Later in 1892 lupus pernio's histology was defined.[163] In 1902 bone involvement was first described by a group of three doctors.[163] Between 1909 and 1910 uveitis in sarcoidosis was first described, and later in 1915 it was emphasised, by Dr. Schaumann, that it was a systemic condition.[163] This same year lung involvement was also described.[163] In 1937 uveoparotid fever was first described and likewise in 1941 Löfgren syndrome was first described.[163] In 1958 the first international conference on sarcoidosis was called in London, likewise the first USA sarcoidosis conference occurred in Washington, D.C., in the year 1961.[163] It has also been called Besnier–Boeck disease or Besnier–Boeck–Schaumann disease.[164] ### Etymology[edit] The word "sarcoidosis" comes from Greek [σάρκο-] sarcο- meaning "flesh", the suffix -(e)ido (from the Greek εἶδος -eidos [usually omitting the initial e in English as the diphthong epsilon-iota in Classic Greek stands for a long "i" = English ee]) meaning "type", " resembles" or "like", and -sis, a common suffix in Greek meaning "condition". Thus the whole word means "a condition that resembles crude flesh". The first cases of sarcoïdosis, which were recognised as a new pathological entity, in Scandinavia, at the end of the 19th century exhibited skin nodules resembling cutaneous sarcomas, hence the name initially given.[citation needed] ## Society and culture[edit] The World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) is an organisation of physicians involved in the diagnosis and treatment of sarcoidosis and related conditions.[165] WASOG publishes the journal Sarcoidosis, Vasculitis and Diffuse Lung Diseases.[166] Additionally, the Foundation for Sarcoidosis Research (FSR) is devoted to supporting research into sarcoidosis and its possible treatments.[167] There have been concerns that World Trade Center rescue workers are at a heightened risk for sarcoidosis.[168][169] Comedian and actor Bernie Mac had sarcoidosis. In 2005, he mentioned that the disease was in remission.[170] His death on 9 August 2008 was caused by complications from pneumonia, though Mac's agent states the sarcoidosis was not related to his fatal pneumonia.[171] Karen "Duff" Duffy, MTV personality and actress, was diagnosed with neurosarcoidosis in 1995.[172] American football player Reggie White died in 2004, with pulmonary and cardiac sarcoidosis being contributing factors to his fatal heart arrhythmia.[173] Singer Sean Levert died in 2008 of sarcoidosis complications.[174] Joseph Rago, Pulitzer Prize-winning writer known for his work at The Wall Street Journal, died of sarcoidosis complications in 2017.[175] Several historical figures are suspected of having suffered from sarcoidosis. In a 2014 letter to the British medical journal The Lancet, it was suggested that the French Revolution leader Maximilien Robespierre may have had sarcoidosis, causing him impairment during his time as head of the Reign of Terror.[176] The symptoms associated with Ludwig van Beethoven's 1827 death have been described as possibly consistent with sarcoidosis.[177] Author Robert Louis Stevenson (1850–1894) had a history of chronic coughs and chest complaints, and sarcoidosis has been suggested as a diagnosis.[178] ## Pregnancy[edit] Sarcoidosis generally does not prevent successful pregnancy and delivery; the increase in estrogen levels during pregnancy may even have a slightly beneficial immunomodulatory effect. In most cases, the course of the disease is unaffected by pregnancy, with improvement in a few cases and worsening of symptoms in very few cases, although it is worth noting that a number of the immunosuppressants (such as methotrexate, cyclophosphamide) used in corticosteroid-refractory sarcoidosis are known teratogens.[179] Increased risks associated with sarcoidosis ranging from 30 to 70% have been reported for preeclampsia/eclampsia, cesarian or preterm delivery as well as (non-cardiac) birth defects in first singleton pregnancies.[180] In absolute numbers, birth defects and other complications such as maternal death, cardiac arrest, placental abruption or venous thromboembolism are extremely rare in sarcoidosis pregnancies.[180] ## References[edit] 1. ^ Konstantinidis G (2005). Elsevier's Dictionary of Medicine and Biology: in English, Greek, German, Italian and Latin. Elsevier. p. 1454. ISBN 978-0-08-046012-3. 2. ^ a b c d e f g h i j k l m n "What Is Sarcoidosis?". NHLBI. June 14, 2013. Archived from the original on 6 April 2016. Retrieved 28 March 2016. 3. ^ a b c d "What Are the Signs and Symptoms of Sarcoidosis?". NHLBI. June 14, 2013. Archived from the original on 7 April 2016. Retrieved 29 March 2016. 4. ^ a b c d e "Who Is at Risk for Sarcoidosis?". NHLBI. June 14, 2013. Archived from the original on 7 April 2016. Retrieved 28 March 2016. 5. ^ a b c d e Wijsenbeek MS, Culver DA (December 2015). "Treatment of Sarcoidosis". Clinics in Chest Medicine. 36 (4): 751–67. doi:10.1016/j.ccm.2015.08.015. PMID 26593147. 6. ^ a b c d Govender P, Berman JS (December 2015). "The Diagnosis of Sarcoidosis". Clinics in Chest Medicine. 36 (4): 585–602. doi:10.1016/j.ccm.2015.08.003. PMID 26593135. 7. ^ Ferri FF (2010). Ferri's differential diagnosis: a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.). Philadelphia, PA: Elsevier/Mosby. p. Chapter S. ISBN 978-0-323-07699-9. 8. ^ a b Drent M, Cremers JP, Jansen TL (May 2014). "Pulmonology meets rheumatology in sarcoidosis: a review on the therapeutic approach". Current Opinion in Rheumatology. 26 (3): 276–84. doi:10.1097/bor.0000000000000052. PMID 24614277. S2CID 24353355. 9. ^ a b c Judson MA (February 2016). "Corticosteroids in Sarcoidosis". Rheumatic Diseases Clinics of North America. 42 (1): 119–35, ix. doi:10.1016/j.rdc.2015.08.012. PMID 26611555. 10. ^ a b GBD 2015 Disease Injury Incidence Prevalence Collaborators (October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. 11. ^ a b GBD 2015 Mortality Causes of Death Collaborators (October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/S0140-6736(16)31012-1. PMC 5388903. PMID 27733281. 12. ^ a b c Baughman RP, Culver DA, Judson MA (March 2011). "A concise review of pulmonary sarcoidosis". American Journal of Respiratory and Critical Care Medicine. 183 (5): 573–81. doi:10.1164/rccm.201006-0865CI. PMC 3081278. PMID 21037016. 13. ^ "What Causes Sarcoidosis?". NHLBI. June 14, 2013. Archived from the original on 6 April 2016. Retrieved 28 March 2016. 14. ^ a b Kobak S (October 2015). "Sarcoidosis: a rheumatologist's perspective". Therapeutic Advances in Musculoskeletal Disease. 7 (5): 196–205. doi:10.1177/1759720x15591310. PMC 4572362. PMID 26425148. 15. ^ a b James DG, Sharma OP (September 2002). "From Hutchinson to now: a historical glimpse" (PDF). Current Opinion in Pulmonary Medicine. 8 (5): 416–23. doi:10.1097/00063198-200209000-00013. PMID 12172446. Archived (PDF) from the original on 2016-03-04. 16. ^ "Lung Diseases: Sarcoidosis: Signs & Symptoms". National Heart, Lung, and Blood Institute. Archived from the original on May 7, 2009. Retrieved May 9, 2009. 17. ^ a b Kamangar N, Rohani P, Shorr AF (6 February 2014). Peters SP, Talavera F, Rice TD, Mosenifar Z (eds.). "Sarcoidosis Clinical Presentation". Medscape Reference. WebMD. Archived from the original on 25 February 2014. Retrieved 19 February 2014. 18. ^ a b c d e f g h i j k l m n o p q r Nunes H, Bouvry D, Soler P, Valeyre D (November 2007). "Sarcoidosis". Orphanet Journal of Rare Diseases. 2: 46. doi:10.1186/1750-1172-2-46. PMC 2169207. PMID 18021432. 19. ^ a b c d King, TE Jr. (March 2008). "Sarcoidosis: Interstitial Lung Diseases: Merck Manual Home Edition". The Merck Manual Home Edition. Merck Sharp & Dohme Corp. Archived from the original on 20 February 2014. Retrieved 19 February 2014. 20. ^ Sweiss NJ, Patterson K, Sawaqed R, Jabbar U, Korsten P, Hogarth K, Wollman R, Garcia JG, Niewold TB, Baughman RP (August 2010). "Rheumatologic manifestations of sarcoidosis". Seminars in Respiratory and Critical Care Medicine. 31 (4): 463–73. doi:10.1055/s-0030-1262214. PMC 3314339. PMID 20665396. 21. ^ a b c d e f g Holmes J, Lazarus A (November 2009). "Sarcoidosis: extrathoracic manifestations". Disease-A-Month. 55 (11): 675–92. doi:10.1016/j.disamonth.2009.05.002. PMID 19857642. 22. ^ a b Dempsey OJ, Paterson EW, Kerr KM, Denison AR (August 2009). "Sarcoidosis". BMJ. 339: b3206. doi:10.1136/bmj.b3206. PMID 19717499. S2CID 220114548. 23. ^ Tolaney SM, Colson YL, Gill RR, Schulte S, Duggan MM, Shulman LN, Winer EP (October 2007). "Sarcoidosis mimicking metastatic breast cancer". Clinical Breast Cancer. 7 (10): 804–10. doi:10.3816/CBC.2007.n.044. PMID 18021484. 24. ^ a b c d e f g Kamangar N, Rohani P, Shorr AF (6 February 2014). Peters SP, Talavera F, Rice TD, Mosenifar Z (eds.). "Sarcoidosis". Medscape Reference. WebMD. Archived from the original on 10 February 2014. Retrieved 19 February 2014. 25. ^ Baughman RP, Lower EE, Gibson K (June 2012). "Pulmonary manifestations of sarcoidosis". Presse Médicale. 41 (6 Pt 2): e289–302. doi:10.1016/j.lpm.2012.03.019. PMID 22579234. 26. ^ a b c d e f g h i j k l m n o p q r Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J (2011). Harrison's Principles of Internal Medicine (18th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07174889-6. 27. ^ Fuhrer G, Myers JN (November 2009). "Intrathoracic sarcoidosis". Disease-A-Month. 55 (11): 661–74. doi:10.1016/j.disamonth.2009.04.009. PMID 19857641. 28. ^ Nunes H, Uzunhan Y, Freynet O, Humbert M, Brillet PY, Kambouchner M, Valeyre D (June 2012). "Pulmonary hypertension complicating sarcoidosis". Presse Médicale. 41 (6 Pt 2): e303–16. doi:10.1016/j.lpm.2012.04.003. PMID 22608948. 29. ^ a b c d e Chen ES, Moller DR (July 2011). "Sarcoidosis--scientific progress and clinical challenges". Nature Reviews. Rheumatology. 7 (8): 457–67. doi:10.1038/nrrheum.2011.93. PMID 21750528. S2CID 21345455. 30. ^ Kumar and Clark, Clinical Medicine, 8th edition, p. 846. 31. ^ a b Mañá J, Marcoval J (June 2012). "Skin manifestations of sarcoidosis". Presse Médicale. 41 (6 Pt 2): e355–74. doi:10.1016/j.lpm.2012.02.046. PMID 22579238. 32. ^ Heath CR, David J, Taylor SC (January 2012). "Sarcoidosis: Are there differences in your skin of color patients?". Journal of the American Academy of Dermatology. 66 (1): 121.e1–14. doi:10.1016/j.jaad.2010.06.068. PMID 22000704. 33. ^ Lodha S, Sanchez M, Prystowsky S (August 2009). "Sarcoidosis of the skin: a review for the pulmonologist". Chest. 136 (2): 583–596. doi:10.1378/chest.08-1527. PMID 19666758. 34. ^ a b James WD, Berger TG, Elston DM (2006). Andrew's Diseases of the Skin: Clinical Dermatology (10th ed.). Philadelphia: Saunders Elsevier. pp. 708–711. ISBN 978-0808923510. 35. ^ House NS, Welsh JP, English JC (August 2012). "Sarcoidosis-induced alopecia". Dermatology Online Journal. 18 (8): 4. PMID 22948054. Archived from the original on 2 March 2014. 36. ^ a b c Yatsynovich Y, Dittoe N, Petrov M, Maroz N (February 2018). "Cardiac Sarcoidosis: A Review of Contemporary Challenges in Diagnosis and Treatment". The American Journal of the Medical Sciences. 355 (2): 113–125. doi:10.1016/j.amjms.2017.08.009. PMID 29406038. S2CID 205477032. 37. ^ Birnie DH, Sauer WH, Bogun F, Cooper JM, Culver DA, Duvernoy CS, Judson MA, Kron J, Mehta D, Cosedis Nielsen J, Patel AR, Ohe T, Raatikainen P, Soejima K (July 2014). "HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis". Heart Rhythm. 11 (7): 1305–23. doi:10.1016/j.hrthm.2014.03.043. PMID 24819193. 38. ^ Doughan AR, Williams BR (February 2006). "Cardiac sarcoidosis". Heart. 92 (2): 282–8. doi:10.1136/hrt.2005.080481. PMC 1860791. PMID 16415205. 39. ^ a b Youssef G, Beanlands RS, Birnie DH, Nery PB (December 2011). "Cardiac sarcoidosis: applications of imaging in diagnosis and directing treatment". Heart. 97 (24): 2078–87. doi:10.1136/hrt.2011.226076. PMID 22116891. S2CID 44374668. 40. ^ Reuhl J, Schneider M, Sievert H, Lutz FU, Zieger G (October 1997). "Myocardial sarcoidosis as a rare cause of sudden cardiac death". Forensic Science International. 89 (3): 145–53. doi:10.1016/S0379-0738(97)00106-0. PMID 9363623. 41. ^ Rajasenan V, Cooper ES (July 1969). "Myocardial sarcoidosis, bouts of ventricular tachycardia, psychiatric manifestations and sudden death. A case report". Journal of the National Medical Association. 61 (4): 306–9. PMC 2611747. PMID 5796402. 42. ^ Chapelon-Abric C (June 2012). "Cardiac sarcoidosis". Presse Médicale. 41 (6 Pt 2): e317–30. doi:10.1016/j.lpm.2012.04.002. PMID 22608949. 43. ^ Hulten E, Aslam S, Osborne M, Abbasi S, Bittencourt MS, Blankstein R (February 2016). "Cardiac sarcoidosis-state of the art review". Cardiovascular Diagnosis and Therapy. 6 (1): 50–63. doi:10.3978/j.issn.2223-3652.2015.12.13. PMC 4731586. PMID 26885492. 44. ^ "About Sarcoidosis". Stanford University Sarcoidosis Program. Retrieved 2019-08-09. 45. ^ Sekhri V, Sanal S, Delorenzo LJ, Aronow WS, Maguire GP (August 2011). "Cardiac sarcoidosis: a comprehensive review". Archives of Medical Science. 7 (4): 546–54. doi:10.5114/aoms.2011.24118. PMC 3258766. PMID 22291785. 46. ^ Bodaghi B, Touitou V, Fardeau C, Chapelon C, LeHoang P (June 2012). "Ocular sarcoidosis". Presse Médicale. 41 (6 Pt 2): e349–54. doi:10.1016/j.lpm.2012.04.004. PMID 22595776. 47. ^ Jamilloux Y, Kodjikian L, Broussolle C, Sève P (August 2014). "Sarcoidosis and uveitis". Autoimmunity Reviews. 13 (8): 840–9. doi:10.1016/j.autrev.2014.04.001. PMID 24704868. 48. ^ Papadia M, Herbort CP, Mochizuki M (December 2010). "Diagnosis of ocular sarcoidosis". Ocular Immunology and Inflammation. 18 (6): 432–41. doi:10.3109/09273948.2010.524344. PMID 21091056. S2CID 10055356. 49. ^ Qazi FA, Thorne JE, Jabs DA (October 2003). "Scleral nodule associated with sarcoidosis". American Journal of Ophthalmology. 136 (4): 752–4. doi:10.1016/S0002-9394(03)00454-9. PMID 14516826. 50. ^ a b c d e f g h Nozaki K, Judson MA (June 2012). "Neurosarcoidosis: Clinical manifestations, diagnosis and treatment". Presse Médicale. 41 (6 Pt 2): e331–48. doi:10.1016/j.lpm.2011.12.017. PMID 22595777. 51. ^ Said G, Lacroix C, Planté-Bordeneuve V, Le Page L, Pico F, Presles O, Senant J, Remy P, Rondepierre P, Mallecourt J (February 2002). "Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinicopathological study of 11 patients". Brain. 125 (Pt 2): 264–75. doi:10.1093/brain/awf027. PMID 11844727. 52. ^ a b c d e f g h Vardhanabhuti V, Venkatanarasimha N, Bhatnagar G, Maviki M, Iyengar S, Adams WM, Suresh P (March 2012). "Extra-pulmonary manifestations of sarcoidosis". Clinical Radiology. 67 (3): 263–76. doi:10.1016/j.crad.2011.04.018. PMID 22094184. 53. ^ Tavee J, Culver D (June 2011). "Sarcoidosis and small-fiber neuropathy". Current Pain and Headache Reports. 15 (3): 201–6. doi:10.1007/s11916-011-0180-8. PMID 21298560. S2CID 6735421. 54. ^ Heij L, Dahan A, Hoitsma E (2012). "Sarcoidosis and pain caused by small-fiber neuropathy". Pain Research and Treatment. 2012: 1–6. doi:10.1155/2012/256024. PMC 3523152. PMID 23304492. 55. ^ Porter N, Beynon HL, Randeva HS (August 2003). "Endocrine and reproductive manifestations of sarcoidosis". QJM. 96 (8): 553–61. doi:10.1093/qjmed/hcg103. PMID 12897340. 56. ^ Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL (August 1981). "Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D". The New England Journal of Medicine. 305 (8): 440–3. doi:10.1056/NEJM198108203050807. PMID 6894783. 57. ^ Rheumatology Diagnosis & Therapies (2nd ed.). Philadelphia: Lippincott Williams & Wilkins. 2005. p. 342. 58. ^ a b Antonelli A, Fazzi P, Fallahi P, Ferrari SM, Ferrannini E (August 2006). "Prevalence of hypothyroidism and Graves disease in sarcoidosis". Chest. 130 (2): 526–32. doi:10.1378/chest.130.2.526. PMID 16899854. 59. ^ Manchanda A, Patel S, Jiang JJ, Babu AR (March–April 2013). "Thyroid: an unusual hideout for sarcoidosis" (PDF). Endocrine Practice. 19 (2): e40–3. doi:10.4158/EP12131.CR. PMID 23337134. 60. ^ a b c d Fausto N, Abbas A (2004). Robbins and Cotran Pathologic Basis of disease (7th ed.). Philadelphia, PA: Elsevier/Saunders. pp. 737–9. ISBN 978-0721601878. 61. ^ Tokala H, Polsani K, Kalavakunta JK (2013-01-01). "Gastric sarcoidosis: a rare clinical presentation". Case Reports in Gastrointestinal Medicine. 2013: 260704. doi:10.1155/2013/260704. PMC 3867894. PMID 24368949. 62. ^ Vera C, Funaro D, Bouffard D (July–August 2013). "Vulvar sarcoidosis: case report and review of the literature". Journal of Cutaneous Medicine and Surgery. 17 (4): 287–90. doi:10.2310/7750.2012.12083. PMID 23815963. S2CID 13481889. 63. ^ a b c d Paknejad O, Gilani MA, Khoshchehreh M (April 2011). "Testicular masses in a man with a plausible sarcoidosis". Indian Journal of Urology. 27 (2): 269–71. doi:10.4103/0970-1591.82848. PMC 3142840. PMID 21814320. 64. ^ Cremers JP, Drent M, Baughman RP, Wijnen PA, Koek GH (September 2012). "Therapeutic approach of hepatic sarcoidosis". Current Opinion in Pulmonary Medicine. 18 (5): 472–82. doi:10.1097/MCP.0b013e3283541626. PMID 22617809. S2CID 9363764. 65. ^ a b "Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999". American Journal of Respiratory and Critical Care Medicine. 160 (2): 736–55. August 1999. doi:10.1164/ajrccm.160.2.ats4-99. PMID 10430755. 66. ^ Wurm K, Löhr G (March 1986). "Immuno-cytological blood tests in cases of sarcoidosis". Sarcoidosis. 3 (1): 52–9. PMID 3033787. 67. ^ Chen HC, Kang BH, Lai CT, Lin YS (July 2005). "Sarcoidal granuloma in cervical lymph nodes". Journal of the Chinese Medical Association. 68 (7): 339–42. doi:10.1016/S1726-4901(09)70172-8. PMID 16038376. 68. ^ a b c d e f g h i j k l m n o Rao DA, Dellaripa PF (May 2013). "Extrapulmonary manifestations of sarcoidosis". Rheumatic Diseases Clinics of North America. 39 (2): 277–97. doi:10.1016/j.rdc.2013.02.007. PMC 3756667. PMID 23597964. 69. ^ Shimamura Y, Taniguchi Y, Yoshimatsu R, Kawase S, Yamagami T, Terada Y (January 2016). "Granulomatous periostitis and tracheal involvement in sarcoidosis". Rheumatology. 55 (1): 102. doi:10.1093/rheumatology/kev319. PMID 26320137. 70. ^ Korkmaz C, Efe B, Tel N, Kabukçuoglu S, Erenoglu E (March 1999). "Sarcoidosis with palpable nodular myositis, periostitis and large-vessel vasculitis stimulating Takayasu's arteritis". Rheumatology. 38 (3): 287–8. doi:10.1093/rheumatology/38.3.287. PMID 10325674. 71. ^ Rossman MD, Kreider ME (August 2007). "Lesson learned from ACCESS (A Case Controlled Etiologic Study of Sarcoidosis)". Proceedings of the American Thoracic Society. 4 (5): 453–6. doi:10.1513/pats.200607-138MS. PMID 17684288. 72. ^ Cathcart S, Sami N, Elewski B (May 2012). "Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors". Journal of Drugs in Dermatology. 11 (5): 609–12. PMID 22527429. 73. ^ a b Rossides M, Grunewald J, Eklund A, Kullberg S, Di Giuseppe D, Askling J, Arkema EV (August 2018). "Familial aggregation and heritability of sarcoidosis: a Swedish nested case-control study". The European Respiratory Journal. 52 (2): 1800385. doi:10.1183/13993003.00385-2018. PMID 29946010. 74. ^ Iannuzzi MC (August 2007). "Advances in the genetics of sarcoidosis". Proceedings of the American Thoracic Society. 4 (5): 457–60. doi:10.1513/pats.200606-136MS. PMID 17684289. 75. ^ Spagnolo P, Grunewald J (May 2013). "Recent advances in the genetics of sarcoidosis". Journal of Medical Genetics. 50 (5): 290–7. doi:10.1136/jmedgenet-2013-101532. PMID 23526832. S2CID 23588871. 76. ^ Grunewald J, Eklund A, Olerup O (March 2004). "Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients". American Journal of Respiratory and Critical Care Medicine. 169 (6): 696–702. CiteSeerX 10.1.1.321.2788. doi:10.1164/rccm.200303-459OC. PMID 14656748. 77. ^ Grunewald J (August 2010). "Review: role of genetics in susceptibility and outcome of sarcoidosis". Seminars in Respiratory and Critical Care Medicine. 31 (4): 380–9. doi:10.1055/s-0030-1262206. PMID 20665388. 78. ^ Gialafos E, Triposkiadis F, Kouranos V, Rapti A, Kosmas I, Manali E, Giamouzis G, Elezoglou A, Peros I, Anagnostopoulou O, Koulouris N, Gazouli M (2014-12-01). "Relationship between tumor necrosis factor-α (TNFA) gene polymorphisms and cardiac sarcoidosis". In Vivo. 28 (6): 1125–9. PMID 25398810. 79. ^ Saidha S, Sotirchos ES, Eckstein C (March 2012). "Etiology of sarcoidosis: does infection play a role?". The Yale Journal of Biology and Medicine. 85 (1): 133–41. PMC 3313528. PMID 22461752. 80. ^ a b c Müller-Quernheim J, Prasse A, Zissel G (June 2012). "Pathogenesis of sarcoidosis". Presse Médicale. 41 (6 Pt 2): e275–87. doi:10.1016/j.lpm.2012.03.018. PMID 22595775. 81. ^ Gupta D, Agarwal R, Aggarwal AN, Jindal SK (September 2007). "Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis". The European Respiratory Journal. 30 (3): 508–16. doi:10.1183/09031936.00002607. PMID 17537780. 82. ^ Almenoff PL, Johnson A, Lesser M, Mattman LH (May 1996). "Growth of acid fast L forms from the blood of patients with sarcoidosis". Thorax. 51 (5): 530–3. doi:10.1136/thx.51.5.530. PMC 473601. PMID 8711683. 83. ^ Morgenthau AS, Iannuzzi MC (January 2011). "Recent advances in sarcoidosis" (PDF). Chest. 139 (1): 174–82. doi:10.1378/chest.10-0188. PMID 21208877. 84. ^ Padilla ML, Schilero GJ, Teirstein AS (March 2002). "Donor-acquired sarcoidosis". Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 19 (1): 18–24. PMID 12002380. 85. ^ Rossides M, Kullberg S, Askling J, Eklund A, Grunewald J, Di Giuseppe D, Arkema EV (November 2020). "Are infectious diseases risk factors for sarcoidosis or a result of reverse causation? Findings from a population-based nested case-control study". European Journal of Epidemiology. 35 (11): 1087–1097. doi:10.1007/s10654-020-00611-w. PMC 7695666. PMID 32048110. 86. ^ Romagnani S (June 1997). "The Th1/Th2 paradigm". Immunology Today. 18 (6): 263–6. doi:10.1016/S0167-5699(97)80019-9. PMID 9190109. 87. ^ Morell F, Levy G, Orriols R, Ferrer J, De Gracia J, Sampol G (April 2002). "Delayed cutaneous hypersensitivity tests and lymphopenia as activity markers in sarcoidosis". Chest. 121 (4): 1239–44. doi:10.1378/chest.121.4.1239. PMID 11948059. 88. ^ a b c Bargagli E, Olivieri C, Rottoli P (December 2011). "Cytokine modulators in the treatment of sarcoidosis". Rheumatology International. 31 (12): 1539–44. doi:10.1007/s00296-011-1969-9. hdl:11365/35698. PMID 21644041. S2CID 13602061. 89. ^ Kettritz R, Goebel U, Fiebeler A, Schneider W, Luft F (October 2006). "The protean face of sarcoidosis revisited" (PDF). Nephrology, Dialysis, Transplantation. 21 (10): 2690–4. doi:10.1093/ndt/gfl369. PMID 16861724. 90. ^ Ahmadzai H, Loke W, Huang S, Herbert C, Wakefield D, Thomas P (2014). "Biomarkers in sarcoidosis: a review". Current Biomarker Findings. 4: 93–106. doi:10.2147/cbf.s46196. 91. ^ Verschueren K, Van Essche E, Verschueren P, Taelman V, Westhovens R (November 2007). "Development of sarcoidosis in etanercept-treated rheumatoid arthritis patients". Clinical Rheumatology. 26 (11): 1969–71. doi:10.1007/s10067-007-0594-1. PMID 17340045. S2CID 10723194. 92. ^ Parrish S, Turner JF (November 2009). "Diagnosis of sarcoidosis". Disease-A-Month. 55 (11): 693–703. doi:10.1016/j.disamonth.2009.06.001. PMID 19857643. 93. ^ Hawtin KE, Roddie ME, Mauri FA, Copley SJ (August 2010). "Pulmonary sarcoidosis: the 'Great Pretender'". Clinical Radiology. 65 (8): 642–50. doi:10.1016/j.crad.2010.03.004. PMID 20599067. 94. ^ Miliauskas S, Zemaitis M, Sakalauskas R (2010). "Sarcoidosis--moving to the new standard of diagnosis?" (PDF). Medicina. 46 (7): 443–6. doi:10.3390/medicina46070063. PMID 20966615. Archived (PDF) from the original on 2014-02-26. 95. ^ a b c Kamangar N, Rohani P, Shorr AF (6 February 2014). Peters SP, Talavera F, Rice TD, Mosenifar Z (eds.). "Sarcoidosis Workup". Medscape Reference. WebMD. Archived from the original on 1 March 2014. Retrieved 19 February 2014. 96. ^ Allmendinger A, Perone R (2009). "Case of the Month". Diagnostic Imaging. 31 (9): 10. 97. ^ Joanne Mambretti (2004). "Chest X-ray Stages of Sarcoidosis" (PDF). Journal of Insurance Medicine: 91–92. Archived (PDF) from the original on July 9, 2014. Retrieved June 3, 2012. 98. ^ Andonopoulos AP, Papadimitriou C, Melachrinou M, Meimaris N, Vlahanastasi C, Bounas A, Georgiou P (2001). "Asymptomatic gastrocnemius muscle biopsy: an extremely sensitive and specific test in the pathologic confirmation of sarcoidosis presenting with hilar adenopathy" (PDF). Clinical and Experimental Rheumatology. 19 (5): 569–72. PMID 11579718. Archived from the original on 2016-02-24. 99. ^ Kusano KF, Satomi K (February 2016). "Diagnosis and treatment of cardiac sarcoidosis". Heart. 102 (3): 184–90. doi:10.1136/heartjnl-2015-307877. PMID 26643814. S2CID 29186632. 100. ^ "FDG-PET is a Superior Tool in the Diagnosis and Management of Cardiac Sarcoidosis". American College of Cardiology. Retrieved 2019-08-12. 101. ^ Baughman RP, Lower EE (August 2015). "Treatment of Sarcoidosis". Clinical Reviews in Allergy & Immunology. 49 (1): 79–92. doi:10.1007/s12016-015-8492-9. PMID 25989728. S2CID 10500902. 102. ^ a b c d Baughman RP, Grutters JC (October 2015). "New treatment strategies for pulmonary sarcoidosis: antimetabolites, biological drugs, and other treatment approaches". The Lancet. Respiratory Medicine. 3 (10): 813–22. doi:10.1016/S2213-2600(15)00199-X. PMID 26204816. 103. ^ Kamangar, N; Rohani, P; Shorr, AF (6 February 2014). Peters, SP; Talavera, F; Rice, TD; Mosenifar, Z (eds.). "Sarcoidosis Treatment & Management". Medscape Reference. WebMD. Archived from the original on 25 February 2014. Retrieved 19 February 2014. 104. ^ White ES, Lynch JP (June 2007). "Current and emerging strategies for the management of sarcoidosis". Expert Opinion on Pharmacotherapy. 8 (9): 1293–311. doi:10.1517/14656566.8.9.1293. PMID 17563264. S2CID 28753020. 105. ^ Paramothayan NS, Lasserson TJ, Jones PW (April 2005). "Corticosteroids for pulmonary sarcoidosis". The Cochrane Database of Systematic Reviews (2): CD001114. doi:10.1002/14651858.CD001114.pub2. PMC 6464973. PMID 15846612. 106. ^ Sahoo DH, Bandyopadhyay D, Xu M, Pearson K, Parambil JG, Lazar CA, Chapman JT, Culver DA (November 2011). "Effectiveness and safety of leflunomide for pulmonary and extrapulmonary sarcoidosis". The European Respiratory Journal. 38 (5): 1145–50. doi:10.1183/09031936.00195010. PMID 21565914. 107. ^ a b Panselinas E, Judson MA (October 2012). "Acute pulmonary exacerbations of sarcoidosis" (PDF). Chest. 142 (4): 827–836. doi:10.1378/chest.12-1060. PMID 23032450. 108. ^ a b c King CS, Kelly W (November 2009). "Treatment of sarcoidosis". Disease-A-Month. 55 (11): 704–18. doi:10.1016/j.disamonth.2009.06.002. PMID 19857644. 109. ^ a b c d e f g h i Baughman RP, Nunes H, Sweiss NJ, Lower EE (June 2013). "Established and experimental medical therapy of pulmonary sarcoidosis". The European Respiratory Journal. 41 (6): 1424–38. doi:10.1183/09031936.00060612. PMID 23397302. 110. ^ Rossides, Marios; Kullberg, Susanna; Giuseppe, Daniela Di; Eklund, Anders; Grunewald, Johan; Askling, Johan; Arkema, Elizabeth V. "Infection risk in sarcoidosis patients treated with methotrexate compared to azathioprine: A retrospective 'target trial' emulated with Swedish real-world data". Respirology. n/a (n/a). doi:10.1111/resp.14001. ISSN 1440-1843. 111. ^ Bhat P, Cervantes-Castañeda RA, Doctor PP, Anzaar F, Foster CS (May–June 2009). "Mycophenolate mofetil therapy for sarcoidosis-associated uveitis". Ocular Immunology and Inflammation. 17 (3): 185–90. doi:10.1080/09273940902862992. PMID 19585361. S2CID 28883517. 112. ^ Androdias G, Maillet D, Marignier R, Pinède L, Confavreux C, Broussolle C, Vukusic S, Sève P (March 2011). "Mycophenolate mofetil may be effective in CNS sarcoidosis but not in sarcoid myopathy". Neurology. 76 (13): 1168–72. doi:10.1212/WNL.0b013e318212aafb. PMID 21444902. S2CID 22559998. 113. ^ Judson MA (October 2012). "The treatment of pulmonary sarcoidosis". Respiratory Medicine. 106 (10): 1351–61. doi:10.1016/j.rmed.2012.01.013. PMID 22495110. 114. ^ Brill AK, Ott SR, Geiser T (2013). "Effect and safety of mycophenolate mofetil in chronic pulmonary sarcoidosis: a retrospective study". Respiration; International Review of Thoracic Diseases. 86 (5): 376–83. doi:10.1159/000345596. PMID 23295253. 115. ^ Tikoo RK, Kupersmith MJ, Finlay JL (April 2004). "Treatment of refractory neurosarcoidosis with cladribine". The New England Journal of Medicine. 350 (17): 1798–9. doi:10.1056/NEJMc032345. PMID 15103013. 116. ^ Maneiro JR, Salgado E, Gomez-Reino JJ, Carmona L (August 2012). "Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish registry of biologics BIOBADASER and a systematic review". Seminars in Arthritis and Rheumatism. 42 (1): 89–103. doi:10.1016/j.semarthrit.2011.12.006. PMID 22387045. 117. ^ Antoniu SA (January 2010). "Targeting the TNF-alpha pathway in sarcoidosis". Expert Opinion on Therapeutic Targets. 14 (1): 21–9. doi:10.1517/14728220903449244. PMID 20001207. S2CID 31755561. 118. ^ a b c Beegle SH, Barba K, Gobunsuy R, Judson MA (2013). "Current and emerging pharmacological treatments for sarcoidosis: a review". Drug Design, Development and Therapy. 7: 325–38. doi:10.2147/DDDT.S31064. PMC 3627473. PMID 23596348. 119. ^ Callejas-Rubio JL, López-Pérez L, Ortego-Centeno N (December 2008). "Tumor necrosis factor-alpha inhibitor treatment for sarcoidosis". Therapeutics and Clinical Risk Management. 4 (6): 1305–13. doi:10.2147/TCRM.S967. PMC 2643111. PMID 19337437. 120. ^ a b c d Dastoori M, Fedele S, Leao JC, Porter SR (April 2013). "Sarcoidosis - a clinically orientated review". Journal of Oral Pathology & Medicine. 42 (4): 281–9. doi:10.1111/j.1600-0714.2012.01198.x. PMID 22845844. 121. ^ Bakker GJ, Haan YC, Maillette de Buy Wenniger LJ, Beuers U (October 2012). "Sarcoidosis of the liver: to treat or not to treat?" (PDF). The Netherlands Journal of Medicine. 70 (8): 349–56. PMID 23065982. Archived from the original on 2014-05-18. 122. ^ Baughman RP, Judson MA, Ingledue R, Craft NL, Lower EE (February 2012). "Efficacy and safety of apremilast in chronic cutaneous sarcoidosis". Archives of Dermatology. 148 (2): 262–4. doi:10.1001/archdermatol.2011.301. PMID 22004880. 123. ^ Clinical trial number NCT01830959 for "Use of Roflumilast to Prevent Exacerbations in Fibrotic Sarcoidosis Patients (REFS)" at ClinicalTrials.gov 124. ^ Belkhou A, Younsi R, El Bouchti I, El Hassani S (July 2008). "Rituximab as a treatment alternative in sarcoidosis". Joint, Bone, Spine. 75 (4): 511–2. doi:10.1016/j.jbspin.2008.01.025. PMID 18562234. 125. ^ Clinical trial number NCT00279708 for "Atorvastatin to Treat Pulmonary Sarcoidosis" at ClinicalTrials.gov 126. ^ Kaura V, Kaura NV, Kaura BN, Kaura CS (2013). "Angiotensin-converting enzyme inhibitors in the treatment of sarcoidosis and association with ACE gene polymorphism: case series". The Indian Journal of Chest Diseases & Allied Sciences. 55 (2): 105–7. PMID 24047001. 127. ^ Kaura V, Kaura SH, Kaura CS (2007). "ACE Inhibitor in the treatment of cutaneous and lymphatic sarcoidosis". American Journal of Clinical Dermatology. 8 (3): 183–6. doi:10.2165/00128071-200708030-00006. PMID 17492847. S2CID 27032512. 128. ^ Rosenbloom J, Castro SV, Jimenez SA (February 2010). "Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies". Annals of Internal Medicine. 152 (3): 159–66. doi:10.7326/0003-4819-152-3-201002020-00007. PMID 20124232. S2CID 13107032. 129. ^ Julian MW, Shao G, Schlesinger LS, Huang Q, Cosmar DG, Bhatt NY, Culver DA, Baughman RP, Wood KL, Crouser ED (February 2013). "Nicotine treatment improves Toll-like receptor 2 and Toll-like receptor 9 responsiveness in active pulmonary sarcoidosis" (PDF). Chest. 143 (2): 461–470. doi:10.1378/chest.12-0383. PMID 22878868. 130. ^ Drake WP, Oswald-Richter K, Richmond BW, Isom J, Burke VE, Algood H, Braun N, Taylor T, Pandit KV, Aboud C, Yu C, Kaminski N, Boyd AS, King LE (September 2013). "Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study". JAMA Dermatology. 149 (9): 1040–9. doi:10.1001/jamadermatol.2013.4646. PMC 3927541. PMID 23863960. 131. ^ Boots AW, Drent M, de Boer VC, Bast A, Haenen GR (August 2011). "Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis". Clinical Nutrition. 30 (4): 506–12. doi:10.1016/j.clnu.2011.01.010. PMID 21324570. 132. ^ a b c d e f Drent M, Strookappe B, Hoitsma E, De Vries J (December 2015). "Consequences of Sarcoidosis". Clinics in Chest Medicine. 36 (4): 727–37. doi:10.1016/j.ccm.2015.08.013. PMID 26593145. 133. ^ Marcellis R, Van der Veeke M, Mesters I, Drent M, De Bie R, De Vries G, Lenssen A (June 2015). "Does physical training reduce fatigue in sarcoidosis?". Sarcoidosis, Vasculitis, and Diffuse Lung Diseases. 32 (1): 53–62. PMID 26237356. 134. ^ a b Strookappe B, Swigris J, De Vries J, Elfferich M, Knevel T, Drent M (October 2015). "Benefits of Physical Training in Sarcoidosis". Lung. 193 (5): 701–8. doi:10.1007/s00408-015-9784-9. PMID 26286208. 135. ^ Karadallı MN, Boşnak-Güçlü M, Camcıoğlu B, Kokturk N, Türktaş H (April 2016). "Effects of Inspiratory Muscle Training in Subjects With Sarcoidosis: A Randomized Controlled Clinical Trial". Respiratory Care. 61 (4): 483–94. doi:10.4187/respcare.04312. PMID 26715771. 136. ^ Spruit MA, Wouters EF, Gosselink R (2005). "Rehabilitation programmes in sarcoidosis: a multidisciplinary approach". Sarcoidosis. European Respiratory Monograph. 32. pp. 316–326. doi:10.1183/1025448x.00032021. ISBN 9781904097372. 137. ^ Baughman RP, Nunes H (February 2013). "Sarcoidosis-associated fatigue: an often forgotten symptom--author reply". Expert Review of Clinical Immunology. 9 (2): 111. doi:10.1586/ECI.12.93. PMID 23390941. S2CID 9750027. 138. ^ "What Is Sarcoidosis?". National Heart, Lung and Blood Institute. National Institutes of Health. 14 June 2013. Archived from the original on 27 February 2014. Retrieved 21 February 2014. 139. ^ a b c Syed J, Myers R (January 2004). "Sarcoid heart disease". The Canadian Journal of Cardiology. 20 (1): 89–93. PMID 14968147. 140. ^ Sadek MM, Yung D, Birnie DH, Beanlands RS, Nery PB (September 2013). "Corticosteroid therapy for cardiac sarcoidosis: a systematic review". The Canadian Journal of Cardiology. 29 (9): 1034–41. doi:10.1016/j.cjca.2013.02.004. PMID 23623644. 141. ^ a b Rossides M, Kullberg S, Askling J, Eklund A, Grunewald J, Arkema EV (February 2018). "Sarcoidosis mortality in Sweden: a population-based cohort study". The European Respiratory Journal. 51 (2): 1701815. doi:10.1183/13993003.01815-2017. PMC 5886843. PMID 29467203. 142. ^ Rossides M, Kullberg S, Eklund A, Di Giuseppe D, Grunewald J, Askling J, Arkema EV (September 2020). "Risk of first and recurrent serious infection in sarcoidosis: a Swedish register-based cohort study". The European Respiratory Journal. 56 (3). doi:10.1183/13993003.00767-2020. PMC 7469972. PMID 32366492. 143. ^ Yafasova A, Fosbøl EL, Schou M, Gustafsson F, Rossing K, Bundgaard H, et al. (August 2020). "Long-Term Adverse Cardiac Outcomes in Patients With Sarcoidosis". Journal of the American College of Cardiology. 76 (7): 767–777. doi:10.1016/j.jacc.2020.06.038. PMID 32792073. 144. ^ Karakantza M, Matutes E, MacLennan K, O'Connor NT, Srivastava PC, Catovsky D (March 1996). "Association between sarcoidosis and lymphoma revisited". Journal of Clinical Pathology. 49 (3): 208–12. doi:10.1136/jcp.49.3.208. PMC 500399. PMID 8675730. 145. ^ Askling J, Grunewald J, Eklund A, Hillerdal G, Ekbom A (November 1999). "Increased risk for cancer following sarcoidosis". American Journal of Respiratory and Critical Care Medicine. 160 (5 Pt 1): 1668–72. doi:10.1164/ajrccm.160.5.9904045. PMID 10556138. 146. ^ Tana C, Giamberardino MA, Di Gioacchino M, Mezzetti A, Schiavone C (April–June 2013). "Immunopathogenesis of sarcoidosis and risk of malignancy: a lost truth?". International Journal of Immunopathology and Pharmacology. 26 (2): 305–13. doi:10.1177/039463201302600204. PMID 23755746. 147. ^ Kornacker M, Kraemer A, Leo E, Ho AD (February 2002). "Occurrence of sarcoidosis subsequent to chemotherapy for non-Hodgkin's lymphoma: report of two cases". Annals of Hematology. 81 (2): 103–5. doi:10.1007/s00277-001-0415-6. PMID 11907791. S2CID 22705333. 148. ^ Suvajdzic N, Milenkovic B, Perunicic M, Stojsic J, Jankovic S (2007). "Two cases of sarcoidosis-lymphoma syndrome". Medical Oncology. 24 (4): 469–71. doi:10.1007/s12032-007-0026-8. PMID 17917102. S2CID 44490347. 149. ^ London J, Grados A, Fermé C, Charmillon A, Maurier F, Deau B, Crickx E, Brice P, Chapelon-Abric C, Haioun C, Burroni B, Alifano M, Le Jeunne C, Guillevin L, Costedoat-Chalumeau N, Schleinitz N, Mouthon L, Terrier B (November 2014). "Sarcoidosis occurring after lymphoma: report of 14 patients and review of the literature". Medicine. 93 (21): e121. doi:10.1097/MD.0000000000000121. PMC 4616278. PMID 25380084. 150. ^ Yao M, Funk GF, Goldstein DP, DeYoung BR, Graham MM (January 2005). "Benign lesions in cancer patients: Case 1. Sarcoidosis after chemoradiation for head and neck cancer". Journal of Clinical Oncology. 23 (3): 640–1. doi:10.1200/JCO.2005.02.089. PMID 15659510. 151. ^ Yamasawa H, Ishii Y, Kitamura S (2000). "Concurrence of sarcoidosis and lung cancer. A report of four cases". Respiration; International Review of Thoracic Diseases. 67 (1): 90–3. doi:10.1159/000029470. PMID 10705270. S2CID 71437158. 152. ^ Zambrana F, Antúnez A, García-Mata J, Mellado JM, Villar JL (June 2009). "Sarcoidosis as a diagnostic pitfall of pancreatic cancer". Clinical & Translational Oncology. 11 (6): 396–8. doi:10.1007/s12094-009-0375-1. PMID 19531456. S2CID 10589338. 153. ^ Schiller G, Said J, Pal S (October 2003). "Hairy cell leukemia and sarcoidosis: a case report and review of the literature". Leukemia. 17 (10): 2057–9. doi:10.1038/sj.leu.2403074. PMID 14513061. 154. ^ Maloisel F, Oberling F (January 1992). "Acute myeloid leukemia complicating sarcoidosis". Journal of the Royal Society of Medicine. 85 (1): 58–9. PMC 1293471. PMID 1548666. 155. ^ Reich JM (January 1985). "Acute myeloblastic leukemia and sarcoidosis. Implications for pathogenesis". Cancer. 55 (2): 366–9. doi:10.1002/1097-0142(19850115)55:2<366::AID-CNCR2820550212>3.0.CO;2-1. PMID 3855267. 156. ^ Jamilloux Y, Valeyre D, Lortholary O, Bernard C, Kerever S, Lelievre L, Neel A, Broussolle C, Seve P (January 2015). "The spectrum of opportunistic diseases complicating sarcoidosis". Autoimmunity Reviews. 14 (1): 64–74. doi:10.1016/j.autrev.2014.10.006. PMID 25305373. 157. ^ Jamilloux Y, Néel A, Lecouffe-Desprets M, Fèvre A, Kerever S, Guillon B, Bouvry D, Varron L, Redares C, Dominique S, Roux M, Chapelon-Abric C, Valeyre D, Ducray F, Bernard C, Broussolle C, Hamidou M, Sève P (April 2014). "Progressive multifocal leukoencephalopathy in patients with sarcoidosis". Neurology. 82 (15): 1307–13. doi:10.1212/WNL.0000000000000318. PMID 24610328. S2CID 2245395. 158. ^ Sam AH, Teo JT (2010). Rapid Medicine. Wiley-Blackwell. ISBN 978-1405183239. 159. ^ Henke CE, Henke G, Elveback LR, Beard CM, Ballard DJ, Kurland LT (May 1986). "The epidemiology of sarcoidosis in Rochester, Minnesota: a population-based study of incidence and survival" (PDF). American Journal of Epidemiology. 123 (5): 840–5. doi:10.1093/oxfordjournals.aje.a114313. PMID 3962966. 160. ^ Rutherford RM, Brutsche MH, Kearns M, Bourke M, Stevens F, Gilmartin JJ (September 2004). "Prevalence of coeliac disease in patients with sarcoidosis". European Journal of Gastroenterology & Hepatology. 16 (9): 911–5. doi:10.1097/00042737-200409000-00016. PMID 15316417. S2CID 24306517. 161. ^ a b Baughman RP, Lower EE, du Bois RM (March 2003). "Sarcoidosis". Lancet. 361 (9363): 1111–8. doi:10.1016/S0140-6736(03)12888-7. PMID 12672326. S2CID 208793787. 162. ^ a b Lazarus A (November 2009). "Sarcoidosis: epidemiology, etiology, pathogenesis, and genetics". Disease-A-Month. 55 (11): 649–60. doi:10.1016/j.disamonth.2009.04.008. PMID 19857640. 163. ^ a b c d e f g Sharma OP (2005). "Chapter 1: Definition and history of sarcoidosis". Sarcoidosis. Sheffield: European Respiratory Society Journals. ISBN 9781904097884. 164. ^ Babalian L (26 January 1939). "Disease of Besnier-Boeck-Schaumann". New England Journal of Medicine. 220 (4): 143–145. doi:10.1056/NEJM193901262200404. 165. ^ "Join WASOG". wasog.org. World Association of Sarcoidosis and Other Granulomatous Disorders. Archived from the original on 1 February 2014. Retrieved 21 February 2014. 166. ^ "Index". Sarcoidosis, Vasculitis and Diffuse Lung Diseases. 2016. Archived from the original on 6 May 2016. Retrieved 9 April 2016. 167. ^ "Mission & Goals". Foundation for Sarcoidosis Research. Archived from the original on 26 February 2014. Retrieved 21 February 2014. 168. ^ Izbicki G, Chavko R, Banauch GI, Weiden MD, Berger KI, Aldrich TK, Hall C, Kelly KJ, Prezant DJ (May 2007). "World Trade Center "sarcoid-like" granulomatous pulmonary disease in New York City Fire Department rescue workers" (PDF). Chest. 131 (5): 1414–23. doi:10.1378/chest.06-2114. PMID 17400664. 169. ^ "9/11 Health – What We Know About the Health Effects of 9/11". NYC. US Government. Archived from the original on 28 January 2014. Retrieved 22 February 2014. 170. ^ Grimes W (10 August 2008). "Bernie Mac, Acerbic Stand-Up Comedian and Irascible TV Dad, Dies at 50". The New York Times. Archived from the original on 14 March 2014. Retrieved 30 April 2014. 171. ^ Le Mignot S (August 9, 2008). "Actor and comedian Bernie Mac dies at age 58". CBS2Chicago. Archived from the original on October 21, 2009. Retrieved 2010-03-27. 172. ^ Kat Carney (September 19, 2003). Former MTV VJ tells of battle with chronic illness CNN.com, accessed 10 August 2019 173. ^ "Thursday roundup: Maddox rides to Ben's defense". May 20, 2005. Retrieved January 30, 2017. 174. ^ Donna J. Miller (????) Coroner says singer Sean Levert died of natural causes. Cleveland.com, accessed 11 August 2019 175. ^ Zolan Kanno-Youngs. "Wall Street Journal's Joseph Rago Died of Natural Causes, Medical Examiner Says". Wall Street Journal. Retrieved 12 September 2017. 176. ^ Charlier P, Froesch P (December 2013). "Robespierre: the oldest case of sarcoidosis?". Lancet. 382 (9910): 2068. doi:10.1016/S0140-6736(13)62694-X. PMID 24360387. S2CID 205971757. 177. ^ Mai FM (2006). "Beethoven's terminal illness and death". The Journal of the Royal College of Physicians of Edinburgh. 36 (3): 258–63. PMID 17214130. 178. ^ Sharma OP (2005). "Murray Kornfeld, American College of Chest Physician, and sarcoidosis: a historical footnote: 2004 Murray Kornfeld Memorial Founders Lecture". Chest. 128 (3): 1830–35. doi:10.1378/chest.128.3.1830. PMID 16162793. 179. ^ Subramanian P, Chinthalapalli H, Krishnan M, Tarlo SM, Lobbedez T, Pineda ME, Oreopoulos DG (September 2004). "Pregnancy and sarcoidosis: an insight into the pathogenesis of hypercalciuria". Chest. 126 (3): 995–8. doi:10.1378/chest.126.3.995. PMID 15364785. S2CID 14434405. 180. ^ a b Köcher L, Rossides M, Remaeus K, Grunewald J, Eklund A, Kullberg S, Arkema EV (August 2020). "Maternal and infant outcomes in sarcoidosis pregnancy: a Swedish population-based cohort study of first births". Respiratory Research. 21 (1): 225. doi:10.1186/s12931-020-01493-y. PMC 7457286. PMID 32854707. ## External links[edit] Classification D * ICD-10: D86 * ICD-9-CM: 135 * OMIM: 181000 * MeSH: D012507 * DiseasesDB: 11797 External resources * MedlinePlus: 000076 * eMedicine: med/2063 * Patient UK: Sarcoidosis * Orphanet: 797 * Sarcoidosis UK Information Hub * Iannuzzi, M. C.; Sah, B. P. (March 2008). Sarcoidosis: Interstitial Lung Diseases. The Merck Manual Home Edition. Merck Sharp & Dohme Corp. Retrieved 19 February 2014. * v * t * e Sarcoidosis * Skin * Lupus pernio * Neurosarcoidosis * Löfgren syndrome * Heerfordt's syndrome Authority control * NDL: 00574579 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Sarcoidosis	c0036202	1,162	wikipedia	https://en.wikipedia.org/wiki/Sarcoidosis	2021-01-18T18:43:36	{"gard": ["7607"], "mesh": ["D012507"], "umls": ["C0036202"], "orphanet": ["797"], "wikidata": ["Q193894"]}
Neurolymphomatosis is a rare syndrome of peripheral and cranial nerve dysfunction in patients with hematologic malignancies, mostly non-Hodgkin's lymphoma or acute leukemia, characterized by painful or painless involvement of peripheral or cranial nerves or nerve roots. The clinical presentation is diverse depending on the site involved and includes plexopathy, mononeuritis multiplex, peripheral neuropathy, radiculopathy and cranial nerve palsies. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neurolymphomatosis	c0024793	1,163	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=206586	2021-01-23T18:02:27	{"mesh": ["D008380"]}
Neonatal hepatitis SpecialtyNeonatology Neonatal hepatitis refers to many forms of liver dysfunction that affects fetuses and neonates.[1] It is most often caused by viruses or metabolic diseases, and many cases are of an unknown cause.[2] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Differential diagnosis * 4 See also * 5 References * 6 External links ## Signs and symptoms[edit] The infant with neonatal hepatitis usually has jaundice that appears at one to two months of age, is not gaining weight and growing normally, and has an enlarged liver and spleen. Infants with this condition are usually jaundiced. Jaundice that is caused by neonatal hepatitis is not the same as physiologic neonatal jaundice. In contrast with physiologic neonatal jaundice, infants with neonatal hepatitis present with dark urine. Infants may also present with delayed growth.[1] ## Causes[edit] The causes of neonatal hepatitis are many. Viruses that have been identified include cytomegalovirus, rubella virus, hepatitis A and B viruses, herpes simplex viruses, coxsackievirus, echovirus, and paramyxovirus.[2]Metabolic and immune disorders can also cause neonatal hepatitis.[2]Giant cell transformation throughout the parenchyma is common.[2] ## Diagnosis[edit] ### Differential diagnosis[edit] Conditions that can present similarly include galactosaemia, hereditary fructose intolerance, cystic fibrosis, and biliary atresia.[2] ## See also[edit] * Neonatal jaundice ## References[edit] 1. ^ a b Pediatric Gastrointestinal and Liver Disease (5 ed.). Elsevier. 2016. pp. 823–837. 2. ^ a b c d e Burt, Alastair (2018). MacSween's Pathology of the Liver (7 ed.). Elsevier. pp. 119–130. ## External links[edit] Classification D * ICD-9-CM: 774.4 * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Neonatal hepatitis	c0027613	1,164	wikipedia	https://en.wikipedia.org/wiki/Neonatal_hepatitis	2021-01-18T19:10:31	{"icd-9": ["774.4"], "icd-10": ["P59.2"], "wikidata": ["Q6993479"]}
A number sign (#) is used with this entry because porphyria cutanea tarda type II, or familial PCT, is caused by heterozygous mutation in the gene encoding uroporphyrinogen decarboxylase (UROD; 613521). Hepatoerythropoietic porphyria (HEP) is caused by homozygous or compound heterozygous mutation in the UROD gene. Description Porphyria cutanea tarda (PCT) is characterized by light-sensitive dermatitis and the excretion of large amounts of uroporphyrin in urine (Elder et al., 1980). De Verneuil et al. (1978) and others classified porphyria cutanea tarda, the most common type of porphyria, into 2 types: type I (176090), or 'sporadic' type, associated with approximately 50% level of uroporphyrinogen decarboxylase (UROD) in liver (Elder et al., 1978; Felsher et al., 1982), and type II, or 'familial' type, characterized by 50% deficient activity of the same enzyme in many tissues (Kushner et al., 1976; Elder et al., 1980). PCT type II is an autosomal dominant disorder with low penetrance and constitutes about 20% of cases of PCT. Recognized exacerbating factors of PCT include iron overload, excessive use of alcohol, exposure to polyhalogenated aromatic chemicals, exposure to estrogens, chronic viral hepatitis C, HIV infections, and mutation in the HFE gene (613609) that are responsible for hereditary hemochromatosis (235200) (review by Lambrecht et al., 2007). Clinical Features Onset of light-sensitive dermatitis in later adult life, associated with the excretion of large amounts of uroporphyrin in urine, characterizes porphyria cutanea tarda, which was so named by Waldenstrom (1937). On areas of skin exposed to sunlight, especially the face, ears, and backs of the hands, chronic ulcerating lesions commence as blisters, and the skin may also be mechanically fragile (Grossman et al., 1979). Hyperpigmentation and hypertrichosis also occur. Acute neuropathic episodes do not occur in this form of porphyria. Onset is often associated with alcoholism, and occasionally with exposure to other agents, such as estrogens. Iron overload is frequently present, and may be associated, coincidentally or causally, with varying degrees of liver damage or fibrosis; liver histology may be characteristic (Cortes et al., 1980). On biopsy, liver parenchyma cells are also loaded with porphyrins and fluoresce bright red in ultraviolet light. The skin lesions are distinctly related to circulating porphyrins (Holti et al., 1958). Malina and Lim (1988) described a 29-year-old woman who first presented with blisters and erosions on the dorsum of the fingers and hands bilaterally 3 weeks after delivery of her second child. The diagnosis of PCT was established enzymatically and by porphyrin studies. Reduced red cell UROD activity was found also in the newborn child and in the patient's mother. Classic congenital erythropoietic porphyria (263700) is due to deficiency of uroporphyrinogen III cosynthase. Kushner et al. (1982) described a remarkable 51-year-old man with congenital erythropoietic porphyria (Gunther disease), first manifested in infancy with eventual development of mutilating skin photosensitivity. The morphologic features of dyserythropoietic bone marrow cells, studied by light and electron microscopy, were identical to those found in congenital dyserythropoietic anemia type I (224120); such had been described before in Gunther disease. A red-orange nuclear fluorescence is not seen in type I dyserythropoietic anemia. The patient of Kushner et al. (1982) showed massive porphyrinuria, but the pattern of porphyrin excretion was atypical for classic Gunther disease: hepta-carboxyl (7-COOH) porphyrin was the major urine porphyrin, much uroporphyrin was present, and both were predominantly of the isomer III type. Erythrocyte uroporphyrinogen III cosynthase activity was normal, but uroporphyrinogen decarboxylase activity was 50% of normal. Two sons showed equally subnormal uroporphyrinogen decarboxylase activity. It was the opinion of the authors that their 51-year-old patient had 2 genetic diseases--uroporphyrinogen decarboxylase deficiency (a heterozygous state) and type I congenital dyserythropoietic anemia (a presumably homozygous state). With coexisting hepatic siderosis, heterozygous uroporphyrinogen decarboxylase deficiency leads to porphyria cutanea tarda. Homozygosity for a deficiency gene leads to hepatoerythropoietic porphyria. Thus, Gunther disease can have more than one cause. Two other reported patients with clinically typical congenital erythropoietic porphyria, but with a pattern of urinary porphyrin excretion similar to porphyria cutanea tarda, were referenced by Kushner et al. (1982). ### Hepatoerythropoietic Porphyria Hepatoerythropoietic porphyria (HEP) is a severe, autosomal recessive form of cutaneous porphyria that presents in infancy and is characterized biochemically by excessive excretion of acetate-substituted porphyrins and accumulation of protoporphyrin in erythrocytes (Hofstad et al., 1973; Simon et al., 1977; Czarnecki, 1980). As in porphyria cutanea tarda, uroporphyrinogen decarboxylase is deficient. However, the enzyme level is very low (7-8%) in erythrocytes and cultured skin fibroblasts, leading Elder et al. (1981) to propose that HEP is the homozygous state for porphyria cutanea tarda. De Verneuil et al. (1984) brought to 9 the number of known cases of HEP and confirmed that these patients are homozygous for mutations in the same gene that causes PCT. The patients of de Verneuil et al. (1984) were twin daughters of a Tunisian couple related as second cousins. Both parents, although asymptomatic, showed intermediate levels of enzymatic and immunoreactive URO decarboxylase. The twins were CRM-negative, in contrast to previously reported homozygous patients. Toback et al. (1987) described a man with relatively mild hepatoerythropoietic porphyria and concluded that the man was a homozygote since both of his parents and his 3 children, all of whom were asymptomatic, showed moderate deficiency of UROD. They concluded that the relative mildness of the clinical symptoms in the proband was probably related to the level of residual enzyme activity and that the genetic defect in UROD in this disorder can be heterogeneous. Fujimoto and Brazil (1992) reported a 23-year-old woman thought to represent the 18th instance of HEP reported worldwide. She had photosensitive skin of early onset, hypertrichosis, and severe scleroderma-like lesions of the hands. ### PCT 'Phenocopy' A syndrome similar to PCT, a 'phenocopy,' is caused by toxic exposure to certain organic chemicals such as hexachlorobenzene, as in the epidemic caused by contaminated seed wheat in Turkey (Cam and Nigogosyan, 1963; Dean, 1972) and by occupational exposure to chlorinated hydrocarbons (Bleiberg et al., 1964). Pathogenesis Felsher et al. (1982) concluded that reduced hepatic uroporphyrinogen decarboxylase activity is a specific and intrinsic hepatic defect in PCT, but modulation of uroporphyrinogen synthesis by extrinsic factors is required for full biochemical expression of the disease. Biochemical Features Reduced liver and red cell uroporphyrinogen decarboxylase activity has been reported in familial (Kushner et al., 1976; Lehr and Doss, 1981) and sporadic cases of porphyria cutanea tarda (Elder et al., 1978; Felsher et al., 1978). Impaired activity of this enzyme step in heme synthesis in liver could possibly explain resulting 'overflow' of uroporphyrin. Hepatic uroporphyrinogen decarboxylase activity was reduced to approximately 50% of normal levels in 17 cases of porphyria cutanea tarda and reduced levels persisted after hepatic iron overload was relieved by phlebotomy (Felsher et al., 1982). Elder et al. (1978) found normal levels of enzyme in red cells and fibroblasts. In assays of UROD activity in red cells, de Verneuil et al. (1978) found 50% levels of uroporphyrinogen decarboxylase in persons with familial porphyria cutanea, but normal enzyme levels in sporadic cases. In hemolysates from 7 unrelated patients with familial PCT, Elder et al. (1983) found that immunoreactive uroporphyrinogen decarboxylase was decreased (average 51% of normal) to the same extent as catalytic activity (average 56% of normal), whereas in 6 sporadic cases both measurements were normal. The failure to find evidence of CRM+ mutations among the familial cases suggested to Elder et al. (1983) that a simple immunoelectrophoretic method can be used for routine diagnosis. Using a UROD cDNA probe in Northern blot analysis, Hansen et al. (1988) found no difference in the levels of UROD mRNA between affected individuals and their normal relatives. Inheritance Most cases of PCT are sporadic and are more common in men than women, but familial cases have been described frequently, and apparent autosomal dominant segregation of the disorder has been reported (Holti et al., 1958; Ziprkowski et al., 1966; Topi and Gandalfo, 1977; Benedetto et al., 1978). Although it is unusual for an enzyme deficiency to produce symptoms in the heterozygous state, i.e., in single gene dose, this is also the pattern in other types of genetic porphyrias (e.g., 121300, 176000, 176200, 177000). It seems likely that a reduced level of activity of uroporphyrinogen decarboxylase may segregate as an autosomal dominant trait, but that additional environmental factors are required for manifestation of the disorder; iron overload may have a direct metabolic role (Kushner et al., 1972; Kushner, 1982). Blekkenhorst et al. (1979) suggested that 2 forms of PCT exist: a rare familial form and a relatively common idiosyncratic form occurring sporadically as an unusual accompaniment of common hepatic disorders such as alcohol-associated liver disease. Hepatoerythropoietic porphyria (HEP) is an autosomal recessive trait (de Verneuil et al., 1984). Population Genetics The incidence of PCT varies from approximately 1 in 25,000 in the United States to approximately 1 in 5,000 in the Czech Republic and Slovakia (review by Lambrecht et al., 2007). PCT is common in the Bantu races in South Africa in association with iron overload (Barnes, 1955). Clinical Management Treatment is directed first to reducing iron overload by regular phlebotomy, as in the management of hemochromatosis (Epstein and Redeker, 1968; Ramsay et al., 1974; Grossman et al., 1979). Porphyrin excretion diminishes, and in many patients skin lesions disappear. When this is ineffective or when a more rapid effect is desired, oral chloroquine therapy usually induces rapid remission (Taljaard et al., 1972; Kowertz, 1973). It may also cause a transient increase in porphyrin excretion, sometimes associated with evidence of acute liver damage (Vogler et al., 1970). Remission is sustained while chloroquine is continued in regular low doses. Several cases of porphyria cutanea tarda have been described in patients on maintenance hemodialysis for chronic renal failure (e.g., Poh-Fitzpatrick et al., 1978). The cause is thought to be insufficient removal of porphyrins through the hemodialysis membrane which leads to markedly increased levels of plasma porphyrins with resulting severe and mutilating skin lesions. The treatment of the disorder is very difficult because chloroquine is ineffective and the anemia that accompanies chronic renal failure contraindicates venesection therapy. Praga et al. (1987) found that deferoxamine was effective therapy in a patient in whom there was evidence of iron overload due to multiple blood transfusions. Molecular Genetics Using hybridization probes for the UROD gene in the study of genomic DNA from patients with familial PCT, Hansen et al. (1988) could not identify any major deletions, rearrangements, or restriction fragment length polymorphisms. In the UROD cDNA from a patient with familial PCT, Garey et al. (1989) demonstrated a gly-to-val substitution at amino acid position 281 (G281V; 613521.0001). The mutation was not detected in affected persons from 7 other PCT pedigrees with an autosomal dominant pattern. They showed that the UROD protein in the patient with the identified mutation had a greatly shortened half-life, both in vitro and in vivo (assuming, as these workers did, that one can call the findings in cultured lymphocytes an 'in vivo' observation). Hepatoerythropoietic porphyria results from a different nucleotide substitution in the same codon (G281E; 613521.0002). The UROD protein resulting from the G281E mutation also has a decreased half-life, but not so severely decreased as in the case of the G281V mutation. Garey et al. (1989) suggested that the former mutation may be so severe in the homozygous state that it is lethal to the embryo; PCT can result in the heterozygote for the first mutation, but only the homozygote for the milder mutation expresses itself (as HEP). Garey et al. (1989) pointed out that familial PCT is relatively common, but only 16 cases of HEP have been described to date. Using a cDNA clone for the UROD gene, de Verneuil et al. (1986) studied DNA from 2 homozygous patients, offspring of consanguineous parents, who suffered from HEP. They could detect neither deletions nor rearrangements in the UROD gene. Synthesis, processing, and cell-free translation of the specific transcripts appeared to be normal. The half-life of the abnormal protein was 12 times shorter than that of the normal enzyme. Thus, rapid degradation in vivo is the probable basis of the enzyme deficiency. Study of homozygous patients avoided the difficulties of studying the enzyme defect in the heterozygous PCT where both normal and abnormal protein is present. The authors suggested that use of oligonucleotide probes complementary to the normal and mutant sequences could allow them to determine if the mutation in familial PCT is the same as that in HEP; in other words, whether HEP is indeed the homozygous state of PCT. In a Spanish family, Moran-Jimenez et al. (1996) found homozygosity for the G281E (613521.0001) mutation as the cause of HEP. A paternal uncle of the proband developed clinically overt porphyria cutanea tarda as an adult and proved to be heterozygous for the G281E mutation. Mendez et al. (1998) sequenced the entire UROD gene, and developed a long-range PCR method to amplify the entire gene for mutation analysis. Four missense mutations (M165R, 613521.0009; L195F, 613521.0010; N304K, 613521.0011; and R332H, 613521.0012), a microinsertion, a deletion, and a novel exonic splicing defect were identified. Expression of the L195F, N304K, and R332H polypeptides revealed significant residual activity, whereas RT-PCR and sequencing demonstrated that the E314E (613521.0008) lesion caused abnormal splicing and exon 9 skipping. Screening of 9 familial PCT probands revealed that 4 (44%) were heterozygous or homozygous for the common hemochromatosis mutations, which suggested that iron overload may predispose to clinical expression. However, there was no clear correlation between the severity of familial PCT and the UROD and/or hemochromatosis genotypes. Presymptomatic molecular diagnosis should now be possible, permitting counseling to enable family members to avoid disease-precipitating factors. ### Role of Mutations in the HFE Gene An association between PCT and HLA-linked hereditary hemochromatosis (HFE; 235200) was suggested by Kushner et al. (1985), but disputed by Beaumont et al. (1986). Santos et al. (1997) assessed the role of HFE (613609) mutations in PCT by an allelic-association study between PCT and the mutations identified in hemochromatosis. They studied 15 unselected, unrelated patients with PCT being treated with regular phlebotomy. The controls were 23 anonymous blood donors and 71 patients with hereditary hemochromatosis. The cys282-to-tyr mutation (C282Y; 613609.0001) was found in 83% of 142 hereditary hemochromatosis chromosomes, 47% of 30 PCT chromosomes, and 9% of 46 normal blood donor chromosomes. Santos et al. (1997) concluded that the hemochromatosis gene contributes to the pathogenesis of PCT. They suggested that all first-degree relatives of patients with PCT should be screened for hereditary hemochromatosis. PCT can be viewed as having a digenic basis. Ivanova et al. (1999) found the C282Y mutation of the HFE gene in only 1 of 48 PCT patients (2.1%). This individual was heterozygous for the mutation. The mutation was found in none of 100 healthy Bulgarian subjects. This indicates a very low frequency of the C282Y mutation in Bulgaria. A similarly low frequency of HFE mutations was found in Japanese cases of PCT and in Japanese patients generally, leading Furuyama et al. (1999) to suggest that abnormal iron metabolism associated with PCT in Japanese patients occurs by a mechanism unrelated to HFE gene mutations. Brady et al. (2000) investigated the relationship between age of onset of skin lesions and mutations (C282Y, 613609.0001; H63D, 613609.0002) in the hemochromatosis gene in 19 familial and 65 sporadic porphyria cutanea tarda patients. Familial porphyria cutanea tarda was identified by mutation analysis of the uroporphyrinogen decarboxylase gene. Five previously described and 8 novel mutations were identified. Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphyria cutanea tarda, the effect being more marked in familial porphyria cutanea tarda where anticipation was demonstrated in family studies. Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is an important susceptibility factor in both types but suggested that heterozygosity for this mutation has much less effect on the development of the disease. Dereure et al. (2001) evaluated 36 consecutive patients with either sporadic or familial PCT for the presence of the 3 main mutations of the HFE gene and identification of the transferrin receptor alleles. Seven patients (19%) showed heterozygous C282Y (613609.0001) mutation, but no C282Y homozygote was present; 5 patients (14%) carried homozygous H63D (613609.0002) mutation, while 8 (22%) were heterozygous for this mutation. One patient was heterozygous for the S65C (613609.0003) mutation (3%). Iron parameters demonstrated overload in all patients, without a clear difference between patients with and without deleterious mutations of the HFE gene. Infection by hepatitis C virus was documented in 20 patients (56%), and was significantly less frequent in patients with deleterious HFE mutations. The profile of transferrin receptor alleles in PCT patients did not show significant variation compared with the general population. Dereure et al. (2001) concluded that there is a high frequency of HFE mutations in patients with PCT and that HFE gene abnormalities might play a significant part in the PCT pathomechanism, probably through iron overload; by contrast, transferrin receptor polymorphisms do not appear to play a significant part in iron overload in PCT. Stolzel et al. (2003) retrospectively analyzed 62 German PCT patients exclusively treated with low-dose chloroquine to determine whether HFE mutations C282Y (613609.0001) and H63D (613609.0002) influenced the clinical response, urinary porphyrin excretion, liver enzyme activities, and serum iron markers. Chloroquine therapy was accompanied by clinical remission and reduced urinary porphyrin excretion in the 24 patients (39%) with HFE wildtype as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum iron markers following chloroquine therapy were limited to patients with PCT and HFE wildtype. All 3 patients homozygous for the C282Y mutation (5%) had high serum iron, ferritin, and transferrin saturation and failed to respond to chloroquine treatment. Stolzel et al. (2003) concluded that the therapeutic response to chloroquine was not compromised by C282Y heterozygosity and compound heterozygosity of HFE mutations. However, because HFE C282Y homozygotes did not respond to chloroquine and a decrease in serum iron concentration was limited to patients with PCT and HFE wildtype, phlebotomy should be first-line therapy in patients with PCT and HFE mutations. ### Role of Mutations in the CYP12A Gene Individuals with PCT are believed to be genetically predisposed to development of clinically overt disease through mutations and polymorphisms in particular genes in response to precipitating factors. Christiansen et al. (2000) examined a group of Danish patients with PCT for the presence of a C/A polymorphism in intron 1 of CYP1A2 (124060). The results demonstrated that the frequency of the highly inducible A/A genotype is increased in both familial and sporadic PCT. This suggested that inheritance of this genotype is a susceptibility factor for PCT. Animal Model The zebrafish mutant 'yquem' shows a photosensitive porphyria syndrome. Wang et al. (1998) showed that the porphyric phenotype is due to an inherited homozygous mutation in the UROD gene. Thus, the zebrafish mutant represented the first genetically 'accurate' model of hepatoerythropoietic porphyria; Wang et al. (1998) suggested that the model would be useful for studying the pathogenesis of UROD deficiency and evaluating gene therapy vectors. Wang et al. (1998) rescued the mutant phenotype by transient and germline expression of the wildtype allele. Most heterozygotes for UROD mutations do not express a porphyric phenotype unless hepatic siderosis is present. Mutations in the hemochromatosis gene are frequently found when the porphyric phenotype is expressed in the heterozygote. Phillips et al. (2001) used homologous recombination to disrupt 1 allele of the murine Urod gene. Urod +/- mice had half-wildtype UROD protein and enzymatic activity in all tissues but did not accumulate hepatic porphyrins, indicating that half-normal UROD activity is not rate limiting. When Urod +/- mice were injected with iron-dextran and given drinking water containing delta-aminolevulinic acid (ALA) for 21 days, hepatic porphyrins accumulated, and hepatic UROD activity was reduced to 20% of weight. Phillips et al. (2001) also bred mice homozygous for the HFE gene disruption (Hfe -/-) to Urod +/- mice, generating mice with the heterozygous Urod genotype and the homozygous null Hfe genotype. These animals developed a porphyric phenotype by 14 weeks of age without ALA supplementation, and UROD activity was reduced to 14% of weight. These data indicated that iron overload alone is sufficient to reduce UROD activity to rate-limiting levels in heterozygous Urod mice. Thus these mice serve as an excellent model of familial PCT and afford the opportunity to define the mechanism by which iron influences UROD activity. INHERITANCE \- Autosomal dominant \- Autosomal recessive ABDOMEN Liver \- Hepatic hemosiderosis \- Hepatic cirrhosis \- Liver biopsy shows red autofluorescence and needle-like cytoplasmic inclusion bodies SKIN, NAILS, & HAIR Skin \- Photosensitivity \- Blisters in sun-exposed areas \- Mechanically fragile skin \- Hyperpigmentation in sun-exposed areas \- Pseudoscleroderma Nails \- Fingernail onycholysis Hair \- Facial hypertrichosis \- Alopecia NEOPLASIA \- Increased incidence of hepatocellular carcinoma LABORATORY ABNORMALITIES \- Reduced liver and red cell uroporphyrinogen decarboxylase (URO decarboxylase) MISCELLANEOUS \- Most common form of porphyria \- Three types of PCT: Type I ( 176090 ) sporadic, presents in adults: Types II and III ( 176100 ) familial, presents in childhood \- Sporadic or acquired PCT precipitated by alcohol, estrogens, iron, and polychlorinated cyclic hydrocarbons \- More common in men than women \- Hepatoerythropoietic porphyria (HEP, 176100.0005 ) is a severe infantile form due to homozygous PCT MOLECULAR BASIS \- Caused by mutation in the uroporphyrinogen decarboxylase gene (UROD, 176100.0001 ) \- Susceptibility conferred by mutation in the HFE gene (HFE, 613609.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	PORPHYRIA CUTANEA TARDA	c0162566	1,165	omim	https://www.omim.org/entry/176100	2019-09-22T16:35:55	{"doid": ["3132"], "mesh": ["D017119"], "omim": ["176100"], "icd-10": ["E80.1"], "orphanet": ["443062", "101330", "95159"], "synonyms": ["UROD DEFICIENCY", "PORPHYRIA CUTANEA TARDA, TYPE II", "PORPHYRIA, HEPATOCUTANEOUS TYPE", "Alternative titles", "UROPORPHYRINOGEN DECARBOXYLASE DEFICIENCY", "PCT", "Porphyria cutanea tarda type II", "PCT, 'FAMILIAL' TYPE", "PCT, TYPE II"], "genereviews": ["NBK143129", "NBK169003"]}
Dermatological condition Atrophodermia vermiculata Other namesAcne vermoulante, Acne vermoulanti, Atrophoderma reticulata symmetrica faciei, Atrophoderma reticulatum, Atrophoderma vermiculata, Atrophoderma vermiculatum, Atrophodermia reticulata symmetrica faciei, Atrophodermia ulerythematosa, Atrophodermie vermiculée des joues avec kératoses folliculaires, Folliculitis ulerythema reticulata, Folliculitis ulerythematous reticulata, Folliculitis ulerythemosa, Honeycomb atrophy, Ulerythema acneforme and Ulerythema acneiforme SpecialtyDermatology Atrophodermia vermiculata presents with erythematous follicular papules on the cheeks in childhood and, with time, the lesions develop into pit-like depressions.[1]:762[2]:714[3]:1511 ## See also[edit] * Skin lesion * Cicatricial alopecia * Ulerythema * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. ## External links[edit] Classification D * OMIM: 209700 This Genodermatoses 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	Atrophodermia vermiculata	c0263429	1,166	wikipedia	https://en.wikipedia.org/wiki/Atrophodermia_vermiculata	2021-01-18T18:51:00	{"gard": ["9744"], "mesh": ["C537412"], "umls": ["C0263429"], "icd-10": ["L66.4"], "orphanet": ["79100"], "wikidata": ["Q16835166"]}
## Summary ### Clinical characteristics. Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Most affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by "focal aware" and "focal impaired-awareness" seizures, with auditory symptoms as a major focal aware seizure manifestation. Some persons have seizures precipitated by sounds such as a ringing telephone. Age at onset is usually in adolescence or early adulthood (range: age 4-50 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy. ### Diagnosis/testing. The clinical diagnosis of ADEAF is established in a proband with characteristic clinical features, normal brain imaging (MRI or CT), and family history consistent with autosomal dominant inheritance. Identification of a heterozygous pathogenic variant in LGI1, MICAL1, or RELN by molecular genetic testing establishes the diagnosis if other findings are inconclusive. ### Management. Treatment of manifestations: Seizure control is usually readily achieved with antiepileptic drugs used routinely in clinical practice (including but not limited to carbamazepine, phenytoin, valproate, and levetiracetam). Evaluation of relatives at risk: Interviewing relatives at risk to identify those with suggestive findings may enable early treatment in those who develop seizures. ### Genetic counseling. ADEAF is inherited in an autosomal dominant manner. Most individuals with ADEAF have an affected parent; the proportion of cases caused by a de novo pathogenic variant is believed to be very low. Each child of an individual with ADEAF has a 50% chance of inheriting the pathogenic variant. The chance that the offspring who inherits the pathogenic variant will manifest ADEAF is between 55% and 78%, depending on the penetrance. While prenatal diagnosis for pregnancies at increased risk and preimplantation genetic diagnosis are possible if the pathogenic variant in the family is known, prenatal testing and preimplantation genetic testing are rarely requested for conditions that (like ADEAF) do not affect intellect and are usually easily treated. ## Diagnosis ### Suggestive Findings Autosomal dominant epilepsy with auditory features (ADEAF) should be suspected in individuals with the following clinical, imaging, and EEG findings and family history. Clinical findings * A history consistent with focal epilepsy from the affected individual and witnesses. Other causes of epilepsy (e.g., antecedent illness or injury to the central nervous system, such as severe head trauma, stroke, and brain tumor) must be excluded. * Auditory symptoms that occur in temporal association with seizures as one of the following: * An aura immediately preceding generalized tonic-clonic convulsions * A component of focal aware or focal impaired-awareness seizures * The only ictal symptom Note: Auditory symptoms may be underreported; therefore, specific questions to elicit occurrence of auditory symptoms should be included in the clinical history. Since tinnitus and other auditory disturbances may be reported as incidental findings in a person with epilepsy, care should be taken in obtaining the medical history to document a consistent temporal association of auditory symptoms with seizure events or to raise a strong suspicion of the ictal nature of the auditory symptom if not associated with other clinical features. * Aphasia that accompanies seizure onset. Aphasia may be difficult to distinguish from nonspecific confusion or alteration of consciousness; therefore, specific questions to assess the inability to understand spoken language in the absence of general confusion should be included in the clinical history. Note: Persons with epilepsy may report the inability to comprehend speech at the onset of seizures as a result of nonspecific confusion or alteration in consciousness; thus, care should be taken in obtaining the medical history to distinguish this confusion from specific symptoms of aphasia (i.e., an inability to understand language in the absence of alteration in consciousness). Brain imaging (MRI or CT). Normal Interictal EEG. Often normal. However, focal epileptiform abnormalities (usually localized to the temporal region) are found in up to two thirds of individuals. Family history. Consistent with autosomal dominant inheritance (with reduced and age-dependent penetrance).Two or more family members (including the proband) must have a history of focal epilepsy with either ictal auditory symptoms or ictal aphasia. Other family members may have different seizure types, usually tonic-clonic (undetermined whether focal or generalized). ### Establishing the Diagnosis The clinical diagnosis of ADEAF is established in a proband with the above clinical features, normal brain imaging studies (MRI or CT), and family history consistent with autosomal dominant inheritance. Identification of a heterozygous pathogenic variant in LGI1, MICAL1, or RELN by molecular genetic testing (Table 1) establishes the diagnosis if other findings are inconclusive. A multigene panel that includes LGI1, MICAL1, RELN, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Note: Serial single-gene testing of LGI1, MICAL1, and RELN is impractical given the relatively large number of exons in the latter two genes. ### Table 1. Molecular Genetic Testing Used in Autosomal Dominant Epilepsy with Auditory Features View in own window Gene 1, 2Proportion of ADEAF 3 Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 4 in Gene Detectable by Method Sequence analysis 5Gene-targeted deletion/duplication analysis 6 LGI130% 795%5% 8 MICAL17% 990%-95%Unknown RELN17%-18% 790%-95%% 10Unknown Unknown 11~50%NA 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. Autosomal dominant inheritance defined as ≥2 family members with idiopathic focal epilepsy with ictal auditory symptoms or receptive aphasia [Michelucci et al 2003, Berkovic et al 2004a, Ottman et al 2004, Michelucci et al 2013]. 4\. See Molecular Genetics for information on allelic variants detected in these genes. 5\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Michelucci et al [2017] 8\. A deletion encompassing the first four exons of LGI1 was identified in one family [Fanciulli et al 2012], and a deletion encompassing the second exon in another family [Dazzo et al 2015b]. No structural variants were identified by MLPA in 43 other families [Magini et al 2014, Manna et al 2014, Dazzo et al 2015b]. 9\. Dazzo et al [2018] 10\. Dazzo et al [2015a] 11\. A locus on 19q13.11-q13.31 likely to harbor a gene associated with ADEAF was identified in a large Brazilian family [Bisulli et al 2014]. In 21 families with ADEAF, 12 rare CNVs were identified by genome-wide SNP microarray analysis that segregated with ADEAF in single families, including rare microdeletions within or near RBFOX1 and NRXN1, and a microduplication in the proximal region of chromosome 1q21.1, where duplications have been associated with various neurodevelopmental disorders and epilepsy [Fanciulli et al 2014]. Deletions/duplications at these loci confer susceptibility to other forms of genetic epilepsy. ## Clinical Characteristics ### Clinical Description Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal epilepsy not caused by a previous illness or injury, with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. Age at onset has ranged from four to 50 years in previously reported families [Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Michelucci et al 2003, Michelucci et al 2013], but is usually in adolescence or early adulthood. The prominent auditory symptoms and aphasia are thought to reflect a localization of the epileptogenic zone in the lateral temporal lobe; accordingly, ADEAF is also known as autosomal dominant lateral temporal epilepsy (ADLTE). Epilepsy. Affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by focal aware or focal impaired-awareness seizures, with auditory symptoms as a major focal aware seizure manifestation occurring in around two thirds of affected individuals. Some individuals have seizures precipitated by specific sounds, such as a telephone ringing [Michelucci et al 2003, Michelucci et al 2004, Michelucci et al 2007]. Although most individuals in families with ADEAF have focal epilepsy, idiopathic generalized epilepsy was reported in four individuals with LGI1 pathogenic variants in two previously reported families [Ottman et al 2004]. The occurrence of idiopathic generalized epilepsies in these families may be explained either as an effect of LGI1 on the risk for idiopathic generalized epilepsy, or by the co-occurring pathogenic variant in these families of another (unidentified) gene that specifically influences risk for idiopathic generalized epilepsy. Febrile seizures do not occur with increased frequency in ADEAF. Auditory symptoms. The most common auditory symptoms are simple unformed sounds such as humming, buzzing, or ringing. Less frequently, other types of auditory symptoms occur, including complex sounds (e.g., specific songs or voices) or distortions (e.g., volume changes). Negative auditory symptoms, such as sudden decrease or disappearance of the surrounding noises, are reported by a minority of patients. Aphasia. Another distinctive feature is ictal receptive aphasia (i.e., sudden onset of an inability to understand language, in the absence of general confusion). Ictal aphasia was the most prominent symptom in one large Norwegian family with an LGI1 pathogenic variant [Brodtkorb et al 2002, Brodtkorb et al 2005a] (although auditory symptoms also occurred) and in a small Japanese family [Kanemoto & Kawasaki 2000]. Aphasia has also been reported in other families with LGI1 pathogenic variants [Michelucci et al 2003, Ottman et al 2004, Di Bonaventura et al 2009]. Other ictal symptoms. In families with ADEAF, affected individuals also have other ictal symptoms, either in isolation or accompanying auditory symptoms or aphasia. These occur less frequently than auditory symptoms and include other sensory symptoms (visual, olfactory, vertiginous, or cephalic) as well as motor, psychic, and autonomic symptoms [Poza et al 1999, Winawer et al 2000, Winawer et al 2002, Michelucci et al 2003, Hedera et al 2004, Ottman et al 2004, Michelucci et al 2013, Dazzo et al 2015b]. Non-epileptic manifestations associated with ADEAF on rare occasion include the following: * Behavioral problems (e.g., explosive violent behaviors, impulsiveness) and depression (with suicide attempts) have been reported in single pedigrees [Chabrol et al 2007, Kawamata et al 2010]. However, a systematic study investigating a possible shared genetic susceptibility to epilepsy and depression in families with an LGI1 pathogenic variant did not find such an association; rather, the depression appeared to be related to the epilepsy or antiepileptic treatment [Heiman et al 2010]. * Migraine segregating with occipito-temporal epilepsy resembling ADEAF has been described in one family [Deprez et al 2007]. Prognosis. The clinical course of ADEAF is usually benign. The following are offered as examples. * In a series of 34 affected individuals in seven Spanish and Italian families, focal to bilateral tonic-clonic seizures occurred only once or twice per year. The frequency of focal aware or focal impaired-awareness seizures ranged from twice per year to several times per month. After initiation of medical therapy, seizures were well controlled by any of a variety of medications (carbamazepine, phenobarbital, or phenytoin), sometimes at low doses [Michelucci et al 2003]. * In a Norwegian family with prominent ictal aphasia, all individuals had been free from focal to bilateral tonic-clonic seizures for two or more years, and focal aware seizures occurred infrequently in most individuals. However, two family members with epilepsy died suddenly in their sleep, both at age 28 years; a relationship to seizures was suspected but could not be confirmed [Brodtkorb et al 2002]. * In one other family with an LGI1 pathogenic variant, an unusual clinical picture with high seizure frequency and antiepileptic drug resistance was described [Di Bonaventura et al 2009]. EEG. Interictal (routine and sleep-deprived) EEGs may be normal in persons with ADEAF; however, epileptiform interictal EEG abnormalities are found in up to two thirds of affected individuals [Poza et al 1999, Winawer et al 2000, Brodtkorb et al 2002, Winawer et al 2002, Fertig et al 2003, Michelucci et al 2003, Pizzuti et al 2003, Hedera et al 2004, Ottman et al 2004, Pisano et al 2005]. Interestingly, a left predominance of the abnormalities has been observed in some clinical series [Michelucci et al 2003, Di Bonaventura et al 2009]. Ictal EEGs have been reported in three persons [Winawer et al 2002, Brodtkorb et al 2005a, Di Bonaventura et al 2009]. One of these showed left mid- and anterior temporal onset [Winawer et al 2002], and another onset in the left frontotemporal region with bilateral and posterior spreading, documented during a video-recorded aphasic seizure [Brodtkorb et al 2005a]. The third was recorded during a prolonged seizure cluster lasting several hours in an individual with prominent ictal aphasia; the EEG pattern consisted of low-voltage fast activity followed by delta activity and rhythmic sharp waves located in the anterior and middle left temporal regions [Di Bonaventura et al 2009]. Findings from magnetoencephalography (MEG) with auditory stimuli showed significantly delayed peak 2 auditory evoked field latency in individuals with LGI1 pathogenic variants [Ottman et al 2008]. Another study using MEG detected significantly large N100m signals in three of five individuals, contralateral to the auditory stimulation [Usui et al 2009]. Neuroimaging. Findings from routine neurologic examination and routine clinical imaging (MRI or CT) are normal. An interictal single-photon emission computed tomographic scan in one person identified hypoperfusion in the left temporal lobe [Poza et al 1999]. A left lateral temporal lobe malformation was identified through high-resolution MRI in ten individuals in a Brazilian family with an LGI1 pathogenic variant [Kobayashi et al 2003]. However, other studies using high-resolution MRI in families with LGI1 pathogenic variants have not confirmed this finding [Tessa et al 2007, Ottman et al 2008]. Diffusion tensor imaging identified a region of increased fractional anisotropy in the left temporal lobe in individuals with an LGI1 pathogenic variant [Tessa et al 2007]. In functional MRI with an auditory description decision task, persons with epilepsy in families with an LGI1 pathogenic variant had significantly less activation than controls [Ottman et al 2008]. These results suggest that individuals with ADEAF have functional impairment in language processing. Other investigations. Asymmetry of long-latency auditory evoked potentials (with reduced left N1-P2 amplitudes) was shown in the Norwegian family with aphasic seizures [Brodtkorb et al 2005b]. Abnormal phonologic processing was demonstrated in four persons in a Sardinian family by means of a fused dichotic listening task [Pisano et al 2005]. The above data, though based on a small sample size, would appear to suggest the existence of some structural abnormalities in the lateral temporal neuronal network. ### Genotype-Phenotype Correlations Auditory symptoms were less frequent with LGI1 pathogenic variants that predict truncation in the terminal epitempin repeat domain than with other LGI1 pathogenic variant type/domain combinations [Ho et al 2012]. Phenotypic features are the same in published familial cases with LGI1, MICAL1, or RELN pathogenic variants [Dazzo et al 2015a, Michelucci et al 2017, Dazzo et al 2018]. No significant clinical differences are observed between families with an LGI1 pathogenic variant and families without an identified pathogenic variant [Michelucci e al 2013]. No phenotypic differences have been found between simplex cases (i.e., a single occurrence in a family) and published familial cases [Bisulli et al 2004a, Bisulli et al 2004b, Flex et al 2005, Michelucci et al 2007, Michelucci et al 2009]. ### Penetrance Estimates of penetrance in studies of families with ADEAF range from 54% to 85% [Ottman et al 1995, Poza et al 1999, Ottman et al 2004, Wang et al 2006]. This variability may in part result from the use of different statistical models. LGI1. Based on analysis of obligate heterozygotes in 24 published families, penetrance of LGI1 pathogenic variants was estimated at 67% (95% CI 55%-77%) [Rosanoff & Ottman 2008]. More recently, in a study of 33 families in which probands were excluded, penetrance for epilepsy was estimated at 61% in ten families with an LGI1 pathogenic variant and 35% in families without an identified pathogenic variant, suggesting that inheritance may be complex in some families [Michelucci et al 2013]. All of these estimates are likely to be inflated by ascertainment bias, since they are based on families selected for study because they comprised many affected individuals. RELN. Twenty (60%) of 33 individuals heterozygous for a RELN pathogenic variant (from 7 families) had epilepsy [Dazzo et al 2015a]. MICAL1. Penetrance is unknown. ### Prevalence The prevalence of ADEAF is unknown but likely to be very low. Fewer than 3% of persons with epilepsy have a significant family history of epilepsy and only a fraction of these have clinical features consistent with ADEAF. Whereas Mendelian epilepsy syndromes account for a very small fraction of all epilepsy, findings from one study suggest that among Mendelian forms of focal epilepsy, ADEAF may not be rare as 9/48 (19%) of families with two or more individuals with idiopathic focal epilepsy met criteria for ADEAF (i.e., they comprised ≥2 individuals with ictal auditory symptoms) [Ottman et al 2004]. ## Differential Diagnosis Table 2 summarizes Mendelian focal epilepsy disorders. Distinguishing among these disorders can be challenging because the manifestations in affected family members are variable and no operational criteria for classification of families are yet available [Picard et al 2000]. Moreover, these different forms of focal epilepsy have shared genetic mechanisms; pathogenic variants in DEPDC5 have been identified in all of them [Poduri 2014], and were found in ten (12%) of 82 families with two or more individuals with focal epilepsy who did not have a detectable structural etiology [Dibbens et al 2013]. However, to date, pathogenic variants in DEPDC5 have not been identified in families with ADEAF. (See also DEPDC5-Related Epilepsy.) ### Table 2. Mendelian Focal Epilepsy Disorders View in own window DisorderGene(s)MOIClinical Features Localization of epileptogenic zoneSeizure semiologyAge at onsetNeuroimagingEEGOther Autosomal dominant epilepsy w/auditory features (ADEAF)LGI1 MICAL1 RELNADLateral temporal * Auditory symptoms are most common. * Autonomic or psychic symptoms occur in <25% of persons. 1 Usually late adolescence or early adulthoodNormal * Interictal EEGs may be normal. * Epileptiform interictal EEG abnormalities found in ≤2/3s of affected individuals 2 * Ictal EEGs reported in 3 persons 3 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)CHRNA4 CHRNB2 CHRNA2 KCNT1 DEPDC5 CRH 4ADFrontal lobe (rarely from extrafrontal areas - e.g., temporal, insular, & parietal regions)Asymmetric tonic/dystonic posturing &/or complex hyperkinetic seizures, mostly during sleep1st 2 decades of life in ~80% (mean onset age 10 yrs)Normal * Interictal & ictal scalp EEG features may be normal. * Prolonged video-EEG recording is best diagnostic test to assess seizure occurrence. * Characterized by clusters of nocturnal motor seizures, often stereotyped & brief (5 secs - 5 mins) * Clinical neurologic exam normal & intellect usually preserved, but psychiatric comorbidity or cognitive deficits may occur * Manifestations may vary considerably w/in a family. Familial mesial temporal lobe epilepsy (FMTLE) (OMIM PS600512)UnknownAD ARMesial temporal lobe 5 * Psychic symptoms (esp. déjà vu) most common * Autonomic or special sensory components in ~50% * Auditory symptoms in <10% Usually late adolescence or early adulthoodNormalInterictal epileptiform EEG abnormalities in ~20% * Febrile seizure frequency as in general population * Benign clinical course, w/long remissions & good response to range of therapies (carbamazepine, phenytoin, or valproate) Familial partial epilepsy w/variable foci (FPEVF) (OMIM PS604364)DEPDC5 NPRL2 NPRL3AD * Epileptogenic zone (frontal, temporal, or occipital) differs among family members. 6 * Frontal lobe seizures most common Auditory symptoms & aphasia not described in families w/FPEVFUsually middle childhood to early adulthoodNormalInterictal & ictal EEG abnormalities localized in different areas (frontal, temporal, occipital)Seizures in FPEVF occur less frequently than in ADNFLE; when they occur it is more often in daytime. AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance 1\. Ottman et al [2004] 2\. Poza et al [1999], Winawer et al [2000], Brodtkorb et al [2002], Winawer et al [2002], Fertig et al [2003], Michelucci et al [2003], Pizzuti et al [2003], Hedera et al [2004], Ottman et al [2004], Pisano et al [2005] 3\. Winawer et al [2002], Brodtkorb et al [2005b], Di Bonaventura et al [2009] 4\. Molecular genetic testing reveals pathogenic variants in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH in approximately 20% of individuals with a positive family history and fewer than 5% of individuals with a negative family history. 5\. Andermann et al [2005] 6\. Scheffer et al [1998], Xiong et al [1999], Callenbach et al [2003], Berkovic et al [2004b] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with autosomal dominant epilepsy with auditory features (ADEAF), consultation with a clinical geneticist and/or genetic counselor is recommended. ### Treatment of Manifestations ADEAF is benign in the great majority of individuals. No clinical trials of different antiepileptic medications have been carried out, but seizure control is achieved in most individuals with medications used routinely in clinical practice (e.g., carbamazepine, phenytoin, valproate). Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. ### Surveillance No surveillance guidelines for ADEAF have been developed. * As in any other form of focal epilepsy, routine interictal EEG may be performed to detect focal epileptiform abnormalities. * Brain MRI may be repeated to rule out structural abnormalities. ### Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and measures to minimize risk in the event of seizure onset (e.g., avoidance of unattended swimming). * If the LGI1, MICAL1, or RELN pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. * If the pathogenic variant in the family is not known, interview of relatives at risk may identify symptoms possibly related to seizures. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation 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. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Autosomal Dominant Epilepsy with Auditory Features	None	1,167	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1537/	2021-01-18T21:41:39	{"synonyms": ["ADEAF", "Autosomal Dominant Lateral Temporal Epilepsy (ADLTE)"]}
A rare hereditary sensory and autonomic neuropathy characterized by anhidrosis, insensitivity to pain, self-mutilating behavior and episodes of fever. ## Epidemiology Whilst several hundred cases have been reported worldwide, the exact prevalence is unknown. Most of the cases described were from the Israeli Bedouin population and Japan where the prevalence is estimated at 1/600,000-950,000. ## Clinical description The disease typically presents in early infancy, but may occasionally present during the neonatal period. Consanguinity has been reported in 50% of patients. Episodic fevers without obvious infections, extreme hyperpyrexia and febrile convulsions due to inability to dissipate heat as a result of anhidrosis as well as self-mutilation are usually the earliest signs of the disease. The cardinal feature is absence of sweating on the trunk and extremities, with occasional patients producing some moisture on the forehead, tip of the nose and gluteal sulcus. The skin becomes thick and callused with lichenification of palms, areas of hypotrichosis on the scalp and dystrophic nails. Deep tendon reflexes are usually present. Pain insensitivity is profound resulting in self-mutilation, auto-amputation, and corneal scarring but some patients retain temperature perception. Vibration sense and proprioception are normal or moderately decreased Bone fractures are slow to heal and large weight bearing joints are particularly susceptible to repeated trauma and frequently go on to the development of Charcot joints and osteomyelitis. Hypotonia and delayed developmental milestones are frequent in the early years, but sometimes normalize with age. Speech is usually clear, but patients have severe learning difficulties, irritability, hyperactivity, and cognitive impairment. Normal intelligence, however, has been reported in a few patients. Mild postural hypotension with compensatory tachycardia may be present, but not episodic hypertension. Around 20% of patients have scoliosis. ## Etiology The disease is due to mutations in the gene NTRK1 (1q21-22). ## Diagnostic methods Diagnosis requires two clinical criteria: anhidrosis and decreased pain perception, and is confirmed by genetic testing identifying variants in NTRK1. Skin biopsy reveals deficient C and A-delta fibers in the epidermis and hypoplastic dermal sweat glands without innervation. Plasma concentration of norepinephrine is extremely low or undetectable but epinephrine, vasopressin and plasma renin activity are normal. ## Differential diagnosis Differential diagnosis includes other hereditary sensory and autonomic neuropathies from which it is distinguished by absent or markedly decreased sweating. ## Genetic counseling The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers. ## Management and treatment Management is supportive and oriented to control hyperthermia, prevention of self-mutilation and treatment of orthopedic problems that potentially can cause severe and invalidating deformities. It is necessary to help families cope with behavioral and educational issues. ## Prognosis The prognosis for independent functions depends on the degree of disease expression and the ability to control the secondary clinical problems. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hereditary sensory and autonomic neuropathy type 4	c0020074	1,168	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=642	2021-01-23T17:49:03	{"gard": ["3006"], "mesh": ["D009477"], "omim": ["256800"], "umls": ["C0020074"], "icd-10": ["G60.8"], "synonyms": ["CIPA", "Congenital insensitivity to pain with anhidrosis", "HSAN4", "Hereditary sensory and autonomic neuropathy type IV"]}
A number sign (#) is used with this entry because 4 known genetic mechanisms can cause Angelman syndrome (AS). Approximately 70% of AS cases result from de novo maternal deletions involving chromosome 15q11.2-q13; approximately 2% result from paternal uniparental disomy of 15q11.2-q13; and 2 to 3% result from imprinting defects. A subset of the remaining 25% are caused by mutations in the gene encoding the ubiquitin-protein ligase E3A gene (UBE3A; 601623) (Kishino et al., 1997). See also X-linked mental retardation, Christianson type (300243), which shows phenotypic overlap with Angelman syndrome. Description Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, movement or balance disorder, typical abnormal behaviors, and severe limitations in speech and language. Most cases are caused by absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Prader-Willi syndrome (PWS; 176270) is a clinically distinct disorder resulting from paternal deletion of the same 15q11-q13 region. In addition, the chromosome 15q11-q13 duplication syndrome (608636) shows overlapping clinical features. Clayton-Smith and Pembrey (1992) provided a review of Angelman syndrome. Cassidy and Schwartz (1998) reviewed the molecular and clinical aspects of both Prader-Willi syndrome and Angelman syndrome. Horsthemke and Wagstaff (2008) provided a detailed review of the mechanisms of imprinting of the Prader-Willi/Angelman syndrome region. Van Buggenhout and Fryns (2009) provided a review of Angelman syndrome and discussed genetic counseling of the disorder, which can show a recurrence risk of up to 50%, depending on the underlying genetic mechanism. Clinical Features Angelman (1965) reported 3 'puppet children,' as he called them. Angelman (1965) emphasized the abnormal cranial shape and suggested that the depressed occiput may reflect a cerebellar abnormality. (Harry Angelman pronounces his name as though it means 'male angel;' in other words, he uses a 'long a' and a 'soft g.') Bower and Jeavons (1967) coined the name 'happy puppet' syndrome for the condition that they observed in 2 patients. Clinical features included severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and unusual facies characterized by a large mandible and open-mouthed expression revealing the tongue. The French refer to the syndrome as that of the 'marionette joyeuse' (Halal and Chagnon, 1976) or 'pantin hilare' (Pelc et al., 1976). Williams and Frias (1982) suggested use of the eponym Angelman syndrome because the term 'happy puppet' may appear derisive and even derogatory to the patient's family. Berg and Pakula (1972) reported a case and reviewed those reported by Angelman (1965) and Bower and Jeavons (1967). All of the patients demonstrated excessive laughter, an occipital groove, a great facility for protruding the tongue, abnormal choroidal pigmentation, and characteristic electroencephalogram (EEG) discharges. Of the 3 patients reported by Angelman (1965), at least 1 developed optic atrophy. Two patients showed jerky movements and had trouble walking, which was believed to result from poor balance. One, a 9-year-old boy who was noticed as an infant to be 'floppy,' could take only a few steps without support. Both patients had major convulsions and showed periods of flapping their arms up and down with the elbows flexed. The EEG pattern seen in these 2 cases and in the cases of Bower and Jeavons (1967) consisted of high amplitude bilateral spike-and-wave activity which was symmetrical, synchronous, and most often monorhythmic, having a slow wave component at 2 cycles per sec. The patient reported by Berg and Pakula (1972) had an unaffected sib who also showed abnormal EEG patterns. Normal karyotype was found in the 5 patients studied. Williams and Frias (1982) demonstrated unilateral cerebellar atrophy by CT imaging in 1 patient with AS. In 6 of 8 children with AS, aged 3 to 10 years, Dickinson et al. (1988) found an association of striking deficiency of choroidal pigment with normal foveal reflexes. All 6 had light blue irides with normal iris architecture. All were isolated cases born to healthy, unrelated parents. The presence or absence of 15q microdeletions did not correlate with the ocular findings. In a review of clinical features in 36 children with Angelman syndrome, Robb et al. (1989) reported global developmental delay, seizures, episodes of paroxysmal laughter, and tongue thrusting. The movement disorder consisted of a wide-based, ataxic gait with frequent jerky limb movements and flapping of the hands. Fryburg et al. (1991) described the clinical features in 4 patients diagnosed at less than 2 years of age. One of their patients had oculocutaneous albinism, and all were hypopigmented compared to their first-degree relatives. All 4 had choroidal pigment hypoplasia, severe to profound global developmental delay and microcephaly of postnatal onset, seizures, hypotonia, hyperreflexia, and hyperkinesis. Clayton-Smith (1993) reported on observations concerning 82 affected individuals. All of them had absent speech or spoke less than 6 words. Thirty-nine percent were hypopigmented compared to their family members. Frequent smiling was present in 96%. King et al. (1993) concluded from the study of 6 individuals with AS that hypopigmentation characterized by light skin, reduced retinal pigment, low hairbulb tyrosinase activity, and incomplete melanization of melanosomes is part of the phenotype of AS, and is similar to that found in Prader-Willi syndrome. Viani et al. (1995) found EEG evidence of transient myoclonic status epilepticus in 9 of 18 Angelman patients, which likely corresponded to recurrent jerky abnormal movements observed in these patients. In addition, 7 patients had partial seizures with eye deviation and vomiting similar to those of childhood occipital epilepsies. Reish and King (1995) established the diagnosis of Angelman syndrome in a 50-year-old woman. She had been healthy without seizures and had a history of pelvic fracture resulting from her unbalanced gait. She was born to a 40-year-old mother. Her height was 148 cm and her IQ was measured at less than 20. She did not speak and had frequent bursts of laughter. Reish and King (1995) demonstrated a 15q11.2-q12 deletion by karyotypic examination and fluorescence in situ hybridization (FISH). Buntinx et al. (1995) compared the main manifestations of Angelman syndrome in 47 patients at different ages. Most patients between the ages of 2 and 16 years showed at least 8 of the major characteristics of the syndrome (bursts of laughter, happy disposition, hyperactivity, micro- and brachycephaly, macrostomia, tongue protrusion, prognathism, widely spaced teeth, puppet-like movements, wide-based gait) in addition to mental retardation and absence of speech. Most patients (80.8%) had epileptic seizures, starting after the age of 10 months. In children under the age of 2 years, bursts of laughter was found in 42.8% and macrostomia in only 13.3%, but protruding tongue was a constant feature. In patients over 16 years of age, protruding tongue was found in 38.8%, whereas prognathism and macrostomia were almost constant findings. A cytogenetic deletion was found in 61% and a molecular deletion in 73% of the patients. No case of paternal disomy was found. Buntinx et al. (1995) found no differences between patients with or without deletion on chromosome 15q. The authors noted that the diagnosis of Angelman syndrome may be hampered in young children because of the absence of some typical manifestations and in older patients because of the changing behavioral characteristics. Smith et al. (1996) reviewed the clinical features of 27 Australian patients with AS, all with a DNA deletion involving 15q11-q13 and spanning markers from D15S9 to D15S12 (approximately 3.5 Mb of DNA). There were 9 males and 18 females, all sporadic cases, ranging in age from 3 to 34 years, and all ataxic, severely retarded, and lacking in recognizable speech. Head circumference at birth was normal in all but skewed in distribution, with 62.5% at the 10th centile. Epilepsy was present in 96% with onset during the third year of life in 20 of 26 patients. Hypopigmentation was present in 19 (73%). One patient had ocular cutaneous albinism. A happy disposition was noted in infancy in 95% and they all had a large, wide mouth. Among 22 institutionalized adults selected for criteria suggestive of Angelman syndrome, Sandanam et al. (1997) found deletion in the 15q11-q13 region in 11 (9 males and 2 females). The mean age at last review was 31.5 years (range 24 to 36 years). Clinical assessment documented findings of large mouth and jaw with deep set eyes and microcephaly in 9 patients (2 having a large head size for height). No patient was hypopigmented; 1 patient was fair. Outbursts of laughter occurred in all patients, but infrequently in 7 of 11 (64%), and a constant happy demeanor was present in 5 of 11 (46%). All had epilepsy, with improvement in 5 (46%), no change in 4 (36%), and deterioration in 2 (18%). The EEG was abnormal in 10 of 10 patients. Ocular abnormalities were reported in 3 of 8 patients (37.5%), with keratoconus present in 2, and 4 of 11 (36%) developed kyphosis. Two had never walked. All 9 who walked were ataxic with an awkward, clumsy, heavy, and/or lilting gait. No patient had a single word of speech, but 1 patient could use sign language for 2 needs, food and drink. The findings of Sandanam et al. (1997) supported the concept that AS resulting from deletion is a severe neurologic syndrome in adulthood. Lossie and Driscoll (1999) described a pregnancy in a 15-year-old female with AS who had been reported by Williams et al. (1989). Williams et al. (1989) had raised the possibility that the proband's mother, who had normal intelligence, was mosaic for a submicroscopic deletion of 15q11-q13, because she displayed brachycephaly, hearing loss, an enlarged foramen magnum, and mild ataxia. However, extensive cytogenetic and molecular analyses of peripheral blood and skin fibroblasts failed to reveal any abnormality in 15q11-q13 in the mother. The daughter had classic AS features, with severe mental retardation, AS-specific behavior, complete lack of speech, and a movement disorder characterized by ataxia. She showed microbrachycephaly with a head circumference of less than -2 standard deviations, relative prognathism, a protruding tongue, excessive drooling, and an inappropriately happy affect with excessive laughter. Menarche began at 11.5 years. Head CT and MRI were remarkable only for an enlarged foramen magnum. The pregnancy was terminated at 15 to 16 weeks' gestation. The fetus had inherited large deletions of maternal 15q11-q13 and demonstrated paternal-only DNA methylation imprints along 15q11-q13. UBE3A was paternally expressed in eye tissue from the fetus. These results indicated that females with AS are fully capable of reproduction and that UBE3A is not imprinted in fetal eye. Valente et al. (2006) reported the features of epilepsy of 19 patients with AS caused by deletion of 15q11-q13. All had generalized seizures, and 10 (53%) also had partial seizures. Types of seizures included atypical absence (84%), myoclonic (68%), generalized tonic-clonic or tonic (63%), simple partial with motor phenomena (32%), complex partial (26%), and myoclonic-astatic (11%). The mean age at seizure onset was 13 months (range 4 months to 2 years and 11 months). In 18 patients, seizure onset preceded diagnosis of AS. Sixteen (84%) patients had status epilepticus, of which 7 cases were recurrent, and 53% of patients had worsening with fever. Although complete seizure control was achieved in only 37% of patients, there was a tendency toward age-related improvement during late childhood and puberty. Michieletto et al. (2011) detailed ophthalmologic findings in 34 consecutive patients with a confirmed diagnosis of Angelman syndrome admitted to their institution for neurologic examination. The patients represented 3 genetic classes: deletion, uniparental disomy, and mutation. Ametropia (refractive error) greater than 1 diopter (D) was present in 97% of cases: myopia in 9%, hyperopia in 76%, and astigmatism in 94%. Myopia and anisometropia (unequal refractive errors) were found only in the genetic deletion group. Strabismus, most frequently exotropia, was found in 24 patients (75%). Ocular hypopigmentation was observed in 18 subjects (53%), with choroidal involvement in 3 cases and isolated iris involvement in 4. Hypopigmentation was observed in all of the genetic classes. Michieletto et al. (2011) stated that ophthalmic alterations were observed more frequently in this study than had previously been reported, except for ocular hypopigmentation, which was observed less frequently. By gathering data from standardized phone interviews with caregivers, Larson et al. (2015) ascertained the primary health issues of 110 adolescents and adults with Angelman syndrome. Important features included active seizures (41%), sleep dysfunction (72%), constipation (85%), obesity (32%), scoliosis (50%), and self-injurious behavior (52%). Only 13% of patients could speak 5 or more words, suggesting that impaired communication is a significant feature of this condition. Diagnosis Boyd et al. (1988) pointed out the usefulness of the EEG in the early diagnosis of Angelman syndrome. Dorries et al. (1988) described 7 cases and concluded that the diagnosis is difficult in the first years of life. The American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfer Committee (1996) reviewed diagnostic testing for Prader-Willi syndrome and Angelman syndrome. Stalker and Williams (1998) addressed the challenges of genetic counseling in this disorder with multiple causes. Most cases result from typical large de novo deletions of 15q11-q13 and are expected to have a low (less than 1%) risk of recurrence. AS due to paternal uniparental disomy, which occurs in the absence of a parental translocation, is likewise expected to have a recurrence risk of less than 1%. Parental transmission of a structurally or functionally unbalanced chromosome complement can lead to 15q11-q13 deletions or to UPD and will result in case-specific recurrence risks. In instances where there is no identifiable large deletion or UPD, the risk of recurrence may be as high as 50% as a result of either a maternally inherited imprinting center mutation or a mutation in the UBE3A gene. Individuals with AS who have none of the above abnormalities comprise a significant proportion of cases, and some may be at a 50% recurrence risk. Misdiagnoses can be represented in this group as well. In light of the many conditions that are clinically similar to AS, it is essential to address the possibility of diagnostic uncertainty and potential misdiagnosis before providing genetic counseling. Stalker and Williams (1998) presented an algorithmic chart summarizing the different causal classes of AS for consideration in determining recurrence risks. Tekin et al. (2000) described a patient with clinical features of Angelman syndrome in whom FISH analysis revealed mosaicism for a deletion in the AS critical region, but whose methylation study results were normal. The authors recommended that FISH studies for detection of mosaicism be done in patients with clinical findings of AS even if methylation studies are normal. Hall (2002) reported an apparently unique response by Angelman syndrome individuals to the vibrating tuning fork when it was held up to their ears. The response was a wide smile, often with an outburst of laughter, followed by a tendency to lean toward the vibrating tuning fork. In 6 consecutive Angelman individuals ranging in ages from 18 months to 43 years, they demonstrated a positive 'tuning fork response.' The 2 oldest individuals, aged 17 and 43 years, tended to be somewhat less demonstrative with mostly smiles and a more controlled laugh. Parents had observed their affected children as liking sound. This feature was manifested by their lying down or leaning against appliances that made a noise as if it relaxed them or made them feel good. Hall (2002) raised the possibility of the potential use of sound in intervention strategies for these individuals. Hall and Cadle (2002) described a 12-month-old child, later confirmed to have Angelman syndrome, who had a positive tuning fork response. The authors suggested that this test, if found to be positive in Angelman syndrome children at ages 2 to 12 months, may aid in the often difficult first-year diagnosis. Williams et al. (2006) provided an updated consensus for diagnostic criteria of Angelman syndrome. The list of associated findings was expanded to include abnormal food related behaviors, obesity, constipation, and scoliosis. In addition, some patients show attraction to or fascination with water and 'crinkly' items, such as papers and plastics. Sleep disturbances include abnormal sleep-wake cycles and diminished need for sleep. The clinical diagnosis of Angelman syndrome is based on the presence of all 4 major criteria, i.e., developmental delay, speech impairment, movement or balance disorder, and behavioral characteristics, as well as the presence of 3 of 6 minor criteria, including postnatal deceleration of head growth, seizures, abnormal EEG, sleep disturbance, attraction to or fascination with water, and drooling (summary by Tan et al., 2011). ### Differential Diagnosis Scheffer et al. (1990) pointed out the possible confusion with Rett syndrome. Pointing out that the diagnosis of Angelman syndrome can be confirmed by a genetic laboratory in only about 80% of cases, Williams et al. (2001) reviewed several mimicking conditions, including microdeletions or microduplications. Single gene conditions include methylenetetrahydrofolate reductase deficiency (236250), Rett syndrome, alpha-thalassemia retardation syndrome (ATRX; 301040), and Gurrieri syndrome (601187). There are, in addition, symptom complexes, including cerebral palsy (see 603513), autism spectrum disorder (209850), and pervasive developmental delay (PDD), that can suggest Angelman syndrome. Inheritance Angelman syndrome results from a lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion in most cases or from uniparental disomy in rare cases. Most families are therefore associated with a low recurrence risk. Although Angelman syndrome is not typically mendelian, familial occurrence has been reported. Pashayan et al. (1982) reported Angelman syndrome in 2 brothers, Hersh et al. (1981) reported affected monozygotic twins, and Kuroki et al. (1980) reported 2 affected sisters. Dijkstra et al. (1986) and Fisher et al. (1987) reported affected brothers and sisters. Baraitser et al. (1987) reported 7 cases of Angelman syndrome from 3 families: 2 brothers in the first family, 3 sisters in the second, and 2 brothers in the third. The EEG changes were striking in all 7 patients. Robb et al. (1989) observed 3 sibships with more than 1 affected sib: 3 affected sisters, 2 affected brothers, and 2 affected sisters. Pashayan et al. (1982) found reports of 27 sporadic cases with a male-to-female ratio of 1:1. Paternal age was not remarkable in the patients of Williams and Frias (1982). Willems et al. (1987) reported what they believed to be the fourth family with affected sibs out of a total of 52 cases in the literature. The findings suggested a low but not negligible recurrence risk. Clayton-Smith et al. (1992) studied 11 AS patients and their parents from 5 families using high resolution chromosome analysis and molecular probes from the region 15q11-q13. No deletions were detected. All sets of sibs inherited the same maternal chromosome 15, whereas in 3 families sibs inherited a different paternal chromosome 15. Polymorphic DNA markers gave the same conclusion. The findings indicated that autosomal recessive inheritance is very unlikely and suggested maternal transmission of a mutation within 15q11-q13. Abaied et al. (2010) reported a large highly consanguineous Tunisian kindred with a severe form of Angelman syndrome, with mental retardation, motor impairment, seizures, hyperactivity, and frequent laughing. Genetic analysis identified a heterozygous truncating mutation in the UBE3A gene (601623.0011). There were 14 affected individuals, who were all in the same generation, and all patients inherited the mutation from their carrier mothers, who were 4 sisters. These 4 sisters apparently inherited the mutation from their unaffected father, who was deceased. Abaied et al. (2010) noted that the detection of mutations in large AS families emphasizes the importance of available genetic counseling and meticulous family history investigation. Cytogenetics ### Maternal 15q Deletions and Genomic Imprinting Approximately 70% of cases of Angelman syndrome result from de novo maternal deletions involving the 15q11.2-q13 critical region (Kishino et al., 1997). Magenis et al. (1987) reported 2 unrelated girls with a deletion of the proximal part of chromosome 15q similar to that observed in Prader-Willi syndrome. However, the girls showed clinical features consistent with Angelman syndrome, including ataxia-like incoordination, frequent, unprovoked and prolonged bouts of laughter, and a facial appearance compatible with that diagnosis. None of the typical features of Prader-Willi syndrome were present. Kaplan et al. (1987) also described deletion in 15q11-q12 in a child with Angelman syndrome. Magenis et al. (1988) proposed that patients with AS and PWS share an identical deletion on chromosome 15q11. Analysis of 6 AS patients and 6 PWS patients suggested that the deletion in AS was slightly larger and also included band q12. Magenis et al. (1988) proposed that genes in band 15q12 are responsible for the greater severity of mental retardation and speech in AS, and that these genes may also suppress or alter the presumed hypothalamic abnormality that results in the uncontrolled appetite and obesity of PWS. By molecular analyses, Donlon (1988), Williams et al. (1988), and Knoll et al. (1989) showed that similar deletions of 15q11.2 were present in patients with Prader-Willi syndrome and Angelman syndrome. However, whereas the deleted chromosome was of paternal origin in PWS, the deleted chromosome was of maternal origin in AS. Otherwise, the deletions in the 2 disorders were indistinguishable cytogenetically or by molecular genetic methods. The findings were interpreted as indicating imprinting of chromosomes, i.e., changes in the chromosome according to the parent of origin, with resulting consequences for early development. By high-resolution cytogenetic studies, Magenis et al. (1990) found that the same proximal band, 15q11.2, was deleted in both PWS and AS. In general, the deletion in patients with Angelman syndrome was larger, though variable, and included bands q12 and part of q13. The authors confirmed the maternal origin of the deleted chromosome in AS, contrasting with the predominant paternal origin of the deletion in patients with Prader-Willi syndrome. After discovering 2 unrelated AS patients with a small deletion of proximal 15q, Pembrey et al. (1987, 1989) reassessed 10 further patients. Four showed a deletion within 15q11-q13, 1 showed an apparent pericentric inversion with breakpoints at 15q11 and q13 inherited from the mother, and 5 showed no discernible abnormality. Of the 5 children without discernible chromosome change, 1 had a definitely affected sib and 1 had a possibly affected sib. Of the 4 sets of parents studied, 3 had normal chromosomes, and in 1 the mother had a deletion of 15q11.2 but not 15q12. Like Pembrey et al. (1989), Fryns et al. (1989) found a visible chromosomal change in half of the patients they studied. No deletion was found in 2 affected sisters. By flow karyotype analysis on lymphoblastoid cell lines, Cooke et al. (1989) confirmed the presence of a de novo 15q deletion in a child with Angelman syndrome. The deleted segment represented 6.1 to 9.5% of chromosome 15, or approximately 6-9.3 million basepairs. Cytogenetic evidence suggested that the deleted chromosome was derived from the smaller chromosome 15 homolog of the mother. Knoll et al. (1990) studied DNA of 19 AS patients, including 2 sib pairs, using 4 DNA markers specific to 15q11-q13. They identified 3 classes: in class I, deletion of 2 markers was detected; in class II, deletion of 1 marker; and in class III, including both sib pairs, no deletion was detected. High resolution cytogenetic data were available on 16 of the patients, and complete concordance between the presence of a cytogenetic deletion and a molecular deletion was observed. No submicroscopic deletions were detected by the DNA studies. DNA samples from the parents of 10 patients with either a class I or a class II deletion were available for study. In 7 of the 10 families, RFLPs were informative as to the parental origin of the deletion, and in all, the deleted chromosome was of maternal origin. Imaizumi et al. (1990) described 6 patients, including 2 sibs, with Angelman syndrome. The 4 sporadic cases showed a microdeletion in the proximal part of 15q, whereas the affected sibs had no visible deletion. No clinical difference between the sporadic cases and the sib cases was discerned. Using 2 DNA probes that detect a molecular deletion in most patients with Prader-Willi syndrome, they found by densitometry that 2 patients had only 1 copy of each probe, whereas the other 4, including the sibs, had 2 copies of each sequence. Imaizumi et al. (1990) concluded that the segment causing AS may be different from that causing PWS. Williams et al. (1990) studied 6 AS patients with de novo deletions of 15q11-q13. In 4 of the patients, cytogenetic studies were informative of parental origin; in all, the deletion was inherited from the mother, suggesting genomic imprinting. Malcolm et al. (1990) studied 37 typical cases. A 15q11-q13 deletion was observed in 18 of 24 isolated cases. No deletion was observed in 13 cases from 6 families with more than 1 affected child. In 11 cases it was possible to elucidate the parental origin of the deleted chromosome and these were shown to be predominantly maternal. Greenstein (1990) presented a kindred in which both the Prader-Willi and Angelman syndromes were found; the inheritance pattern was consistent with genetic imprinting. Hulten et al. (1991) reported an extraordinary family showing segregation of a balanced translocation t(15;22)(q13;q11) and 2 cases of Prader-Willi syndrome and 1 of Angelman syndrome. It appeared that the females carrying the balanced translocation had a high risk of having children with AS, while their brothers had a high risk of having children with PWS, again indicating genomic imprinting. All 4 AS patients described by Fryburg et al. (1991) had deletions in the 15q11.2-q13 region. Parental chromosomes were available for study in 3 of these cases; in all 3 the deleted chromosome 15 was maternally derived. Similarly, Smith et al. (1992) found the deletion of band 15q12 to be of maternal origin in all 25 cases of AS that they examined. The parental origin was determined using cytogenetic markers in 13 of the cases, by the pattern of inheritance of RFLPS in 9, and by both techniques in 3. Tonk et al. (1992) found cytogenetic deletion of 15q12 in 3 cases of AS and by heteromorphism studies showed that the deleted chromosome was maternal in all 3. Chan et al. (1993) presented a series of 93 Angelman syndrome patients, showing the relative contribution of the various genetic mechanisms. Sporadic cases accounted for 81 AS patients, while 12 cases came from 6 families. Deletions in 15q11-q13 were detected in 60 cases by use of a set of highly polymorphic (CA)n repeat markers and conventional RFLPs. In 10 sporadic cases and in all 12 familial cases, no deletion was detectable. In addition, 2 cases of de novo deletions occurred in a chromosome 15 carrying a pericentric inversion. In one of these the AS child had a cousin with Prader-Willi syndrome arising from a de novo deletion in an inverted chromosome 15 inherited from his father. The other case arose from a maternal balanced t(9;15)(p24;q15) translocation. There were 3 cases of uniparental disomy. In the familial cases, all affected sibs inherited the same maternal chromosome 15 markers for the region 15q11-q13. Cytogenetic analysis detected only 42 of the 60 deletion cases. Chan et al. (1993) stated that cytogenetic analysis was still essential to detect chromosomal abnormalities other than deletions such as inversions and balanced translocations, both of which have an increased risk for deletions. To elucidate the mechanism underlying the deletions that lead to PWS and AS, Amos-Landgraf et al. (1999) characterized the regions containing 2 proximal breakpoint clusters and a distal cluster. Analysis of rodent-human somatic cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences, termed 'END' repeats, at or near the breakpoints. END-repeat units are derived from large genomic duplications of the HERC2 gene (605837) (Ji et al., 1999). Many copies of the HERC2 gene are transcriptionally active in germline tissues. Amos-Landgraf et al. (1999) postulated that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, they proposed that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process. In a study of 45 Finnish AS patients, Kokkonen and Leisti (2000) found 2 affected sibs, a 16-year-old boy and a 5-year-old girl, in whom the diagnosis was made at 8 years and at 3 months of age, respectively. Both parents and an 18-year-old brother were healthy. The 2 sibs were found to have del(15)(q11q13); the mother's chromosomes 15 were structurally normal, whereas the patients and their unaffected brother shared an identical maternally derived haplotype outside the deletion region. These findings were suggestive of maternal germline mosaicism of del(15)(q11q13). Angelman syndrome deletions and rearrangements tend to occur at specific 'hotspots' or breakpoint (BP) clusters in proximal 15q (see Pujana et al., 2002): 2 proximal clusters, referred to as BP1 and BP2, are the breakpoints for class I and class II patients, respectively. The most common distal breakpoint, BP3, is located between markers D15S12 and D15S24. Two other breakpoint regions called BP4 and BP5 have been mapped distal to BP3, between markers D15S24 and D15S144. Gimelli et al. (2003) reported that some mothers of AS patients with deletions of the 15q11-q13 region have a heterozygous inversion involving the region that is deleted in the affected offspring. The inversion was detected in the mothers of 4 of 6 AS cases with the breakpoint 2-3 (BP2/3) 15q11-q13 deletion, but not in 7 mothers of AS cases due to paternal UPD 15. Variable inversion breakpoints were identified within breakpoint segmental duplications in the inverted AS mothers, as well as in AS deleted patients. The BP2-BP3 chromosome 15q11-q13 inversion was detected in 4 of 44 control subjects. Gimelli et al. (2003) hypothesized that the BP2/3 inversion may be an intermediate state that facilitates the occurrence of 15q11-q13 BP2/3 deletions in the offspring. Approximately one-third of Angelman patients have an imprinting defect (ID) but no imprinting center deletion, suggesting that they may mosaicism of ID cells and normal cells. In 2 patients studied, Nazlican et al. (2004) demonstrated somatic mosaicism by molecular and cellular cloning. X-inactivation studies of cloned fibroblasts from 1 patient suggested that ID occurred before the blastocyst stage. Using a quantitative methylation assay based on real-time PCR, the authors detected from less than 1% to 40% normal cells among 24 Angelman patients tested. Regression analysis suggested that patients with a higher percentage of normally methylated cells tended to have milder clinical symptoms. ### Paternal Uniparental Disomy Approximately 2% of cases of Angelman syndrome result from paternal uniparental disomy (UPD) of 15q11-q13 (Kishino et al., 1997). Malcolm et al. (1991) found evidence of uniparental paternal disomy in 2 patients with AS. Knoll et al. (1991) examined the DNA from 10 AS patients, at least 7 of whom were familial cases, with no cytogenetic or molecular deletion of chromosome 15q11-q13. In each case, 1 maternal copy and 1 paternal copy of 15q11-q13 was observed. The authors concluded that UPD is not a frequent cause of familial AS. Engel (1991), who introduced the concept of uniparental disomy in 1980 (Engel, 1980), took Knoll et al. (1991) to task for their conclusion that uniparental disomy may be rare in this disorder and urged further studies. Paternal uniparental disomy was demonstrated by Freeman et al. (1993) in a child with a balanced 15;15 translocation. DNA polymorphisms demonstrated that the patient was homozygous at all loci for which the father was heterozygous, suggesting that the structural rearrangement was an isochromosome 15q and not a Robertsonian translocation. Engel (1993) reviewed the possible mechanisms for uniparental disomy. One possibility is gamete complementation, i.e., the gamete from one parent containing both chromosomes of the pair and that from the other parent containing neither. When gamete complementation is the mechanism, the centromeres of the resulting pair will be heterodisomic if resulting from a meiosis 1 error, and isodisomic if resulting from a meiosis 2 error. Beyond that, meiosis 1 UPD, depending on crossing-over and segregation, may be wholly heterodisomic (holo-heterodisomy) or partially isodisomic (mero-isodisomy); meiosis 2 UPD should always result in an element of isodisomy embodied in the 2 segments of the nonseparated chromatids left unaffected by crossing-over. This unaffected segment thus tends to be juxtacentromeric. Gametic complementation UPD was reported by Wang et al. (1991), who found paternal heterodisomy for chromosome 14 in a 45,XX,t(13q14q)der pat proposita, whose 2 parents were balanced heterozygotes for a translocation involving chromosome 14. This situation is analogous to the effects of biparental translocation as in the mouse experiments of Cattanach and Kirk (1985). A second mechanism of UPD is so-called trisomy rescue or correction. It is expected that the remaining pair, after loss of the extra homolog, will be biparental in two-thirds of cases and uniparental in one-third of cases. In such instances, as in gamete complementation, isodisomy may or may not be present. Cases of UPD in Prader-Willi syndrome whose chromosomal 15 maternal disomy could be traced to a placental mosaicism for trisomy 15 documented at the time of choriocentesis (chorion villus sampling) performed for advanced maternal age were reported by Cassidy et al. (1992) and Purvis-Smith et al. (1992). A third situation is akin to the second; the abnormal initial zygotic situation is monosomy rather than trisomy and the abnormality is 'corrected' through duplication of the single available homolog. The case of cystic fibrosis with maternal chromosome 7 isodisomy and growth delay reported by Spence et al. (1988) may have been of this type, although there is at least one other explanation. Donnai (1993) pointed out that Robertsonian translocations, occurring with a frequency of about 1 in 10,000 live births, may be an important cause of UPD; such has been demonstrated to be the case for 13/15, 13/14, 14/14, and 22/22 translocations. Dysmorphologic features and/or mental retardation are clinical clues for uniparental disomy in apparently balanced offspring of translocation carriers. Among abortion products of balanced Robertsonian translocation carriers, an excess of 'normal balanced' conceptions has been noted. Robertsonian translocations involving chromosomes 13 and/or 21 are frequently ascertained through a trisomic child. Among those ascertained through a mentally retarded but nontrisomic proband, there appears to be overrepresentation of translocations involving chromosome 14. Since nonmosaic trisomy 14 is nonviable, such a conception would survive a pregnancy only by reducing to disomy. Fridman et al. (1998) reported a patient with AS and the chromosome constitution 45,XY,t(15q15q). She had some unusual clinical features, including hyperphagia and obesity. Methylation analysis with a probe for small nuclear ribonucleoprotein N (SNRPN; 182279) at 15q12, microsatellite analyses of D15S11, GABRB3 (137192) and D15S113 loci, and FISH using SNRPN and GABRB3 probes indicated paternal isodisomy. This was the fourth reported case of translocation 15q15q with paternal uniparental disomy. Fridman et al. (1998) discussed possible explanations such as homozygosity due to paternal isodisomy for sequence variation (mutation) in one of the genes involved in the pathogenesis of Prader-Willi syndrome. They pointed out that hyperphagia and obesity may occur specifically in association with AS in the context of certain genetic backgrounds, as mice with paternal UPD for the Ube3a region have a postnatal onset of severe obesity (Cattanach et al., 1997). In studies reported by Robinson et al. (1993), most cases of paternal UPD leading to Angelman syndrome were meiosis II errors or, more likely, mitotic errors. In contrast, in more than 82% of cases of maternal UPD leading to Prader-Willi syndrome, the extra chromosome was due to a meiosis I nondisjunction event. A similar observation has been made for trisomy 21: the majority (78%) of maternal errors leading to trisomy 21 are attributable to meiosis I events, whereas most paternal errors are attributed to either meiosis II or mitotic events (40% and 33%, respectively) (Antonarakis et al., 1993). ### Defects in the Imprinting Center Approximately 2 to 3% of cases of Angelman syndrome result from an imprinting defect (Kishino et al., 1997; Buiting et al., 1998). Reis et al. (1994) demonstrated defects in methylation in 2 AS sibs, 2 patients with sporadic AS, and 2 sibs from another family with PWS with nondeletion, nonuniparental disomy. In the AS patients, the maternal AS chromosome carried a paternal methylation imprint, and the authors postulated an 'imprinting mutation.' Reis et al. (1994) postulated that in some affected families, a germline mutation in 1 of the grandparents results in failure to reset the imprinting signal in the parental germline, thus resulting in an imprinting defect in parental offspring. Buiting et al. (1995) identified inherited microdeletions of 15q11-q13 between D15S63 and SNRPN (182279) in 2 families with AS and 3 families with PWS. Some of the families had been reported by Reis et al. (1994). In the AS families, the deletions were found on the maternal chromosomes of the patients and on the paternal chromosomes of the phenotypically normal mothers. The authors suggested that the deleted region contains an 'imprinting center' (IC), and that mutations in this region can be transmitted silently through the germline of 1 sex and manifest themselves only after transmission through the germline of the opposite sex. Thus, it is the grandparental legacy of an imprinting mutation that determines the clinical phenotype. Beuten et al. (1996) reported an extended consanguineous Dutch kindred in which 3 patients with nondeletion AS, 2 males and 1 female, occurred in 3 separate sibships sharing common ancestral couples through all 6 parents. Paternal uniparental disomy of chromosome 15 was detected in 1 case, while the other 2 patients had abnormal methylation of D15S9, D15S63, and SNRPN, consistent with an imprinting mutation. Although the 3 patients were distantly related, the chromosome 15q11-q13 haplotypes were different, suggesting that independent mutations gave rise to AS in this family. Approximately 6% of AS patients have a paternal imprint on the maternal chromosome. In a few cases, this is due to an inherited microdeletion in the 15q11-q13 imprinting center that blocks the paternal-to-maternal imprint switch in the maternal germline. Burger et al. (1997) determined the segregation of 15q11-q13 haplotypes in 9 families with AS and with an imprinting defect. One family, with 2 affected sibs, had a microdeletion affecting the IC transcript. In the other 8 patients, no mutation was found at that locus. In 2 families, the patient and a healthy sib shared the same maternal alleles. In 1 of these families and in 2 others, grandparental DNA samples were available, and the chromosomes with the imprinting defect were found to be of grandmaternal origin. These findings suggested that germline mosaicism or de novo mutations account for a significant fraction of imprinting defects among patients who have an as-yet-undetected mutation in a cis-acting element. Alternatively, Burger et al. (1997) suggested that these data might indicate that some imprinting defects are caused by a failure to maintain or to reestablish the maternal imprint in the maternal germline or by a failure to replicate the imprint postzygotically. Depending on the underlying cause of the imprinting defect, different recurrence risks need to be considered. Buiting et al. (1998) described the molecular analysis of 13 PWS patients and 17 AS patients who had an imprinting defect but no IC deletion. Furthermore, heteroduplex and partial sequence analyses did not reveal any point mutations in the known IC elements. All of these patients represented sporadic cases, and some shared the paternal PWS or maternal AS 15q11-q13 haplotype with an unaffected sib. In each of the 5 PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and 4 cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggested that the grandmaternal imprint was not erased in the father's germline. In 7 informative AS patients reported by Buiting et al. (1998) and in 3 previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding was not compatible with an imprint-switch failure, but it suggested that a paternal imprint developed either in the maternal germline or postzygotically. Buiting et al. (1998) concluded that (1) the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error; (2) these cases have a low recurrence risk; and (3) the paternal imprint may be the default imprint. In several patients with Angelman syndrome or Prader-Willi syndrome, microdeletions upstream of the SNRPN gene have been identified, defining an imprinting center that appears to control the imprint switch process in the male and female germlines. Ohta et al. (1999) identified 2 large families segregating an Angelman syndrome imprinting mutation; one of these families was originally described in the first genetic linkage study of Angelman syndrome that mapped the AS gene to 15q11-q13 (Wagstaff et al., 1993). Identification of the imprinting mutation demonstrated that the original linkage was for the imprinting center at 15q11-q13. Affected patients in these 2 Angelman syndrome families had either a 5.5- or a 15-kb microdeletion, one of which narrowed the shortest region of deletion overlap to 1.15 kb in all 8 cases. This small region defined a component of the imprinting center involved in Angelman syndrome, i.e., the paternal-to-maternal switch element. The presence of an inherited imprinting mutation in multiple unaffected members of these 2 families, who are at risk for transmitting the mutation to affected children or children of their daughters, raised important genetic counseling issues. Imprinting in 15q11-q13 is controlled by a bipartite imprinting center which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome. Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome. In all sibs affected by Angelman syndrome, an inherited imprinting center deletion had been identified. Buiting et al. (2001) reported 2 sibs with Angelman syndrome who did not have a deletion of the imprinting center but instead had a 1-to-1.5 Mb inversion separating the 2 imprinting center elements. The inversion was transmitted silently through a male germline but impaired maternal imprinting after transmission through the female germline. The findings suggested that the close proximity of the 2 imprinting center elements and their correct orientation, or both, are necessary for the establishment of a maternal imprint. ### Imprinting Defects Associated with Infertility Treatment Cox et al. (2002) reported 2 children conceived by intracytoplasmic sperm injection (ICSI) who developed Angelman syndrome. Molecular studies, including DNA methylation and microsatellite and quantitative Southern blot analysis, revealed a sporadic imprinting defect in both patients. In germ cells and the early embryo, the mammalian genome undergoes widespread epigenetic reprogramming. Animal studies had suggested that this process is vulnerable to external factors. The authors discussed the possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo. Orstavik et al. (2003) described a third case of imprinting defect in a girl with Angelman syndrome who was conceived by ICSI. Biparental origin of normal chromosomes 15 and absence of the common large deletion of 15q11-q13 was found. Methylation-specific Southern blot analysis and methylation-specific PCR for the SNRPN locus showed the presence of a normal unmethylated paternal band and the complete absence of a methylated maternal band, indicating that the patient had an imprinting defect. Among 16 Angelman syndrome patients born to subfertile couples who conceived with or without infertility treatment, Ludwig et al. (2005) found that 4 had an imprinting defect. The relative risk in untreated couples with time to pregnancy exceeding 2 years was identical to that of those treated by ICSI or by hormonal stimulation alone (RR, 6.25; 95% CI, 0.70 to 22.57), and it was twice as high in couples who had received treatment and also had time to pregnancy greater than 2 years (RR, 12.5; 95% CI, 1.40 to 45.13). Ludwig et al. (2005) suggested that imprinting defects and subfertility might have a common cause, and that superovulation rather than ICSI might further increase the risk of conceiving a child with an imprinting defect. Mapping ### Angelman Syndrome Critical Gene Region Rare reports of familial AS have enabled linkage analysis to determine the 'Angelman syndrome critical gene region.' Hamabe et al. (1991) described transmission of a submicroscopic deletion between D15S11 and D15S10 in a 3-generation family which resulted in AS only upon maternal transmission of the deletion. No clinical phenotype was associated with paternal transmission. Greger et al. (1993) cloned and sequenced the breakpoint of the submicroscopic deletion identified by Hamabe et al. (1991). The findings suggested that the imprinted gene responsible for the PWS phenotype is proximal to that responsible for the AS phenotype. Sato et al. (2007) reported a Japanese family in which a boy with AS and his asymptomatic mother and maternal grandfather all had a 1,487-kb deletion on chromosome 15, encompassing HBII-52 (SNORD115-1; 609837), HBII-438B, UBE3A, ATP10C (605855), and part of GABRB3. The breakpoints were identical to those found by Greger et al. (1993) in the submicroscopic deletion of the Japanese family described by Hamabe et al. (1991). Although a relationship between the 2 families could not be confirmed, Sato et al. (2007) noted that they lived in neighboring prefectures in Japan. Meijers-Heijboer et al. (1992) reported findings in an unusually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-q13 were excluded. However, linkage analysis yielded a maximum lod score of 5.40 for GABRB3 (137192) and the marker D15S10. The size of the pedigree allowed calculation of an odds ratio in favor of genomic imprinting of 9.25 x 10(5). Wagstaff et al. (1992) reported a family in which 3 sisters had given birth to 4 patients with AS who had no evidence of deletion or paternal disomy. The inferred mutation had been transmitted by the grandfather to 3 of his daughters without phenotypic effects, indicating that the presumed mutation results in disease only when transmitted maternally, not paternally. The findings suggested that the loci responsible for PWS and AS, although closely linked, are distinct. Wagstaff et al. (1993) indicated that this was the first instance in which the origin of a new mutation in nondeletion AS could be pinpointed. A sister of the grandfather had transmitted the same AS-associated haplotype to 4 of her children, all of whom were phenotypically normal. The authors concluded that there was either germline mosaicism in the grandfather, with the mutation transmitted to at least 3 of his 5 children, or that the grandfather inherited a new AS mutation from his father. Linkage analysis yielded a maximum lod score of 3.52 at GABRB3. In addition, linkage analysis of the 2 affected brothers reported by Pashayan et al. (1982) identified a locus distal to D15S63, a localization consistent with the submicroscopic deletion described by Hamabe et al. (1991). Before the study of Buxton et al. (1994), the AS region had been narrowed to approximately 1.5 Mb, as defined by an affected family carrying a small inherited deletion (Kuwano et al., 1992) and another patient with an unbalanced translocation (Reis et al., 1993). Buxton et al. (1994) identified an individual with typical features of AS who had a deletion of the maternal chromosome shown to be less than 200 kb. Burke et al. (1996) reported a case of AS resulting from an unbalanced cryptic translocation with a breakpoint at 15q11.2. The proband was diagnosed clinically as having AS, but no cytogenetic deletion was detected. Fluorescence in situ hybridization detected a deletion of D15S11, with an intact GABRB3 locus. Subsequent studies of the proband's mother and sister detected a cryptic reciprocal translocation between chromosomes 14 and 15 with the breakpoint being between SNRPN and D15S10. The proband was found to have inherited an unbalanced form, being monosomic from 15pter through SNRPN and trisomic for 14pter-q11.2. DNA methylation studies showed that the proband had a paternal-only DNA methylation pattern at SNRPN, D15S63, and ZNF127 (MKRN3; 603856). The mother and unaffected sister, both having the balanced translocation, demonstrated normal DNA methylation patterns at all 3 loci. These data suggested to Burke et al. (1996) that the gene for AS most likely lies proximal to D15S10, in contrast to the previously published position, although a less likely possibility is that the maternally inherited imprinting center acts in trans in the unaffected balanced translocation carrier sister. Trent et al. (1997) reported 2 families that further defined the Angelman syndrome critical region. The first analysis, of a 5-year-old girl with typical features of AS, her 14-year-old brother, and an 11-year-old male cousin with less typical clinical features, showed that the 3 shared a common segment of the same grandpaternal chromosome defined by markers D15S122 to GABRB3. The typically affected 5-year-old girl had in addition a maternal recombination between markers D15S210 and D15S113. Trent et al. (1997) proposed that the 3 affected individuals shared a mutation involving the UBE3A gene and that the severe phenotype in the 5-year-old girl was the result of the recombination event, affecting a 5-prime regulatory or controlling region. Trent et al. (1997) analyzed a second family in which a mother and son had a deletion extending from D15S986 telomeric of the UBE3A gene. These individuals had mental retardation, but no other features of AS. Trent et al. (1997) concluded that together, these 2 families identified a region between D15S210 and D15S986, which contains a potential regulatory or controlling region for the UBE3A gene. Clinical Management In patients with Angelman syndrome, caused by deficiency of the maternal copy of the imprinted gene UBE3A (601623), the paternal copy of UBE3A is intact but silenced by a nuclear-localized long noncoding RNA, UBE3A antisense transcript (UBE3AATS, or SNHG14; 616259). Meng et al. (2015) developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3aats with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3aats and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of Ube3a protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Meng et al. (2015) concluded that they had developed a sequence-specific and clinically feasible method to activate expression of the paternal UBE3A allele. Molecular Genetics In 3 patients, including 2 sibs, with nondeletion/nonuniparental disomy/nonimprinting AS, Kishino et al. (1997) identified 2 different mutations in the UBE3A gene (601623.0001; 601623.0002). The findings suggested that AS is the first recognized example of genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It also may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products. Precedent for the production of imprinted and nonimprinted transcripts from a single locus exists for insulin growth factor-2 (IGF2; 147470), where 4 promoters, 3 imprinted and 1 biallelically expressed, account for differential expression. Matsuura et al. (1997) identified de novo truncating mutations in the UBE3A gene (601623.0003; 601623.0004) in patients with Angelman syndrome, indicating that UBE3A is the AS gene and suggesting the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript of the UBE3A gene. Greger et al. (1997) reported a patient with AS who had a paracentric inversion with a breakpoint located approximately 25 kb proximal to the reference marker D15S10. This inversion was inherited from a phenotypically normal mother. No deletion was evident by molecular analysis in this case, by use of cloned fragments mapped to within approximately 1 kb of the inversion breakpoint. Among the possible explanations for the AS phenotype put forth by Greger et al. (1997) was the possibility that the inversion disrupted the UBE3A gene. Among 1,272 patients suspected of having Angelman syndrome, Burger et al. (2002) found 1 with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF-SNRPN locus revealed a normal pattern in the patient. The deletion was only detected through allelic loss at 3 microsatellite loci, and confirmed with FISH using BAC probes derived from those 3 loci. The deletion extended approximately 570 kb, encompassing the UBE3A locus, and was familial: it was present in the mother, the maternal grandfather, and his sister. Haplotype studies suggested that the proband's great-grandfather, who was deceased, already carried the deletion, and that it causes Angelman syndrome when inherited through female germline, but not Prader-Willi syndrome when paternally inherited. The findings supported the hypothesis that the functional loss of maternal UBE3A is sufficient to cause Angelman syndrome and that the deletion does not contain genes or other structures that are involved in the pathogenesis of Prader-Willi syndrome. The case also emphasized that methylation tests can fail to detect some familial Angelman syndrome cases with a recurrence risk of 50%. 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 15q11.2-q13 (BP2-BP3) deletion was identified in 41 cases and no controls for a p value of 2.77 x 10(-9) and a frequency of 1 in 384 cases. Genotype/Phenotype Correlations On the basis of molecular and cytogenetic findings, Saitoh et al. (1994) classified 61 Angelman syndrome patients into 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had maternal deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from 1 family had a maternal deletion involving only 2 loci, D15S10 and GABRB3, which defined the critical region for AS phenotypes. Among sporadic and familial cases without deletion, no uniparental disomy was found. Of 23 patients with a normal karyotype, 10 (43%) showed a molecular deletion. Except for hypopigmentation of skin or hair, neurologic signs and facial characteristics were not distinctive in a particular group. Familial cases with submicroscopic deletion were not associated with hypopigmentation, suggesting that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted. Minassian et al. (1998) found severe intractable epilepsy in patients with maternally inherited chromosome 15q11-q13 deletions but relatively mild epilepsy in patients with uniparental disomy methylation imprinting abnormalities or mutations in the UBE3A gene. Moncla et al. (1999) compared 20 nondeletion AS patients with 20 age-matched 15q11-q12 deletion AS patients. A less severe phenotype with regard to both physical anomalies and neurologic manifestations was found to be associated with nondeletion AS. The nondeletion cases included patients with paternal uniparental disomy, imprinting mutations, and UBE3A mutations. The clinical severity scale from more to less severe was deletion cases to UBE3A mutation cases to imprinting mutations and/or UPD cases. The molecular cases, however, have a potential high risk for recurrence. Gillessen-Kaesbach et al. (1999) described 7 patients who lacked most of the features of Angelman syndrome: severe mental retardation, postnatal microcephaly, macrostomia and prognathia, absence of speech, ataxia, and a happy disposition. They presented, however, with obesity, muscular hypotonia, and mild mental retardation. Based on the latter findings, the patients were initially suspected of having Prader-Willi syndrome. DNA methylation analysis of SNRPN and D15S63, however, revealed the pattern of Angelman syndrome, i.e., the maternal band was faint or absent. Cytogenetic studies and microsatellite analysis demonstrated apparently normal chromosomes 15 of biparental origin. Gillessen-Kaesbach et al. (1999) concluded these patients had an imprinting defect and a previously unrecognized form of AS. They suggested that the mild phenotype may have been due to an incomplete imprinting defect or by cellular mosaicism. In 25 patients with Angelman syndrome, Fridman et al. (2000) detected 21 with deletion and 4 with paternal UPD, 2 isodisomies originating by postzygotic error, and 1 meiotic stage II nondisjunction event. By comparison of the clinical data from these and published UPD patients with data from patients with deletions, they observed the following: the age at diagnosis was higher in the UPD group, microcephaly was more frequent among deletion patients, UPD children started walking earlier, epilepsy started later in UPD patients, weight above the 75th centile was reported mainly in UPD patients, and complete absence of speech was more common in the deletion patients. UPD patients had somewhat better verbal development and occipital frontal circumference in the upper normal range. Lossie et al. (2001) studied 104 patients with a classic AS phenotype from 93 families. Twenty of the 104 patients (22%) had normal DNA methylation at 15q11-q13 and of these, 7 of 16 (44%) sporadic patients had mutations within the UBE3A gene. Lossie et al. (2001) identified 4 phenotypic patient groups based on molecular analysis: those with deletions, UPD and imprinting defects, UBE3A mutations, and those with unknown etiology. Patients with deletions were the most severely affected, while those with UPD and imprinting defects were the least severely affected. Patients with UPD and imprinting defects and UBE3A mutations were taller and heavier than those with deletions or of unknown etiology. Those with UPD and imprinting defects were the least likely to have microcephaly. Seizures began earlier in patients with deletions or AS of unknown etiology, and those with deletions were more likely to require anticonvulsive medication. Molfetta et al. (2004) reported 2 first cousins with AS who had inherited the same UBE3A frameshift mutation (601623.0010) from their asymptomatic mothers but presented discordant phenotypes. The proband had typical AS features, whereas her cousin had a more severe phenotype with asymmetric spasticity that originally led to the diagnosis of cerebral palsy. Brain MRI showed mild cerebral atrophy in the proband and severe malformation in her cousin. Because the mutation was transmitted from the cousins' grandfather to only 2 of 8 sibs, Molfetta et al. (2004) raised the possibility of mosaicism. Varela et al. (2004) analyzed the phenotypic and behavioral variability in 49 AS patients with different classes of deletions and 9 patients with UPD. All BP1-BP3 (class I) patients had complete absence of vocalization, compared to only 62% of BP2-BP3 (class II) patients (p = 0.03); and the age of sitting without support was lower in BP2-BP3 patients (p = 0.04). Patients with deletions had a higher incidence of swallowing disorders and hypotonia compared to UPD patients (p = 0.015 and 0.031, respectively). UPD patients also showed significantly better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia, and higher cognitive skills. Varela et al. (2004) suggested that because of their milder or less typical phenotype, AS patients with UPD may remain undiagnosed, leading to overall underdiagnosis of the disease. Tan et al. (2011) reported the clinical features of 92 patients with molecularly confirmed Angelman syndrome between the ages of 5 and 60 months. Class I (BP1-BP3) deletions were present in 32%, class II (BP2-BP3) deletions in 38%, other deletions in 4%, UPD/imprinting defects in 14%, and UBE3A mutations in 12%. Those with deletions were diagnosed significantly earlier (median age of 14 months) than those without deletions (median age of 24 months). Those with deletions, particularly class I deletions, weighed significantly less than the general population, and those with UPD/imprinting defects were significantly heavier than the general population. Twenty (22%) of all patients were underweight, all of whom had deletions or UBE3A mutations. Eight patients were obese, including 6 with UPD/imprinting defects and 2 with UBE3A mutations. Relative microcephaly was found in 80% of all patients and was most common in those with deletions. The most common behavioral findings were mouthing behavior (95%), short attention span (92%), ataxic or broad-based gait (88%), history of sleep difficulties (80%), and fascination with water (75%). Frequent, easily provoked laughter was observed in 60%. Clinical seizures were reported in only 65%, but all had an abnormal EEG. Seizures occurred in 83% of patients with a class I deletion. Those with deletions also had lower cognitive scales compared to patients without deletions. Tan et al. (2011) concluded that the most characteristic feature of AS is the neurobehavioral phenotype, but specific EEG findings are highly sensitive. The absence of seizures or of inappropriate laughter should not discourage consideration of this diagnosis. Animal Model Cattanach et al. (1992) described a putative mouse model of Prader-Willi syndrome, occurring with maternal duplication (partial maternal disomy) for the region of mouse chromosome 7 homologous to human 15q11-q13. Cattanach et al. (1997) showed that mice with paternal duplication for the same region exhibited characteristics of Angelman syndrome. An elevated frequency of postnatal loss was observed among the mice. Although of normal weight at birth, the mice exhibited a reduced growth rate over the first 4 to 5 weeks. Subsequently, however, their growth rate increased so that by early adulthood (8 weeks) their body weights were similar to those of their sibs. Animals kept to later ages continued to increase in weight and by 6 months they were grossly obese. Despite this, tail and femur lengths were significantly shorter than those of sibs, suggesting a smaller overall skeletal size. Most males proved to be fertile, but, perhaps because of the developing obesity, females were often infertile. Neurobehavioral differences were also suggested: at 10 to 14 days of age, the mice with the paternal duplication displayed a mild gait ataxia with slight eversion of the hindlimbs; at 16 to 18 days they showed abnormal limb clasping when suspended briefly by the tail and exhibited a startle reflex when dropped onto their feet from a height of about 10 cms; after weaning (3 to 16 weeks) they showed marked behavioral hyperactivity relative to their normal sibs in the open field testing. Neuropathologic examinations revealed that total brain weight was diminished by about 10%. Electrocorticographic recordings on paternally duplicated mice showed a striking diffuse cortical excitability disturbance that was identical in all animals. The gross obesity of a 6-month-old AS mouse was pictured. Cattanach et al. (1997) noted that both PWS and AS patients may exhibit hypopigmentation and early feeding difficulties, and that a late-onset obesity, rather than the early-onset obesity of PWS, may be seen in a subset of AS patients (Clayton-Smith, 1992; Smith et al., 1996). Jiang et al. (1998) generated transgenic mice with the maternal or paternal UBE3A genes knocked out and compared them with their wildtype (m+/p+) littermates. Mice with paternal deficiency (m+/p-) were essentially similar to wildtype mice. The phenotype of mice with maternal deficiency (m-/p+) resembles that of human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. The absence of detectable expression of UBE3a in hippocampal neurons and Purkinje cells in m-/p+ mice, indicating imprinting with silencing of the paternal allele, correlated well with the neurologic and cognitive impairments. Long-term potentiation in the hippocampus was severely impaired. The cytoplasmic abundance of p53 was found to be greatly increased in Purkinje cells and in a subset of hippocampal neurons in m-/p+ mice, as well as in a deceased AS patient. Jiang et al. (1998) suggested that failure of Ube3a to ubiquitinate target proteins and promote their degradation could be a key aspect of the pathogenesis of AS. Wu et al. (2008) determined that the Drosophila Dube3a gene is the counterpart of the human UBE3A gene. In normal flies, Dube3a showed ubiquitous and cytoplasmic expression in the central nervous system starting early in embryogenesis. Expression of Dube3a was enriched in the adult mushroom body, the seat of learning and memory. Dube3a-null flies appeared normal externally but showed abnormal locomotive behavior and circadian rhythms and defective long-term memory. Mutant flies that overexpressed Dube3a in the nervous system also showed locomotion defects, as well as aberrant eye and wing morphology. The locomotion defects in flies with both null and overexpression of Dube3a were dependent on ubiquitin ligase activity. Introduction of missense UBE3A mutations into Dube3a behaved as loss-of-function mutations. Wu et al. (2008) stated that the simplest model for Angelman syndrome suggests that in the absence of UBE3A, particular substrates fail to be ubiquitinated and proteasomally degraded, accumulate in the brain, and interfere with brain function. Huang et al. (2012) used an unbiased, high-content screen in primary cortical neurons from mice, to identify 12 topoisomerase I (126420) inhibitors and 4 topoisomerase II (see 126430) inhibitors that unsilence the paternal Ube3a allele. These drugs included topotecan, irinotecan, etoposide, and dexrazoxane. At nanomolar concentrations, topotecan upregulated catalytically active UBE3A in neurons from maternal Ube3a-null mice. Topotecan concomitantly downregulated expression of the Ube3a antisense transcript (Ube3aats) that overlaps the paternal copy of Ube3a. These results indicated that topotecan unsilences Ube3a in cis by reducing transcription of an imprinted antisense RNA. When administered in vivo, topotecan unsilenced the paternal Ube3a allele in several regions of the nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum, and spinal cord. Paternal expression of Ube3a remained elevated in a subset of spinal cord neurons for at least 12 weeks after cessation of topotecan treatment, indicating that transient topoisomerase inhibition can have enduring effects on gene expression. Huang et al. (2012) concluded that, although potential off-target effects remain to be investigated, their findings suggested a therapeutic strategy for reactivating the functional but dormant allele of Ube3a in patients with Angelman syndrome. INHERITANCE \- Autosomal dominant (loss of maternal allele) GROWTH Weight \- Obesity (older children) HEAD & NECK Head \- Microcephaly, postnatal \- Brachycephaly \- Flat occiput \- Occipital groove Face \- Prognathia Eyes \- Strabismus, most frequently exotropia \- Ocular hypopigmentation \- Refractive errors (astigmatism, hyperopia, myopia) Mouth \- Protruding tongue \- Macrostomia \- Excessive drooling Teeth \- Widely spaced teeth ABDOMEN Gastrointestinal \- Feeding difficulties in neonatal period \- Excessive chewing/mouthing behaviors \- Abnormal food-related behaviors \- Constipation SKELETAL Spine \- Scoliosis SKIN, NAILS, & HAIR Skin \- Hypopigmentation (seen only in deletion cases) NEUROLOGIC Central Nervous System \- Developmental delay \- Severe mental retardation \- Absent speech \- Ataxia with jerky arm movements \- Wide-based gait \- Clumsiness, unsteadiness \- Tremor of limbs \- Hypotonia \- Seizures \- Hyperreflexia \- Characteristic arm position with wrist and elbow flexion \- Abnormal sleep-wake cycles \- Decreased need for sleep \- Characteristic electroencephalogram (EEG) discharges \- Mild cortical atrophy on CT or MRI Behavioral Psychiatric Manifestations \- Paroxysmal laughter \- Easily excitable \- Attraction to/fascination with water, crinkly items (paper, plastic) MISCELLANEOUS \- Imprinted disorder \- Onset between 6 and 12 months of age \- Increased sensitivity to heat \- Incidence of 1 in 10,000 to 1 in 20,000 \- 70% due to de novo maternal deletion of 15q11.2-q13 \- 2% due to paternal uniparental disomy of 15q11.2-q13 \- 2-3% due to imprinting defects \- 25% due to mutations in UBE3A ( 601623 ) MOLECULAR BASIS \- Caused by mutation in the ubiquitin protein ligase E3A gene (UBE3A, 601623.0001 ) ▲ 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	ANGELMAN SYNDROME	c0162635	1,169	omim	https://www.omim.org/entry/105830	2019-09-22T16:45:10	{"doid": ["1932"], "mesh": ["D017204"], "omim": ["105830"], "icd-10": ["Q93.51"], "orphanet": ["72"], "synonyms": ["Alternative titles", "HAPPY PUPPET SYNDROME, FORMERLY"], "genereviews": ["NBK1144"]}
A number sign (#) is used with this entry because vitelliform macular dystrophy-2 (VMD2), also known as Best disease, is caused by heterozygous mutation in the bestrophin gene (BEST1; 607854) on chromosome 11q12. Description Best vitelliform macular dystrophy is an early-onset autosomal dominant disorder characterized by large deposits of lipofuscin-like material in the subretinal space, which creates characteristic macular lesions resembling the yolk of an egg ('vitelliform'). Although the diagnosis of Best disease is often made during the childhood years, it is more frequently made much later and into the sixth decade of life. In addition, the typical egg yolk-like lesion is present only during a limited period in the natural evolution of the disease; later, the affected area becomes deeply and irregularly pigmented and a process called 'scrambling the egg' occurs, at which point the lesion may appear as a 'bull's eye.' The disorder is progressive and loss of vision may occur. A defining characteristic of Best disease is a light peak/dark trough ratio of the electrooculogram (EOG) of less than 1.5, without aberrations in the clinical electroretinogram (ERG). Even otherwise asymptomatic carriers of BEST1 mutations, as assessed by pedigree, will exhibit an altered EOG. Histopathologically, the disease has been shown to manifest as a generalized retinal pigment epithelium (RPE) abnormality associated with excessive lipofuscin accumulation, regions of geographic RPE atrophy, and deposition of abnormal fibrillar material beneath the RPE, similar to drusen. Occasional breaks in the Bruch membrane with accompanying neovascularization have also been reported, although Best disease is not noted for extensive choroidal neovascularization. Many of these features are also found in age-related macular degeneration (see 603075) (summary by Braley, 1966; White et al., 2000; Marmorstein et al., 2000; Leroy, 2012). For a discussion of genetic heterogeneity of vitelliform macular dystrophy, see VMD1 (153840). Clinical Features Best (1905) described a family in which 8 persons were affected with hereditary vitelliform macular dystrophy. Follow-up of this family by Vossius (1921) and Jung (1936) increased the number of affected individuals to 22. Friedenwald and Maumenee (1951) observed affected mother and daughter. Davis and Hollenhorst (1955) described a kindred containing at least 24 affected persons in 5 generations. The age of onset of manifest visual disability varied from very early childhood to adolescence. Cystoid macular degeneration was described in a dominant pedigree pattern by Falls (1949) and Sorsby et al. (1956). Vail and Shoch (1965) followed up on an extensively affected kindred and reported histologic findings in a patient who died at 78 years of age. Braley and Spivey (1964) examined 27 members of a large 4-generation Iowa family of Dutch ancestry, 10 of whom had vitelline macular degeneration. Onset of disease was before age 10 years in 3 cases, before age 20 in 3, before age 30 in 3, and in the early 30s in 2. At least 4 patients had sudden onset of visual loss that improved to some degree. Good visual acuity was present in some patients despite severe macular changes. In every patient with visual loss, a central scotoma was present that conformed to the position and size of the macular lesion. Dark adaptation was normal in all family members; color vision was normal in all unaffected family members, whereas most affected family members showed red-green deficiency. Braley and Spivey (1964) noted that not all patients exhibit the classic 'sunny side up' vitelliform lesion as the initial stage of macular degeneration. In Sweden, Nordstrom and Barkman (1977) and Nordstrom and Thorburn (1980) traced 250 cases of Best disease to one gene source in the 17th century. An apparently homozygous father had 11 children, all of whom were affected. Age of onset varied from early childhood to the 40s and 50s. The electrooculogram (EOG) was helpful in preclinical detection. The range of severity was wide among the 11; indeed, one, aged 24, could be identified only by pathologic EOGs. The homozygotic state did not differ from the heterozygotic state. O'Gorman et al. (1988) described the histopathologic findings in the postmortem eyes of a 69-year-old man with this disorder. Retinal pigment epithelial (RPE) cells across the entire fundus had accumulated an excessive amount of lipofuscin as defined by ultrastructural appearance, autofluorescence, and staining properties. An accumulation of heterogeneous material located between Bruch membrane and the pigment epithelium in the fovea was interpreted as representing a previtelliform lesion. The material appeared to be derived from degenerating pigment epithelial cells and contained few intact lipofuscin granules. Foveal photoreceptor loss occurred above the lesion. Brecher and Bird (1990) investigated the families of 12 probands who presented with foveal lesions typical of adult vitelliform macular dystrophy and found familial involvement compatible with autosomal dominant inheritance in 10 families. In the remaining 2 families, no familial involvement was detected, but both parents were not available for examination. Over half (14 of 25) of patients with abnormal fundi were asymptomatic, and most had good visual acuity, although 2 patients had visual acuities of less than 20/60 in both eyes. Weber et al. (1994) identified a 37-year-old male who appeared to represent nonpenetrance of Best disease because he had inherited the haplotype associated in his family with the disorder, but showed no signs of the disease on repeated examination and EOG. By optical coherence tomography (OCT) in a case of BMD, Vedantham and Ramasamy (2005) found that lipofuscin accumulated in a cystic space under the retinal pigment epithelium in the 'pseudohypopyon' stage of the disease, and that disruption of photoreceptors occurred in the 'scrambled egg' stage. The authors suggested that these findings explain the retention of good visual acuity in the pseudohypopyon stage and the loss of visual acuity in the scrambled egg stage. Using indocyanine green angiography (ICG), Maruko et al. (2006) observed hyperfluorescent spots throughout the peripheral fundus in all 8 eyes of 4 patients with Best disease. The extensive distribution of the spots was consistent with the wide-ranging abnormalities of the retinal pigment epithelium, Bruch membrane, and choroid that have been observed histopathologically. In an eye from a Best disease donor with a T6R mutation in the BEST1 gene, Mullins et al. (2007) found deposits containing lipid and glycoconjugates within the eye's central retinal scar. Immunohistochemical localization of bestrophin in a series of 22 unaffected eyes revealed a pattern in which macular labeling was less robust than labeling outside the macular area in 18 of the 22. Mullins et al. (2007) concluded that topographic differences in the levels of bestrophin protein might in part explain the propensity for the macula to develop lesions. ### Clinical Variability Mullins et al. (2005) restudied a male patient from the Iowa family of Dutch ancestry originally reported by Braley and Spivey (1964), in which a missense mutation in the BEST1 gene (607854.0004) was identified by Petrukhin et al. (1998). The patient had photographically documented normal maculae at age 51 years, but subsequently developed small vitelliform lesions at age 75 years, followed by widespread flecks in the midperiphery; 2 additional family members exhibited similar multifocal lesions. Histologic examination showed that the flecks represented clusters of vesicular drusen that were less eosinophilic than typical drusen but were otherwise of similar composition. Mullins et al. (2005) noted that vitelliform lesions had been documented to develop as late as 60 years of age in a patient with classic Best disease (Sorr and Goldberg, 1976), and that midperipheral flecks, while uncommon, may be present. Review of 77 consecutive photofiles of patients with a clinical and molecular diagnosis of Best disease revealed 7 patients (9.1%) from 3 unrelated families who also exhibited multifocal lesions consisting of small peripheral flecks. Boon et al. (2007) studied 15 unrelated patients with multifocal vitelliform lesions. Age at onset was highly variable, ranging from 5 to 59 years. The peripheral lesions varied in number, size, and overall appearance, but showed similar characteristics on autofluorescence imaging and OCT compared with the central vitelliform lesion. Lee et al. (2012) studied 2 unrelated, initially asymptomatic male patients who exhibited incidentally discovered bilateral macular atrophic lesions at age 30 years and 51 years, respectively, with serous retinal detachment in the macula on OCT and multiple leakages around the central hypofluorescent area as well as partially dilated choroidal vessels on fluorescein angiography. The lesions were thought to represent chronic central serous chorioretinopathy but were unresponsive to treatment. Reevaluation revealed yellowish deposits at the border of serous retinal detachment areas; OCT showed hyperreflective lesions between the RPE and outer segment layers of the retina, and fundus autofluorescence (FAF) showed ring-like hyperautofluorescence around the serous retinal detachment. Both patients also had decreased Arden ratios on EOG and were found to have mutations in the BEST1 gene, resulting in a diagnosis of atypical vitelliform macular dystrophy. Parodi et al. (2014) studied the fundus autofluorescence patterns in the eyes of 4 patients with a bilateral subclinical form of Best disease (positive testing for BEST1 gene mutation, fully preserved best-corrected visual acuity, normal fundus appearance) and the clinically unaffected eyes of 2 patients with unilateral Best disease. Short-wavelength FAF findings were consistently normal, whereas near-infrared FAF showed an abnormal pattern marked by a central hypoautofluorescence surrounded by a round area of hyperautofluorescence. Microperimetry corroborated the near-infrared FAF pattern. No changes were found in a 24- to 36-month follow-up of the patients. Mapping Definitive mapping of the locus for Best macular dystrophy was achieved by Stone et al. (1992), who studied a 5-generation family with 29 affected persons. Linkage analysis located the gene on chromosome 11q13. Multipoint analysis yielded a maximum lod score of 9.3 for location in the interval between INT2 (FGF3; 164950) and D11S871. Using 8 microsatellite markers, Weber et al. (1994) studied 3 multigenerational Best disease families and refined the localization of the disease gene to a 3.7-cM interval between markers at D11S903 and PYGM (608455). PCR-hybrid mapping sublocalized this interval to the pericentromeric region of chromosome 11. Identification of 3 distinct haplotypes associated with the disease in the 3 families strongly suggested independent origins of the mutations. In a large Swedish family with more than 250 cases of Best macular dystrophy (see Nordstrom and Barkman, 1977), descended from a couple born in central Sweden in the 17th century, Forsman et al. (1992) obtained a lod score of 15.12 at a recombination fraction 0.01 for linkage with an INT2 marker on chromosome 11q13. Thus, the gene for rod outer segment protein-1 (ROM1; 180721), which maps to the same region, became the leading candidate for the site of the mutation in this disorder. Stone et al. (1992) likewise demonstrated genetic linkage of Best disease to 11q13, and Bascom et al. (1992) presented evidence that the ROM1 gene may be the site of the mutation in Best disease. Using highly polymorphic markers, Nichols et al. (1994) narrowed the genetic region that contains the Best disease gene to the 10-cM region between markers D11S871 and PYGM. Marker D11S956 demonstrated no recombinants with Best disease in 3 large kindreds and resulted in a lod score of 18.2. Using a combination of single-strand conformation polymorphism (SSCP) analysis, denaturing gradient gel electrophoresis, and DNA sequencing to screen the entire coding region of the ROM1 gene in 11 different unrelated patients with Best disease, Nichols et al. (1994) could find no nucleotide changes in the coding sequence of any affected patient. They concluded that mutations within the coding sequence of ROM1 are unlikely to cause Best disease. Graff et al. (1994) localized the VMD2 locus to the 6-cM genetic interval between 2 DNA markers, one of which was associated with ROM1 in a large Swedish 12-generation kindred. Mutation analyses of ROM1 revealed no mutations that could explain the disease phenotype. Furthermore, one recombinant event between intragenic ROM1 polymorphisms and the Best disease phenotype was detected. Thus, ROM1 was excluded as the site of the disease-causing mutations in this kindred. Coding sequence mutations in ROM1 were also excluded by Hou et al. (1996) in 2 affected members of a large 5-generation North American pedigree with Best macular degeneration mapping to 11q. By studying the large Swedish VMD2 family dating back to the 17th century (Nordstrom and Barkman, 1977), Graff et al. (1997) refined the VMD2 region to a span of approximately 980 kb flanked by D11S4076 and uteroglobin (UGB; 192020). Stohr et al. (1998), who gave the location of the VMD2 gene as a region of approximately 1.4 Mb on 11q12-q13.1, assembled a high-coverage YAC contig of this region. They constructed a primary transcript map that placed 19 genes within the region. ### Genetic Heterogeneity Mansergh et al. (1995) established genetic heterogeneity in this disorder by finding linkage to chromosome 11 in an Irish family and excluding linkage to chromosome 11 in a German family. Diagnosis Chacon-Camacho et al. (2011) performed optical coherence tomography (OCT) in symptomatic and asymptomatic individuals from 2 Mexican families segregating Best disease caused by mutation in the BEST1 gene. Symptomatic patients showed severe retinal serous retinal detachment in both families. In 1 family, an 8-year-old carrying a Q293K mutation was demonstrated to have Best disease-related retinal lesions, i.e., bilateral subfoveal lesions and unilateral serous retinal detachment. Conversely, in the other family, an asymptomatic 6-year-old carrying a W24C mutation did not demonstrate retinal abnormalities. Chacon-Camacho et al. (2011) suggested that OCT can be used during early childhood for presymptomatic diagnosis of some cases of the disease. Molecular Genetics In several Swedish and Dutch families with Best macular dystrophy, including the large Swedish family reported by Nordstrom and Barkman (1977) and studied by Graff et al. (1997), and the Iowa family of Dutch ancestry originally reported by Braley and Spivey (1964), Petrukhin et al. (1998) identified 5 different mutations in the VMD2 gene (607854.0001-607854.0005) that segregated with the disease. Caldwell et al. (1999) analyzed the bestrophin gene in 13 families with Best macular dystrophy and identified heterozygous mutations in 9 families, including 6 missense mutations and a 2-bp deletion (607854.0012). In 3 of the families, there was a parent carrying the missense mutation who lacked the clinical phenotype, suggesting variable expression of the disease gene. Caldwell et al. (1999) found no mutations in the bestrophin gene in the large North American family with Best macular dystrophy previously mapped to chromosome 11q by Hou et al. (1996). In 2 unrelated women who had vitelliform macular dystrophy diagnosed in the sixth decade of life, Allikmets et al. (1999) identified heterozygous missense mutations in the BEST1 gene (E119Q, 607854.0008 and A146K 607854.0009). Kramer et al. (2000) identified several mutations in the VMD2 gene in German patients with macular dystrophy of juvenile and adult onset (see, e.g., 607854.0005 and 607854.0010-607854.0011) and suggested that the adult-onset patients represented a mild form of Best disease. White et al. (2000) stated that 48 different mutations, predominantly missense mutations, had been described in the VMD2 gene in Best disease families. Schatz et al. (2006) identified mutations in the BEST1 gene in all 6 affected members of a 3-generation Swedish family with Best macular dystrophy. One was heterozygous for an arg141-to-his (R141H; 607854.0013) mutation, 3 were heterozygous for a tyr29-to-ter (Y29X; 607854.0014) mutation, and 2 were compound heterozygous for these mutations. The 2 members who were compound heterozygous had a more severe phenotype. In 9 (60%) of 15 unrelated patients with multifocal vitelliform lesions, Boon et al. (2007) identified heterozygosity for mutations in the BEST1 gene (see, e.g., 607854.0005). In a 15-year-old proband with multifocal VMD, Wittstrom et al. (2011) identified compound heterozygosity for 2 mutations in the BEST1 gene: the R141H mutation and a de novo P233A substitution. The R141H mutation was present in heterozygosity in her asymptomatic mother and brother, both of whom showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses. Genotype/Phenotype Correlations Boon et al. (2007) compared the clinical findings in patients with multifocal vitelliform retinal dystrophy with or without mutations in the BEST1 gene. All 9 patients with BEST1 mutations had abnormal EOG findings compared with 2 of 6 patients without BEST1 mutations; in addition, those with a mutation had a highly variable but seemingly younger age at onset and a more pronounced loss of visual acuity. Meunier et al. (2014) reviewed 76 families with vitelliform macular dystrophy and found that 24 (53%) of 45 families with onset of disease before 40 years of age had a mutation in the BEST1 gene, whereas 3 (9.7%) of 31 families with onset after 40 years of age had a mutation in the PRPH2 gene (179605). For the remaining 49 families without a mutation in BEST1 or PRPH2, 3 (6%) had a mutation in the IMPG1 gene and 1 (2%) in the IMPG2 gene (607056). Meunier et al. (2014) stated that the IMPG1 and IMPG2 vitelliform macular dystrophies are characterized by late-onset moderate visual impairment, frequent association with drusen-like lesions, preservation of RPE reflectivity, lack of sub-RPE deposits on spectral-domain optical coherence tomography (SD-OCT), and normal or borderline results on EOG. The authors noted that although patients with a BEST1 mutation were most frequently symptomatic before the age of 40 years, there was overlap with PRPH2 patients in terms of age of onset; in addition, the presence of small satellite drusen-like lesions in the foveal area appeared to implicate the IMPG1 or IMPG2 genes. Animal Model In dogs with canine multifocal retinopathy (cmr), which resembles human Best disease, Guziewicz et al. (2007) identified 2 disease-specific sequence alterations in the VMD2 gene: a 73C-T stop mutation (R25X), designated cmr1, and a 482G-A missense mutation (G161D), designated cmr2. Guziewicz et al. (2007) proposed that canine cmr is a relevant animal model for Best disease. Zhang et al. (2010) generated knockin mice carrying the Best vitelliform macular dystrophy-causing mutation W93C (607854.0001) in Best1. Both Best1(+/W93C) and Best1(W93C/W93C) mice had normal ERG a- and b-waves, but exhibited an altered light peak luminance response reminiscent of that observed in Best macular dystrophy patients. Morphologic analysis identified fluid- and debris-filled retinal detachments in mice as young as 6 months of age. By 18 to 24 months of age, Best1(+/W93C) and Best1(W93C/W93C) mice exhibited enhanced accumulation of lipofuscin in the retinal pigment epithelium (RPE), and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. The RPE cells from Best1(W93C) mice exhibited normal chloride conductances, and ATP-stimulated changes in calcium concentration in RPE cells from Best1(+/W93C) and Best1(W93C/W93C) mice were suppressed relative to Best1 +/+ littermates. The authors hypothesized that Best vitelliform macular dystrophy does not occur because of Best1 deficiency, as the phenotypes of Best1(+/W93C0) and Best1(W93C/W93C) mice are distinct from that of Best1 -/- mice with regard to lipofuscin accumulation and changes in the light peak and ATP calcium responses. History Rivas et al. (1986) proposed that the segment 6q25-qter contained the locus for a dominant macular degeneration. This proposal was based on the finding of macular degeneration in an 8-month-old girl with a de novo deletion of 6q25 and in another case of terminal deletion of 6q reported by Hagemeijer et al. (1977). In linkage studies in 9 kindreds, Yoder et al. (1988) found no firm evidence for linkage with 18 informative markers; the highest positive lod score was 0.57 for glutamate-pyruvate transaminase (GPT; 138200) on chromosome 8q24 at a recombination fraction of 0.30. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Decreased visual acuity \- Vitelliform ('egg-yolk') deposits, macular or multifocal \- Abnormal accumulation of lipofuscin within and beneath the retinal Pigment epithelium (RPE) on optical coherence tomography (OCT) \- Thickening and elevation of the outer retina-RPE-choroid complex on OCT \- Intraretinal and subretinal fluid in cystic spaces with splitting of retina on OCT \- Normal or reduced responses on electroretinography \- Low Arden ratio on electrooculography MISCELLANEOUS \- Variable age of onset, from early childhood to seventh decade of life \- Some patients with vitelliform macular dystrophy are homozygous or compound heterozygous for mutations in BEST1, with their heterozygous relatives showing milder forms of eye disease MOLECULAR BASIS \- Caused by mutation in the bestrophin-1 gene (BEST1, 607854.0001 ) ▲ 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	MACULAR DYSTROPHY, VITELLIFORM, 2	c0339510	1,170	omim	https://www.omim.org/entry/153700	2019-09-22T16:38:44	{"doid": ["0050661"], "mesh": ["D057826"], "omim": ["153700"], "orphanet": ["1243"], "synonyms": ["Alternative titles", "VITELLIFORM MACULAR DYSTROPHY, EARLY-ONSET", "VITELLIFORM MACULAR DYSTROPHY, JUVENILE-ONSET", "BEST MACULAR DYSTROPHY", "MACULAR DEGENERATION, POLYMORPHIC VITELLINE", "BEST VITELLIFORM MACULAR DYSTROPHY, MULTIFOCAL"], "genereviews": ["NBK1167"]}
Cyclosporiasis Other namescyclosporosis Cyclospora cayetanensis SpecialtyInfectious disease Cyclosporiasis is a disease caused by infection with Cyclospora cayetanensis, a pathogenic protozoan transmitted by feces or feces-contaminated food and water.[1] Outbreaks have been reported due to contaminated fruits and vegetables. It is not spread from person to person, but can be a hazard for travelers as a cause of diarrhea. ## Contents * 1 Cause * 2 Diagnosis * 3 Prevention * 4 Treatment * 5 Epidemiology * 5.1 Cyclosporiasis in AIDS patients * 6 Outbreaks * 7 References * 8 External links ## Cause[edit] Cyclosporiasis primarily affects humans and other primates. When an oocyst of Cyclospora cayetanensis enters the small intestine, it invades the mucosa, where it incubates for about one week. After incubation, the infected person begins to experience severe watery diarrhea, bloating, fever, stomach cramps, and muscle aches. The parasite particularly affects the jejunum of the small intestine. Of nine patients in Nepal who were diagnosed with cyclosporiasis, all had inflammation of the lamina propria along with an increase of plasma in the lamina propria. Oocysts were also observed in duodenal aspirates.[2] Oocysts are often present in the environment as a result of using contaminated water or human feces as fertilizer. ## Diagnosis[edit] Diagnosis can be difficult due to the lack of recognizable oocysts in the feces. PCR-based DNA tests and acid-fast staining can help with identification. ## Prevention[edit] There is no vaccine to prevent cyclosporiasis in humans at present, but one is available for reduction of fetal losses in sheep. ## Treatment[edit] The infection is often treated with trimethoprim/sulfamethoxazole, also known as Bactrim or co-trimoxazole, because traditional anti-protozoal drugs are not sufficient. To prevent transmission, food should be cooked thoroughly and drinking water from streams should be avoided. ## Epidemiology[edit] The first recorded cases of cyclosporiasis in humans were as recent as 1977, 1978, and 1979. They were reported by Ashford, a British parasitologist who discovered three cases while working in Papua New Guinea. Ashford found that the parasite had very late sporulation, from 8–11 days, making the illness difficult to diagnose. When examining feces, the unsporulated oocysts can easily be mistaken for fungal spores, and thus can be easily overlooked.[3] In 2007, Indian researchers published a case report that found an association between Cyclospora infection and Bell's palsy. This was the first reported case of Bell’s palsy following chronic Cyclospora infection.[4] In addition to other extra-intestinal reports, cyclosporiasis might be involved in either reversible neuronal damage or other unknown mechanisms to lead to Guillain-Barré syndrome or Bell's palsy. In 2010, a report of Cyclospora transmission via swimming in the Kathmandu Valley was published in the Journal of Institute of Medicine.[5] The researchers found that openly defecated human stool samples around the swimmer's living quarters and near the swimming pool were positive for Cyclospora. However, they did not find the parasite in dog stool, bird stool, cattle dung, vegetable samples, or water samples. They concluded that pool water contaminated via environmental pollution might have caused the infection, as the parasite can resist chlorination in water.[6] Cyclosporiasis infections have been well reported in Nepal. In one study, Tirth Raj Ghimire, Purna Nath Mishra, and Jeevan Bahadur Sherchan collected samples of vegetables, sewage, and water from ponds, rivers, wells, and municipal taps in the Kathmandu Valley from 2002 to 2004.[7] They found Cyclospora in radish, cauliflower, cabbage, and mustard leaves, as well as sewage and river water. This first epidemiological study determined the seasonal character of cyclosporiasis outbreaks in Nepal during the rainy season, from May to September.[8] ### Cyclosporiasis in AIDS patients[edit] At the beginning of the AIDS epidemic in the early 1980s, cyclosporiasis was identified as one of the most important opportunistic infections among AIDS patients.[9] In 2005, Ghimire and Mishra reported a case of cyclosporiasis in a patient with low hemoglobin and suggested that this coccidian might be involved in reducing hemoglobin due to lack of immune system.[10] In 2006, their groups published a paper about the role of cyclosporiasis in HIV/AIDS patients and non-HIV/AIDS patients in the Kathmandu Valley.[11] In 2008, Indian researchers published a report about the epidemiology of Cyclospora in HIV/AIDS patients in Kathmandu.[12] They examined samples of soil, river water, sewage, chicken stool, dog stool, and stool in the streets, and found them positive for Cyclospora. They also evaluated several risk factors for cyclosporiasis in AIDS patients.[12] ## Outbreaks[edit] Although it was initially thought that Cyclospora was confined to tropical and subtropical regions, occurrences of cyclosporiasis are becoming more frequent in North America. According to the Centers for Disease Control and Prevention, there have been 11 documented cyclosporiasis outbreaks in the U.S. and Canada since the 1990s. The CDC also recorded 1,110 laboratory-confirmed sporadic instances of cyclosporiasis.[13] Between June and August 2013, multiple independent outbreaks of the disease in the U.S. sickened at least 631 people across 25 states.[14][15] Investigations later identified a bagged salad mixture as the cause of an outbreak in Iowa and Nebraska.[16] In 2015, the CDC was notified of 546 persons with confirmed cyclosporiasis infection across 31 states. Cluster investigations in Texas, where the greatest number of infections was reported, indicated that contaminated cilantro was the culprit.[17] During July 21–August 8, 2017, the Texas Department of State Health Services (DSHS) was notified of 20 cases of cyclosporiasis among persons who dined at a Mediterranean-style restaurant chain (chain A) in the Houston area.[18] On July 31, 2018, the United States Department of Agriculture (USDA) issued a public health alert for certain beef, pork and poultry salad and wrap products potentially contaminated with Cyclospora.[19] The contamination came from the chopped romaine lettuce used in these products. In June 2020, the CDC and other regulatory bodies began investigating an outbreak of Cyclosporiasis in the Midwestern United States linked to bagged salad mix.[20] On June 27, 2020, Fresh Express announced a voluntary recall of over 91 Fresh Express and private label salad products.[21] ## References[edit] 1. ^ Talaro, Kathleen P., and Arthur Talaro. Foundations in Microbiology: Basic Principles. Dubuque, Iowa: McGraw-Hill, 2002. 2. ^ Sanchez, Roxana; Ortega, Ynés R. (2005-10-26). "Update on Cyclospora cayetanensis, a Food-Borne and Waterborne Parasite \| Clinical Microbiology Reviews". Clinical Microbiology Reviews. Cmr.asm.org. 23 (1): 218–234. doi:10.1128/CMR.00026-09. PMC 2806662. PMID 20065331. Retrieved 2019-08-21. 3. ^ Strausbaugh, Larry (1 October 2000). "Cyclospora cayetanensis: A Review, Focusing on the Outbreaks of Cyclosporiasis in the 1990s". Infectious Disease Society of America. 31 (4): 1040–57. doi:10.1086/314051. PMID 11049789. 4. ^ Ghimire TR, Mishra PN, Sherchand JB, Ghimire LV: Bell’s Palsy and Cyclosporiasis: Causal or Coincidence? Nepal Journal of Neuroscience 4:86- 88, 2007. http://neuroscience.org.np/neuro/issues/uploads/abstract_K3M0aH6IUP.pdf 5. ^ T. R. Ghimire, L.V. Ghimire, R.K. Shahu, P.N. Mishra (April 2010). "Cryptosporidium and Cyclospora infection transmission by swimming". Journal of Institute of Medicine. 32 (1). Retrieved 2019-08-21.CS1 maint: uses authors parameter (link) 6. ^ Ghimire TR, Ghimire LV, Shahu RK, Mishra PN. Cryptosporidium and Cyclospora infection transmission by swimming. Journal of Institute of Medicine. 2010; 32 (1): 43–45.https://www.nepjol.info/index.php/JIOM/article/download/4003/3392 7. ^ Ghimire TR, Mishra PN, Sherchand JB. The seasonal outbreaks of Cyclospora and Cryptosporidium in Kathmandu, Nepal. Journal of Nepal Health Research Council. 2005; 3(1): 39–48.http://jnhrc.com.np/index.php/jnhrc/article/view/99/96 8. ^ Ghimire TR, Mishra PN, Sherchand JB. The seasonal outbreaks of Cyclospora and Cryptosporidium in Kathmandu, Nepal. Journal of Nepal Health Research Council. 2005; 3(1): 39–48. http://jnhrc.com.np/index.php/jnhrc/article/view/99/96 9. ^ Ortega YR, Sanchez R. Update on Cyclospora cayetanensis, a Food-Borne and Waterborne Parasite. Clinical Microbiology Reviews 2010 23(1): 218-234. http://cmr.asm.org/content/23/1/218.full" 10. ^ Ghimire TR, Mishra PN. Intestinal parasites and Haemoglobin concentration in the people of two different areas of Nepal. Journal of Nepal Health Research Council. 2005; 3(2): 1–7.http://jnhrc.com.np/index.php/jnhrc/article/view/103/100 11. ^ Ghimire TR, Mishra PN. Intestinal parasites in the Human Immunodeficiency Virus Infected Patients in Kathmandu, Nepal. The Nepalese Journal of Zoology. 2006; 1(1): 9–19. 12. ^ a b Ghimire TR, Mishra PN, Sherchan JB. Epidemiology of Cyclospora cayetanensis and other intestinal parasites in the HIV infected patients in Kathmandu, Nepal. Journal of Nepal Health Research Council. 2008; 6(12): 28–37.https://www.nepjol.info/index.php/JNHRC/article/download/2441/2177 13. ^ "Surveillance for Laboratory-Confirmed Sporadic Cases of Cyclosporiasis --- United States, 1997--2008". cdc.gov. 14. ^ "Case Count Maps - Outbreak Investigations 2013 - Cyclosporiasis - CDC". cdc.gov. 2019-04-12. 15. ^ "CDC: 425 cases of cyclospora infection identified across 16 states". cbsnews.com. 5 August 2013. 16. ^ http://www.idph.state.ia.us/IDPHChannelsService/file.ashx?file=2721EA4A-DB6B-4746-9FF4-0BF09C9BF3BE Archived 2016-03-04 at the Wayback Machine Iowa Cyclospora Outbreak 2013 /Outbreak Update 7.31.13, Iowa State Department of Public Health. Downloaded 6 Aug 2013. 17. ^ "Outbreak Investigations 2015 \| Cyclosporiasis \| CDC". Cdc.gov. 2019-04-12. Retrieved 2019-08-21. 18. ^ Keaton, A. A.; Hall, N. B.; Chancey, R. J.; Heines, V.; Cantu, V.; Vakil, V.; Long, S.; Short, K.; Franciscus, E.; Wahab, N.; Haynie, A.; Gieraltowski, L.; Straily, A. (2018-06-01). "Notes from the Field: Cyclosporiasis Cases Associated with Dining at a Mediterranean-Style Restaurant Chain — Texas, 2017 \| MMWR". MMWR. Morbidity and Mortality Weekly Report. Cdc.gov. 67 (21): 609–610. doi:10.15585/mmwr.mm6721a5. PMC 6038903. PMID 29851947. 19. ^ "FSIS Issues Public Health Alert for Beef, Pork and Poultry Salad and Wrap Products due to Concerns about Contamination with Cyclospora". usda.gov. 31 July 2018. 20. ^ "Cyclosporiasis Outbreak Investigations — United States, 2020". www.cdc.gov. 2020-06-26. Retrieved 2020-06-27. 21. ^ https://www.foodpoisoningnews.com/update-new-bagged-salad-products-linked-to-cyclospora-outbreak/ ## External links[edit] Classification D * ICD-10: A07.8 * ICD-10-CM: A07.4 * ICD-9-CM: 007.5 * MeSH: D021866 * DiseasesDB: 32228 * SNOMED CT: 240372001 External resources * eMedicine: article/996978 * Patient UK: Cyclosporiasis * Cyclosporiasis at Centers for Disease Control & Prevention * Cyclospora Infection at MayoClinic.com * v * t * e Protozoan infection: SAR and Archaeplastida SAR Alveolate Apicomplexa Conoidasida/ Coccidia * Coccidia: Cryptosporidium hominis/Cryptosporidium parvum * Cryptosporidiosis * Cystoisospora belli * Isosporiasis * Cyclospora cayetanensis * Cyclosporiasis * Toxoplasma gondii * Toxoplasmosis Aconoidasida * Plasmodium falciparum/vivax/ovale/malariae/knowlesi * Malaria * Blackwater fever * Babesia * Babesiosis Ciliophora * Balantidium coli * Balantidiasis Heterokont * Blastocystis * Blastocystosis * Pythium insidiosum * Pythiosis Archaeplastida * Algaemia: Prototheca wickerhamii * Protothecosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Cyclosporiasis	c0343398	1,171	wikipedia	https://en.wikipedia.org/wiki/Cyclosporiasis	2021-01-18T18:47:38	{"gard": ["9528"], "mesh": ["D021866"], "umls": ["C0343398"], "orphanet": ["210"], "wikidata": ["Q3008595"]}
Dihydropteridine reductase deficiency (DHPR) is a severe form of hyperphenylalaninemia (high levels of the amino acid phenylalanine in the blood) due to impaired renewal of a substance known as tetrahydrobiopterin (BH4). Tetrahydrobiopterin normally helps process several amino acids, including phenylalanine, and it is also involved in the production of neurotransmitters. If little or no tetrahydrobiopterin is available to help process phenylalanine, this amino acid can build up in the blood and other tissues and the levels of neurotransmitters (dopamine, serotonin) and folate in cerebrospinal fluid are also decreased. This results in neurological symptoms such as psychomotor delay, low muscle tone (hypotonia), seizures, abnormal movements, too much salivation, and swallowing difficulties. DHPR deficiency is caused by mutations in the QDPR gene. It is inherited in an autosomal recessive manner. Treatment should be started as soon as possible and includes BH4 supplementation usually combined with a diet without phenylalanine, folate supplementation, and specific medications to restore the levels of neurotransmitters in the brain. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Dihydropteridine reductase deficiency	c0268465	1,172	gard	https://rarediseases.info.nih.gov/diseases/4319/dihydropteridine-reductase-deficiency	2021-01-18T18:00:51	{"mesh": ["D010661"], "omim": ["261630"], "orphanet": ["226"], "synonyms": ["DHPR deficiency", "Hyperphenylalaninemia, BH-4-deficient, C", "Hyperphenylalaninemia due to dihydropteridine reductase deficiency", "Phenylketonuria type 2", "Quinoid dihydropteridine reductase deficiency", "QDPR deficiency", "PKU type 2"]}
A number sign (#) is used with this entry because spinocerebellar ataxia-7 (SCA7) is caused by a heterozygous expanded trinucleotide repeat in the gene encoding ataxin-7 (ATXN7; 607640) on chromosome 3p14. Description Spinocerebellar ataxia-7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia associated with pigmental macular dystrophy. In her classification of ataxia, Harding (1982) referred to progressive cerebellar ataxia with pigmentary macular degeneration as type II ADCA (autosomal dominant cerebellar ataxia). The age at onset, degree of severity, and rate of progression vary among and within families. Associated neurologic signs, such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss, or dementia, are also variable. Genetic anticipation is observed and is greater in paternal than in maternal transmissions (Benomar et al., 1994; summary by David et al., 1996). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Froment et al. (1937) described a neurologic lesion, which they referred to as spinocerebellar degeneration, in association with retinal degeneration, in 4 affected persons in 3 successive generations. The character of the retinopathy was variable, being peripheral in the first generation, macular in the second, and macular and circumpapillary in the third. Retinal degeneration with cerebellar ataxia in a dominant pedigree pattern was also reported by Bjork et al. (1956). Havener (1951) described macular degeneration with cerebellar ataxia in a 28-year-old black. Cerebellar involvement was much less severe than in a daughter who died at 3 years of age with profound involvement. Jampel et al. (1961) reported spinocerebellar ataxia with external ophthalmoplegia and retinal degeneration in 8 members of a black family (in 4 sibships of 3 generations). Ophthalmoplegia was progressive and appeared to have a supranuclear basis. Ptosis never occurred. Retinal degeneration began in the macular area and progressed to the periphery. Reports of the same syndrome were found in the literature, e.g., Alfano and Berger (1957). In other reports only external ophthalmoplegia or only retinal degeneration was associated with ataxia. Foster and Ingram (1962) described a family with at least 7 affected members of 3 generations. Severity varied widely with infant death in at least 1 case and survival to middle age in other affected persons. Weiner et al. (1967) found 27 affected persons in 5 generations of a black family. The proband had a 'peculiar glistening pale area sprinkled with fine pigment granules in the macular region' of each eye. Blurred vision and a periodic slight head tremor were first noted at age 22. Weiner et al. (1967) suggested that the families of Woodworth et al. (1959) and of Carpenter and Schumacher (1966) may have suffered from the same entity. Halsey et al. (1967) found degenerative changes in the retina and cerebellum of 11 persons in 3 generations of a North Carolina black family. Blindness and ataxia were the clinical features. Fundus changes were mainly macular. Onset was usually in middle age although 3 had onset in adolescence. Consanguinity and skipped generations suggest recessive inheritance. However, a high illegitimacy rate in this population could explain the pedigree pattern by accounting for apparently 'skipped' generations with a dominant trait. In Finland, Anttinen et al. (1986) observed a family with 9 affected persons. The first symptom was insidious, progressive visual loss caused by macular degeneration. Another early sign was slow saccades (Wadia and Swami, 1971). Gradually progressing cerebellar dysfunction and pyramidal signs developed some years after the visual symptoms. Cerebellar and pontine atrophy was demonstrated by computerized tomography (CT scan). Anttinen et al. (1986) found reports of 20 similar families with 120 affected persons, including families reported by Duinkerke-Eerola et al. (1980) and by Harding (1982). Anttinen et al. (1986) stated a preference for 'macular degeneration' rather than 'retinal degeneration.' (One of the patients described by Duinkerke-Eerola et al. (1980) was restudied by Cruysberg et al. (2002), who concluded that he had a separate neurodegenerative entity characterized by autosomal recessive cerebellar ataxia and progressive macular dystrophy with a bull's eye pattern. The patient did not show CAG trinucleotide repeat expansion in various SCA genes, including ATXN7.) Cooles et al. (1988) described a black Dominican family in which a large number of individuals in at least 5 generations had cerebellar and retinal degeneration with morphologically abnormal mitochondria. Cooles et al. (1988) suggested that the clinical picture most closely resembled that of the black families reported by Jampel et al. (1961) and Weiner et al. (1967). Abnormally large mitochondria with irregular cristae were found in muscle biopsy specimens. None of the affected males in this family had offspring. Enevoldson et al. (1994) described 8 families segregating autosomal dominant cerebellar ataxia associated with pigmentary macular degeneration. Two-thirds of the 14 patients presented with ataxia, and the other third with visual failure with or without ataxia. Pedigree analysis demonstrated nonmanifesting obligate carriers and anticipation in the offspring of affected fathers. Dysarthria was invariably present early in the disease. Deep tendon reflexes were usually brisk, but extrapyramidal features were rare and were limited to small choreic movements in the distal limbs. Only 1 patient had orofacial dyskinesias. Sphincter control was normal until terminal disease. Saccadic slowing occurred early in the disease and developed into almost complete external ophthalmoparesis. Progressive visual loss occurred in all patients, although in 1 patient it followed the onset of ataxia by 22 years. All 3 children who developed symptoms before the age of 14 months were dead by 22 months. Unlike the adult-onset cases, early-onset cases presented with depressed or absent deep tendon reflexes. Although linkage analysis was not performed on these patients, the authors argued that the macular degeneration and the presence of early onset of fulminant disease after transmission from fathers are distinctive features of this disorder, clearly distinguishing it from spinocerebellar atrophy types I and II. Gouw et al. (1995) reported 4 families with SCA and associated retinal degeneration. Two of the kindreds were Caucasian and 2 were African American. The disorder was manifested by early loss of color discrimination in the tritan axis (blue-yellow) followed by loss of vision and progressive ataxia. Index cases presented initially with visual problems and subsequent episodes of instability and incoordination that worsened inexorably. Dysmetria and dysarthria were present on examination, although no extrapyramidal signs or dementia were seen. Tritan colorblindness (190900) is an exceedingly rare dichromatic deficiency; thus it is a highly sensitive and specific symptom seen before the other manifestations in this disease. David et al. (1997) noted that SCA7 is the first of the neurodegenerative disorders caused by an expanded trinucleotide repeat in which the degenerative process also affects the retina. In 5 families with 18 affected individuals, the mean age at onset of visual failure was 22 years with a range from 1 to 45 years. Decreased visual acuity occurred in 83%, with blindness in 28%. Optic atrophy was present in 69%; pigmentary retinopathy in 43%; supranuclear ophthalmoplegia in 56%; and viscosity of eye movements in 79%. In 19 of 27 (70%) patients with confirmed SCA types 1, 2 (183090), 3 (109150), 6 (183086), or 7, van de Warrenburg et al. (2004) found electrophysiologic evidence of peripheral nerve involvement. Eight patients (30%) had findings compatible with a dying-back axonopathy, whereas 11 patients (40%) had findings consistent with a primary neuronopathy involving dorsal root ganglion and/or anterior horn cells; the 2 types were clinically almost indistinguishable. Two of 4 patients with SCA7 had an axonopathy and 2 had a neuronopathy. ### Pathologic Findings Holmberg et al. (1998) performed postmortem brain examination of a 10-year-old boy with genetically confirmed SCA7 (85 CAG repeats). Neuronal intranuclear inclusions, identified by an antibody directed against the expanded polyglutamine domain, were identified in multiple areas of the brain. Inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7, the lateral geniculate body, and the substantia nigra, but were also present in other brain regions, including the cerebral cortex which is not considered to be affected in the disease. Some cytoplasmic staining was also identified. Some inclusions stained positively for ubiquitin, but the degree was highly variable. Holmberg et al. (1998) noted that nuclear inclusions are a common feature of polyglutamine disorders. Michalik et al. (2004) presented a detailed clinical, pathologic, and molecular review of SCA7. Ansorge et al. (2004) reported an infant with SCA7 and 180 CAG repeats in the ATXN7 gene. Signs and symptoms appeared at 9 months of age with developmental delay, failure to thrive, and limb tremor. Retinal pigmentary degeneration, nystagmus, hypotonia, and cerebellar ataxia were present by 19 months, and the patient died at 29 months. Postmortem examination showed severe olivopontocerebellar atrophy and thinning of the spinal cord. Ataxin-7 nuclear inclusions were seen throughout the nervous system; however, inclusions were not always associated with neuronal loss, as was particularly evident in the hippocampus. Nuclear inclusions were also present in endothelial cells, cardiac and skeletal muscle, pancreas, and epithelial cells of Brunner glands in the duodenum. In contrast to neuronal inclusions, nonneuronal inclusions did not stain with ubiquitin. Ansorge et al. (2004) discussed differential ubiquitination of aggregates and the effect on cell survival. Diagnosis Koob et al. (1998) described a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process called Repeat Analysis, Pooled Isolation, and Detection (RAPID cloning) of individual clones containing expanded trinucleotide repeats. They used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample from an individual affected with ataxia and retinal degeneration. Mapping Gouw et al. (1994) excluded linkage to SCA1 (164400) and SCA2 (183090) in a 4-generation pedigree segregating retinal degeneration, cerebellar ataxia, slow saccades, ophthalmoparesis, and pyramidal dysfunction. Autopsy of the proband showed degeneration of cerebellum, basis pontis, inferior olive, and retinal ganglion cells. Gouw et al. (1994) concluded that OPCA III is genetically distinct from SCA1 and SCA2. Benomar et al. (1995) mapped the gene for this disorder to 3p21.1-p12. No genetic heterogeneity was found among the 4 Moroccan, Belgian, and French families studied. Multipoint analysis identified a candidate interval of 8-cM around D3S1285. Gouw et al. (1995) mapped the disorder to 3p21.1-p14 in 4 families. Holmberg et al. (1995) found linkage to microsatellite markers on 3p21.1-p12 in a Swedish family with ataxia, dysarthria, and severely impaired vision in an autosomal dominant pedigree pattern. David et al. (1996) investigated 2 families with the disorder that they referred to as ADCA type II. Linkage analysis of these families of different geographic origins (one from Brazil and the other from the UK) confirmed the genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. They mapped the gene to a 5-cM region on 3p13-p12. In contrast to the genetic homogeneity, considerable clinical heterogeneity was demonstrated by variability in age at onset, initial symptoms, and associated signs. Krols et al. (1997) refined the assignment of the SCA7 locus on 3p. Inheritance SCA7 is an autosomal dominant disorder. Gonadal instability is pronounced and is associated with paternal transmission (David et al., 1997). Mittal et al. (2005) reported an Indian patient with SCA7 confirmed by genetic analysis. There was no family history of the disorder. Genetic analysis identified a de novo expansion of 59 CAG repeats on the paternal allele of the ATXN7 gene. His unaffected father had an expansion in the intermediate range, with 31 repeats. Analysis of the father's sperm sample did not show gonadal mosaicism, suggesting that the expansion was postzygotic. Molecular Genetics Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (600075), expanded huntingtin (613004), expanded ataxin-1 (601556), and 3 expanded proteins from individuals affected with SCA3 (109150), Trottier et al. (1995) demonstrated a 130-kD protein in 2 unrelated patients with SCA7. By analogy with other triplet repeat disorders, the authors suggested that this was the protein encoded by the gene whose mutation causes this disorder. Using repeat expansion detection (RED), a method in which a thermolabile ligase is used to detect repeat expansions directly from genomic DNA, Lindblad et al. (1996) analyzed 8 SCA7 families for the presence of (CAG)n repeat expansion. RED products of 150 to 240 bp were found in all affected individuals and were found to cosegregate with the disease, suggesting strongly that a (CAG)n expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease (109150), they were able to estimate the average expansion size in SCA7 to be 64 CAG copies. In 18 patients from 5 families with SCA7, David et al. (1997) identified expanded CAG repeats in the ATXN7 gene (607640.0001). CAG repeat size was highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranged from 7 to 17 repeats. Gonadal instability in SCA7 was greater than that observed in any of the known neurodegenerative disorders caused by translated CAG repeat expansions, and the instability was particularly striking on paternal transmission. ### Genetic Anticipation Gouw et al. (1995) found genetic anticipation in one family with the disorder. Two affected members of generation II first noted mild symptoms at ages 52 and 53; in generation III, onset of symptoms was between ages 31 and 49 with more marked phenotype; in generation IV, 2 members were reported ataxic at birth, both dying within 2 years; other members of generation IV were affected between the ages of 14 and 34 with earlier onset corresponding to more rapid progression to severe disease. Notably, no affected children in any of the 4 kindreds had age of onset later than their parents. Holmberg et al. (1995) reported a 5-generation Swedish family with the disorder descended from a couple born in the latter part of the 19th century in the Province of Vasterbotten in northern Sweden. DNA was studied from 9 patients in 3 generations alive at the beginning of the study, as well as from 2 deceased patients. The family showed anticipation resulting in infantile onset in the latest generation with severe and rapid course of disease; earlier generations had onset in the fourth or fifth decade with relatively slow progression. Analysis of 23 affected parent-child pairs by David et al. (1996) demonstrated marked anticipation that was greater in paternal than in maternal transmissions and a more rapid clinical course in successive generations. Stevanin et al. (1998) stated that normal ATXN7 alleles carry from 4 to 35 CAG repeats, whereas pathologic alleles carry from 37 to approximately 200. Intermediate ATXN7 alleles, with 28 to 35 repeats, are exceedingly rare in the general population and are not associated with the SCA7 phenotype, although they were found among relatives of 4 SCA7 patients. In 2 such families, intermediate alleles bearing 35 and 28 CAG repeats gave rise, during paternal transmission, to ATXN7 expansions of 57 and 47 repeats, respectively, that were confirmed by haplotype reconstructions in one case and by inference in the other. Furthermore, in these and 2 other families in which relatives had intermediate alleles, the 4 haplotypes segregating with the intermediate alleles were identical to the expanded alleles in each family, but differed among the families, indicating multiple origins of the ATXN7 mutation in these families with different geographic origins. The results provided the first evidence of de novo ATXN7 expansions from intermediate alleles that are not associated with the phenotype but can expand to the pathologic range during some paternal transmissions. Intermediate alleles that segregate in unaffected branches of the pedigrees may, therefore, constitute a reservoir for future de novo mutations that occur in a recurrent but random manner. This would explain the persistence of the disorder in spite of the great anticipation (approximately 20 years per generation) characteristic of SCA7. Previously, de novo expansions among the disorders caused by translated CAG repeat expansion (polyglutamine repeat) have been demonstrated only in Huntington disease. In Spain, the Ataxia Study Group (Pujana et al., 1999) found that it was in a family with SCA7 that the highest CAG repeat variation in meiotic transmission of expanded alleles was detected, this being an expansion of 67 units in 1 paternal transmission, giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Analysis of CAG repeat variation in meiosis also showed a tendency to more frequent paternal transmission of expanded alleles in SCA1 (164400) and SCA7. Giunti et al. (1999) found the SCA7 mutation in 54 patients and 7 at-risk subjects from 17 families who had autosomal dominant cerebellar ataxia with progressive pigmentary maculopathy. Haplotype reconstruction through 3 generations of 1 family confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with a clinical phenotype did not have the CAG expansion, thus indicating locus heterogeneity. Distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into 2 ranges; most of the alleles were in the range of 7 to 19 CAG repeats. A second range could be identified with 28 to 35 repeats, and Giunti et al. (1999) provided evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathologic allele, said to be the widest reported for any CAG-repeat disorder, ranged from 37 to approximately 220. The repeat size showed negative correlation with both age at onset and age at death. The most frequently associated features in patients with SCA7 were pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with repeat numbers less than 49 tended to have a less complicated neurologic phenotype and a longer disease duration, whereas the converse applied to subjects with 49 repeats or more. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 was observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission. Gu et al. (2000) evaluated 4 Chinese kindreds with autosomal dominant cerebellar ataxia and decreased visual acuity for mutations in the ATXN7 gene. A mutation was identified in 2 families which showed great variation in age of onset, initial symptoms, and associated signs. Marked inter- and intrafamilial clinical variability was manifest. Analysis of 11 parent-child couples demonstrated the existence of marked anticipation. The CAG repeats ranged from 44 to 85, with strong negative correlation between repeat size and age of onset. Repeat length of expanded alleles showed somatic mosaicism in leukocyte DNA. Van de Warrenburg et al. (2005) applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et al. (2005) acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases. Population Genetics Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin. Whereas SCA7 is considered to be one of the most rare forms of genetically verified autosomal dominant cerebellar ataxia, Jonasson et al. (2000) found it to be the most frequent subtype in Sweden and Finland in a survey of hereditary ataxias in Scandinavia. They identified SCA7 in 8 Swedish and 7 Finnish families but found no affected Norwegian or Danish families. All 37 affected patients displayed expanded CAG repeats, and 9 clinically unaffected relatives also showed CAG expansions ranging from 38 to 53 repeats. Two carriers with 39 and 40 CAG repeats were still healthy at ages 68 and 85, respectively, and 1 individual with 39 CAG repeats presented with symptoms as late as age 74. Haplotype analysis using 9 microsatellite markers and 1 intragenic polymorphism covering a 10.2-cM region of chromosome 3p containing the ATXN7 gene showed that all 15 Swedish/Finnish families shared a common haplotype for the intragenic polymorphism and the centromeric markers D3S1287 and D3S1228, covering more than 1.9 cM of the ATXN7 gene region. Larger haplotypes were shared by families within a geographic region than by families from different geographic regions within the 2 countries. Linkage disequilibrium calculations were highly significant for the segregation of 1 haplotype on disease-bearing chromosomes, providing evidence for a strong founder effect for SCA7 in Scandinavia. In South Africa, spinocerebellar ataxia type 7 occurs exclusively in indigenous Black African patients and seems to have a higher incidence in South Africa compared with the rest of the world (Bryer et al., 2003). Greenberg et al. (2006) performed haplotype studies in 13 SCA7 families from the indigenous Black African population and found a probable SCA7 founder effect. Most of the 13 Black SCA7 families originated in different geographic regions of South Africa. Greenberg et al. (2006) suggested an alternative hypothesis, namely that the area centromeric to the SCA7 mutation harbors a susceptibility factor rendering the SCA7 locus unstable and at risk for repeated expansion to premutation and mutation states. Magana et al. (2014) used a PCR-based method to screen 10 families with late-onset cerebellar ataxia from the Veracruz state of Mexico for SCA1, SCA2, SCA3, SCA6, and SCA7 mutations. Eight of the 10 families were determined to have SCA7 and 2 had SCA2. The 8 SCA7 families comprised 55 affected individuals, most of whom came from 1 very large 6-generation family. Expanded pathogenic ataxin-7 alleles ranged from 34 to 72 CAG repeats. The patients had typical symptomatology of their respective diseases. The findings indicated a high prevalence of SCA7 (85.94%) among all forms of SCA in this Mexican population, consistent with a founder effect. Animal Model By using constructs with tissue-specific promoters, Yvert et al. (2000) generated transgenic mice that expressed mutant human ataxin-7 in either Purkinje cells or retinal rod photoreceptors. Mice overexpressing full-length mutant ataxin-7(Q90) either in Purkinje cells or in rod photoreceptors had deficiencies in motor coordination and vision, respectively. In both models, an N-terminal fragment of mutant ataxin-7 accumulated within ubiquitinated nuclear inclusions that recruited a distinct set of chaperone/proteasome subunits. A severe degeneration was caused by overexpression of ataxin-7(Q90) in rods, whereas a similar overexpression of normal ataxin-7(Q10) had no obvious effect. The degenerative process was not limited to photoreceptors, and secondary alterations were seen in postsynaptic neurons. The authors suggested that proteolytic cleavage of mutant ataxin-7 and transneuronal responses are implicated in the pathogenesis of SCA7. To study the mechanism of polyglutamine neurotoxicity in SCA7, La Spada et al. (2001) generated a transgenic mouse model of SCA7 that expressed ataxin-7 with 92 glutamines in the CNS and retina. They observed a cone-rod dystrophy type of retinal degeneration. Using yeast 2-hybrid studies, La Spada et al. (2001) demonstrated that ataxin-7 interacts with CRX (602225), a nuclear transcription factor predominantly expressed in retinal photoreceptor cells. Mutations in the CRX gene cause cone-rod dystrophy-2 (120970) in humans. Coimmunoprecipitation experiments colocalized ataxin-7 with CRX in nuclear aggregates. Using a rhodopsin promoter-reporter construct, La Spada et al. (2001) observed that polyglutamine-expanded ataxin-7 suppressed CRX transactivation. With electrophoretic mobility shift assays and RT-PCR analysis, they observed a reduction in CRX binding activity and reductions in CRX-regulated genes in SCA7 transgenic retinas. The data suggested that the SCA7 transgenic mice faithfully recapitulated the process of retinal degeneration observed in human SCA7 patients. The authors hypothesized that ataxin-7-mediated transcription interference of photoreceptor-specific genes may account for the retinal degeneration in SCA7, and thus may provide an explanation for how cell-type specificity is achieved in this polyglutamine repeat disorder. By coimmunoprecipitation analysis of CRX and ATXN7 truncation and point mutants, Chen et al. (2004) determined that the ATXN7-interacting domain of CRX localized to its glutamine-rich region and that the CRX-interacting domain of ATXN7 localized to its glutamine tract. Nuclear localization of ataxin-7 was required to repress Crx transactivation, and the likely nuclear localization signals were mapped to the C-terminal region of ataxin-7. Using chromatin immunoprecipitation, the authors showed that both Crx and ataxin-7 occupied the promoter and enhancer regions of Crx-regulated retinal genes in vivo. Chen et al. (2004) suggested that one mechanism of SCA7 disease pathogenesis may be transcription dysregulation, and that CRX transcription interference may be a predominant factor in SCA7 cone-rod dystrophy retinal degeneration. Yoo et al. (2003) generated a transgenic mouse model of severe infantile SCA7 with 266 CAG repeats. At 5 weeks of age, the mice demonstrated progressive weight loss, ptosis, ataxia, muscle wasting, kyphosis, and tremor. Electroretinogram (ERG) studies showed cone and rod photoreceptor defects, and there was progressive shortening of the outer segments of the retina with accumulation of mutant ataxin-7. Mutant ataxin-7 accumulated in various neuronal subtypes throughout the brain, suggesting that polyglutamine expansion stabilizes mutant ataxin-7. The authors suggested that accumulation of the mutant protein may cause downstream molecular events that hinder cell function and survival. Bowman et al. (2005) assessed the ubiquitin-proteasome system (UPS) using transgenic mice with 266 CAG repeats and a ubiquitin (191339) reporter gene. Reporter levels were low during the initial phase of disease, suggesting that neuronal dysfunction occurs in the presence of a functional UPS. Late in disease, there was a significant increase in reporter levels specific to the most vulnerable neurons, resulting from increase in ubiquitin reporter mRNA. No evidence for general UPS impairment or reduction of proteasome activity was seen. The differential increase of ubiquitin reporter among individual neurons directly correlated with the downregulation of a marker of selective pathology and neuronal dysfunction in SCA7. There was an inverse correlation between the neuropathology revealed by the reporter and ataxin-7 nuclear inclusions in the vulnerable neurons. Bowman et al. (2005) proposed a protective role for polyglutamine nuclear inclusions against neuronal dysfunction and excluded significant impairment of the UPS in polyglutamine neuropathology. Using gene profiling and other techniques, Abou-Sleymane et al. (2006) showed that polyQ expansion caused retinal degeneration in animal models of Huntington disease (HD; 143100) and SCA7 by downregulating a large cohort of genes involved in phototransduction function and morphogenesis of differentiated rod photoreceptors and in rod photoreceptor differentiation. Transcription factors that inhibit photoreceptor differentiation were also aberrantly reactivated. Using microarray analysis of the cerebellum in mouse models of SCA1 and SCA7, Gatchel et al. (2008) found that both disorders were associated with significant downregulation of Igfbp5 (146734) in the granular cell layer. Further analysis showed additional misregulation in both models, including activation of the IGF pathway and the Igf1 receptor (IGF1R; 147370) in Purkinje cells. Janer et al. (2010) identified ATXN7 as target for sumoylation in vitro and in vivo. Sumoylation did not influence the subcellular localization of ATXN7 nor its interaction with components of the TFTC/STAGA complex. Expansion of the polyglutamine stretch did not impair the sumoylation of ATXN7. SUMO1 (601912) and SUMO2 (603042) colocalized with ATXN7 in a subset of neuronal intranuclear inclusions in the brain of SCA7 patients and Atxn7 knockin mice. In a COS-7 cellular model of SCA7, there were 2 populations of extranuclear inclusions: homogeneous and nonhomogeneous. Nonhomogeneous inclusions showed significantly reduced colocalization with SUMO1 and SUMO2, but were highly enriched in Hsp70 (HSPA1A; 140550), 19S proteasome, and ubiquitin. These were characterized by increased staining with the apoptotic marker caspase-3 (CASP3; 600636) and by disruption of PML nuclear bodies. Preventing the sumoylation of expanded ATXN7 by mutating the SUMO site increased both the amount of SDS-insoluble aggregates and of CASP3-positive nonhomogeneous inclusions, which are toxic to the cells. Janer et al. (2010) concluded that sumoylation influences the multistep aggregation process of ATXN7, and they implicated a role for ATXN7 sumoylation in SCA7 pathogenesis. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Macular degeneration \- Pigmentary retinal degeneration \- Vision loss, progressive \- Slow saccades \- Optic atrophy \- Supranuclear ophthalmoplegia NEUROLOGIC Central Nervous System \- Progressive cerebellar ataxia \- Dysarthria \- Dysphagia \- Pyramidal signs \- Extrapyramidal signs \- Chorea \- Hyperreflexia \- Extensor plantar responses \- Spasticity \- Orofacial dyskinesia \- Cognitive dysfunction (rare) \- Dysmetria \- Olivopontocerebellar degeneration MISCELLANEOUS \- Mean age at onset 32 years \- Genetic anticipation \- Paternal anticipation bias MOLECULAR BASIS \- Caused by mutations in the ataxin 7 gene (SCA7, 607640.0001 ) ▲ 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	SPINOCEREBELLAR ATAXIA 7	c0752125	1,173	omim	https://www.omim.org/entry/164500	2019-09-22T16:37:10	{"doid": ["0050958"], "mesh": ["D020754"], "omim": ["164500"], "orphanet": ["94147"], "synonyms": ["Alternative titles", "OLIVOPONTOCEREBELLAR ATROPHY III", "OPCA III", "OPCA WITH RETINAL DEGENERATION", "OPCA WITH MACULAR DEGENERATION AND EXTERNAL OPHTHALMOPLEGIA", "AUTOSOMAL DOMINANT CEREBELLAR ATAXIA, TYPE II", "ADCA, TYPE II"], "genereviews": ["NBK1256"]}
A popliteal artery aneurysm is a bulging (aneurysm) of the popliteal artery.[1] A PAA is diagnosed when a focal dilation greater than 50% of the normal vessel diameter is found (the normal diameter of a popliteal artery is 0.7-1.1 cm). PAAs are the most common aneurysm of peripheral vasculature, accounting for 85% of all cases. PAAs are bilateral in some 50% of cases, and are often (40-50%) associated with an abdominal aortic aneurysm.[2] Popliteal aneurysms are rarely symptomatic; they are typically discovered during routine physical examinations. The cause of these aneurysms is unknown, but they are more common in older people and men and occur in both legs about 50% of the time.[1] ## Contents * 1 Presentation * 2 Risk factors * 3 Pathophysiology * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 References ## Presentation[edit] PAAs are most often asymptomatic.[2] Chronic symptoms are most often secondary to the mass effect exerted upon adjoining structures by the aneurysm (e.g. pain and paresthesias due to tibial nerve compression, calf swelling due to compression of the popliteal vein).[2] Thrombosis within the aneurysm and subsequent luminal narrowing may result in claudication of gradual onset, while an acute thrombosis (occluding the vessel at the side of the aneurysm or lodging distally as the vessel narrows) may lead to acute lower extremity ischaemia and associated symptomatology (pain, paresthesia, paresis, pallor, poikilothermia). Thrombotic occlusion of distal vessels may result in blue toe syndrome, and acrocyanosis. Untreated, some 30% of those affected develop acute thrombosis and distal embolization, risking potential limb loss. In cases with acute thrombosis/embolism, amputation rate is 15%.[2] ## Risk factors[edit] Risk factors predisposing to the development of a PAA include: tobacco smoking, atherosclerosis, connective tissue disorders (e.g. Marfan syndrome, and Ehler-Danlos syndrome), advanced age (peaking in the 6th to 7th decade of life), male gender, White race, and a family history of aneurysm.[2] ## Pathophysiology[edit] A PAA seldom presents with a size greater than 5cm as symptoms typically develop before the aneurysm reaches such a size. Unlike aneurysms elsewhere in the body, the typical course of PAAs is to embolize and produce ischaemia, rather than to progress to rupture.[3] ## Diagnosis[edit] The popliteal fossa is to be examined bilaterally with the knee in a semi-flexed position. In some 60% of cases, the popliteal aneurysm presents as a palpable pulsatile mass at the level of the knee joint. Doppler ultrasonography is the preferred diagnostic method. CT and MR angiography may also be employed.[2] ### Differential diagnosis[edit] Differential diagnoses include; popliteal cyst, adventitial cyst,[3][2] lymphadenopathy, varicose vein.[2] ## Treatment[edit] It is unclear whether stenting or open surgery is a better for those with aneurysms that are not causing symptoms.[4] ## References[edit] 1. ^ a b "Popliteal Artery Aneurysm". Vasculardoc.com. Retrieved 5 October 2014. 2. ^ a b c d e f g h Kassem, Mohammed M.; Gonzalez, Lorena (2020), "Popliteal Artery Aneurysm", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 28613613, retrieved 2020-09-18 3. ^ a b Drake, Richard L. (Richard Lee), 1950- (15 November 2015). Gray's anatomy for students. Vogl, Wayne,, Mitchell, Adam W. M.,, Gray, Henry, 1825-1861. (Third ed.). Philadelphia, PA. p. 679. ISBN 978-0-7020-5131-9. OCLC 881508489.CS1 maint: multiple names: authors list (link) 4. ^ Joshi, Dhiraj; Gupta, Yuri; Ganai, Bhaskar; Mortensen, Chloe (23 December 2019). "Endovascular versus open repair of asymptomatic popliteal artery aneurysm". The Cochrane Database of Systematic Reviews. 12: CD010149. doi:10.1002/14651858.CD010149.pub3. ISSN 1469-493X. PMC 6927522. PMID 31868929. This cardiovascular 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	Popliteal artery aneurysm	c0264964	1,174	wikipedia	https://en.wikipedia.org/wiki/Popliteal_artery_aneurysm	2021-01-18T19:01:22	{"umls": ["C0264964"], "icd-10": ["I72.4"], "wikidata": ["Q18343639"]}
Lujo hemorrhagic fever, caused by the Lujo virus (a newly discovered Old World arenavirus) is a zoonotic disease from Zambia, Africa, whose reservoir is unknown and is characterized by fever and hemorrhagic manifestations with an extremely high fatality rate of 80% (in the 5 reported cases to date) and a moderate to high level of nosocomial transmission. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Lujo hemorrhagic fever	c4274433	1,175	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319213	2021-01-23T17:30:57	{"icd-10": ["A96.8"], "synonyms": ["Zambian hemorrhagic fever"]}
CYLD cutaneous syndrome causes the growth of several types of non-cancerous (benign) skin tumors. Tumors mainly grow on the scalp and face, but can also grow on the torso, genitals and armpits. Tumors usually first appear in the teens or early adulthood. The types of tumors that occur in CYLD cutaneous syndrome may include cylindromas, spiradenomas, and trichoepitheliomas. The number of tumors increases over time, and in severe cases, tumors can cover most of the scalp. Rarely, a tumor will become cancerous. Other complications may include an increased risk to develop basal cell cancer of the salivary gland or deafness due to the growth of a tumor in the ear canal. CYLD cutaneous syndrome is caused by genetic variants in the CYLD gene and is inherited in an autosomal dominant pattern. Diagnosis of CYLD cutaneous syndrome is based on the symptoms, clinical exam, and microscopic exam of the tumor tissue. Results of genetic testing may help confirm the diagnosis. Treatment is focused on managing the symptoms, and typically involves many surgeries to remove the tumors. The conditions known as Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma are now recognized to be part of CYLD cutaneous syndrome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	CYLD cutaneous syndrome	c1857941	1,176	gard	https://rarediseases.info.nih.gov/diseases/10179/cyld-cutaneous-syndrome	2021-01-18T18:01:00	{"mesh": ["C536611"], "omim": ["605041"], "orphanet": ["79493"], "synonyms": ["BRSS", "Spiegler-Brooke syndrome", "SBS", "Ancell-Spiegler cylindromas", "Brooke-Spiegler syndrome", "Familial cylindromatosis", "Multiple familial trichoepitheliomas"]}
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: "Fibrillary astrocytoma" – news · newspapers · books · scholar · JSTOR (April 2010) (Learn how and when to remove this template message) Fibrillary astrocytoma Other namesLow-grade or diffuse astrocytomas Diffuse fibrillary astrocytomas arising in the brain stem favor the pons: The tumor here produces the classic hypertrophy of the affected region. SpecialtyOncology Fibrillary astrocytomas are a group of primary slow-growing brain tumors that typically occur in adults between the ages of 20 and 50.[citation needed] ## Contents * 1 Symptoms * 2 Pathology * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Symptoms[edit] Seizures, frequent mood changes, and headaches are among the earliest symptoms of the tumor. Hemiparesis (physical weakness on one side of the body) is also common.[1] ## Pathology[edit] Fibrillary astrocytomas arise from neoplastic astrocytes, a type of glial cell found in the central nervous system. They may occur anywhere in the brain, or even in the spinal cord,[1] but are most commonly found in the cerebral hemispheres. As the alternative name "diffuse astrocytoma" implies, the outline of the tumour is not clearly visible in scans, because the borders of the neoplasm tend to send out tiny microscopic fibrillary tentacles that spread into the surrounding brain tissue. These tentacles intermingle with healthy brain cells, making complete surgical removal difficult. However, they are low-grade tumors, with a slow rate of growth, so patients commonly survive longer than those with otherwise similar types of brain tumours, such as glioblastoma multiforme.[1] ## Diagnosis[edit] A continuous EEG recording of the brain's electrical activity may help to identify and localize seizure activity, especially in children. CT scans and MRI scans of the brain may show the presence of a diffuse mass that fails to light up when a contrast dye is given.[citation needed] In some cases, a biopsy may be required to confirm the nature of the tumour. ## Treatment[edit] Treatment options include surgery, radiotherapy, radiosurgery, and chemotherapy. The infiltrating growth of microscopic tentacles in fibrillary astrocytomas makes complete surgical removal difficult or impossible without injuring brain tissue needed for normal neurological function. However, surgery can still reduce or control tumor size.[citation needed] Possible side effects of surgical intervention include brain swelling, which can be treated with steroids, and epileptic seizures. Complete surgical excision of low-grade tumors is associated with a good prognosis. However, the tumor may recur if the resection is incomplete, in which case further surgery or the use of other therapies may be required. Standard radiotherapy for fibrillary astrocytoma requires 10 to 30 sessions, depending on the subtype of the tumor, and may sometimes be performed after surgical resection to improve outcomes and survival rates. Side effects include the possibility of local inflammation, leading to headaches, which can be treated with oral medication. Radiosurgery uses computer modelling to focus minimal radiation doses at the exact location of the tumour, while minimising the dose to the surrounding healthy brain tissue. Radiosurgery may be a complementary treatment after regular surgery, or it may represent the primary treatment technique.[citation needed] Although chemotherapy for fibrillary astrocytoma improves overall survival, it is effective only in about 20% of cases. Researchers[who?] are currently investigating a number of promising new treatment techniques including gene therapy, immunotherapy, and novel chemotherapies.[citation needed] ## References[edit] 1. ^ a b c Low-Grade Astrocytoma at eMedicine ## External links[edit] * Pediatric lowgrade astrocytomas * v * t * e Tumours of the nervous system Endocrine Sellar: * Craniopharyngioma * Pituicytoma Other: * Pinealoma CNS Neuroepithelial (brain tumors, spinal tumors) Glioma Astrocyte * Astrocytoma * Pilocytic astrocytoma * Pleomorphic xanthoastrocytoma * Subependymal giant cell astrocytoma * Fibrillary astrocytoma * Anaplastic astrocytoma * Glioblastoma multiforme Oligodendrocyte * Oligodendroglioma * Anaplastic oligodendroglioma Ependyma * Ependymoma * Subependymoma Choroid plexus * Choroid plexus tumor * Choroid plexus papilloma * Choroid plexus carcinoma Multiple/unknown * Oligoastrocytoma * Gliomatosis cerebri * Gliosarcoma Mature neuron * Ganglioneuroma: Ganglioglioma * Retinoblastoma * Neurocytoma * Dysembryoplastic neuroepithelial tumour * Lhermitte–Duclos disease PNET * Neuroblastoma * Esthesioneuroblastoma * Ganglioneuroblastoma * Medulloblastoma * Atypical teratoid rhabdoid tumor Primitive * Medulloepithelioma Meninges * Meningioma * Hemangiopericytoma Hematopoietic * Primary central nervous system lymphoma PNS: * Nerve sheath tumor * Cranial and paraspinal nerves * Neurofibroma * Neurofibromatosis * Neurilemmoma/Schwannoma * Acoustic neuroma * Malignant peripheral nerve sheath tumor Other * WHO classification of the tumors of the central nervous system Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Fibrillary astrocytoma	c0334582	1,177	wikipedia	https://en.wikipedia.org/wiki/Fibrillary_astrocytoma	2021-01-18T19:08:07	{"mesh": ["D001254"], "umls": ["C0334582"], "orphanet": ["251601"], "wikidata": ["Q953330"]}
A rare syndrome with combined immunodeficiency characterized by intrauterine and postnatal growth retardation, chronic neutropenia, and natural killer (NK) cell deficiency due a defect in DNA replication leading to blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells. Other clinical features include recurrent viral and bacterial infections and eczema, as well as mild facial dysmorphism. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Combined immunodeficiency due to GINS1 deficiency	c4693356	1,178	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=505227	2021-01-23T17:44:03	{"omim": ["617827"], "synonyms": ["CID due to GINS1 deficiency", "Combined immunodeficiency with intrauterine growth retardation-NK cell deficiency-neutropenia", "Combined immunodeficiency with intrauterine growth retardation-natural killer cell deficiency-neutropenia"]}
A number sign (#) is used with this entry because of evidence that hypochromic microcytic anemia with iron overload-2 (AHMIO2) is caused by heterozygous mutation in the STEAP3 gene (609671) on chromosome 2q14. One such family has been reported. For a discussion of genetic heterogeneity of hypochromic microcytic anemia with iron overload, see AHMIO1 (206100). Clinical Features Grandchamp et al. (2011) reported 3 sibs, born of nonconsanguineous Pakistani parents, who had transfusion-dependent hypochromic microcytic anemia with iron overload. The proband was a 24-year-old man who had been pale since infancy and was documented to be anemic at 7.5 years of age. Follow-up revealed chronic hypochromic anemia, and biochemical data suggested the onset of iron overload. He presented with increasing fatigue at 19 years of age, at which time his spleen was palpable and he was severely anemic; regular transfusions were begun to maintain a hemoglobin level permitting normal physical activity. Blood smears revealed distinct aniso-poikilocytosis with hypochromasia and microcytosis, ovalocytes, a few target cells, and basophilic stippled cells, with single mature nucleated red cells present. There was moderate erythropoietic hyperplasia of the bone marrow, with dysplastic features in less than 3% of erythroblasts; late basophilic and polychromatophilic erythroblasts had a small rim of poorly hemoglobinized cytoplasm, with small inclusions in some cells. Perls staining showed iron-positive inclusions in most red cell precursors, with 40% ringed sideroblasts, and Pappenheimer bodies in a few red cells. Under transmission electron microscopy, deposits of iron could be seen inside as well as outside the mitochondria. The proband's 2 affected sibs had similar biochemical and morphologic data. The 23-year-old sister had only mild symptoms of anemia in childhood and began regular transfusions at 15 years of age, whereas the 18-year-old brother had a more severe form of anemia since infancy, requiring transfusions beginning at 7 years of age, with growth retardation, massive hepatosplenomegaly and high iron overload, and cafe-au-lait spots visible on his skin. All 3 sibs had high serum ferritin and low transferrin values, as well as distinctly increased transferrin saturation despite regular treatment with deferasirox. In addition, they all had hypogonadism, with azoospermia in the males and atrophy of the gonads in the female; complex dysfunction of the hypothalamo-pituitary-gonadal axis was present in all 3 patients, suggesting a primary defect of the gonads in addition to secondary hypogonadism. Latent adrenal and thyroid failure was also detected in the younger brother. Their father had normal blood counts and iron data, whereas their mother had mild microcytic anemia with a low serum ferritin, which responded to iron supplementation. She had had 2 miscarriages in addition to the 3 live births. Molecular Genetics In 3 sibs with hypochromic microcytic anemia and iron overload, born of nonconsanguineous Pakistani parents, Grandchamp et al. (2011) analyzed 7 candidate genes and identified heterozygosity for a nonsense mutation in the STEAP3 gene (C100X; 609671.0001) that was inherited from their unaffected father. Quantitative RT-PCR from blood mRNA of all 5 family members and 10 controls showed that the STEAP3 mRNA level was considerably lower in the 3 patients, whereas both parents had a level of STEAP3 mRNA corresponding to the low-normal range found in controls. In B-lymphocyte cell lines treated to prevent degradation due to nonsense-mediated mRNA decay, quantitative sequencing of a cDNA fragment encompassing the mutated nucleotide demonstrated that expression of the normal allele relative to that of the mutated allele was significantly higher in the father than in the 3 sibs. Grandchamp et al. (2011) suggested that the father was heterozygous with 1 null allele and 1 normal, highly expressed allele, whereas the mother had 2 weakly expressed alleles, and each affected offspring had inherited the mutated allele from their father and 1 of the weakly expressed alleles from their mother. This was supported by the fact that expression of both alleles from the mother produced an amount of mRNA that was roughly equivalent to the expression products from the single normal allele of the father. INHERITANCE \- Autosomal dominant GROWTH \- Growth retardation (in some patients) HEAD & NECK Eyes \- Marked pallor of mucous membranes Mouth \- Marked pallor of mucous membranes ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly GENITOURINARY External Genitalia (Male) \- Hypogonadism Internal Genitalia (Male) \- Azoospermia Internal Genitalia (Female) \- Gonadal atrophy SKIN, NAILS, & HAIR Skin \- Marked skin pallor \- Cafe au lait spots (in some patients) ENDOCRINE FEATURES \- Dysfunction of hypothalamo-pituitary-gonadal axis \- Adrenal failure (in some patients) \- Thyroid failure (in some patients) HEMATOLOGY \- Anemia, severe \- Hypochromia \- Microcytosis \- Elevated serum ferritin \- Low serum transferrin \- Increased transferrin saturation \- Aniso-poikilocytosis on blood smear \- Erythropoietic hyperplasia of bone marrow MISCELLANEOUS \- Patients have severe anemia requiring regular transfusions for normal activity \- One family reported (last curated May 2013) MOLECULAR BASIS \- Caused by mutation in the STEAP3 metalloreductase gene (STEAP3, 609671.0001 ) ▲ 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	ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 2	c3808920	1,179	omim	https://www.omim.org/entry/615234	2019-09-22T15:52:46	{"doid": ["0050642"], "omim": ["615234"], "orphanet": ["300298"], "synonyms": ["Severe congenital hypochromic sideroblastic anemia"]}
Carpenter syndrome is a condition characterized by premature fusion of skull bones (craniosynostosis); finger and toe abnormalities; and other developmental problems. The features in affected people vary. Craniosynostosis can give the head a pointed appearance; cause asymmetry of the head and face; affect the development of the brain; and cause characteristic facial features. Other signs and symptoms may include dental abnormalities; vision problems; hearing loss; heart defects; genital abnormalities; obesity; various skeletal abnormalities; and a range of intellectual disability. Carpenter syndrome can be caused by mutations in the RAB23 or MEGF8 gene and is inherited in an autosomal recessive manner. Treatment focuses on the specific features in each affected person. Life expectancy is shortened but very variable. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Carpenter syndrome	c1275078	1,180	gard	https://rarediseases.info.nih.gov/diseases/6003/carpenter-syndrome	2021-01-18T18:01:36	{"mesh": ["C563187"], "omim": ["201000"], "orphanet": ["65759"], "synonyms": ["Acrocephalopolysyndactyly type 2", "ACPS 2", "Acrocephalosyndactyly, type II", "Carpenter syndrome 1", "CRPT1"]}
Kisch and Nasuhoglu (1953) described a mediosternal, longitudinally directed streak of hypopigmentation in 5 blacks. I have observed this, but no systematic family studies have been done. See Futcher line (137000) and raindrop depigmentation (179500) for other pigment peculiarities in blacks. Inheritance \- Autosomal dominant Skin \- Mediosternal, longitudinal streak of hypopigmentation ▲ 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	MEDIOSTERNAL DEPIGMENTATION LINE	c1835085	1,181	omim	https://www.omim.org/entry/155200	2019-09-22T16:38:30	{"omim": ["155200"]}
A mitochondrially inherited degeneration of retinal cells in human Leber's hereditary optic neuropathy Other namesLeber hereditary optic atrophy Leber’s hereditary optic neuropathy has a mitochondrial inheritance pattern. SpecialtyOphthalmology Frequency1:30,000 to 1:50,000 Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. LHON is only transmitted through the mother, as it is primarily due to mutations in the mitochondrial (not nuclear) genome, and only the egg contributes mitochondria to the embryo. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria. Men cannot pass on the disease to their offspring.[1] ## Contents * 1 Signs and symptoms * 1.1 LHON with demyelinating lesions or LHON Plus * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 5.1 Idebenone * 5.2 Estrogen Replacement Therapy * 6 Epidemiology * 7 History * 8 Research * 9 See also * 10 References * 11 Further reading * 12 External links ## Signs and symptoms[edit] Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-75 is reported. The age of onset is slightly higher in females (range 19–55 years: mean 31.3 years) than males (range 15–53 years: mean 24.3). The male to female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C. This typically evolves to very severe optic atrophy and a permanent decrease of visual acuity. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely only one eye may be affected. In the acute stage, lasting a few weeks, the affected eye demonstrates an oedematous appearance of the nerve fiber layer especially in the arcuate bundles and enlarged or telangiectatic and tortuous peripapillary vessels (microangiopathy). The main features are seen on fundus examination, just before or subsequent to the onset of visual loss. A pupillary defect may be visible in the acute stage as well. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma on visual field examination. ### LHON with demyelinating lesions or LHON Plus[edit] "LHON Plus" is a name given to a rare variant of the disorder with eye disease together with other conditions.[2] The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia.[3] Many cases of LHON plus have been comparable to multiple sclerosis because of the lack of muscular control[4] and because of the presence of demyelinating lesions in the CNS. It is therefore a subtype of MS according to McDonalds definition.[5] ## Genetics[edit] Leber hereditary optic neuropathy is a condition related to changes in mitochondrial DNA. Although most DNA is packaged in chromosomes within the nucleus, mitochondria have a distinct mitochondrial genome composed of mtDNA. Mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes cause Leber hereditary optic neuropathy.[6] These genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. Oxidative phosphorylation uses a series of four large multienzyme complexes, which are all embedded in the inner mitochondrial membrane to convert oxygen and simple sugars to energy. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy. ## Pathophysiology[edit] The eye pathology is limited to the retinal ganglion cell layer especially the maculopapillary bundle. Degeneration is evident from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nuclei. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells. Also, experiments suggest that normal non LHON affected retinal ganglion cells produce less of the potent superoxide radical than other normal central nervous system neurons.[7] Viral vector experiments which augment superoxide dismutase 2 in LHON cybrids[8] or LHON animal models or use of exogenous glutathione in LHON cybrids[9] have been shown to rescue LHON affected retinal ganglion cells from apoptotic death. These experiments may in part explain the death of LHON affected retinal ganglion cells in preference to other central nervous system neurons which also carry LHON affected mitochondria. ## Diagnosis[edit] Without a known family history of LHON the diagnosis usually requires a neuro-ophthalmological evaluation and blood testing for mitochondrial DNA assessment.[10] It is important to exclude other possible causes of vision loss and important associated syndromes such as heart electrical conduction system abnormalities. ## Treatment[edit] The prognosis for those affected left untreated is almost always that of continued significant visual loss in both eyes. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is beneficial treatment available for some cases of this disease especially for early onset disease.[11] Also, experimental treatment protocols are in progress.[12] Genetic counselling should be offered. Health and lifestyle choices should be reassessed particularly in light of toxic and nutritional theories of gene expression. Vision aids assistance and work rehabilitation should be used to assist in maintaining employment. For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress.[13] For example, fundus photography can monitor nerve fiber layer swelling. Optical coherence tomography can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament blood markers may predict conversion to affected status. Cyanocobalamin (a form of B12) may also be used.[14] Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk. Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. In fact, toxic and nutritional optic neuropathies may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management.[15] Of note, when a patient carrying or suffering from LHON or toxic/nutritional optic neuropathy suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia in response to this anti-hypertensive in particular.[16] Idebenone[11][17][18] has been shown in a small placebo controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset. α-Tocotrienol-quinone, a vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss.[12][19] There are various treatment approaches which have had early trials or are proposed, none yet with convincing evidence of usefulness or safety for treatment or prevention including brimonidine,[20] minocycline,[21] curcumin,[22] glutathione,[9] near infrared light treatment,[23] and viral vector techniques.[8] "Three person in vitro fertilization" is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.[24] ### Idebenone[edit] Idebenone is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration. When used in individuals with LHON, it is believed to allow electrons to bypass the dysfunctional complex I.[25] Successful treatment using idebenone was initially reported in a small number of patients.[18][26] Two large-scale studies have demonstrated the benefits of idebenone. The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) evaluated the effects of idebenone in 85 patients with LHON who had lost vision within the prior five years.[11][27] In this study, the group taking idebenone 900 mg per day for 24 weeks showed a slight improvement in visual acuity compared to the placebo group, though this difference was not statistically significant. Importantly, however, patients taking idebenone were protected from further vision loss, whereas the placebo group had a steady decline in visual acuity. Further, individuals taking idebenone demonstrated preservation of color vision and persistence of the effects of idebenone 30 months after discontinuing therapy.[27][28] A retrospective analysis of 103 LHON patients by Carelli et al. builds upon these results.[29] This study highlighted that 44 subjects who were treated with idebenone within one year of onset of vision loss had better outcomes, and, further, that these improvements with idebenone persisted for years. Idebenone, combined with avoidance of smoke and limitation of alcohol intake, is the preferred standard treatment protocol for patients affected by LHON.[30] Idebenone doses are prescribed to be taken spaced out throughout the day, rather than all at one time. For example, to achieve a dose of 900 mg per day, patients take 300 mg three times daily with meals. Idebenone is fat soluble, and may be taken with a moderate amount of dietary fat in each meal to promote absorption. It is recommended that patients on idebenone also take vitamin C 500 mg daily to keep idebenone in its reduced form,[30] as it is most active in this state.[31] ### Estrogen Replacement Therapy[edit] Estrogens have been shown to have a protective role in the pathogenesis of LHON. Experiments using LHON cybrids have demonstrated that the estrogen receptor localizes to the mitochondria where it directly mediates mitochondrial biogenesis. Estrogens upregulate the antioxidant enzyme superoxide dismutase 2 and mitochondrial DNA synthesis. These experiments helped to explain the mechanism behind the lower penetrance of disease among female carriers.[32][33][34] While additional factors have been theorized, the protective role of estrogens appears to be a significant contributor. In addition to the experimental evidence, clinical data also points towards the protective role of estrogens. Penetrance among female carriers is substantially lower (between 3 and 8 to 1 male to female ratios depending on the mutation) while average age at onset is significantly higher. Multiple case series of various LHON pedigrees have described female carriers converting after menopause or cessation of hormone replacement therapies.[35][36] Together, these form a shifting paradigm towards considering reduced estrogen states, such as menopause, as potential triggers of visual loss similar to smoking or excessive alcohol consumption. Hormone replacement therapy (HRT) is emerging as an effective therapeutic target for female mutation carriers. In one recent case study where the affected female converted following cessation of HRT, idebenone, and HRT were given together.[35] Visual acuity improved much faster than is typically expected. The patient’s vision returned to 20/40 and 20/60 from 20/60 and 20/200 in the right and left eyes respectively after only one month and was back normal by 8 months compared to the months to years timeframe seen in most cases. While the balance between risks and benefits of HRT remains controversial, the decision to start HRT requires an individualized approach based on the patient’s context. While not applicable for all post-menopausal women, prophylactic (and therapeutic) HRT should be considered in all female carriers of a known LHON mutation given the substantial risk of vision loss associated with menopause.[33][37][35] ## Epidemiology[edit] In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.[38] [39] There is a prevalence of between 1:30,000 to 1:50,000 in Europe. The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world with 70% of Northern European cases and 90% of Asian cases. Due to a Founder effect, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec, Canada.[40] More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict the likelihood of penetrance, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter. Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,[41] [42] contribute to the development of signs and symptoms. The degree of heteroplasmy, the percentage of mitochondria which have mutant alleles, may play a role.[43] Patterns of mitochondrial alleles called haplogroup may also affect expression of mutations.[44] ## History[edit] This disease was first described by the German ophthalmologist Theodor Leber (1840–1917) in 1871.[45] In this paper Leber described four families in which a number of young men suffered abrupt loss of vision in both eyes either simultaneously or sequentially. This disease was initially thought to be X linked but was subsequently shown to be mitochondrial.[46] The nature of the causative mutation was first identified in 1988 by Wallace et al. who discovered the guanine (G) to adenosine (A) mutation at nucleotide position 11778 in nine families.[47] This mutation converts a highly conserved arginine to histidine at codon 340 in the NADH dehydrogenase subunit 4 of complex I of the mitochondrial respiratory chain. The other two mutations known to cause this condition were identified in 1991 (G to A point mutation at nucleotide position 3460)[48] and 1992 (thymidine (T) to cytosine (C) mutation at nucleotide 14484).[49] These three mutations account for over 95% of cases: the 11778 mutation accounts for 50-70% of cases, the 14484 mutation for 10-15% and the 3460 mutation for 8-25%. ## Research[edit] Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in LHON. In these trials, participants affected by LHON with the G11778A mutation will have a virus expressing the functional version of ND4 – the gene mutated in this variant of LHON – injected into one eye. A sham injection will be administered to the other eye for comparison. It is hypothesized that introduction of the viral vector may be able to rescue the function of the mutant gene. Preliminary results have demonstrated tolerability of the injections in a small number of subjects.[50] Stealth BioTherapeutics is presently investigating the potential use of elamipretide (MTP-131), a mitochondrial protective agent, as a therapy for LHON. Elamipretide helps stabilize cardiolipin [51][52] – an important component of mitochondrial inner membranes – and has been shown to reduce damaging reactive oxygen species in animal models.[53] Clinical trials in LHON patients are planned for the future. ## See also[edit] * Amaurosis * Dominant optic atrophy * Glaucoma * Ischemic optic neuropathy * Optic atrophy * Toxic and nutritional optic neuropathy ## References[edit] 1. ^ Bandelt HJ, Kong QP, Parson W, Salas A (December 2005). "More evidence for non-maternal inheritance of mitochondrial DNA?". J. Med. Genet. 42 (12): 957–60. doi:10.1136/jmg.2005.033589. PMC 1735965. PMID 15923271. 2. ^ Nikoskelainen EK, Marttila RJ, Huoponen K, et al. (August 1995). "Leber's "plus": neurological abnormalities in patients with Leber's hereditary optic neuropathy". J. Neurol. Neurosurg. Psychiatry. 59 (2): 160–4. doi:10.1136/jnnp.59.2.160. PMC 485991. PMID 7629530. 3. ^ cardiac arrythmia 4. ^ Mayo Clinic: Multiple Sclerosis 5. ^ David Bargiela, Patrick F Chinnery, Mitochondria in neuroinflammation – Multiple sclerosis (MS), leber hereditary optic neuropathy (LHON) and LHON-MS, https://doi.org/10.1016/j.neulet.2017.06.051 6. ^ Online Mendelian Inheritance in Man (OMIM): LEBER OPTIC ATROPHY - 535000 7. ^ Hoegger MJ, Lieven CJ, Levin LA (2008). "Differential production of superoxide by neuronal mitochondria". BMC Neurosci. 9: 4. doi:10.1186/1471-2202-9-4. PMC 2266764. PMID 18182110. 8. ^ a b Qi X, Sun L, Hauswirth WW, Lewin AS, Guy J (February 2007). "Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation". Arch. Ophthalmol. 125 (2): 268–72. doi:10.1001/archopht.125.2.268. PMID 17296905. 9. ^ a b Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M (February 2008). "Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids". Invest. Ophthalmol. Vis. Sci. 49 (2): 671–6. doi:10.1167/iovs.07-0880. PMID 18235013. 10. ^ Yu-Wai-Man P, Chinnery PF (June 23, 2016). "Leber Hereditary Optic Neuropathy". NCBI. Genereviews. Retrieved February 25, 2018. 11. ^ a b c Klopstock, T.; Yu-Wai-Man, P.; Dimitriadis, K.; Rouleau, J.; Heck, S.; Bailie, M.; Atawan, A.; Chattopadhyay, S.; Schubert, M.; Garip, A.; Kernt, M.; Petraki, D.; Rummey, C.; Leinonen, M.; Metz, G.; Griffiths, P. G.; Meier, T.; Chinnery, P. F. (2011). "A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy". Brain. 134 (9): 2677–2686. doi:10.1093/brain/awr170. ISSN 0006-8950. PMC 3170530. PMID 21788663. 12. ^ a b Shrader, W. D.; Amagata, A.; Barnes, A.; Enns, G. M.; Hinman, A.; Jankowski, O.; Kheifets, V.; Komatsuzaki, R.; Lee, E.; Mollard, P.; Murase, K.; Sadun, A. A.; Thoolen, M.; Wesson, K.; Miller, G. (2011). "Α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging". Bioorganic & Medicinal Chemistry Letters. 21 (12): 3693–3698. doi:10.1016/j.bmcl.2011.04.085. PMID 21600768. 13. ^ Sadun AA, Salomao SR, Berezovsky A, et al. (2006). "Subclinical carriers and conversions in Leber hereditary optic neuropathy: A prospective psychophysical study". Trans Am Ophthalmol Soc. 104: 51–61. PMC 1809912. PMID 17471325. 14. ^ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 251. hdl:10665/44053. ISBN 9789241547659. 15. ^ Carelli V, Ross-Cisneros FN, Sadun AA (January 2004). "Mitochondrial dysfunction as a cause of optic neuropathies". Prog Retin Eye Res. 23 (1): 53–89. doi:10.1016/j.preteyeres.2003.10.003. PMID 14766317. 16. ^ Katz, Jason; Patel, Chetan (2006). Parkland Manual of Inpatient Medicine. Dallas, TX: FA Davis. p. 903. 17. ^ Clinical Idebenone trial recruiting at Newcastle University UK http://lhon.ncl.ac.uk 18. ^ a b Mashima Y, Kigasawa K, Wakakura M, Oguchi Y (September 2000). "Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy?". J Neuroophthalmol. 20 (3): 166–70. doi:10.1097/00041327-200020030-00006. PMID 11001192. 19. ^ Sadun, A et al. "EPI-743 alters the natural history of progression of Leber hereditary optic neuropathy". AOS meeting. May 2011 Archived 2011-09-04 at the Wayback Machine 20. ^ Newman NJ, Biousse V, David R, et al. (September 2005). "Prophylaxis for second eye involvement in leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite". Am. J. Ophthalmol. 140 (3): 407–15. doi:10.1016/j.ajo.2005.03.058. PMID 16083844. 21. ^ Haroon MF, Fatima A, Schöler S, et al. (2007). "Minocycline, a possible neuroprotective agent in Leber's hereditary optic neuropathy (LHON): Studies of cybrid cells bearing 11778 mutation". Neurobiol Dis. 28 (3): 237–50. doi:10.1016/j.nbd.2007.07.021. PMID 17822909. 22. ^ Clinical Curcurmin trial recruiting at ClinicalTrials.nlm.nih.gov Archived 2009-02-13 at the Wayback Machine 23. ^ Wisconsin near infrared trial Archived 2008-05-15 at the Wayback Machine 24. ^ Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM (May 2010). "Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease". Nature. 465 (7294): 82–85. Bibcode:2010Natur.465...82C. doi:10.1038/nature08958. PMC 2875160. PMID 20393463. 25. ^ Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier Fruh I, Anklin C, Dallmann R, Gueven N (March 2011). "NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels". PLOS ONE. 6 (3): e17963. Bibcode:2011PLoSO...617963H. doi:10.1371/journal.pone.0017963. PMC 3069029. PMID 21483849. 26. ^ Eng, J.G.; Aggarwal, D.; Sadun, A.A. (April 2009). "Idebenone treatment in patients with Leber hereditary optic neuropathy". Invest Ophthalmol Vis Sci. 50 (13). Retrieved March 22, 2016. 27. ^ a b Klopstock T; Metz G; Yu-Wai-Man P; et al. (2013). "Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy". Brain. 136 (2): e230. doi:10.1093/brain/aws279. PMC 3572931. PMID 23388409. 28. ^ Rudolph, G.; Dimitriadis, K.; Büchner, B.; Heck, S.; Al-Tamami, J.; Seidensticker, F.; Rummey, C.; Leinonen, M.; Meier, T.; Klopstock, T. (March 2013). "Effects of idebenone on color vision in patients with Leber hereditary optic neuropathy". J Neuroophthalmol. 33 (1): 30–36. doi:10.1097/WNO.0b013e318272c643. PMC 3658961. PMID 23263355. 29. ^ Carelli V; La Morgia C; Valentino ML; et al. (September 2011). "Idebenone treatment in Leber's hereditary optic neuropathy". Brain. 134 (Part 9): e188. doi:10.1093/brain/awr180. PMID 21810891. 30. ^ a b Karanjia, R.; Sadun, A.A. (2015). "Advances in therapeutic strategies for Leber's hereditary optic neuropathy". Expert Opinion on Orphan Drugs. 3 (12): 1439–1446. doi:10.1517/21678707.2015.1098531. 31. ^ Mordente, A.; Martorana, G.E.; Minotti, G; Giardina, B (January 1998). "Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone)". Chem Res Toxicol. 11 (1): 54–63. doi:10.1021/tx970136j. PMID 9477226. 32. ^ Giordano, C.; Iommarini, L; Giordano, L; Maresca, A; Pisano, A; Valentino, M L; Caporali, L; Liguori, R; Deceglie, S; Roberti, M; Fanelli, F; Fracasso, F; Ross-Cisneros, F N; D’Adamo, P; Hudson, G; Pyle, A; Yu-Wai-Man, P; Chinnery, P F; Zeviani, M; Salomao, S R; Berezovsky, A; Belfort Jr, R; Ventura, D F; Moraes, M; Filho, M.M.; Barboni, P; Sadun, F; De Negri, A; Sadun, A.A.; Tancredi, A; Mancini, M; d’Amati, G; Polosa, P L; Cantatore, P; Carelli, V (2013). "Efﬁcient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy". Brain. 137 (Pt 2): 335–353. doi:10.1093/brain/awt343. PMC 3914475. PMID 24369379. 33. ^ a b Giordano, C.; Montopoli, M; Perli, E; Orlandi, M; Fantin, M; Ross-Cisneros, F.N. L; Caparrotta, L; Martinuzzi, A; Ragazzi, E; Ghelli, A; Sadun, A.A.; d'Amati, G; Carelli, V (2011). "Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy". Brain. 134 (Pt 1): 220–234. doi:10.1093/brain/awq276. PMC 3025718. PMID 20943885. 34. ^ Pisano, A.; Preziuso, C; Iommarini, L; Perli, E; Grazioli, P; Campese, A.F.; Maresca, A; Montopoli, M; Masuelli, L; Sadun, A.A.; d'Amati, G; Carelli, V; Ghelli, A.M.; Giordano, C (2015). "Targeting estrogen receptor β as preventive therapeutic strategy for Leber's hereditary optic neuropathy". Human Molecular Genetics. 24 (24): 6921–6931. doi:10.1093/hmg/ddv396. PMID 26410888. 35. ^ a b c Fantini, M.; Asanad, S; Karanjia, R; Sadun, A.A. (2019). "Hormone replacement therapy in Leber's hereditary optic neuropathy: Accelerated visual recovery in vivo". Journal of Current Ophthalmology. 31: 102–105. doi:10.1016/j.joco.2018.10.003. PMC 6407313. PMID 30899856. 36. ^ Hwang, T.J.; Karanjia, R; Moraes-Filho, M.N.; Gale, J; Show Tran, J.; Chu, E.R.; Salomao, S.R.; Berezovsky, A; Belfort Jr., R; Nunes Moraes, M; Sadun, F; DeNegri, A.M.; La Morgia, C; Barboni, P; Ramos, C.; Chicani, C.F.; Quiros, P.A.; Carelli, V; Sadun, A.A. (2017). "Natural History of Conversion of Leber's Hereditary Optic Neuropathy". Ophthalmology. 124 (6): 843–850. doi:10.1016/j.ophtha.2017.01.002. PMID 28196731. 37. ^ Hutchinson, C.V.; Walker, J.A.; Davidson, C (2014). "Oestrogen, ocular function and low-level vision: a review". Journal of Endocrinology. 223 (2): R9–R18. doi:10.1530/JOE-14-0349. PMID 25143633. 38. ^ Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (February 2003). "The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England". Am. J. Hum. Genet. 72 (2): 333–9. doi:10.1086/346066. PMC 379226. PMID 12518276. 39. ^ Puomila A, Hämäläinen P, Kivioja S, et al. (October 2007). "Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland". Eur. J. Hum. Genet. 15 (10): 1079–89. doi:10.1038/sj.ejhg.5201828. PMID 17406640. 40. ^ Laberge AM, Jomphe M, Houde L, et al. (2005). "A "Fille du Roy" Introduced the T14484C Leber Hereditary Optic Neuropathy Mutation in French Canadians". Am. J. Hum. Genet. 77 (2): 313–7. doi:10.1086/432491. PMC 1224533. PMID 15954041. 41. ^ Hudson G, Carelli V, Horvath R, Zeviani M, Smeets HJ, Chinnery PF (2007). "X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy". Mol. Vis. 13: 2339–43. PMID 18199976. 42. ^ Hudson G, Keers S, Yu Wai Man P, et al. (December 2005). "Identification of an X-Chromosomal Locus and Haplotype Modulating the Phenotype of a Mitochondrial DNA Disorder". Am. J. Hum. Genet. 77 (6): 1086–91. doi:10.1086/498176. PMC 1285165. PMID 16380918. 43. ^ Chinnery PF, Andrews RM, Turnbull DM, Howell NN (January 2001). "Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?". Am. J. Med. Genet. 98 (3): 235–43. doi:10.1002/1096-8628(20010122)98:3<235::AID-AJMG1086>3.0.CO;2-O. PMID 11169561. 44. ^ Hudson G, Carelli V, Spruijt L, et al. (August 2007). "Clinical Expression of Leber Hereditary Optic Neuropathy Is Affected by the Mitochondrial DNA–Haplogroup Background". Am. J. Hum. Genet. 81 (2): 228–33. doi:10.1086/519394. PMC 1950812. PMID 17668373. 45. ^ Leber T. Ueber hereditaere und congenital angelegte sehnervenleiden (1871) Graefes Arch Clin Exp Ophthalmol. 17:249–291 46. ^ Erickson RP (May 1972). "Leber's optic atrophy, a possible example of maternal inheritance". American Journal of Human Genetics. 24 (3): 348–9. PMC 1762279. PMID 5063796. 47. ^ Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK (December 1988). "Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy". Science. 242 (4884): 1427–30. Bibcode:1988Sci...242.1427W. doi:10.1126/science.3201231. PMID 3201231. 48. ^ Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus ML (1991). "A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy". Am J Hum Genet. 48 (6): 1147–1153. PMC 1683111. PMID 1674640. 49. ^ Johns DR, Neufeld MJ, Park RD (1992). "An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy". Biochem Biophys Res Commun. 187 (3): 1551–1557. doi:10.1016/0006-291x(92)90479-5. PMID 1417830. 50. ^ Sahel, J.A.; Uretsky, S.; Combal, J.P.; Galy, A.; Thomasson, N.; Fitoussi, S.; Corral-Debrinsky, M.; Honnet, G.; Vignal, C. (June 2015). "Preliminary safety and tolerability results of intravitreal administration of GS010, a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing human wildtype mitochondrial NADH dehydrogenase 4 (ND4) gene in patients with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial DNA mutation". Invest. Ophthalmol. Vis. Sci. 56 (7): 1088. Retrieved March 22, 2016. 51. ^ Birk, A.V.; Liu, S.; Soong, Y.; Mills, W.; Singh, P.; Warren, J.D.; Seshan, S.V.; Pardee, J.D.; Szeto, H.H. (July 2013). "The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin". J Am Soc Nephrol. 24 (8): 1250–61. doi:10.1681/ASN.2012121216. PMC 3736700. PMID 23813215. 52. ^ Thomas, D.A.; Stauffer, C.; Zhao, K.; Yang, H.; Sharma, V.K.; Szeto, H.H.; Suthanthiran, M. (January 2007). "Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function". J Am Soc Nephrol. 18 (1): 213–222. doi:10.1681/asn.2006080825. PMID 17151329. Retrieved March 22, 2016. 53. ^ Brown DA; Hale SL; Baines CP; et al. (January 2014). "Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia". J Cardiovasc Pharmacol Ther. 19 (1): 121–132. doi:10.1177/1074248413508003. PMC 4103197. PMID 24288396. ## Further reading[edit] * Leber's hereditary optic neuropathy at NLM Genetics Home Reference * Kerrison JB, Newman NJ (1997). "Clinical spectrum of Leber's hereditary optic neuropathy" (IFOND reprints). Clin. Neurosci. 4 (5): 295–301. PMID 9292259. * Carelli V, Ross-Cisneros FN, Sadun AA (January 2004). "Mitochondrial dysfunction as a cause of optic neuropathies". Prog Retin Eye Res. 23 (1): 53–89. doi:10.1016/j.preteyeres.2003.10.003. PMID 14766317. ## External links[edit] Classification D * ICD-10: H47.2 * ICD-9-CM: 377.16 * OMIM: 535000 * MeSH: D029242 * DiseasesDB: 7340 * NCBI Genetic Testing Registry * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis * v * t * e Mitochondrial diseases Carbohydrate metabolism * PCD * PDHA Primarily nervous system * Leigh disease * LHON * NARP Myopathies * KSS * Mitochondrial encephalomyopathy * MELAS * MERRF * PEO No primary system * DAD * MNGIE * Pearson syndrome Chromosomal * OPA1 * Kjer's optic neuropathy * SARS2 * HUPRA syndrome * TIMM8A * Mohr–Tranebjærg syndrome see also mitochondrial proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Leber's hereditary optic neuropathy	c0917796	1,182	wikipedia	https://en.wikipedia.org/wiki/Leber%27s_hereditary_optic_neuropathy	2021-01-18T18:45:59	{"gard": ["6870"], "mesh": ["D029242"], "umls": ["C0917796"], "icd-9": ["377.16"], "orphanet": ["104"], "wikidata": ["Q1262161"]}
Pregnancy-associated malaria (PAM) or placental malaria is a presentation of the common illness that is particularly life-threatening to both mother and developing fetus.[1] PAM is caused primarily by infection with Plasmodium falciparum,[1][2] the most dangerous of the four species of malaria-causing parasites that infect humans.[3] During pregnancy, a woman faces a much higher risk of contracting malaria and of associated complications.[4] Prevention and treatment of malaria are essential components of prenatal care in areas where the parasite is endemic – tropical and subtropical geographic areas.[5][6] While the average adult citizen of an endemic region possesses some immunity to the parasite,[7] pregnancy causes complications that leave the woman and fetus extremely vulnerable.[1] The parasite interferes with transmission of vital substances through the fetal placenta,[1][8] often resulting in stillbirth, spontaneous abortion, or dangerously low birth weight.[1] The tragedy of malaria in developing countries, particularly sub-Saharan Africa, receives abundant attention from the international health community, but until recently PAM and its unique complications were not adequately addressed.[6] ## Contents * 1 Cause * 1.1 Transmission * 1.2 Risk Factors * 2 Mechanism * 3 Signs and symptoms * 4 Maternal and fetal outcomes * 5 Prevention and treatment * 5.1 Prevention * 5.2 Non-pharmacological treatment * 5.3 Pharmacological treatment * 6 Epidemiology * 7 Research Directions * 8 References * 9 Further reading ## Cause[edit] ### Transmission[edit] Transmission of malaria occurs when humans get bitten by infected mosquitos carrying the parasite known as Plasmodium falciparum. The saliva from the mosquito transfers the P. falciparum into the blood as sporozoites which then travel to the liver where they are converted to the merozite form and further replicated.[9] After undergoing these changes in the liver, the parasite is then able to infect erythrocytes in the bloodstream. It can take 7 to 30 days after being bitten by a mosquito before symptoms start to arise. It is believed that pregnant women are more susceptible to malaria infection due to being immunocompromised and because infected erythrocytes tend to congregate around the placenta.[10] As a result, the WHO recommends that pregnant women avoid traveling to high endemic regions.[11] ### Risk Factors[edit] The disease results from the aggregation of erythrocytes infected by Plasmodium falciparum which have been shown to adhere to chondroitin sulfate A (CSA) on placental proteoglycans causing them to accumulate in the intervillous spaces of the placenta, blocking the crucial flow of nutrients from mother to embryo.[1] Infected erythrocytes express the VAR2CSA variant of P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) which allows them to bind to CSA on the placenta.[12] The accumulation of infected erythrocytes in the placenta inhibit the exchange of nutrients between the mother and fetus and also causes local inflammation.[13] In areas of high malaria transmission such as Africa, women experiencing their first pregnancies have the highest risk of infection compared to in lower transmission areas where the number of pregnancies has less of an effect on infection rates.[14] This is because women who are pregnant for the first time generally lack antibodies to VAR2CSA on erythrocytes that have been infected by the parasite. Women are most susceptible to malaria infection early on in the first trimester but the risk of infection decreases in the second trimester due to the development of antibodies to the infectious agent over time following the initial exposure. The infection risk also decreases after successive pregnancies.[15] Women that are infected with human immunodeficiency virus (HIV) are also at a high risk of having a higher parasite burden within the placenta during pregnancy.[16] This increased parasite burden can show up as increased reporting of symptoms associated with PAM and an increased likelihood of adverse maternal and fetal outcomes. There is also an increased risk of an HIV positive woman developing pregnancy-associated malaria in subsequent pregnancies.[16] Although the exact biological mechanism around how HIV and malaria disease states affect each other, it is thought that each condition affects how the immune system reacts to the other condition.[17] ## Mechanism[edit] P. falciparum expresses proteins on the surface of parasite-infected erythrocytes (IE) helping them bind to an unusually low-sulfated form of chondroitin sulfate A (CSA) in the placental intervillous space.[18][19] By this process, the parasite avoids being filtered through the spleen where it would be cleared from the bloodstream and killed.[20][21] When selected in vitro for CSA-binding, the only upregulated gene expressed in the P. falciparum parasites was the var2csa gene.[22] Parasite clones where the var2csa gene was disrupted lost the ability to adhere to CSA by blocking the binding of IE.[19][23] Its protein, VAR2CSA (Variant Surface antigen 2-CSA), belongs to the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family and contains six Duffy binding-like (DBL) domains. The regions that mediate binding to CSA have not been defined, but DBL2, DBL3, and DBL6 have shown the highest affinity for CSA binding when testing with recombinant single-domains.[19][24] A unique var gene (PFL0030c or var2csa) encodes this particular PfEMP1, which is differently regulated than other genes from the var family.[25] It is also only expressed as protein in pregnant women, even though the transcript is present in children, men and non-pregnant women.[26] It has a unique regulatory region, a uORF located upstream from the ORF that codes for the VAR2CSA protein. The expression of a protein named PTEF (after Plasmodium falciparum translation-enhancing factor) has been described to be necessary for the translation machinery to overcome the uORF and produce VAR2CSA protein,[27] but the mechanism behind it remains to be elucidated. ## Signs and symptoms[edit] Some initial symptoms of malaria include feeling unwell, experiencing headaches and fatigue, and having muscle aches and abdominal pain. This can eventually progress to a fever. Other common symptoms consist of nausea, vomiting, and orthostatic hypertension. Malaria can also lead to seizures which may precede going into a comatose state.[28] In regions of high transmission, such as Africa, women experiencing PAM may exhibit normal symptoms of malaria, but may also be asymptomatic or present with more mild symptoms, including a lack of the characteristic fever. This is due to the fact that these women most likely have partial immunity, which may prevent a woman from seeking treatment despite the danger to herself and her unborn child.[14][29] Conversely, in regions of low malaria transmission, PAM is associated with a higher likelihood of symptoms as these women most likely did not acquire immunity.[14] ## Maternal and fetal outcomes[edit] In general, women with PAM have a higher likelihood of premature birth and their infants having a low birthweight.[30] In examination of possible malarial immunity, some studies have shown that the presence of P. falciparum antibodies (specifically CSA adhesion inhibitory antibodies or IgG antibodies) may decrease the likelihood of low birthweight in the infants of women who have had pregnancy-associated malaria, but these findings do not specifically correlate to malarial immunity during pregnancy.[31] However, the relationship between many P. falciparum antibodies during pregnancy and maternal and birth outcomes remains variable. Lower birthweight of infants born from mothers with PAM can be attributed to placental infection, as well as other complications such as anemia and malnutrition, since the malarial parasite can be passed vertically from mother to the infant via infected red blood cells.[32] Children who are born with a below-average birthweight are at risk for other health problems, including increased risk of mortality.[32] Anemia is a great concern as an adverse effect of pregnancy-associated malaria, since it can be life-threatening to the mother.[32] Its cause is often compounded with other factors, such as nutrition and genetics. Some studies have suggested that iron supplementation can help with maternal anemia, but more research on malaria-endemic regions is required to make a better recommendation for mothers with PAM.[33] One systematic review showed that children of women with PAM are also more likely to contract clinical malaria and P. falciparum parasitaemia, although the reasoning for this is uncertain.[34] Maternal death is one of the biggest complications of malaria in some areas during epidemics. Furthermore, its cause is compounded with other malarial complications, such as anemia. ## Prevention and treatment[edit] ### Prevention[edit] Prevention of pregnancy-associated malaria can be done with the use of various antimalarial drugs that are given before or during pregnancy to susceptible populations.[35] Some of the antimalarial drugs used include Chloroquine, Mefloquine, and Sulfadoxine/pyrimethamine since they are safe for use during pregnancy.[35][36] For regions of moderate or high malaria risk, preventative measures include insecticide-treated nets (ITNs) and intermittent preventive treatment in pregnancy (IPTp).[37][38] ITNs act as two layers of protection, one from the physical net and another from the chemical nature and effects of the insecticide.[39] Because IPTp plays a role in altering the immune response that the infant can display, the World Health Organization recommends starting IPTp as soon as possible during the 2nd trimester.[37] These treatments are with doses of Sulfadoxine/pyrimethamine and are given at each antenatal visit, as long as the visits are one month apart.[40] One concern with the use of Sulfadoxine/pyrimethamine along with other antimalarial drugs is P. falciparum developing resistance. In areas that have higher rates of resistance to the antimalarial Sulfadoxine/pyrimethamine, two doses of the drug is effective in reducing maternal parasitemia in women that do not have HIV while more doses are needed to reduce maternal parasitemia in HIV positive women.[41] ### Non-pharmacological treatment[edit] Non-pharmacological treatment of PAM consists of utilizing the Artemisia annua plant as an herbal remedy. The basis for this reasoning is because A. annua acts as the plant source for Artemisinin-based combination therapy (ACT), a commonly used pharmacological treatment of PAM. However, the WHO currently does not support the use of A. annua as there are no standardization guidelines for plant harvest and preparation. Additionally, its clinical safety and efficacy have not yet been proven.[42] ### Pharmacological treatment[edit] Treatment of PAM is highly dependent on the mother's current pregnancy stage (i.e. trimester) and the species responsible for the disease transmission. For infection caused by P. falciparum, the WHO recommends during the first trimester a treatment consisting of both Quinine and Clindamycin for a duration of 7 days. During the second and third trimester, the WHO recommendations of ACT, are the same as ones for non-pregnant individuals.[43][44] For infection caused by the other species, which include Plasmodium malariae, Plasmodium vivax, and Plasmodium ovale, the WHO recommends Chloroquine or Quinine during the first trimester. Quinine is used as an alternative if chloroquine-resistance is detected. During the second and third trimester, the WHO recommends either ACT or Chloroquine. If chloroquine-resistance is detected, ACT is the treatment of choice.[43][44] The Centers for Disease Control and Prevention (CDC) has similar recommendations to the WHO.[45] ## Epidemiology[edit] Globally, an estimated 125 million or more pregnant women per year risk contracting PAM.[46] Pregnancy-related malaria causes around 100,000 infant deaths each year, due in large part to low birth weight.[14] Due to the nature of disease transmission (i.e. via mosquitoes) and life cycle of the parasite, malaria is prevalent in warm, humid climates, such as tropical and subtropical regions.[47] Consistent with previous years, the incidence of malaria in general is greatest in African regions, specifically sub-Saharan Africa, as defined by the World Health Organization (WHO), although there was a decline in numbers from 2010 to 2018.[32] Particularly, in Central and West Africa, the number of pregnancies with malarial infection reached around 35% of all pregnancies in those regions in 2018.[32] The regions that follow Africa in terms of malaria cases are Southeast Asia and the Mediterranean, although it is important to note that Africa has the largest number of cases by far; these regions comprise over 90% of the global incidences of malaria.[32] In the realm of pregnancy, individual immunity and level of transmission within the area play an important role in the malarial complications that manifest.[32] For example, areas with high level of transmission are also associated with higher incidence of immunity. Therefore, infection from P. falciparum is usually associated with no symptoms in pregnant women.[32] However, it is not to conclude that the presence of P. falciparum is completely benign, as it has been associated with maternal anaemia.[32] Specifically, in these settings, women in their first pregnancy are at greatest risk of complications that arise from P. falciparum.[48] Similarly to P. falciparum, Plasmodium vivax (P. vivax), another malarial pathogen found primarily in Asia and South America, has also been associated with maternal anaemia and low birthweight.[32][49] On the contrary, women who live in areas with lower transmission are at a very high risk of adverse malarial outcomes despite their number of pregnancies.[48] ## Research Directions[edit] Each VAR2CSA domain has a potential affinity to CSA, but there are large areas not exposed to the immune system and appear to be buried in the quaternary structure.[21][50] Data has indicated that these domains interact, forming a binding site that is specific for low-sulfated CSA found in the placenta.[21][51][52] The binding of antibodies to one of these domains would prevent adhesion of parasitic IE in the placenta. Moreover, studies have shown that women acquire immunity to PAM through antibody recognition of the VAR2CSA domain, also known as VSAPAM, after exposure during their first pregnancy. By measuring circulating levels of IgG antibodies that presumably target VAR2SCA, the study demonstrated that subsequent pregnancies confer progressively greater protection to PAM. Thus, PfEMP1 proteins such as the VAR2CSA domain could prove attractive as potential candidates for vaccine targets.[12] Additional genetic testing relating to pregnancy-associated malaria is currently being researched which involves looking at glucose-6-phosphate dehydrogenase (G6PD) which is an enzyme that is responsible for keeping red blood cells protected from being destroyed too soon by things such as foods and medications.[53][54] The gene for this enzyme is found on the X chromosome which means that women in particular can have G6PD function that is normal, intermediate (which often shows up on lab tests as normal), and deficient.[53] This gene is important in determining if certain antimalarial drugs such as Primaquine and Tafenoquine can be used since these antimalarial drugs are more likely to cause red blood cell hemolysis in women with a G6PD deficiency and worsen any anemia that comes from the malaria infection.[54] Although these drugs would most likely be used after delivery for treatment of pregnancy-associated malaria, this genetic testing can help avoid inducing anemia in women more prone to red blood cell breakdown. A vaccine to prevent a pregnancy-associated malaria called PAMVAC is currently undergoing clinical trials. PAMVAC is based on a recombinant form of the VAR2CSA domain and has been shown to be well-tolerated when injected in malaria-naive volunteers while also successfully inducing the production of antibodies against VAR2CSA.[55] Although the vaccine was injected in healthy participants who did not have malaria, the study provided insight into the vaccine's safety before administration into the target population – women with PAM.[55][56] A second vaccine candidate against pregnancy-associated malaria called PRIMVAC is also currently undergoing clinical trials in healthy adult women as a 3 dose course. This vaccine is based on the DBL1x-2x domain of VAR2CSA which is able to bind to CSA in the placenta. In preclinical studies, PRIMVAC injected in rats led to the production of antibodies against VAR2CSA on infected erythrocytes and also resulted in reduction of their binding to CSA. The vaccine was also shown to be well-tolerated in rats without any notable adverse reactions.[57] ## References[edit] 1. ^ a b c d e f Srivastava A, Gangnard S, Round A, Dechavanne S, Juillerat A, Raynal B, et al. (March 2010). "Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific, high-affinity binding to CSA". Proceedings of the National Academy of Sciences of the United States of America. 107 (11): 4884–9. Bibcode:2010PNAS..107.4884S. doi:10.1073/pnas.1000951107. PMC 2841952. PMID 20194779. Lay summary – ScienceDaily (March 12, 2010). 2. ^ "CDC-Malaria-Malaria Parasites". Centers for Disease Control and Prevention. 2019-01-28. 3. ^ Perlmann P, Troye-Blomberg M (2000). "Malaria blood-stage infection and its control by the immune system". Folia Biologica. 46 (6): 210–8. PMID 11140853. 4. ^ "Lives at Risk: Malaria in Pregnancy". WHO. Retrieved March 30, 2011. 5. ^ Duffy PE, Fried M (2005). Malaria in the Pregnant Woman. Current Topics in Microbiology and Immunology. 295. pp. 169–200. doi:10.1007/3-540-29088-5_7. ISBN 978-3-540-25363-1. PMID 16265891. 6. ^ a b "Roll Back Malaria: Malaria in Pregnancy". WHO. Archived from the original on 6 August 2006. Retrieved 18 April 2011. 7. ^ Doolan DL, Dobaño C, Baird JK (January 2009). "Acquired immunity to malaria". Clinical Microbiology Reviews. 22 (1): 13–36, Table of Contents. doi:10.1128/CMR.00025-08. PMC 2620631. PMID 19136431. 8. ^ Matteelli A, Caligaris S, Castelli F, Carosi G (October 1997). "The placenta and malaria". Annals of Tropical Medicine and Parasitology. 91 (7): 803–10. doi:10.1080/00034989760563. PMID 9625937. 9. ^ Kumar H, Tolia NH (September 2019). "Getting in: The structural biology of malaria invasion". PLOS Pathogens. 15 (9): e1007943. doi:10.1371/journal.ppat.1007943. PMC 6728024. PMID 31487334. 10. ^ Schantz-Dunn J, Nour NM (2009). "Malaria and pregnancy: a global health perspective". Reviews in Obstetrics & Gynecology. 2 (3): 186–92. PMC 2760896. PMID 19826576. 11. ^ "WHO \| Information for travellers". WHO. Retrieved 2020-08-04. 12. ^ a b Hviid L, Salanti A (2007). "VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria". Parasitology. 134 (Pt 13): 1871–6. doi:10.1017/S0031182007000121. PMID 17958922. 13. ^ Zakama AK, Gaw SL (September 2019). "Malaria in Pregnancy: What the Obstetric Provider in Nonendemic Areas Needs to Know". Obstetrical & Gynecological Survey. 74 (9): 546–556. doi:10.1097/OGX.0000000000000704. PMC 7560991. PMID 31830300. 14. ^ a b c d Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD (February 2007). "Epidemiology and burden of malaria in pregnancy". The Lancet. Infectious Diseases. 7 (2): 93–104. doi:10.1016/S1473-3099(07)70021-X. PMID 17251080. 15. ^ Gamain B, Smith JD, Viebig NK, Gysin J, Scherf A (March 2007). "Pregnancy-associated malaria: parasite binding, natural immunity and vaccine development". International Journal for Parasitology. 37 (3–4): 273–83. doi:10.1016/j.ijpara.2006.11.011. PMID 17224156. 16. ^ a b Kwenti TE (2018). "Malaria and HIV coinfection in sub-Saharan Africa: prevalence, impact, and treatment strategies". Research and Reports in Tropical Medicine. 9: 123–136. doi:10.2147/rrtm.s154501. PMC 6067790. PMID 30100779. 17. ^ Frischknecht F, Fackler OT (July 2016). "Experimental systems for studying Plasmodium/HIV coinfection". FEBS Letters. 590 (13): 2000–13. doi:10.1002/1873-3468.12151. PMID 27009943. 18. ^ Fried M, Duffy PE (June 1996). "Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta". Science. New York, N.Y. 272 (5267): 1502–4. Bibcode:1996Sci...272.1502F. doi:10.1126/science.272.5267.1502. PMID 8633247. S2CID 43040825. 19. ^ a b c Nielsen MA, Pinto VV, Resende M, Dahlbäck M, Ditlev SB, Theander TG, Salanti A (June 2009). "Induction of adhesion-inhibitory antibodies against placental Plasmodium falciparum parasites by using single domains of VAR2CSA". Infection and Immunity. 77 (6): 2482–7. doi:10.1128/IAI.00159-09. PMC 2687338. PMID 19307213. 20. ^ David PH, Hommel M, Miller LH, Udeinya IJ, Oligino LD (August 1983). "Parasite sequestration in Plasmodium falciparum malaria: spleen and antibody modulation of cytoadherence of infected erythrocytes". Proceedings of the National Academy of Sciences of the United States of America. 80 (16): 5075–9. Bibcode:1983PNAS...80.5075D. doi:10.1073/pnas.80.16.5075. PMC 384191. PMID 6348780. 21. ^ a b c Resende M, Ditlev SB, Nielsen MA, Bodevin S, Bruun S, Pinto VV, Clausen H, Turner L, Theander TG, Salanti A, Dahlbäck M (September 2009). "Chondroitin sulphate A (CSA)-binding of single recombinant Duffy-binding-like domains is not restricted to Plasmodium falciparum Erythrocyte Membrane Protein 1 expressed by CSA-binding parasites". International Journal for Parasitology. 39 (11): 1195–204. doi:10.1016/j.ijpara.2009.02.022. PMID 19324047. 22. ^ Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, Hviid L, Theander TG (July 2003). "Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria". Molecular Microbiology. 49 (1): 179–91. doi:10.1046/j.1365-2958.2003.03570.x. PMID 12823820. 23. ^ Viebig NK, Gamain B, Scheidig C, Lépolard C, Przyborski J, Lanzer M, Gysin J, Scherf A (August 2005). "A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A". EMBO Reports. 6 (8): 775–81. doi:10.1038/sj.embor.7400466. PMC 1369142. PMID 16025132. 24. ^ Gamain B, Trimnell AR, Scheidig C, Scherf A, Miller LH, Smith JD (March 2005). "Identification of multiple chondroitin sulfate A (CSA)-binding domains in the var2CSA gene transcribed in CSA-binding parasites". The Journal of Infectious Diseases. 191 (6): 1010–3. doi:10.1086/428137. PMID 15717280. 25. ^ Bancells C, Deitsch KW (November 2013). "A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria". Molecular Microbiology. 90 (3): 472–88. doi:10.1111/mmi.12379. PMC 3938558. PMID 23980802. 26. ^ Duffy MF, Caragounis A, Noviyanti R, Kyriacou HM, Choong EK, Boysen K, et al. (August 2006). "Transcribed var genes associated with placental malaria in Malawian women". Infection and Immunity. 74 (8): 4875–83. doi:10.1128/IAI.01978-05. PMC 1539630. PMID 16861676. 27. ^ Chan S, Frasch A, Mandava CS, Ch'ng JH, Quintana MD, Vesterlund M, et al. (May 2017). "Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor". Nature Microbiology. 2 (7): 17068. doi:10.1038/nmicrobiol.2017.68. PMID 28481333. S2CID 2276480. 28. ^ White NJ, Pukrittayakamee S, Hien TT, Faiz MA, Mokuolu OA, Dondorp AM (2014). "Malaria". The Lancet. 383 (9918): 723–735. doi:10.1016/s0140-6736(13)60024-0. PMID 23953767. S2CID 208794141. 29. ^ "Burden of Malaria in Pregnancy in Latin America Not Known". Centers for Disease Control and Prevention. Retrieved April 14, 2011. 30. ^ Thompson JM, Eick SM, Dailey C, Dale AP, Mehta M, Nair A, et al. (June 2020). "Relationship Between Pregnancy-Associated Malaria and Adverse Pregnancy Outcomes: a Systematic Review and Meta-Analysis". Journal of Tropical Pediatrics. 66 (3): 327–338. doi:10.1093/tropej/fmz068. PMID 31598714. 31. ^ Cutts JC, Agius PA, Powell R, Moore K, Draper B, Simpson JA, Fowkes FJ (January 2020). "Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review". BMC Medicine. 18 (1): 14. doi:10.1186/s12916-019-1467-6. PMC 6964062. PMID 31941488. 32. ^ a b c d e f g h i j World Malaria Report 2019. World Health Organization. 2019. ISBN 978-92-4-156572-1. OCLC 1156338614. 33. ^ Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T (July 2015). "Daily oral iron supplementation during pregnancy". The Cochrane Database of Systematic Reviews (7): CD004736. doi:10.1002/14651858.CD004736.pub5. PMC 4233117. PMID 26198451. 34. ^ Park S, Nixon CE, Miller O, Choi NK, Kurtis JD, Friedman JF, Michelow IC (July 2020). "Impact of Malaria in Pregnancy on Risk of Malaria in Young Children: Systematic Review and Meta-Analyses". The Journal of Infectious Diseases. 222 (4): 538–550. doi:10.1093/infdis/jiaa139. PMC 7377293. PMID 32219317. 35. ^ a b Cot M, Deloron P (2003). "Malaria prevention strategies". British Medical Bulletin. 67 (1): 137–48. doi:10.1093/bmb/ldg003. PMID 14711760. 36. ^ CDC-Centers for Disease Control and Prevention (2019). "CDC - Malaria - Travelers - Choosing a Drug to Prevent Malaria". www.cdc.gov. Retrieved 2020-07-31. 37. ^ a b Moya-Alvarez V, Abellana R, Cot M (July 2014). "Pregnancy-associated malaria and malaria in infants: an old problem with present consequences". Malaria Journal. 13 (1): 271. doi:10.1186/1475-2875-13-271. PMC 4113781. PMID 25015559. 38. ^ Agboghoroma CO (2014). "Current management and prevention of malaria in pregnancy: a review". West African Journal of Medicine. 33 (2): 91–9. PMID 25236824. 39. ^ "Fact sheet about Malaria". www.who.int. Retrieved 2020-08-02. 40. ^ Gueneuc A, Deloron P, Bertin GI (January 2017). "Usefulness of a biomarker to identify placental dysfunction in the context of malaria". Malaria Journal. 16 (1): 11. doi:10.1186/s12936-016-1664-0. PMC 5209802. PMID 28049536. 41. ^ ter Kuile FO, van Eijk AM, Filler SJ (June 2007). "Effect of sulfadoxine-pyrimethamine resistance on the efficacy of intermittent preventive therapy for malaria control during pregnancy: a systematic review". JAMA. 297 (23): 2603–16. doi:10.1001/jama.297.23.2603. PMID 17579229. 42. ^ "The use of non-pharmaceutical forms of Artemisia". www.who.int. Retrieved 2020-08-04. 43. ^ a b Guidelines for the treatment of malaria. World Health Organization (Third ed.). Geneva. 13 August 2015. ISBN 978-92-4-154912-7. OCLC 908628497.CS1 maint: others (link) 44. ^ a b Bauserman M, Conroy AL, North K, Patterson J, Bose C, Meshnick S (August 2019). "An overview of malaria in pregnancy". Seminars in Perinatology. 43 (5): 282–290. doi:10.1053/j.semperi.2019.03.018. hdl:1805/22076. PMID 30979598. 45. ^ "Malaria - Diagnosis & Treatment (United States) - Treatment (U.S.) - Guidelines for Clinicians (Part 3)". www.cdc.gov. CDC-Centers for Disease Control and Prevention. 2019-03-27. Retrieved 2020-08-02. 46. ^ Worldwide Antimalarial Resistance Network (WWARN) (2016-01-28). "Malaria in Pregnancy Consortium". Worldwide Antimalarial Resistance Network. Retrieved 2020-08-04. 47. ^ "CDC - Malaria - About Malaria - Where Malaria Occurs". www.cdc.gov. CDC-Centers for Disease Control and Prevention. 2020. Retrieved 2020-07-31. 48. ^ a b World Health Organization. "Malaria in pregnant women". WHO. Retrieved 2020-07-31. 49. ^ United Kingdom National Health Service (2018). "Malaria - Causes". nhs.uk. Retrieved 2020-07-31. 50. ^ Andersen P, Nielsen MA, Resende M, Rask TS, Dahlbäck M, Theander T, Lund O, Salanti A (February 2008). "Structural insight into epitopes in the pregnancy-associated malaria protein VAR2CSA". PLOS Pathogens. 4 (2): e42. doi:10.1371/journal.ppat.0040042. PMC 2242842. PMID 18282103. 51. ^ Avril M, Gamain B, Lépolard C, Viaud N, Scherf A, Gysin J (2006). "Characterization of anti-var2CSA-PfEMP1 cytoadhesion inhibitory mouse monoclonal antibodies". Microbes and Infection. 8 (14–15): 2863–71. doi:10.1016/j.micinf.2006.09.005. PMID 17095277. 52. ^ Fernandez P, Viebig NK, Dechavanne S, Lépolard C, Gysin J, Scherf A, Gamain B (September 2008). "Var2CSA DBL6-epsilon domain expressed in HEK293 induces limited cross-reactive and blocking antibodies to CSA binding parasites". Malaria Journal. 7: 170. doi:10.1186/1475-2875-7-170. PMC 2543044. PMID 18771584. 53. ^ a b "G6PD gene". Genetics Home Reference. Retrieved 2020-08-05. 54. ^ a b Brummaier T, Gilder ME, Gornsawun G, Chu CS, Bancone G, Pimanpanarak M, et al. (January 2020). "Vivax malaria in pregnancy and lactation: a long way to health equity". Malaria Journal. 19 (1): 40. doi:10.1186/s12936-020-3123-1. PMC 6977346. PMID 31969155. 55. ^ a b Mordmüller B, Sulyok M, Egger-Adam D, Resende M, de Jongh WA, Jensen MH, et al. (October 2019). "First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria". Clinical Infectious Diseases. 69 (9): 1509–1516. doi:10.1093/cid/ciy1140. PMC 6792113. PMID 30629148. 56. ^ GEN (2019-01-10). "Pregnancy-Associated Malaria Vaccine Passes First Human Trial". GEN - Genetic Engineering and Biotechnology News. Retrieved 2020-08-02. 57. ^ Chêne A, Gangnard S, Guadall A, Ginisty H, Leroy O, Havelange N, et al. (April 2019). "Preclinical immunogenicity and safety of the cGMP-grade placental malaria vaccine PRIMVAC". EBioMedicine. 42: 145–156. doi:10.1016/j.ebiom.2019.03.010. PMC 6491931. PMID 30885725. ## Further reading[edit] Scholia has a profile for pregnancy-associated malaria (Q7239883). * Brabin BJ (1983). "An analysis of malaria in pregnancy in Africa". Bulletin of the World Health Organization. 61 (6): 1005–16. PMC 2536236. PMID 6370484. * "Prevention and Treatment of Malaria in Pregnancy in Sub-Saharan Africa" (PDF). United States Agency for International Development. February 2007. * "Malaria in Pregnancy Resource Package". Jhpiego. Archived from the original on 2010-12-16. 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Spinocerebellar ataxia type 6 Other namesDiseasesDB = 12339 This condition is inherited in an autosomal dominant manner SpecialtyNeurology Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, peripheral neuropathy, and ataxia of the gait, stance, and limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel α subunit. These mutations tend to be trinucleotide repeats of CAG, leading to the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Screening * 5 Treatment * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] SCA6 is typified by progressive and permanent cerebellar dysfunction. These cerebellar signs include ataxia and dysarthria, likely caused by cerebellar atrophy. Prior to diagnosis and the onset of major symptoms, patients often report a feeling of "wooziness" and momentary imbalance when turning corners or making rapid movements. The age at which symptoms first occur varies widely, from age 19 to 71, but is typically between 43 and 52. Other major signs of SCA6 are the loss of vibratory and proprioceptive sensation and nystagmus.[1] While most patients present with these severe progressive symptoms, others, sometimes within the same family, display episodic non-progressive symptoms more similar to episodic ataxia. Still others present with symptoms common to both SCA6 and familial hemiplegic migraine. ## Pathophysiology[edit] Most cases of SCA6 are a result of CAG repeat expansion beyond the normal range, i.e., more than 19 repeats, in the Cav2.1 calcium channel encoding gene CACNA1A.[1] This gene has two splice forms, "Q-type" and "P-type", and the polyglutamine coding CAG expansion occurs in the P-type splice form. This form is expressed heavily in the cerebellum where it is localized in Purkinje cells. In Purkinje cells from SCA6 patients, mutant Cav2.1 proteins form ovular intracellular inclusions, or aggregations, similar in many ways to those seen in other polyglutamine expansion disorders such as Huntington's disease. In cell culture models of the disease, this leads to early apoptotic cell death.[2] Mutant channels that are able to traffic properly to the membrane have a negatively shifted voltage-dependence of inactivation. The result of this is that the channels are active for a shorter amount of time and, consequently, cell excitability is decreased.[3] There are also a number of point mutations resulting in patients with phenotypes reminiscent of episodic ataxia and SCA6 (C271Y, G293R and R1664Q) or familial hemiplegic migraine and SCA6 (R583Q and I1710T). C287Y and G293R are both located in the pore region of domain 1 and are present in a single family each. Expression of these mutant channels results in cells with drastically decreased current density compared to wild-type expressing cells. In cell-based assays, it was found that these mutant channels aggregate in the endoplasmic reticulum, not dissimilar from that seen in the CAG expansion mutants above.[4] R1664Q is in the 4th transmembrane spanning segment of domain 4 and, presumably, affects the channel's voltage dependence of activation.[5] Little is known about the point mutations resulting in overlapping phenotypes of familial hemiplegic migraine and episodic ataxia. R583Q is present in the 4th transmembrane spanning region of domain 2 while the I1710T mutation is segment 5 of domain 4.[6][7] ## Diagnosis[edit] Spinocerebellar Ataxia Diagnosis is done via genetic testing. Your Neurologist can administer the test. Spinocerebellar Ataxia is often misdiagnosed as other diseases such as ALC or Parkinson's Disease.[citation needed] ## Screening[edit] There is no known prevention of spinocerebellar ataxia. Those who are believed to be at risk can have genetic sequencing of known SCA loci performed to confirm inheritance of the disorder.[citation needed] ## Treatment[edit] There are no drug based treatments currently available for SCA Type 6, however, there are supportive treatments that may be useful in managing symptoms. Physical Therapy, Speech Pathology can help patients manage the symptoms.[citation needed] ## Epidemiology[edit] The prevalence of SCA6 varies by culture. In Germany, SCA6 accounts for 10-25% of all autosomal dominant cases of SCA (SCA itself having a prevalence of 1 in 100,000).[8][9] This prevalence in lower in Japan, however, where SCA6 accounts for only ~6% of spinocerebellar ataxias.[10] In Australia, SCA6 accounts for 30% of spinocerebellar ataxia cases while 11% in the Dutch.[11][12] ## See also[edit] * Calcium channel * Cerebellum * Episodic ataxia * Familial hemiplegic migraine * Huntington's disease * Spinocerebellar ataxia ## References[edit] 1. ^ a b Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton D, Amos C, Dobyns W, Subramony S, Zoghbi H, Lee C (1997). "Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel". Nat Genet. 15 (1): 62–9. doi:10.1038/ng0197-62. PMID 8988170. S2CID 9116828. 2. ^ Ishikawa K, Fujigasaki H, Saegusa H, Ohwada K, Fujita T, Iwamoto H, Komatsuzaki Y, Toru S, Toriyama H, Watanabe M, Ohkoshi N, Shoji S, Kanazawa I, Tanabe T, Mizusawa H (1999). "Abundant expression and cytoplasmic aggregations of [alpha]1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6". Hum Mol Genet. 8 (7): 1185–93. doi:10.1093/hmg/8.7.1185. PMID 10369863. 3. ^ Toru S, Murakoshi T, Ishikawa K, Saegusa H, Fujigasaki H, Uchihara T, Nagayama S, Osanai M, Mizusawa H, Tanabe T (2000). "Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function". J Biol Chem. 275 (15): 10893–8. doi:10.1074/jbc.275.15.10893. PMID 10753886. 4. ^ Wan J, Khanna R, Sandusky M, Papazian D, Jen J, Baloh R (2005). "CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics". Neurology. 64 (12): 2090–7. doi:10.1212/01.WNL.0000167409.59089.C0. PMID 15985579. S2CID 5679518. 5. ^ Tonelli A, D'Angelo M, Salati R, Villa L, Germinasi C, Frattini T, Meola G, Turconi A, Bresolin N, Bassi M (2006). "Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene". J Neurol Sci. 241 (1–2): 13–7. doi:10.1016/j.jns.2005.10.007. PMID 16325861. S2CID 36806418. 6. ^ Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P (2003). "Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family". Arch Neurol. 60 (4): 610–4. doi:10.1001/archneur.60.4.610. hdl:10400.16/349. PMID 12707077. 7. ^ Kors E, Vanmolkot K, Haan J, Kheradmand Kia S, Stroink H, Laan L, Gill D, Pascual J, van den Maagdenberg A, Frants R, Ferrari M (2004). "Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2". Neuropediatrics. 35 (5): 293–6. doi:10.1055/s-2004-821082. PMID 15534763. 8. ^ Riess O, Schöls L, Bottger H, Nolte D, Vieira-Saecker A, Schimming C, Kreuz F, Macek M, Krebsová A, Klockgether T, Zühlke C, Laccone F (1997). "SCA6 is caused by moderate CAG expansion in the alpha1A-voltage-dependent calcium channel gene". Hum Mol Genet. 6 (8): 1289–93. doi:10.1093/hmg/6.8.1289. PMID 9259275. 9. ^ Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen J, Riess O (1997). "Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes?". Ann Neurol. 42 (6): 924–32. doi:10.1002/ana.410420615. PMID 9403486. S2CID 32742844. 10. ^ Watanabe H, Tanaka F, Matsumoto M, Doyu M, Ando T, Mitsuma T, Sobue G (1998). "Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6". Clin Genet. 53 (1): 13–9. doi:10.1034/j.1399-0004.1998.531530104.x. PMID 9550356. 11. ^ Storey E, du Sart D, Shaw J, Lorentzos P, Kelly L, McKinley Gardner R, Forrest S, Biros I, Nicholson G (2000). "Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia". Am J Med Genet. 95 (4): 351–7. doi:10.1002/1096-8628(20001211)95:4<351::AID-AJMG10>3.0.CO;2-R. PMID 11186889. 12. ^ Sinke R, Ippel E, Diepstraten C, Beemer F, Wokke J, van Hilten B, Knoers N, van Amstel H, Kremer H (2001). "Clinical and molecular correlations in spinocerebellar ataxia type 6: a study of 24 Dutch families". Arch Neurol. 58 (11): 1839–44. doi:10.1001/archneur.58.11.1839. PMID 11708993. ## External links[edit] * sca6 at NIH/UW GeneTests Classification D * ICD-10: G11.2 * ICD-9-CM: 334.9 * OMIM: 183086 * SNOMED CT: 715752006 External resources * eMedicine: neuro/556 * Orphanet: 98758 * v * t * e Diseases of ion channels Calcium channel Voltage-gated * CACNA1A * Familial hemiplegic migraine 1 * Episodic ataxia 2 * Spinocerebellar ataxia type-6 * CACNA1C * Timothy syndrome * Brugada syndrome 3 * Long QT syndrome 8 * CACNA1F * Ocular albinism 2 * CSNB2A * CACNA1S * Hypokalemic periodic paralysis 1 * Thyrotoxic periodic paralysis 1 * CACNB2 * Brugada syndrome 4 Ligand gated * RYR1 * Malignant hyperthermia * Central core disease * RYR2 * CPVT1 * ARVD2 Sodium channel Voltage-gated * SCN1A * Familial hemiplegic migraine 3 * GEFS+ 2 * Febrile seizure 3A * SCN1B * Brugada syndrome 6 * GEFS+ 1 * SCN4A * Hypokalemic periodic paralysis 2 * Hyperkalemic periodic paralysis * Paramyotonia congenita * Potassium-aggravated myotonia * SCN4B * Long QT syndrome 10 * SCN5A * Brugada syndrome 1 * Long QT syndrome 3 * SCN9A * Erythromelalgia * Febrile seizure 3B * Paroxysmal extreme pain disorder * Congenital insensitivity to pain Constitutively active * SCNN1B/SCNN1G * Liddle's syndrome * SCNN1A/SCNN1B/SCNN1G * Pseudohypoaldosteronism 1AR Potassium channel Voltage-gated * KCNA1 * Episodic ataxia 1 * KCNA5 * Familial atrial fibrillation 7 * KCNC3 * Spinocerebellar ataxia type-13 * KCNE1 * Jervell and Lange-Nielsen syndrome * Long QT syndrome 5 * KCNE2 * Long QT syndrome 6 * KCNE3 * Brugada syndrome 5 * KCNH2 * Short QT syndrome * KCNQ1 * Jervell and Lange-Nielsen syndrome * Romano–Ward syndrome * Short QT syndrome * Long QT syndrome 1 * Familial atrial fibrillation 3 * KCNQ2 * BFNS1 Inward-rectifier * KCNJ1 * Bartter syndrome 2 * KCNJ2 * Andersen–Tawil syndrome * Long QT syndrome 7 * Short QT syndrome * KCNJ11 * TNDM3 * KCNJ18 * Thyrotoxic periodic paralysis 2 Chloride channel * CFTR * Cystic fibrosis * Congenital absence of the vas deferens * CLCN1 * Thomsen disease * Myotonia congenita * CLCN5 * Dent's disease * CLCN7 * Osteopetrosis A2, B4 * BEST1 * Vitelliform macular dystrophy * CLCNKB * Bartter syndrome 3 TRP channel * TRPC6 * FSGS2 * TRPML1 * Mucolipidosis type IV Connexin * GJA1 * Oculodentodigital dysplasia * Hallermann–Streiff syndrome * Hypoplastic left heart syndrome * GJB1 * Charcot–Marie–Tooth disease X1 * GJB2 * Keratitis–ichthyosis–deafness syndrome * Ichthyosis hystrix * Bart–Pumphrey syndrome * Vohwinkel syndrome) * GJB3/GJB4 * Erythrokeratodermia variabilis * Progressive symmetric erythrokeratodermia * GJB6 * Clouston's hidrotic ectodermal dysplasia Porin * AQP2 * Nephrogenic diabetes insipidus 2 See also: ion channels [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Spinocerebellar ataxia type 6	c0752124	1,184	wikipedia	https://en.wikipedia.org/wiki/Spinocerebellar_ataxia_type_6	2021-01-18T19:01:40	{"gard": ["10351"], "mesh": ["D020754"], "umls": ["C0752124"], "icd-9": ["334.9"], "icd-10": ["G11.2"], "orphanet": ["98758"], "wikidata": ["Q2868788"]}
High-grade neuroendocrine carcinoma of the corpus uteri is an extremely rare, aggressive, primary uterine neoplasm, originating from neuroendocrine cells scattered within the endometrium, characterized, macroscopically, by a bulky, frequently polypoid, mass with abundant necrosis located in the uterus and, histologically, by rosette-like and cord-like structures consisting of small, rounded cells with oval nuclei and scarce cytoplasm. Patients often present with dysfunctional uterine bleeding, pelvic or abdominal mass and, especially in later stages of the disease, abdominal pain. Symptomatic metastatic spread or symptoms related to a paraneoplastic syndrome, such as retinopathy, or Cushing syndrome due to ectopic ACTH production, may be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	High-grade neuroendocrine carcinoma of the corpus uteri	None	1,185	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=213731	2021-01-23T17:40:42	{"icd-10": ["C54.0", "C54.1", "C54.2", "C54.3", "C54.8"], "synonyms": ["High-grade neuroendocrine carcinoma of the uterine corpus", "Poorly differentiated neuroendocrine carcinoma of the corpus uteri", "Poorly differentiated neuroendocrine carcinoma of the endometrium"]}
Sulfatidosis SpecialtyEndocrinology Sulfatidosis is a form of lysosomal storage disease resulting in a proliferation of sulfatide. ## Contents * 1 Causes * 2 Diagnosis * 2.1 Types * 3 Treatment * 4 See also * 5 References * 6 External links ## Causes[edit] It is caused by a genetic insufficiency of sulfatase enzymes.[1] ## Diagnosis[edit] ### Types[edit] Metachromatic leukodystrophy and multiple sulfatase deficiency are classified as sulfatidoses.[2][3] ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## See also[edit] * Sphingolipidoses#Overview for an overview table, including sulfatidosis ## References[edit] 1. ^ "Definition: sulfatidosis from Online Medical Dictionary". 2. ^ Sulfatidosis at the US National Library of Medicine Medical Subject Headings (MeSH) 3. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. p. 161. ISBN 978-0-7216-0187-8. ## External links[edit] Classification D * MeSH: D052516 * v * t * e Lysosomal storage diseases: Inborn errors of lipid metabolism (Lipid storage disorders) Sphingolipidoses (to ceramide) From ganglioside (gangliosidoses) * Ganglioside: GM1 gangliosidoses * GM2 gangliosidoses (Sandhoff disease * Tay–Sachs disease * AB variant) From globoside * Globotriaosylceramide: Fabry's disease From sphingomyelin * Sphingomyelin: phospholipid: Niemann–Pick disease (SMPD1-associated * type C) * Glucocerebroside: Gaucher's disease From sulfatide (sulfatidoses * leukodystrophy) * Sulfatide: Metachromatic leukodystrophy * Multiple sulfatase deficiency * Galactocerebroside: Krabbe disease To sphingosine * Ceramide: Farber disease NCL * Infantile * Jansky–Bielschowsky disease * Batten disease Other * Cerebrotendineous xanthomatosis * Cholesteryl ester storage disease (Lysosomal acid lipase deficiency/Wolman disease) * Sea-blue histiocytosis 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	Sulfatidosis	c1706192	1,186	wikipedia	https://en.wikipedia.org/wiki/Sulfatidosis	2021-01-18T18:40:32	{"mesh": ["D052516"], "wikidata": ["Q7636192"]}
Infectious bacterial disease Scanning electron microphotograph depicting a mass of Yersinia pestis bacteria (the cause of bubonic plague) in the foregutte of the flea vector Sylvatic plague is an infectious bacterial disease caused by the plague bacterium (Yersinia pestis) that primarily affects rodents, such as prairie dogs. It is the same bacterium that causes bubonic and pneumonic plague in humans. Sylvatic, or sylvan, means 'occurring in wildlife,' and refers specifically to the form of plague in rural wildlife. Urban plague refers to the form in urban wildlife. It is primarily transmitted among wildlife through flea bites and contact with infected tissue or fluids. Sylvatic plague is most commonly found in prairie dog colonies and some mustelids, like the black-footed ferret.[1] ## Contents * 1 Transmission vector * 2 Epidemiology and distribution * 3 Wildlife disease control and prevention * 4 See also * 5 References * 6 External links ## Transmission vector[edit] The flea that feeds on prairie dogs and other mammals serves as the vector for transmission of sylvatic plague to the new host, primarily through flea bites, or contact with contaminated fluids or tissue, through predation or scavenging. Humans can contract plague from wildlife through flea bites and handling animal carcasses.[1] ## Epidemiology and distribution[edit] Yersinia pestis circulates in rodent reservoirs on all continents except Australia. Sylvatic plague affects over 50 species of rodents worldwide. It is vectored by a variety of flea species. Non-rodent animals susceptible to the disease include shrews, lagomorphs, ferrets, badgers, skunks, weasels, coyotes, domestic dogs and cats, bobcats, cougars, camels, goats, sheep, pigs, deer, and primates, including humans. Birds are not known to be susceptible.[2] Sylvatic plague is normally enzootic, meaning it occurs at regular, predictable rates in populations and specific areas. At unpredictable times, it becomes epizootic in unexpected places. It is during these epizootic outbreaks that transmission to humans is most common. Factors that predispose to epizootic cycles include dense populations of rodents, multiple species of rodents in a particular area, and multiple rodent species in diverse habitats.[3] Prairie dog colonies reach nearly 100% mortality rates during outbreaks. Prairie dogs are a keystone species and play a vital role as the primary prey of black-footed ferrets. Developing methods to control plague is of high concern for preserving ferrets and the conservation of Western prairie and grassland ecosystems.[1] ## Wildlife disease control and prevention[edit] Prairie dogs evolved over 3,000,000 years ago, and have been surviving sylvatic plague as a species for a long time. In the absence of understanding the natural prairie dog/plague cycles, dusting rodent dens with pesticides to kill fleas is currently the main method of controlling sylvatic plague in the wild, with some interest in using vaccines developing.[4] An oral live vaccine for prairie dogs was developed by the U.S. Geological Survey, National Wildlife Health Center, from a recombinant raccoon poxvirus expressing plague antigens. It was originally developed by a Fort Detrick company in 2003 which showed it protected mice against lethal plague.[5] ## See also[edit] * Black Death * Grasshopper mouse * Sylvatic cycle * Epizootic ## References[edit] 1. ^ a b c Abbott, R.C.; Rocke, T.E (2012). "Plague: U.S. Geological Survey Circular 1372". Cite journal requires `\|journal=` (help) 2. ^ "History of the Black Footed Ferret". Black-footed Ferret Recovery Implementation Team. Retrieved 25 Oct 2013. 3. ^ "Plague Symptoms". Center for Disease Control. 4. ^ USGS (July 2013). "Sylvatic Plague Immunization in Black-footed Ferrets and Prairie Dogs". USGS National Wildlife Health Center. 5. ^ Osorio JE, Powell TD, Frank RS, Moss K, Haanes EJ, Smith SR, Rocke TE, Stinchcomb DT (2003). "Recombinant raccoon pox vaccine protects mice against lethal plague". Vaccine. 21 (11–12): 1232–8. doi:10.1016/S0264-410X(02)00557-1. PMID 12559803.CS1 maint: uses authors parameter (link) ## External links[edit] * Black Death on In Our Time at the BBC * Black Death at BBC * v * t * e Black Death Thematic * Second plague pandemic * Migration * Causes * Consequences * Notable deaths * Persecution of Jews during the Black Death * Cronaca fiorentina di Marchionne di Coppo Stefani * In medieval culture By geography * In Denmark * In England * In France * In the Holy Roman Empire * In Italy * In Norway * In Spain * In Sweden * Category * Commons [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Sylvatic plague	None	1,187	wikipedia	https://en.wikipedia.org/wiki/Sylvatic_plague	2021-01-18T18:51:04	{"wikidata": ["Q16992883"]}
A disorder of carnitine cycle and carnitine transport that is characterized classically by early childhood onset cardiomyopathy often with weakness and hypotonia, failure to thrive and recurrent hypoglycemic hypoketotic seizures and/or coma. ## Epidemiology Systemic primary carnitine deficiency (SPCD) exact prevalence is unknown and varies depending on ethnicity. The estimated prevalence is 1/20,000 - 1/70,000 newborns in Europe and the USA while the estimated incidence in Japan is 1/40,000 births. In the Faroe Islands, the prevalence is 1/1,300 and the incidence is 1/720. ## Clinical description Disease onset typically occurs in infancy between the ages of 3 months to 2 years. Infants often present with hypoketotic hypoglycemia, poor feeding, irritability, lethargy, and hepatomegaly, triggered by fasting stress or common illnesses including gastoenteritis and respiratory tract infections. Roughly half of clinically presenting patients present with muscle hypotonia and progressive childhood cardiomyopathy leading to heart failure. Anemia is sometimes observed as carnitine plays a role in red blood cell metabolism. Adulthood presentation is associated with minor symptoms like fatigue and decreased stamina but dilated cardiomyopathy and arrhythmias and sudden cardiac death have also been reported. Asymptomatic adults are also described. During pregnancy, minor symptoms as well as cardiac arrhythmias can worsen. ## Etiology SPCD is caused by mutations in the SLC22A5 gene on chromosome 5q31.1 that encodes the plasma membrane sodium-dependent high affinity carnitine transporter (OCTN2) which is expressed in most tissues including cultured fibroblasts, lymphocytes, muscle, kidney, gut and heart. OCTN2 is necessary for L-carnitine transport across the plasma membrane and L-carnitine is necessary for transporting long chain fatty acids into the mitochondria for fatty acid oxidation. When fat cannot be used for fatty acid oxidation due to SPCD, glucose is consumed (resulting in hypoglycemia) and the fat released from adipose tissue accumulates in the liver, heart and skeletal muscle (leading to hepatic steatosis and lipid myopathy). ## Diagnostic methods Diagnosis is based on a finding of very low plasma free and total carnitine concentrations (<5-10 micromol/L) and confirmed by demonstrating significantly reduced carnitine transport in skin fibroblasts or biallelic pathogenic mutations in the SLC22A5 gene. There is lipid myopathy with microvesicular lipid accumulation found in the muscle and liver as well as elevated liver transaminases and hyperammonemia. A marked renal loss of carnitine even in the presence of very low plasma and tissue carnitine concentrations is also noted. Newborn screening is available in Austria, Denmark, Hungary, Iceland, Portugal, Spain and Isreal. ## Differential diagnosis Differential diagnoses include other fat oxidation defects such as medium chain acyl-CoA dehydrogenase deficiency and very long chain acyl-CoA dehydrogenase deficiency. ## Genetic counseling SPCD is an autosomal recessive disorder and genetic counseling can be offered to families with a known mutation. ## Management and treatment Carnitine therapy is the standard treatment. Oral levocarnitine (L-carnitine) supplementation of 100-400 mg/kg/day in three divided doses is usually required. Oral carnitine treatment is required for lifelong treatment of the disease. ## Prognosis The prognosis is extremely good as long as oral carnitine supplementation is maintained. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Systemic primary carnitine deficiency	c0342788	1,188	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=158	2021-01-23T18:58:16	{"gard": ["5104"], "mesh": ["C536778"], "omim": ["212140"], "umls": ["C0342788"], "icd-10": ["E71.3"], "synonyms": ["CDSP", "CUD", "Carnitine transporter defect", "Carnitine uptake deficiency", "Deficiency of plasma-membrane carnitine transporter", "SPCD"]}
Human jaw cyst Glandular odontogenic cyst Other namesSialo-Odontogenic cyst Relative incidence of odontogenic cysts.[1] Glandular odontogenic cyst is labeled at bottom. SymptomsJaw expansion, swelling, impairment to the tooth, root and cortical plate [2][3] CausesCellular mutation, cyst maturation at glandular, BCL-2 protein [2][4] Diagnostic methodBiopsy, CT scans, Panoramic x-rays [5][6] Differential diagnosisCentral mucoepidermoid carcinoma, odontogenic keratocyst [7][6] PreventionPost-surgery follow-ups are commonly proposed to prevent the chances of recurrence [6] TreatmentEnucleation, curettage, marginal or partial resection, marsupialization[6] Frequency0.12 to 0.13% of people [2] A glandular odontogenic cyst (GOC) is a rare and usually benign odontogenic cyst developed at the odontogenic epithelium of the mandible or maxilla.[2][8][9][10] Originally, the cyst was labeled as "sialo-odontogenic cyst" in 1987.[7] However, the World Health Organization (WHO) decided to adopt the medical expression "glandular odontogenic cyst".[9] Following the initial classification, only 60 medically documented cases were present in the population by 2003.[6] GOC was established as its own biological growth after differentiation from other jaw cysts such as the "central mucoepidermoid carcinoma (MEC)", a popular type of neoplasm at the salivary glands.[7][11] GOC is usually misdiagnosed with other lesions developed at the glandular and salivary gland due to the shared clinical signs.[12] The presence of osteodentin supports the concept of an odontogenic pathway.[10] This odontogenic cyst is commonly described to be a slow and aggressive development.[13] The inclination of GOC to be large and multilocular is associated with a greater chance of remission.[10][3] GOC is an infrequent manifestation with a 0.2% diagnosis in jaw lesion cases.[14] Reported cases show that GOC mainly impacts the mandible and male individuals.[3] The presentation of GOC at the maxilla has a very low rate of incidence.[8] The GOC development is more common in adults in their fifth and sixth decades.[1] GOC has signs and symptoms of varying sensitivities, and dysfunction.[13][14] In some cases, the GOC will present no classic abnormalities and remains undiagnosed until secondary complications arise.[13] The proliferation of GOC requires insight into the foundations of its unique histochemistry and biology.[7] The comparable characteristics of GOC with other jaw lesions require the close examination of its histology, morphology, and immunocytochemistry for a differential diagnosis.[10] Treatment modes of the GOC follow a case-by-case approach due to the variable nature of the cyst.[5] The selected treatment must be accompanied with an appropriate pre and post-operative plan.[5] ## Contents * 1 Signs and Symptoms * 2 Causes * 3 Diagnosis * 3.1 Radiology * 3.2 Histology * 3.2.1 Intraepithelial Hemosiderin * 3.3 Immunocytochemistry * 3.3.1 MAML2 rearrangement * 4 Treatment * 4.1 Pre-treatment protocols * 4.2 Treatment process * 4.3 Post-treatment protocols * 5 Epidemiology * 6 References * 7 Bibliography * 8 Further reading ## Signs and Symptoms[edit] The appearance of a protrusive growth will be present at their mandible or maxilla.[2] The expansive nature of this cyst may destruct the quality of symmetry at the facial region and would be a clear physical sign of abnormality.[2][7] The area of impact may likely be at the anterior region of mandible as described in a significant amount of reported cases.[8] At this region, GOC would eventually mediate expansion at the molars.[7] A painful and swollen sensation at the jaw region caused by GOC may be reported.[14] Detailing of a painless feeling or facial paraesthesia can be experienced.[7][14] Alongside GOC, "root resorption, cortical bone thinning and perforation, and tooth displacement may occur".[3] Experience of swelling at the buccal and lingual zones can occur.[6] Usually, the smaller sized GOCs present no classical signs or symptoms to the case (i.e "asymptomatic").[4] GOC is filled with cystic a fluid that differs in viscosity and may appear as transparent, brownish-red, or creamy in colour.[3] ## Causes[edit] The molecular arrangement of BCL-2 protein, a potential cause to the development of the GOC. The protein can inhibit the process of apoptosis when at a high abundance. The GOC can arise through a number of causes:[7] The origin of the GOC can be understood through its biological and histochemistry foundations.[4] It has been suggested that GOC can be a result of a traumatic event.[12] The occurrence of GOC may be from a mutated cell from "the oral mucosa and the dental follicle" origin.[15] Another probable cause is from pre-existing cysts or cancerous constituents.[12] A potential biological origin of GOC is a cyst developed at a salivary gland or simple epithelium, which undergoes maturation at the glandular.[4] Another origin is a primordial cyst that infiltrates the glandular epithelial tissue through a highly organised cellular differentiation.[4] Pathologists discovered a BCL-2 protein, commonly present in neoplasms, to exist in the tissue layers of the GOC.[4][15] The protein is capable of disrupting normal cell death function at the odontogenic region.[4][15] The analysis of PTCH, a gene that specialises in neoplasm inhibition, was carried out to determine if any existing mutations played a role in the initiation of the GOC.[7] It is confirmed that the gene had no assistance in triggering cystic advancement.[7] ## Diagnosis[edit] ### Radiology[edit] The performance of radiographic imaging i.e. computed tomography, at the affected area is considered essential.[13] Radiographic imaging of the GOC can display a defined unilocular or multilocular appearance that may be "rounded or oval" shaped upon clinical observation.[5][4] Scans may present a distribution of the GOC at the upper jaw as it presents a 71.8% prevalence in cases.[2] The margin surrounding the GOC is usually occupied with a scalloped definition.[2] A bilateral presentation of the GOC is possible but is not common at either the maxilla or mandible sites.[13] The GOC has an average size of 4.9 cm that can develop over the midline when positioned at the mandible or maxilla region.[3][14] Analysis of scans allow for the differentiation of GOC from other parallel lesions, i.e. "ameloblastoma, odontogenic myxoma, or dentigerous cyst" in order to minimise the chance of a misdiagnosis.[5] These scans can display the severity of cortical plate, root, and tooth complications, which is observed to determine the necessary action for reconstruction.[5] ### Histology[edit] Histological features related to the GOC differ in each scenario; however, there is a general criterion to identify the cyst.[14] The GOC usually features a "stratified squamous epithelium" attached to connective tissue that is filled with active immune cells.[2][7] The lining of the epithelium features a very small diameter that is usually non-keratinised.[8][13] In contrast, the lining of the GOC has rather an inconsistent diameter.[2] The basal cells of the GOC usually has no association to a cancerous origin.[12] Tissue cells can be faced with an abnormal increase in the concentration of calcium, which can cause the region to calcify.[7] The transformation of the epithelium is associated with a focal luminal development.[2] Eosinophilic organelles such as columnar and cuboidal cells can be observed during microscopy.[11] Intra-epithelial crypts may be identified in the internal framework of the epithelium or at the external space where it presents itself as papillae protrusions.[8][13] Mucin is observable after the application of "alcian blue dye" on the tissue specimen.[8] The histological observation of goblet cells is a common feature with the "odontogenic dentigerous cyst".[11] In some circumstances, the epithelium can have variable plaque structures that appear as swirls in the tissue layers.[8] Interestingly, histologists were able to identify hyaline bodies within the tissue framework of the GOC.[7] It is encouraged that the histological identification of at least seven of these biological characteristics is required to accurately distinguish the presence of the GOC.[11] #### Intraepithelial Hemosiderin[edit] Pathologists have identified hemosiderin pigments that are considered unique to the GOC.[12] The discovery of this pigment can be pivotal to the differentiation of the GOC from other lesions.[12] The staining at the epithelium is due to the haemorrhaging of the lining.[12] The cause of the haemorrhaging can be triggered by the type of treatment, cellular degradation, or structural deformation inflicted during GOC expansion.[12] Examination of the GOC tissue section indicated that red blood cells from the intraluminal space had combined with the extracellular constituents.[12] This process is carried out through transepithelial elimination.[12] This clinical procedure is beneficial to confirm the benign or malignant nature of the GOC.[12] ### Immunocytochemistry[edit] The examination of cytokeratin profiles is deemed useful when observing the differences between the GOC and the central MEC.[14] These two lesions show individualised expression for cytokeratin 18 and 19.[7] Past studies observed Ki-67, p53, and PCNA expression in common jaw cysts that shared similar characteristics.[7] There was a lack of p53 expression found in radicular cysts.[7] Similarly, Ki-67 was seen less in the central MEC compared to the other lesions, though this discovery is not essential to the process of differential diagnosis.[7][14] Proliferating cell nuclear antigen readings were established to have no role in the differentiation process.[14] The TGF-beta marker is present in the GOC and can explain the limited concentration of normal functioning cells.[15] #### MAML2 rearrangement[edit] The observation of a MAML2 rearrangement is described as a procedure useful in the differential diagnosis of the GOC and its closely related lesion, the central MEC.[11] A second cystic development displayed the presence of CRTC3-MAML2 fusion after an in-vitro application.[11] The MAML2 rearrangement represents the developmental growth of the central MEC from the GOC.[11] The use of fusion-gene transcript may be helpful towards the differentiation of the GOC from the central MEC of the jaw and salivary glands.[11] ## Treatment[edit] ### Pre-treatment protocols[edit] Panoramic radiography used to provide visualisations of the maxilla and mandible. X-rays will display the degree of impact on case, caused by the GOC. A computed tomography and panoramic x-ray must be undertaken in order to observe the severity of internal complications.[5] These scans allow for the observation of the GOC size, radiolucency, cortical bone, dentition, root, and vestibular zone.[5] In some cases, the dentition may be embedded into the cavity walls of the lesion, depending on the position of expansion at the odontogenic tissue.[13] The diagnosis of a smaller sized GOC is related to the attachment of only two teeth.[6] While, a greater sized GOC develops over two teeth.[6] Presentation of a greater sized lesion usually requires a biopsy for a differential diagnosis and a precise treatment plan.[6] ### Treatment process[edit] The unilocular and multilocular nature is imperative to the determination of treatment style.[6] Local anesthesia is regularly provided as the GOC is embedded within the tissue structure of the jaw and requires an invasive procedure for a safe and accurate extraction.[2] For unilocular GOCs with minimal tissue deterioration, "enucleation, curettage, and marsupialization" is a suitable treatment plan.[6] Notably, the performance of enucleation or curettage as the primary action is linked to an incomplete extraction of the GOC and is only recommended to the less invasive lesions.[6] Multilocular GOCs require a more invasive procedure such as "peripheral ostectomy, marginal resection, or partial jaw resection".[6] GOCs associated with a more severe structural damage are encouraged to undergo marsupialization as either an initial or supplementary surgery.[6] The frequency of reappearance is likely due to the lingering cystic tissue structures that remain after the performance of curettage.[13] The incorporation of a "dredging method i.e. repetition of enucleation and curettage" is also suggested until the remnants of the GOC diminishes for certain.[9] The treatment ensures scar tissue is removed to promote the successful reconstruction of osseous material for jaw preservation.[9] Alongside the main treatments, bone allograft application, cryosurgery, and apicoectomy are available but have not been consistently recommended.[9][13][5] Though Carnoy's solution, the chloroform-free version, is recommended with the treatment as it degenerates the majority of the damaged dental lamina.[13] The most effective type of treatment remains unknown due to the lack of detailed data from reported cases.[3] ### Post-treatment protocols[edit] Follow-up appointments are necessary after the removal of the GOC as there is a high chance of remission, which may be exacerbated in cases dealing with "cortical plate perforation".[13][5] The GOC has a significant remission rate of 21 to 55% that can potentially develop during the period of 0.5 to 7 years post-surgery.[7][6] Cases occupied with a lower risk lesion are expected to continue appointments with physicians for up to 3 years post-surgery.[6] A higher risk lesion is encouraged to consistently consult with physicians during a 7 year period after treatment.[13] Remission events require immediate attention and appropriate procedures such as enucleation or curettage.[6] In more damaging cases of remission, tissue resection, and marsupialization may have to be performed.[7] ## Epidemiology[edit] The clinical presentation of the GOC is very low in the population as noted by the 0.12 to 0.13% occurrence rate, extrapolated from a sample size of the 181 individuals.[2] The GOC mainly affects older individuals in the population, especially those that are in their 40 to 60s.[8] However, the GOC can affect younger individuals i.e. 11, and more older individuals i.e. 82 in the population.[2] The age distribution starts at a much lower number for people living in Asia and Africa.[2] Those in their first 10 years of life have not been diagnosed with the GOC.[14] The GOC does present a tendency to proliferate in more males than females.[3] There is no definitive conclusion towards the relevance of gender and its influence on the rate of incidence.[7] ## References[edit] 1. ^ a b Borges, Leandro Bezerra; Fechine, Francisco Vagnaldo; Mota, Mário Rogério Lima; Sousa, Fabrício Bitu; Alves, Ana Paula Negreiros Nunes (March 2012). "Odontogenic lesions of the jaw: a clinical-pathological study of 461 cases". Revista Gaúcha de Odontologia. 60 (1): 71–78. S2CID 46982083. 2. ^ a b c d e f g h i j k l m n o Faisal, Mohammad; Ahmad, Syed Ansar; Ansari, Uzma (September 2015). "Glandular odontogenic cyst – Literature review and report of a paediatric case". Journal of Oral Biology and Craniofacial Research. 5 (3): 219–225. doi:10.1016/j.jobcr.2015.06.011. PMC 4623883. PMID 26587384. 3. ^ a b c d e f g h Momeni Roochi, Mehrnoush; Tavakoli, Iman; Ghazi, Fatemeh Mojgan; Tavakoli, Ali (1 July 2015). "Case series and review of glandular odontogenic cyst with emphasis on treatment modalities". Journal of Cranio-Maxillofacial Surgery. 43 (6): 746–750. doi:10.1016/j.jcms.2015.03.030. PMID 25971944. 4. ^ a b c d e f g h Patel, Govind; Shah, Monali; Kale, Hemant; Ranginwala, Amena (2014). "Glandular odontogenic cyst: A rare entity". Journal of Oral and Maxillofacial Pathology. 18 (1): 89–92. doi:10.4103/0973-029X.131922. PMC 4065455. PMID 24959044. 5. ^ a b c d e f g h i j Cano, Jorge; Benito, Dulce María; Montáns, José; Rodríguez-Vázquez, José Francisco; Campo, Julián; Colmenero, César (1 July 2012). "Glandular odontogenic cyst: Two high-risk cases treated with conservative approaches". Journal of Cranio-Maxillofacial Surgery. 40 (5): e131–e136. doi:10.1016/j.jcms.2011.07.005. PMID 21865053. 6. ^ a b c d e f g h i j k l m n o p q Kaplan, Ilana; Gal, Gavriel; Anavi, Yakir; Manor, Ronen; Calderon, Shlomo (April 2005). "Glandular odontogenic cyst: Treatment and recurrence". Journal of Oral and Maxillofacial Surgery. 63 (4): 435–441. doi:10.1016/j.joms.2004.08.007. PMID 15789313. 7. ^ a b c d e f g h i j k l m n o p q r s t Shear, Mervyn; Speight, Paul, eds. (2007). "Glandular Odontogenic Cyst (Sialo-Odontogenic Cyst)". Cysts of the Oral and Maxillofacial Regions. pp. 94–99. doi:10.1002/9780470759769.ch7. ISBN 978-0-470-75976-9. 8. ^ a b c d e f g h Prabhu, Sudeendra; Rekha, K; Kumar, GS (2010). "Glandular odontogenic cyst mimicking central mucoepidermoid carcinoma". Journal of Oral and Maxillofacial Pathology. 14 (1): 12–5. doi:10.4103/0973-029X.64303. PMC 2996005. PMID 21180452. 9. ^ a b c d e Motooka, Naomi; Ohba, Seigo; Uehara, Masataka; Fujita, Syuichi; Asahina, Izumi (1 January 2015). "A case of glandular odontogenic cyst in the mandible treated with the dredging method". Odontology. 103 (1): 112–115. doi:10.1007/s10266-013-0143-0. PMID 24374982. S2CID 21059170. 10. ^ a b c d Shah, AmishaA; Sangle, Amit; Bussari, Smita; Koshy, AjitV (2016). "Glandular odontogenic cyst: A diagnostic dilemma". Indian Journal of Dentistry. 7 (1): 38–43. doi:10.4103/0975-962X.179371. PMC 4836096. PMID 27134453. 11. ^ a b c d e f g h Nagasaki, Atsuhiro; Ogawa, Ikuko; Sato, Yukiko; Takeuchi, Kengo; Kitagawa, Masae; Ando, Toshinori; Sakamoto, Shinnichi; Shrestha, Madhu; Uchisako, Kaori; Koizumi, Koichi; Toratani, Shigeaki; Konishi, Masaru; Takata, Takashi (January 2018). "Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report: Central MEC arising from GOC". Pathology International. 68 (1): 31–35. doi:10.1111/pin.12609. PMID 29131467. S2CID 8932602. 12. ^ a b c d e f g h i j k AbdullGaffar, Badr; Koilelat, Mohamed (May 2017). "Glandular Odontogenic Cyst: The Value of Intraepithelial Hemosiderin". International Journal of Surgical Pathology. 25 (3): 250–252. doi:10.1177/1066896916672333. PMID 27829208. S2CID 46588216. 13. ^ a b c d e f g h i j k l m Akkaş, İsmail; Toptaş, Orçun; Özan, Fatih; Yılmaz, Fahri (1 March 2015). "Bilateral Glandular Odontogenic Cyst of Mandible: A Rare Occurrence". Journal of Maxillofacial and Oral Surgery. 14 (1): 443–447. doi:10.1007/s12663-014-0668-y. PMC 4379287. PMID 25848155. 14. ^ a b c d e f g h i j Neville, Brad W. (2016). "Cyst, Glandular Odontogenic". In Slootweg, Pieter (ed.). Dental and Oral Pathology. Springer International Publishing. pp. 89–93. doi:10.1007/978-3-319-28085-1_677. ISBN 978-3-319-28084-4.CS1 maint: date and year (link) 15. ^ a b c d Alaeddini, Mojgan; Eshghyar, Nosratollah; Etemad‐Moghadam, Shahroo (2017). "Expression of podoplanin and TGF-beta in glandular odontogenic cyst and its comparison with developmental and inflammatory odontogenic cystic lesions". Journal of Oral Pathology & Medicine. 46 (1): 76–80. doi:10.1111/jop.12475. PMID 27391558. S2CID 40879254. ## Bibliography[edit] * AbdullGaffar, Badr; Koilelat, Mohamed (May 2017). "Glandular Odontogenic Cyst: The Value of Intraepithelial Hemosiderin". International Journal of Surgical Pathology. 25 (3): 250–252. doi:10.1177/1066896916672333. PMID 27829208. S2CID 46588216. * Akkaş, İsmail; Toptaş, Orçun; Özan, Fatih; Yılmaz, Fahri (1 March 2015). "Bilateral Glandular Odontogenic Cyst of Mandible: A Rare Occurrence". Journal of Maxillofacial and Oral Surgery. 14 (1): 443–447. doi:10.1007/s12663-014-0668-y. PMC 4379287. PMID 25848155. * Alaeddini, Mojgan; Eshghyar, Nosratollah; Etemad‐Moghadam, Shahroo (2017). "Expression of podoplanin and TGF-beta in glandular odontogenic cyst and its comparison with developmental and inflammatory odontogenic cystic lesions". Journal of Oral Pathology & Medicine. 46 (1): 76–80. doi:10.1111/jop.12475. PMID 27391558. S2CID 40879254. * Borges, Leandro Bezerra; Fechine, Francisco Vagnaldo; Mota, Mário Rogério Lima; Sousa, Fabrício Bitu; Alves, Ana Paula Negreiros Nunes (March 2012). "Odontogenic lesions of the jaw: a clinical-pathological study of 461 cases". Revista Gaúcha de Odontologia. 60 (1): 71–78. S2CID 46982083. * Cano, Jorge; Benito, Dulce María; Montáns, José; Rodríguez-Vázquez, José Francisco; Campo, Julián; Colmenero, César (1 July 2012). "Glandular odontogenic cyst: Two high-risk cases treated with conservative approaches". Journal of Cranio-Maxillofacial Surgery. 40 (5): e131–e136. doi:10.1016/j.jcms.2011.07.005. PMID 21865053. * Faisal, Mohammad; Ahmad, Syed Ansar; Ansari, Uzma (September 2015). "Glandular odontogenic cyst – Literature review and report of a paediatric case". Journal of Oral Biology and Craniofacial Research. 5 (3): 219–225. doi:10.1016/j.jobcr.2015.06.011. PMC 4623883. PMID 26587384. * Kaplan, Ilana; Gal, Gavriel; Anavi, Yakir; Manor, Ronen; Calderon, Shlomo (April 2005). "Glandular odontogenic cyst: Treatment and recurrence". Journal of Oral and Maxillofacial Surgery. 63 (4): 435–441. doi:10.1016/j.joms.2004.08.007. PMID 15789313. * Motooka, Naomi; Ohba, Seigo; Uehara, Masataka; Fujita, Syuichi; Asahina, Izumi (1 January 2015). "A case of glandular odontogenic cyst in the mandible treated with the dredging method". Odontology. 103 (1): 112–115. doi:10.1007/s10266-013-0143-0. PMID 24374982. S2CID 21059170. * Nagasaki, Atsuhiro; Ogawa, Ikuko; Sato, Yukiko; Takeuchi, Kengo; Kitagawa, Masae; Ando, Toshinori; Sakamoto, Shinnichi; Shrestha, Madhu; Uchisako, Kaori; Koizumi, Koichi; Toratani, Shigeaki; Konishi, Masaru; Takata, Takashi (January 2018). "Central mucoepidermoid carcinoma arising from glandular odontogenic cyst confirmed by analysis of MAML2 rearrangement: A case report: Central MEC arising from GOC". Pathology International. 68 (1): 31–35. doi:10.1111/pin.12609. PMID 29131467. S2CID 8932602. * Neville, Brad W. (2016). "Cyst, Glandular Odontogenic". In Slootweg, Pieter (ed.). Dental and Oral Pathology. Springer International Publishing. pp. 89–93. doi:10.1007/978-3-319-28085-1_677. ISBN 978-3-319-28084-4.CS1 maint: date and year (link) * Prabhu, Sudeendra; Rekha, K; Kumar, GS (2010). "Glandular odontogenic cyst mimicking central mucoepidermoid carcinoma". Journal of Oral and Maxillofacial Pathology. 14 (1): 12–5. doi:10.4103/0973-029X.64303. PMC 2996005. PMID 21180452. * Momeni Roochi, Mehrnoush; Tavakoli, Iman; Ghazi, Fatemeh Mojgan; Tavakoli, Ali (1 July 2015). "Case series and review of glandular odontogenic cyst with emphasis on treatment modalities". Journal of Cranio-Maxillofacial Surgery. 43 (6): 746–750. doi:10.1016/j.jcms.2015.03.030. PMID 25971944. * Patel, Govind; Shah, Monali; Kale, Hemant; Ranginwala, Amena (2014). "Glandular odontogenic cyst: A rare entity". Journal of Oral and Maxillofacial Pathology. 18 (1): 89–92. doi:10.4103/0973-029X.131922. PMC 4065455. PMID 24959044. * Shah, AmishaA; Sangle, Amit; Bussari, Smita; Koshy, AjitV (2016). "Glandular odontogenic cyst: A diagnostic dilemma". Indian Journal of Dentistry. 7 (1): 38–43. doi:10.4103/0975-962X.179371. PMC 4836096. PMID 27134453. * Shear, Mervyn; Speight, Paul, eds. (2007). "Glandular Odontogenic Cyst (Sialo-Odontogenic Cyst)". Cysts of the Oral and Maxillofacial Regions. pp. 94–99. doi:10.1002/9780470759769.ch7. ISBN 978-0-470-75976-9. ## Further reading[edit] * Kahn MA (2001). Basic Oral and Maxillofacial Pathology. 1. * v * t * e Cystic diseases Respiratory system * Langerhans cell histiocytosis * Lymphangioleiomyomatosis * Cystic bronchiectasis Skin * stratified squamous: follicular infundibulum * Epidermoid cyst and Proliferating epidermoid cyst * Milia * Eruptive vellus hair cyst * outer root sheath * Trichilemmal cyst and Pilar cyst and Proliferating trichilemmal cyst and Malignant trichilemmal cyst * sebaceous duct * Steatocystoma multiplex and Steatocystoma simplex * Keratocyst * nonstratified squamous: Cutaneous ciliated cyst * Hidrocystoma * no epithelium: Pseudocyst of the auricle * Mucocele * other and ungrouped: Cutaneous columnar cyst * Keratin implantation cyst * Verrucous cyst * Adenoid cystic carcinoma * Breast cyst Human musculoskeletal system * Cystic hygroma Human digestive system * oral cavity: Cysts of the jaws * Odontogenic cyst * Periapical cyst * Dentigerous cyst * Odontogenic keratocyst * Nasopalatine duct cyst * liver: Polycystic liver disease * Congenital hepatic fibrosis * Peliosis hepatis * bile duct: Biliary hamartomas * Caroli disease * Choledochal cysts * Bile duct hamartoma Nervous system * Cystic leukoencephalopathy Genitourinary system * Polycystic kidney disease * Autosomal dominant polycystic kidney * Autosomal recessive polycystic kidney * Medullary cystic kidney disease * Nephronophthisis * Congenital cystic dysplasia Other conditions * Hydatid cyst * Von Hippel–Lindau disease * Tuberous sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Glandular odontogenic cyst	c0399558	1,189	wikipedia	https://en.wikipedia.org/wiki/Glandular_odontogenic_cyst	2021-01-18T18:49:22	{"wikidata": ["Q5566618"]}
Patulous Eustachian tube Other namesPatent Eustachian tube SpecialtyENT surgery Patulous Eustachian tube (PET) is the name of a physical disorder where the Eustachian tube, which is normally closed, instead stays intermittently open. When this occurs, the person experiences autophony, the hearing of self-generated sounds. These sounds, such as one's own breathing, voice, and heartbeat, vibrate directly onto the ear drum and can create a "bucket on the head" effect. PET is a form of eustachian tube dysfunction (ETD), which is said to be present in about 1 percent of the general population.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[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. (April 2016) (Learn how and when to remove this template message) With patulous Eustachian tube, variations in upper airway pressure associated with respiration are transmitted to the middle ear through the Eustachian tube. This causes an unpleasant fullness feeling in the middle ear and alters the auditory perception. Complaints seem to include muffled hearing and autophony. In addition, patulous Eustachian tube generally feels dry with no clogged feeling or sinus pressure. Some patients with this condition are disturbed by the perceived volume of their voice, causing them to speak very quietly. Their own voice may also sound lower to other people, because the trachea has more volume when the Eustachian tube is open. The patient may also sound as if they have congestion when speaking. Some sufferers may have difficulty in normal activities. They may also experience increased breathing rate, such as that brought on by physical activity. The increased activity not only increases the rate and force of pressure changes in the airway, which is therefore transmitted more forcefully into the middle ear, but also drives increased blood flow to peripheral muscles, compounding the problem by further depleting the Eustachian tube of extracellular fluid and increasing patency. The combination can lead to severe exacerbation of the symptoms. The urge to clear the ear is often mentioned. Autophonia (self-hearing from inside, strongly amplified) seems to be a common symptom to all PET patients. Unfortunately, its presence also reveals an advanced degree of patency, requiring in most cases surgical management. Other symptoms of PET, such as tinnitus, fullness and ear blockage, can also be reported by patients suffering from obstructive ET dysfunction. This differential diagnosis problem unfortunately leads to some surgeries proposed by well-intentioned but inexperienced ENT surgeons. Some of these surgeries may make things worse. At the beginning, patients hear their own voice or its echo from inside.[2][3] They describe it as being amplified and unpleasant. Patients frequently avoid speaking and retire in a rising solitude. Lying head down may help since it increases venous blood pressure and congestion of the mucosa. ## Causes[edit] Patulous Eustachian tube is a physical disorder. The exact causes may vary depending on the person. Weight loss is a commonly cited cause of the disorder due to the nature of the Eustachian tube itself and is associated with approximately one-third of reported cases.[4] Fatty tissues hold the tube closed most of the time in healthy individuals. When circumstances cause overall body fat to diminish, the tissue surrounding the Eustachian tube shrinks and this function is disrupted.[5] Activities and substances which dehydrate the body have the same effect and are also possible causes of patulous Eustachian tube. Examples are stimulants (including caffeine) and exercise. Exercise may have a more short-term effect than caffeine or weight loss in this regard. Pregnancy can also be a cause of patulous Eustachian tube due to the effects of pregnancy hormones on surface tension and mucus in the respiratory system.[6] Granulomatosis with polyangiitis can also be a cause of this disorder. It is yet unknown why. PET can occur as a result of liquid residue in the Eustachian tube, after suffering a middle ear infection (otitis media). ## Diagnosis[edit] This article may require cleanup to meet Wikipedia's quality standards. No cleanup reason has been specified. Please help improve this article if you can. (August 2011) (Learn how and when to remove this template message) Upon examination of a suspected case of patulous Eustachian tube, a doctor can directly view the tympanic membrane with a light and observe that it vibrates with every breath taken by the patient. A tympanogram may also help with the diagnosis. Patulous Eustachian tube is likely if brisk inspiration causes a significant pressure shift. Patulous Eustachian tube is frequently misdiagnosed as standard congestion due to the similarity in symptoms and rarity of the disorder. Audiologists are more likely to recognize the disorder, usually with tympanometry or nasally delivered masking noise during a hearing assessment, which is highly sensitive to this condition.[7] When misdiagnosis occurs, a decongestant medication is sometimes prescribed. This type of medication aggravates the condition, as the Eustachian tube relies on sticky fluids to keep closed and the drying effect of a decongestant would make it even more likely to remain open and cause symptoms. The misdiagnosed patient may also have tubes surgically inserted into the eardrum, which increases the risk of ear infection and will not alleviate patulous Eustachian tube. If these treatments are tried and failed, and the doctor is not aware of the actual condition, the symptoms may even be classified as psychological. Incidentally, patients who instead suffer from the even rarer condition of superior canal dehiscence are at risk for misdiagnosis of patulous Eustachian tube due to the similar autophony in both conditions. ## Treatment[edit] Estrogen nasal drops or saturated potassium iodide have been used to induce edema of the eustachian tube opening. Nasal medications containing diluted hydrochloric acid, chlorobutanol, and benzyl alcohol have been reported to be effective in some patients, with few side effects. Food and Drug Administration approval is still pending, however.[8] Nasal sprays have also been a very effective temporary treatment for this disease, as well.[9] In extreme cases surgical intervention may attempt to restore the Eustachian tube tissues with fat, gel foam, or cartilage or scar it closed with cautery. These methods are not always successful. For example, there is the case of the early attempts at surgical correction involving the injections of tetrafluoroetheylene (Teflon) paste but, although this treatment was able to give transient relief, it was discontinued due to several deaths that resulted from inadvertent intracarotid injections.[10] ## References[edit] 1. ^ Dornhoffer, John; Gluth, Michael (2016). The Chronic Ear. Stuttgart: Thieme. ISBN 9781604068658. 2. ^ Gopen, Quinton (2013). Fundamental Otology: Pediatric and Adult Practice. New Delhi: Jaypee Brothers Medical Publishers Pvt. Ltd. p. 181. ISBN 9789350902691. 3. ^ Sataloff, Joseph; Sataloff, Robert (2005). Hearing Loss, 4th ed. Boca Raton, FL: CRC Press. p. 186. ISBN 9780824754358. 4. ^ Gulya, Aina; Minor, Lloyd; Poe, Dennis (2010). Glasscock-Shambaugh Surgery of the Ear 6th ed. Shelton, CT: PMPH-USA. p. 252. ISBN 9781607950264. 5. ^ Patulous Eustachian Tube Overview at eMedicine 6. ^ Hillman, Edawrd J. (1995). Otolaryngologic Manifestations Of Pregnancy. BCM 7. ^ Hori, Y., Kawase, T., Hasegawa, J., Sato, T., Yoshida, N., et al. (2006). Audiometry with nasally presented masking noise: Novel diagnostic method for patulous eustachian tube. Otol Neurotol, 27, 596-599. 8. ^ Patel, K and Levine S (July 31, 2010). "Emedicine - Patulous Eustachian Tube". 9. ^ "Patulous Eustachian Tube \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-12-12. 10. ^ Snow, James; Ballenger, John Jacob (2009). Ballenger's Otorhinolaryngology: Head and Neck Surgery. Sheldon, CT: PMPH-USA. p. 207. ISBN 9781550093377. ## External links[edit] Classification D * ICD-10: H69.0 * ICD-9-CM: 381.7 External resources * eMedicine: ent/359 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Patulous Eustachian tube	c0155434	1,190	wikipedia	https://en.wikipedia.org/wiki/Patulous_Eustachian_tube	2021-01-18T18:41:02	{"gard": ["10812"], "umls": ["C0155434"], "wikidata": ["Q1361850"]}
A number sign (#) is used with this entry because heterozygous mutation in the PALB2 gene (610355) on chromosome 16p12 confers susceptibility to pancreatic cancer. For background, phenotypic description, and a discussion of genetic heterogeneity of pancreatic carcinoma, see 260350. Molecular Genetics To explore the utility of personal genome sequencing, Jones et al. (2009) screened 20,661 coding genes for germline mutations in a patient with pancreatic cancer whose tumor DNA had previously been sequenced. They detected 15,461 germline variants. Three genes, including PALB2, carried variants in both germline and tumor DNA. PALB2 was considered the best candidate for a pancreatic cancer susceptibility gene because of the rarity of terminating PALB2 mutations in healthy individuals and because PALB2 had previously been implicated in breast cancer and Fanconi anemia. This patient harbored a germline deletion of 4 basepairs that resulted in a frameshift (610355.0007). Jones et al. (2009) also identified truncating mutations in 3 of 96 patients with familial pancreatic cancer (e.g., 610355.0008). The average age of onset of pancreatic cancer in these families was 66.7 years, similar to the mean age of onset of 65.3 years in the families without PALB2 mutations. Truncating mutations in PALB2 are rare in individuals without cancer; none were reported among 1,084 normal participants in a previous study that used a cohort of similar ethnicity (primarily Caucasian) (Rahman et al., 2007). Although some families that Jones et al. (2009) identified with a PALB2 stop mutation had a history of both breast and pancreatic cancer, breast cancer was not observed in all families. Jones et al. (2009) concluded that PALB2 appears to be the second most commonly mutated gene for hereditary pancreatic cancer. The most commonly mutated gene is BRCA2 (600185), whose protein product is a binding partner for the PALB2 protein. Zhen et al. (2015) tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 (113705) and BRCA2 (including deletions and rearrangements), PALB2, and CDKN2A (600160). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	PANCREATIC CANCER, SUSCEPTIBILITY TO, 3	c2931038	1,191	omim	https://www.omim.org/entry/613348	2019-09-22T15:58:53	{"mesh": ["C535837"], "omim": ["613348"], "orphanet": ["1333"], "synonyms": ["Alternative titles", "PNCA3"]}
A number sign (#) is used with this entry because of evidence that bradyopsia is caused by mutations in RGS9 (604067) or its anchor protein R9AP (607814). Clinical Features Kooijman et al. (1991) described 3 unrelated Dutch patients with prolonged electroretinal response suppression (PERRS) and stationary subnormal visual acuity and photophobia. Nishiguchi et al. (2004) identified an additional Dutch patient and 1 Guatemalan patient with similar visual complaints. All 5 patients had difficulty adjusting to changes in luminance. Walking out of a house into sunlight caused temporary blindness so severe that it necessitated immobility or assistance for 5 to 10 seconds. Visual compromise was also experienced when traveling from a bright environment to a dark one, e.g., daytime driving into a tunnel. Patients tended to avoid environments with high luminance; such environments required frequent blinking or dark sunglasses. Some patients stated that they could not participate in ball games because they could not see a moving ball. The patients' symptoms were present from early childhood. Neither the patients' symptoms nor their ocular findings, including ERGs, appreciably changed during repeat evaluations extending up to 14 years, suggesting that they may have had a stationary condition. Standard visual acuity testing (high contrast letters) revealed normal to subnormal acuities (20/20 to 20/80), with a measured acuity fluctuating from visit to visit. Optically corrected visual acuity increased in most patients by a factor of 2 with the use of pinholes, possibly owing to a reduction in retinal illuminance. One patient had a unilateral decrease in acuity (20/240 to 20/399) interpreted as amblyopia. Nishiguchi et al. (2004) evaluated the effect of contrast and movement on visual acuity in 1 patient, found to carry a homozygous mutation in the R9AP gene (607814). In this patient movement had a pronounced effect, with the most severe reduction in acuity (to a level corresponding to less than 20/200) occurring with moving, low-contrast letters. Following direct ophthalmoscopic presentation of a 9-degree diameter spot of light centered on the fovea for 10 seconds through a dilated pupil, the patient required 115 seconds to recover central visual acuity versus 11.2 +/- 3.4 seconds in controls; an heterozygote relative had a normal recovery time (11 seconds). Color vision and visual fields were normal. Final dark-adaptation thresholds were normal. Ophthalmoscopy showed no abnormalities in any of the patients' fundi. Routine ERGs showed normal rod responses to flashes of dim blue light. There was no attenuation in ERG amplitudes in response to subsequent dim blue flashes separated by 2 seconds. Rod-plus-cone ERGs to 0.5-Hz bright white flashes also showed a normal response, but only the first flash. The responses to the second flash and all subsequent flashes were markedly reduced in amplitude. As the majority of ERG amplitude in response to this flash intensity is normally mediated by rods, this reduction in amplitude suggested a rod dysfunction to Nishiguchi et al. (2004). A dysfunction also involving cones in these patients was revealed by the cone ERG responses elicited by 30-Hz white light flashes. Early responses were of normal amplitude and timing, but the responses rapidly decreased in amplitude so that the 30-Hz ERGs became nondetectable without computer averaging in about 2 seconds. On the basis of patients' symptoms and vision test results, Nishiguchi et al. (2004) concluded that their photoreceptors required an abnormally long time to adjust to changes in luminance. Slow adaptation to dim light, as exhibited by the abnormal photostress test, is also experienced by some patients who have retinitis pigmentosa or congenital stationary night blindness. What was unusual about the patients described by Nishiguchi et al. (2004) was that they were also slow to adapt to bright light. The slow adaptation of the photoreceptor resulted in a transient, incapacitating blindness when patients were suddenly confronted with a brightly lit environment. The photoreceptor defect also resulted in a severe reduction in acuity if low-contrast objects move against a bright background. The high conservation of RGS9 among vertebrates suggested that these visual abnormalities have been strictly selected against during evolution. With the recognition of the underlying photoreceptor defect and a better understanding of the patients' difficulty in adapting to changes in luminance, Nishiguchi et al. (2004) proposed the term bradyopsia (slow vision) for this clinical entity. Molecular Genetics In the 3 Dutch patients reported by Kooijman et al. (1991) and in a fourth Dutch patient theretofore unreported, Nishiguchi et al. (2004) detected a trp299-to-arg mutation in the RGS9 gene (604067.0001). In a Guatemalan patient from a consanguineous family, Nishiguchi et al. (2004) found a frameshift mutation in the R9AP gene (607814.0001). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	PROLONGED ELECTRORETINAL RESPONSE SUPPRESSION	c1842073	1,192	omim	https://www.omim.org/entry/608415	2019-09-22T16:07:54	{"doid": ["0050335"], "mesh": ["C564243"], "omim": ["608415"], "orphanet": ["75374"], "synonyms": ["PERRS", "Alternative titles", "BRADYOPSIA", "Prolonged electroretinal response suppression"]}
## Summary ### Clinical characteristics. Hemophilia B is characterized by deficiency in factor IX clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor IX clotting activity. * In individuals with severe hemophilia B, spontaneous joint or deep-muscle bleeding is the most frequent sign. Individuals with severe hemophilia B are usually diagnosed during the first two years of life; without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month. * Individuals with moderate hemophilia B seldom have spontaneous bleeding; however, they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies from once a month to once a year. * Individuals with mild hemophilia B do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life. In any individual with hemophilia B, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. Approximately 30% of heterozygous females have factor IX clotting activity lower than 40% and are at risk for bleeding (even if the affected family member has mild hemophilia B), although symptoms are usually mild. After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity. ### Diagnosis/testing. The diagnosis of hemophilia B is established in individuals with low factor IX clotting activity. Identification of a hemizygous F9 pathogenic variant on molecular genetic testing in a male proband confirms the diagnosis. Identification of a heterozygous F9 pathogenic variant on molecular genetic testing in a symptomatic female confirms the diagnosis. ### Management. Treatment of manifestations: Referral to a hemophilia treatment center (HTC) for assessment, education, genetic counseling, and treatment. Intravenous infusion of plasma-derived or recombinant factor IX for bleeding episodes within an hour of noticing symptoms. Training and home infusions for those with severe hemophilia B. Prevention of primary manifestations: For those with severe disease, prophylactic infusions of factor IX concentrate twice weekly to maintain factor IX clotting activity higher than 1% nearly eliminates spontaneous bleeding and prevents chronic joint disease. Some individuals require higher trough levels for this effect. Longer-acting products that allow weekly or biweekly dosing are now available. Prevention of secondary complications: Recombinant factor IX produced without human- or animal-derived proteins and virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV and hepatitis B and C viruses. Surveillance: For individuals with severe or moderate hemophilia B, assessments every six to 12 months at an HTC; for individuals with mild hemophilia B, assessments at least every two to three years. Agents/circumstances to avoid: Circumcision of at-risk males until hemophilia B is either excluded or treated with factor IX concentrate regardless of severity; intramuscular injections; activities with a high risk of trauma, particularly head injury; aspirin and all aspirin-containing products. Cautious use of other medications and herbal remedies that affect platelet function. Evaluation of relatives at risk: To clarify genetic status of females at risk before pregnancy or early in pregnancy in order to facilitate management. Pregnancy management: Maternal factor IX levels do not increase during pregnancy and heterozygous females are more likely to need factor infusion support for delivery or to treat or prevent postpartum hemorrhage; monitor heterozygous mothers for delayed bleeding post partum. Therapies under investigation: Clinical trials of additional longer-acting recombinant factor IX concentrates and gene therapy using intravenous infusion of an adeno-associated viral vector expressing factor IX are underway. Other: Vitamin K does not prevent or control bleeding in hemophilia B. ### Genetic counseling. Hemophilia B is inherited in an X-linked manner. The risk to sibs of a proband depends on the carrier status of the mother. Carrier females have a 50% chance of transmitting the F9 pathogenic variant in each pregnancy. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant are carriers. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Carrier testing for family members at risk and prenatal testing for pregnancies at increased risk are possible if the F9 pathogenic variant has been identified in a family member or if informative intragenic linked markers have been identified. ## Diagnosis ### Suggestive Findings Hemophilia B should be suspected in an individual with any of the following clinical features and/or laboratory features. Clinical features * Hemarthrosis, especially with mild or no antecedent trauma * Deep-muscle hematomas * Intracranial bleeding in the absence of major trauma * Neonatal cephalohematoma or intracranial bleeding * Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision * * Prolonged or delayed bleeding or poor wound healing following surgery or trauma * * Unexplained GI bleeding or hematuria * * Heavy menstrual bleeding, especially with onset at menarche (in symptomatic carriers) * * Prolonged nosebleeds, especially recurrent and bilateral * * Excessive bruising, especially with firm, subcutaneous hematomas * Of any severity, or especially in more severely affected persons Laboratory features * Normal platelet count * Prolonged activated partial thromboplastin time (aPTT) in severe and moderate hemophilia B. Normal or mildly prolonged aPTT in mild hemophilia B. * Normal prothrombin time (PT) ### Establishing the Diagnosis The diagnosis of hemophilia B is established in a male proband by identification of deceased factor IX clotting activity. * Severe hemophilia B. <1% factor IX * Moderate hemophilia B. 1%-5% factor IX * Mild hemophilia B. >5%-40% factor IX Note: (1) The normal range for factor IX clotting activity is approximately 50%-150% [Khachidze et al 2006]. Individuals with factor IX clotting activity higher than 40% usually have normal coagulation in vivo. However, some increased bleeding can occur with low to low-normal factor IX clotting activity in hemophilia B carrier females [Plug et al 2006]. (2) Somatic mosaicism in males with hemophilia B has been described [Ketterling et al 1999]. Identification of a hemizygous pathogenic variant in F9 by molecular genetic testing can help predict the clinical phenotype and allow family studies (see Table 1). Heterozygous females. The diagnosis of hemophilia B is established by determination of low factor IX clotting activity. Approximately 30% of heterozygous females have a factor IX clotting activity below 40%, regardless of the severity of hemophilia B in their family. Bleeding symptoms may be present in those with factor IX activity in the low-normal range [Plug et al 2006]. Carrier status is determined by identification of a heterozygous pathogenic variant in F9 by molecular genetic testing (see Table 1). Factor IX clotting activity is unreliable in the detection of heterozygous females; the majority of obligate carriers, even of severe hemophilia B, have normal factor IX clotting activities. #### Molecular Testing Approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of F9 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes F9 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) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * 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 Hemophilia B View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method F9Sequence analysis 3, 4, 597%-100% 6 Gene-targeted deletion/duplication analysis 72%-3% 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. Routine sequence analysis should detect pathogenic variants in F9 proximal promoter located immediately upstream of the start codon (e.g., c.-20A>T, one variant associated with hemophilia B Leyden). Detection of disease-associated variants located farther upstream may require a targeted assay [Funnell & Crossley 2014]; see also Genotype-Phenotype Correlations and Table A, Locus-Specific Databases). 6\. Mitchell et al [2010]; Goodeve [2015]; data from the MyLifeOurFuture project 7\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics ### Clinical Description Hemophilia B in the untreated individual is characterized by immediate or delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery or renewed bleeding after initial bleeding has stopped [Josephson 2013, Peyvandi et al 2016]. Muscle hematomas or intracranial bleeding can occur immediately or up to four to five days after the original injury. Intermittent oozing may last for days or weeks after tooth extraction. Prolonged or delayed bleeding or wound hematoma formation after surgery is common. After circumcision, males with hemophilia B of any severity may have prolonged oozing, or they may heal normally. In severe hemophilia B, spontaneous joint bleeding is the most frequent sign. The age of diagnosis and frequency of bleeding episodes are generally related to the factor IX clotting activity (see Table 2). In any affected individual, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. To some extent, this greater frequency is a function of both physical activity levels and vulnerability during more rapid growth. Individuals with severe hemophilia B are usually diagnosed as newborns due to birth- or neonatal-related procedures or during the first year of life [Kulkarni et al 2009]. In untreated toddlers, bleeding from minor mouth injuries and large "goose eggs" from minor head bumps are common; these are the most frequent presenting symptoms of severe hemophilia B. Intracranial bleeding may also result from head injuries. The untreated child almost always has subcutaneous hematomas; some have been referred for evaluation of possible non-accidental trauma. As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and young adults with severe hemophilia B who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding; other sites include the muscles, kidneys, gastrointestinal tract, brain, and nose. Without prophylactic treatment, individuals with hemophilia B have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions. Individuals with moderate hemophilia B seldom have spontaneous bleeding but bleeding episodes may be precipitated by relatively minor trauma. Without pretreatment (as for elective invasive procedures) they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years. The frequency of bleeding episodes requiring treatment with factor IX concentrates varies from once a month to once a year. Signs and symptoms of bleeding are otherwise similar to those found in severe hemophilia B. Individuals with mild hemophilia B do not have spontaneous bleeding. However, without treatment, abnormal bleeding occurs with surgery, tooth extractions, and major injuries. The frequency of bleeding may vary from once a year to once every ten years. Individuals with mild hemophilia B are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [Plug et al 2006]. ### Table 2. Symptoms Related to Severity of Untreated Hemophilia B View in own window Clinical SeverityFactor IX Clotting Activity 1SymptomsUsual Age of Diagnosis Severe<1% * Frequent spontaneous bleeding * Excessive and/or prolonged bleeding after minor injuries, surgery, or tooth extractions Age ≤2 years Moderate1%-5% * Spontaneous bleeding rare * Excessive and/or prolonged bleeding after minor injuries, surgery, or tooth extractions Age <5-6 years Mild>5%-40% * No spontaneous bleeding * Excessive and/or prolonged bleeding after major injuries, surgery, or tooth extractions Often later in life, depending on hemostatic challenges 1\. Clinical severity does not always correlate with the in vitro assay result. Complications of untreated bleeding. The leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is chronic joint disease [Luck et al 2004]. Currently available treatment with clotting factor concentrates is normalizing life expectancy and reducing chronic joint disease for children and adults with hemophilia B. Prior to the availability of such treatment, the median life expectancy for individuals with severe hemophilia B was 11 years (the current life expectancy for affected individuals in several developing countries). Excluding death from HIV, life expectancy for those severely affected individuals receiving adequate treatment was 63 years in 2000 [Darby et al 2007], having been greatly improved with factor replacement therapy [Tagliaferri et al 2010]. Other. Since the late1960s, the mainstay of treatment of bleeding episodes has been factor IX concentrates that initially were derived solely from donor plasma. By the late 1970s, more purified preparations became available, reducing the risk for thrombogenicity. Viral inactivation methods and donor screening of plasmas were introduced by 1990 and a recombinant factor IX concentrate became available shortly thereafter [Monahan & Di Paola 2010]. A second recombinant factor IX concentrate was FDA licensed in 2013. Two long-acting modified recombinant factor IX concentrates are now FDA approved, extending the factor IX half-life three- to fivefold compared to unmodified products [Powell et al 2013, Santagostino et al 2016] . HIV transmission from concentrates occurred between 1979 and 1985. Approximately half of these individuals died of AIDS prior to the advent of effective HIV therapy. Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination introduced in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of the hepatitis C virus. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have essentially eliminated hepatitis C transmission from plasma-derived concentrates. Alloimmune inhibitors occur much less frequently than in hemophilia A. Approximately 2% of individuals with severe hemophilia B develop alloimmune inhibitors to factor IX [Puetz et al 2014]. These individuals usually have partial- or whole-gene deletions or certain nonsense variants (see Genotype-Phenotype Correlations and Table A, Locus-Specific Databases). At times, the onset of an alloimmune response has been associated with anaphylaxis to transfused factor IX or development of nephrotic syndrome [DiMichele 2007, Chitlur et al 2009]. ### Genotype-Phenotype Correlations Disease severity * Large deletions, nonsense variants, and most frameshift variants cause severe disease. * Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved. Alloimmune inhibitors * Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (>50-bp) deletions, whole-gene deletions or early termination (<100 predicted amino acids) variants [Goodeve 2015, Saini et al 2015]. * Missense variants are rarely associated with inhibitors. Unlike hemophilia A, severe hemophilia B is often caused by a missense variant and several of these are associated with normal cross-reacting material (factor IX antigen) levels (see Table A, Locus-Specific Databases). Uncommon variants within the carboxylase-binding domain of the propeptide cause increased sensitivity to warfarin anticoagulation in individuals without any baseline bleeding tendency [Oldenburg et al 2001] (see Management). In hemophilia B Leyden, more than 20 different causative variants in the proximal F9 promoter region have been described [Funnell & Crossley 2014]; the severity of disease decreases after puberty; mild disease disappears and severe disease becomes mild, depending on the specific pathogenic variant. ### Penetrance All males with an F9 pathogenic variant are affected and will have hemophilia B of approximately the same severity as all other affected males in the family; however, other genetic and environmental effects may modify the clinical severity to some extent. Approximately 30% of females with one F9 pathogenic variant and one normal allele have a factor IX clotting activity lower than 40% and a bleeding disorder; mild bleeding can occur in carriers with low-normal factor IX activities [Plug et al 2006]. ### Prevalence The birth prevalence of hemophilia B is approximately one in 30,000 live male births worldwide. Hemophilia B is about one fifth as prevalent as hemophilia A. The birth prevalence is the same in all countries and all races, presumably because of the high spontaneous mutation rate of F9 and its presence on the X chromosome. ## Differential Diagnosis Increased bleeding during or immediately after major trauma, after a tonsillectomy, or for a few hours following tooth extraction may not be suggestive of a bleeding disorder. In contrast, prolonged or intermittent oozing that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. A detailed history of bleeding episodes can help determine if the individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder. An older individual with severe or moderate hemophilia B may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present, but individuals with a mild bleeding disorder usually have no outward signs except during an acute bleeding episode. Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia B. Bleeding disorders with a low factor IX clotting activity: * Combined vitamin K-dependent factor deficiency (OMIM 277450) is associated with deficiency of prothrombin, factors VII, IX, and X, and proteins C and S. It is very rare, usually presenting in childhood with severe bleeding. Coagulation laboratory analysis shows a markedly elevated PT and activated partial thromboplastin time (aPTT). The elevated PT, multiple coagulation factor deficiencies, and autosomal recessive inheritance would differentiate this from hemophilia B. Pathogenic variants in GGCX and VKORC1 are causative. * Common acquired deficiencies of vitamin K-dependent factors occur in individuals receiving warfarin treatment or those with liver disease. Vitamin K deficiency usually presents in the setting of other illnesses, although it may be solely nutritional. Warfarin therapy is by history. Clinical manifestations of liver disease are usually present when coagulation factors are decreased. These diagnoses can be distinguished from hemophilia B by a PT that is prolonged greater than the prolongation of the aPTT (versus an isolated prolonged aPTT in hemophilia B) and multiple coagulation factor deficiencies. Bleeding disorders with normal factor IX clotting activity: * Hemophilia A is clinically indistinguishable from hemophilia B. Diagnosis is based on a factor VIII clotting activity level lower than 40% in the presence of a normal von Willebrand factor (VWF) level. Pathogenic variants in F8 are causative. Inheritance is X-linked. * von Willebrand disease (VWD) * Type 1 VWD is characterized by a partial quantitative deficiency of von Willebrand factor (low VWF antigen, low factor VIII clotting activity, and low VWF activity). Mucous membrane bleeding including heavy menstrual bleeding and prolonged oozing after surgery or tooth extractions are the predominant symptoms. Individuals with hemophilia B have a normal VWF level and a normal factor VIII activity. * Type 2A and Type 2B VWD are characterized by a qualitative deficiency of VWF, with a decrease of the high molecular-weight multimers. Measures of VWF platelet or collagen binding activity are decreased, while VWF antigen and factor VIII clotting activity may be low-normal to mildly decreased. Type 2A VWD is caused by pathogenic variants resulting in abnormal multimer formation or stability. Type 2B VWD is caused by a gain of function in platelet binding and is often accompanied by thrombocytopenia. Molecular genetic testing can aid in diagnosis. Type 2A and 2B VWD are typically inherited in an autosomal dominant manner. * Type 2M VWD is also characterized by a qualitative deficiency of VWF with a similar decrease in function as seen in type 2A; however, it is associated with a normal multimer pattern. Molecular genetic testing can aid in the diagnosis. Inheritance is autosomal dominant. * Type 2N VWD is an uncommon clinical variant resulting from one of several missense variants in the amino terminus of the circulating VWF protein, resulting in defective binding of factor VIII to VWF. VWF platelet binding is completely normal. Clinically and biochemically, type 2N VWD is indistinguishable from mild hemophilia A; however, mild hemophilia A can be distinguished from type 2N VWD by molecular genetic testing of F8 and molecular genetic testing of VWF. Inheritance is autosomal recessive. * Type 3 VWD is characterized by a complete or near-complete quantitative deficiency of VWF. Affected individuals experience frequent episodes of mucous membrane bleeding and joint and muscle bleeding similar to that seen in individuals with hemophilia A. The VWF level is often lower than 1% and the factor VIII clotting activity level is commonly 2%-8%. Inheritance is autosomal recessive. Heterozygous parents may have type 1 VWD but more often are asymptomatic. * Factor XI deficiency (OMIM 612416) is caused by mutation of F11. Heterozygotes have a factor XI coagulant activity of 25% to 75% of normal while homozygotes have activity of less than 1% to 15% [Duga & Salomon 2013]. Two pathogenic variants are common among individuals of Ashkenazi Jewish descent. Both compound heterozygotes and homozygotes may exhibit bleeding similar to that seen in mild or moderate hemophilia B. A specific factor XI clotting assay establishes the diagnosis. * Factor XII (OMIM 234000), prekallikrein (OMIM 612423), or high molecular-weight kininogen deficiencies (OMIM 228960) do not cause clinical bleeding but can cause a long aPTT. * Prothrombin (factor II) (OMIM 613679), factor V (OMIM 227400), factor X (OMIM 227600), and factor VII (OMIM 227500) deficiencies are rare bleeding disorders inherited in an autosomal recessive manner. Individuals may display easy bruising and hematoma formation, epistaxis, heavy menstrual bleeding, and bleeding after trauma and surgery. Hemarthroses are uncommon. Spontaneous intracranial bleeding can occur. Factor VII deficiency should be suspected if the PT is prolonged and aPTT is normal. Individuals with deficiency of factors II, V, or X usually have prolonged PT and aPTT, but specific coagulation factor assays establish the diagnosis. * Inherited fibrinogen disorders include complete (afibrinogenemia) or partial (hypofibrinogenemia) fibrinogen deficiency. Afibrinogenemia (OMIM 202400) is a rare disorder inherited in an autosomal recessive manner with manifestations similar to hemophilia B except that bleeding from minor cuts is prolonged because of the lack of fibrinogen to support platelet aggregation. Hypofibrinogenemia (OMIM 616004) can be inherited either in an autosomal dominant or autosomal recessive manner. In dysfibrinogenemia (OMIM 616004) there is discordance between the functional and antigenic level, with the latter usually in the normal range. Dysfibrinogenemia is inherited in an autosomal dominant manner. Individuals with hypofibrinogenemia or dysfibrinogenemia have mild-to-moderate bleeding symptoms or may be asymptomatic; rare individuals with dysfibrinogenemia are at risk for thrombosis. For all fibrinogen disorders, the thrombin and reptilase times are almost always prolonged and functional measurements of fibrinogen decreased. * Factor XIII deficiency (OMIM 613225, 613235) is a rare autosomal recessive disorder. Umbilical stump bleeding occurs in more than 80% of individuals. Intracranial bleeding that occurs spontaneously or following minor trauma is seen in 30% of individuals. Subcutaneous hematomas, muscle hematomas, defective wound healing, and recurrent spontaneous abortion are also seen. Joint bleeding is rare. All coagulation screening tests are normal; a screening test for clot solubility or a specific assay for factor XIII (FXIII) activity can confirm the diagnosis. * Platelet function disorders including Bernard-Soulier syndrome (OMIM 231200), Glanzmann thrombasthenia (OMIM 273800), and storage pool and nonspecific secretory defects. Individuals with platelet function disorders have skin and mucous membrane bleeding, recurring epistaxis, gastrointestinal bleeding, heavy menstrual bleeding, and excessive bleeding during or immediately after trauma and surgery. Joint, muscle, and intracranial bleeding is rare. Diagnosis is made using platelet aggregation assays, flow cytometry, and platelet electron microscopy. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hemophilia B, the following evaluations are recommended if they have not already been completed: * A personal and family history of bleeding to help predict disease severity * A joint and muscle evaluation, particularly if the individual describes a history of hemarthrosis or deep-muscle hematomas * Screening for hepatitis A, B, and C as well as HIV if blood products or plasma-derived clotting factor concentrates were administered prior to 1990 * Baseline CBC including platelet count and ferritin, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding, or in females, heavy menstrual bleeding or postpartum hemorrhage * Referral to a hemophilia treatment center. For locations: * Worldwide, see World Federation of Hæmophilia; * US only, see National Hemophilia Foundation. * Identification of the specific F9 pathogenic variant in an individual to aid in determining disease severity, the likelihood of inhibitor development, and the risk of anaphylaxis if an inhibitor does develop * Consultation with a clinical geneticist and/or genetic counselor, particularly if a new diagnosis in the family and for females of childbearing years ### Treatment of Manifestations The World Federation of Hæmophilia has published treatment guidelines for the management of individuals with hemophilia. Treatment should be coordinated through a hemophilia treatment center (for locations in the USA: see National Hemophilia Foundation; elsewhere worldwide: see World Federation of Hæmophilia). Intravenous infusion of plasma-derived or recombinant factor IX for bleeding episodes should be initiated within an hour of noticing symptoms. * Dosing is weight based and target levels and duration of treatment vary by the severity of bleeding and/or the risk associated with the surgery or procedure. * Identify staff members who are expert in performing venipunctures in infants and toddlers because frequent venipunctures may be necessary. * Parents of children age two to five years with severe hemophilia B should be trained to administer the infusions as soon as is feasible. Home treatment allows for prompt treatment and facilitates prophylactic therapy. Pediatric issues. Special considerations for care of infants and children with hemophilia B include the following [Chalmers et al 2011]: * Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure. * Immunizations should be administered subcutaneously; intramuscular injections should be avoided unless under factor coverage. * Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children. Inhibitors. Alloimmune inhibitors to factor IX, seen in 1%-3% of persons with severe hemophilia B, greatly compromise the ability to manage bleeding episodes [Hay et al 2006]. Their onset can be associated with anaphylactic reactions to factor IX infusion and nephrotic syndrome [DiMichele 2007, Chitlur et al 2009]. Immune tolerance can be challenging and long-term bypassing therapy may be needed for treatment. ### Prevention of Primary Manifestations Prophylactic treatment is recommended by the National Hemophilia Foundation and the World Federation of Hæmophilia for children with severe hemophilia and is usually administered as infusion of factor IX concentrate twice weekly or every other day to maintain factor IX clotting activity above 1%, although a less intense regimen may provide protection for some affected boys [Fischer et al 2002]. Also, some individuals will require troughs higher than 1% to prevent bleeding. Longer-acting factor IX concentrates that extend the half-life three- to fivefold are now available. Choice of product should be individualized based on clinical factors and activity levels. Initiation of prophylactic infusions of factor IX concentrate in young boys before or just after their first few joint bleeds has been shown to nearly eliminate spontaneous bleeding and prevent chronic joint disease [Manco-Johnson et al 2007]. Prophylaxis in adults is standard of care in many countries and has been shown to decrease bleeding and improve joint function and quality of life [Josephson 2013, Manco-Johnson et al 2013] ### Prevention of Secondary Complications Many recombinant products are now produced without human- or animal-derived proteins in the process or final product. Virucidal treatment of plasma-derived concentrates has eliminated the risk of HIV transmission since 1985, and of hepatitis B and C viruses since 1990. ### Surveillance Persons with hemophilia followed at hemophilia treatment centers (HTCs) (see Resources) have lower mortality than those who are not [Soucie et al 2000, Pai et al 2016]. Young children with severe or moderate hemophilia B should be evaluated at an HTC (accompanied by the parents) every six to 12 months to review their history of bleeding episodes and adjust treatment plans as needed. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, and a discussion of any other problems related to the individual's hemophilia and family and community support. Screening for alloimmune inhibitors is usually done in those with severe hemophilia B after treatment with factor IX concentrates has been initiated for either bleeding or prophylaxis. Affected individuals at increased risk for inhibitor formation should be closely monitored during initial infusions and additional screening is usually performed up to a few years of age when the genotype is a large partial deletion, complete F9 deletion, or early termination variant (<100 predicted amino acids) (see Genotype-Phenotype Correlations and Molecular Genetics, Pathogenic variants). Testing for inhibitors should also be performed in any individual with hemophilia B whenever a suboptimal clinical response to treatment is suspected, regardless of disease severity; with hemophilia B, the onset may be heralded by an allergic reaction to infused factor IX concentrate. Older children and adults with severe or moderate hemophilia B benefit from at least yearly assessments at an HTC (see Resources) and periodic assessments to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for an inhibitor, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia. Individuals with mild hemophilia B can benefit from an assessment at an HTC every one to two years. ### Agents/Circumstances to Avoid The following should be avoided: * Circumcision of infant males with a family history of hemophilia B unless hemophilia B is excluded; OR if circumcision is performed on an infant with hemophilia B, the infant should be treated with factor IX concentrate directly before and after the procedure. * Intramuscular injections * Activities that involve a high risk of trauma, particularly of head injury * Medications and herbal remedies that affect platelet function, including aspirin unless there is strong medical indication (e.g., in individuals with atherosclerotic cardiovascular disease). Individuals with severe hemophilia usually require clotting factor prophylaxis to allow aspirin and other platelet inhibitory drugs to be used safely [Angelini et al 2016]. Older, intermediate purity plasma-derived “prothrombin complex” concentrates should be used cautiously (if at all) in hemophilia B because of their thrombogenic potential. ### Evaluation of Relatives at Risk Identification of at-risk relatives. A thorough family history may identify other male relatives who are at risk but have not been tested (particularly in families with mild hemophilia B). Early determination of the genetic status of males at risk. Either assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue) or molecular genetic testing for the family-specific F9 pathogenic variant can establish or exclude the diagnosis of hemophilia B in newborn males at risk. Infants with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing. Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one-tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1%, but is equivocal in an infant with moderately low (15%-20%) activity. Determination of genetic status of females at risk. Approximately 30% of heterozygous females have factor IX clotting activity lower than 40% and may have abnormal bleeding. In a recent Dutch survey of heterozygous females, bleeding symptoms correlated with baseline factor clotting activity; there was suggestion of a very mild increase in bleeding even in those with 40% to 60% factor IX clotting activity [Plug et al 2006]. Joint range of motion in female carriers with factor VIII or factor IX activity lower than 40% was found to be significantly different from that measured in normal controls and inversely related to factor level [Sidonio et al 2014]. All daughters and mothers of an affected male and other at-risk females should have a baseline factor IX clotting activity assay to determine if they are at increased risk for bleeding (unless they are known to be non-carriers based on molecular genetic testing). Very occasionally, a female will have particularly low factor IX clotting activity that may result from heterozygosity for an F9 pathogenic variant associated with skewed X-chromosome inactivation or, on rare occasion, compound heterozygosity for two F9 pathogenic variants. It is recommended that the carrier status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Obstetric issues. It is recommended that the carrier status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible. Unlike for factor VIII (FVIII), maternal factor IX levels do not increase during pregnancy and carriers are more likely to need factor infusion support for delivery or to treat or prevent postpartum hemorrhage. In carriers, postpartum hemorrhage has been a prominent feature, despite the absence of heavy menstrual bleeding [Yang & Ragni 2004]. If the female has a baseline factor IX clotting activity below approximately 40%, she by definition has hemophilia and is at risk for excessive bleeding, particularly post partum, and may require therapy with factor IX concentrate [Yang & Ragni 2004]. Newborn males. Controversy remains as to indications for cesarean section versus vaginal delivery [James & Hoots 2010, Ljung 2010]. For elective deliveries, the relative risks of cesarean section versus vaginal delivery should be considered, especially if a male has been diagnosed with severe hemophilia B prenatally. At birth or in the early neonatal period, intracranial hemorrhage is uncommon (<1%-2%), even in males with severe hemophilia B who are delivered vaginally. ### Therapies Under Investigation Recombinant factor IX (FIX) proteins with prolonged survival. Two products with modifications to prolong half-life (Fc or albumin fusion proteins) are now FDA approved and others, including with site-specific PEGylation, have completed Phase III clinical trials [Powell et al 2013, Peyvandi et al 2016, Santagostino et al 2016]. Clinical trial data show a three- to five fold prolongation of FIX half-life with the fusion proteins. Gene therapy for hemophilia B. Several clinical trials of gene therapy using intravenous infusion of an adeno-associated viral vector expressing factor IX are underway; some have shown sustained factor levels [Lheriteau et al 2015]. These vectors use liver-restricted promoters to target synthesis to the natural site of FIX synthesis. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. ### Other Vitamin K does not prevent or control bleeding caused by hemophilia B. Fresh frozen plasma is no longer recommended to treat hemophilia B because it is not treated with a virucidal agent. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hemophilia B	c0008533	1,193	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1495/	2021-01-18T21:22:03	{"mesh": ["D002836"], "synonyms": ["Christmas Disease", "Factor IX Deficiency"]}
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: "Pinta" disease – news · newspapers · books · scholar · JSTOR (May 2018) (Learn how and when to remove this template message) Pinta (disease) SpecialtyInfectious disease Pinta (also known as azul, carate, empeines, lota, mal del pinto, and tina) is a human skin disease caused by infection with the spirochete, Treponema carateum, which is morphologically and serologically indistinguishable from the bacterium that causes syphilis. The disease is endemic to Mexico, Central America, and South America.[1] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Pinta, the least severe of treponemal infections being limited to the skin, is thought to be transmitted by skin-to-skin contact (similar to bejel and yaws), and after an incubation period of two to three weeks, produces a raised papule, which enlarges and becomes hyperkeratotic (scaly/flaky). Lesions are usually present in the exposed surface of arms and legs. Local lymph nodes might be enlarged. Three to nine months later, further thickened and flat lesions (pintids) appear all over the body. These generally resolve, but a proportion of people with pinta will go on to develop late-stage disease, characterised by widespread pigmentary change with a mixture of hyperpigmentation and depigmentation which can be disfiguring.[2] ## Cause[edit] Pinta is caused by the bacterium Treponema carateum. It is related to the more well-known T. pallidum, which can cause endemic syphilis. ## Diagnosis[edit] Diagnosis is usually clinical, but as with yaws and bejel, serological tests for syphilis, such as rapid plasma reagin (RPR) and TPHA, will be positive, and the spirochetes can be seen on dark field microscopy of samples taken from the early papules. ## Treatment[edit] The disease can be treated with penicillin, tetracycline (not to be used in pregnant women), azithromycin or chloramphenicol, and can be prevented through contact tracing by public health officials. A single intramuscular injection of long-acting penicillin is effective against endemic treponematoses including pinta, yaws, and bejel.[3] ## See also[edit] Wikimedia Commons has media related to Pinta (disease). * List of cutaneous conditions ## References[edit] 1. ^ "Pinta". Medscape. WebMD. Retrieved 3 September 2012. 2. ^ Torok, E (2009). Oxford Handbook of Infectious Diseases and Microbiology (first ed.). Oxford University Press. p. 388. ISBN 978-0-19-856925-1. 3. ^ Fine, Steven. "Treponematosis (Endemic Syphilis) Medication". Medscape. WebMD. Retrieved 15 September 2014. ## External links[edit] Classification D * ICD-10: A67 * ICD-9-CM: 103 * MeSH: D010874 * DiseasesDB: 13270 * v * t * e Bacterial diseases due to gram negative non-proteobacteria (BV4) Spirochaete Spirochaetaceae Treponema * Treponema pallidum * Syphilis/bejel * Yaws * Treponema carateum (Pinta) * Treponema denticola Borrelia * Borrelia burgdorferi/Borrelia afzelii * Lyme disease * Erythema migrans * Neuroborreliosis * Borrelia recurrentis (Louse borne relapsing fever) * Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever) Leptospiraceae Leptospira * Leptospira interrogans (Leptospirosis) Chlamydiaceae Chlamydia * Chlamydia psittaci (Psittacosis) * Chlamydia pneumoniae * Chlamydia trachomatis * Chlamydia * Lymphogranuloma venereum * Trachoma Bacteroidetes * Bacteroides fragilis * Tannerella forsythia * Capnocytophaga canimorsus * Porphyromonas gingivalis * Prevotella intermedia Fusobacteria * Fusobacterium necrophorum (Lemierre's syndrome) * Fusobacterium nucleatum * Fusobacterium polymorphum * Streptobacillus moniliformis (Rat-bite fever/Haverhill fever) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Pinta (disease)	c0031946	1,194	wikipedia	https://en.wikipedia.org/wiki/Pinta_(disease)	2021-01-18T19:01:37	{"gard": ["7397"], "mesh": ["D010874"], "umls": ["C0153242", "C0153243", "C0153244", "C0031946", "C0153241"], "wikidata": ["Q922029"]}
Kelley-Seegmiller syndrome (KSS) is the mildest form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO) leading to urolithiasis, and early-onset gout. ## Epidemiology The exact prevalence is unknown but is probably underestimated due to misdiagnosis. KSS may represent about 15% of HPRT deficient patients. ## Clinical description Age of onset is usually in infancy but can also be in adulthood (up to 30 years). Males are generally affected and heterozygous females are carriers (usually asymptomatic). Patients are normal at birth. The first manifestation is the presence of orange crystals in diapers. Urolithiasis, uric acid nephropathy, urinary infections and renal obstruction are often the presenting symptoms. Gout may appear after puberty with acute arthritis or tophi. In contrast to Lesch-Nyhan syndrome (LNS; see this term), dystonia may be mild or even absent. Patients have normal intelligence associated with various degrees of attention deficit. Compulsive self-injurious behavior is absent. ## Etiology The disease is caused by partial HPRT deficiency due to mutations in the HPRT1 gene (Xq26). Inheritance is X-linked recessive. UAO may be due to deficient recycling of purine bases with increased synthesis of purine nucleotides leading to hyperuricemia that increases the risk of UA crystal precipitation in tissues to form tophi, in joints leading to inflammatory processes and gouty arthritis, and renal UA excretion causing urolithiasis. ## Diagnostic methods Diagnosis may be suspected when nephrolithiasis and/or obstructive nephropathy occur and is based on biochemical, enzymatic and molecular tests. Hyperuricemia and UAO are detectable in serum and urine. Plasmatic levels and urinary excretion of urate, hypoxanthine, and, to a lesser extent, xanthine are elevated. HPRT activity in hemolysate ranges from 0.5% to 10%. ## Differential diagnosis Differential diagnosis includes glucose 6-phosphate dehydrogenase deficiency, Lesch-Nyhan syndrome and phosphoribosylpyrophosphate (PRPP) synthetase superactivity (see these terms). ## Antenatal diagnosis Antenatal diagnosis is usually not required. ## Management and treatment UAO, nephrolithiasis, gouty arthritis and tophi can be managed with allopurinol, urine alkalinization (sodium bicarbonate or citrate) and generous hydration. Doses must be carefully adjusted to avoid xanthine lithiasis. ## Prognosis With appropriated treatment renal function remains stable and patients have a normal life expectancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Hypoxanthine guanine phosphoribosyltransferase partial deficiency	c0268117	1,195	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79233	2021-01-23T18:34:33	{"mesh": ["C562583"], "omim": ["300323"], "umls": ["C0268117"], "icd-10": ["E79.8"], "synonyms": ["HPRT deficiency, grade I", "HPRT partial deficiency", "HPRT-related gout", "HPRT-related hyperuricemia", "HPRT1 partial deficiency", "Hypoxanthine guanine phosphoribosyltransferase 1 partial deficiency", "Hypoxanthine guanine phosphoribosyltransferase deficiency, grade I", "Kelley-Seegmiller syndrome"]}
Periorbital dermatitis Other namesPeriocular dermatitis[1] Periorbital dermatitis SpecialtyDermatology Periorbital dermatitis is a skin condition, a variant of perioral dermatitis, occurring on the lower eyelids and skin adjacent to the upper and lower eyelids.[2] ## See also[edit] * Granulomatous perioral dermatitis * Perioral dermatitis ## 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; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Page 249. ISBN 0-7216-2921-0. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Periorbital dermatitis	None	1,196	wikipedia	https://en.wikipedia.org/wiki/Periorbital_dermatitis	2021-01-18T18:58:23	{"wikidata": ["Q7168677"]}
A number sign (#) is used with this entry because transient neonatal cyanosis is caused by heterozygous mutation in the HBG2 gene (142250) on chromosome 11p15.5. Description Neonatal cyanosis is characterized by symptoms in the fetus and neonate that gradually abate by 5 to 6 months of age. The disorder is caused by a defect in the fetal hemoglobin chain, which causes reduced affinity for oxygen due to steric inhibition of oxygen binding and/or due to increased oxidation of the fetal hemoglobin molecule to methemoglobin (Hb FM), which has decreased oxygen-binding capacity. Some patients develop anemia resulting from increased destruction of red cells containing abnormal or unstable hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months of age or earlier, as the adult beta-globin chain (HBB; 141900) is produced and replaces the fetal gamma-globin chain (summary by Crowley et al., 2011). Clinical Features Hayashi et al. (1980) reported a premature Japanese baby with severe cyanosis and jaundice. Priest et al. (1989) reported a well newborn who was cyanotic at birth. He was found to have a mutant gamma-globin chain, leading to functionally abnormal fetal hemoglobin. This patient showed no clinical evidence of cyanosis at 5 weeks of age as gamma-chain synthesis was replaced by beta-chain synthesis. A sib born 20 months later was also affected. Urabe et al. (1996) described a full-term baby who was cyanotic from birth but did not require special treatment. Prehu et al. (2003) reported a newborn male in southwest France who presented at birth with marked cyanosis. He was of normal weight and was born uneventfully at 41 weeks from a 28-year-old mother. Studies excluded a cardiovascular origin of the cyanosis, which persisted under oxygen therapy. The intensity of cyanosis decreased after a few months. Dainer et al. (2008) reported a male with neonatal cyanosis. The patient's oxygen saturation was 85% on room air and he required supplemental oxygen. His 4-year-old sister had a similar neonatal course and had required supplemental oxygen for the first 4 to 5 months of life, at which time she became asymptomatic. High performance liquid chromatography of the male infant's blood showed 68.4% HbF, 17.5% HbA, and 14.0% HbX, eluting between HbF and HbA. Spectroscopic analysis was not performed. Crowley et al. (2011) reported a female infant with cyanosis and moderate hepatomegaly at birth. Hemoglobin oxygen saturation in ambient air was 30 to 50%. She also had moderate anemia with reticulocytosis, but methemoglobin levels were normal. Electrophoresis showed that total hemoglobin consisted of about 90% HbF and 10% HbA, with no variant bands. She received transfusions, which raised the hemoglobin oxygen saturation levels. By 2 months of age, her hemoglobin oxygen saturation was consistently higher than 95%. The patient's father also had transient neonatal cyanosis, which resolved within 1 to 2 months. Molecular Genetics A methemoglobinemic (M) variant of fetal hemoglobin (HbF), known as Hb FM-Osaka (H63Y; 142250.0025), was found in a premature Japanese baby with severe jaundice and cyanosis (Hayashi et al., 1980). The Osaka variant was also found in newborns with cyanosis by Glader et al. (1989), Urabe et al. (1996), and Prehu et al. (2003). Glader (1989) identified Hb FM-Fort Ripley, caused by a heterozygous mutation in the HBG2 gene (H92Y; 142250.0034), in a healthy but cyanotic newborn girl. The patient reported by Priest et al. (1989) had the Hb FM-Fort Ripley variant. Kohli-Kumar et al. (1995) reported a term infant with mild cyanosis. Standard hemoglobin electrophoresis, including isoelectric focusing, was normal. However, by reverse-phase HPLC on a C(4) column, they detected an abnormal globin chain. Amino acid and DNA sequencing revealed a heterozygous F41S (142250.0041) substitution in the HBG2 chain. This substitution, designated hemoglobin F-Cincinnati, presumably decreased oxygen affinity of the hemoglobin. The corresponding substitution in the beta-globin gene is found in hemoglobin Denver (HBB; 141900.0441) and is associated with cyanosis. In 2 sibs with neonatal transient cyanosis, Dainer et al. (2008) identified a heterozygous mutation in the HBG2 gene (H63L; 142250.0050), which was termed Hb F-Circleville. The heterozygous mutation was found in the father, who had no recollection of neonatal cyanosis. Position his63 in HBG2 coordinates with heme iron and is mutant in Hb FM-Osaka (H63Y; 142250.0025). Dainer et al. (2008) noted that the presence of a tyrosine at codon 63 in Hb FM-Osaka causes the formation of a covalent link with heme iron, so that the iron is stabilized in the ferric (3+) form. When this occurs, methemoglobin is formed, oxygen can no longer bind to heme, and cyanosis occurs. In a female infant with neonatal cyanosis and anemia, Crowley et al. (2011) identified a heterozygous mutation in the HBG2 gene (V67M; 142250.0051). The variant was named Hb-Toms River. This mutation modified the ligand-binding pocket of fetal hemoglobin via 2 mechanisms. First, the relatively large side chain of methionine decreases both the affinity of oxygen for binding to the mutant hemoglobin subunit via steric hindrance and the rate at which it does so. Second, the mutant methionine is converted to aspartic acid posttranslationally, probably through oxidative mechanisms. The presence of this polar amino acid in the heme pocket was predicted to enhance hemoglobin denaturation, causing anemia. The patient's father, who was also heterozygous for the mutation, had transient neonatal cyanosis, which resolved within 1 to 2 months. INHERITANCE \- Autosomal dominant ABDOMEN Liver \- Hepatomegaly (in some) SKIN, NAILS, & HAIR Skin \- Cyanosis \- Jaundice (in some) HEMATOLOGY \- Decreased oxygen-binding capacity of hemoglobin \- Decreased hemoglobin oxygen saturation \- Anemia (in some) \- Reticulocytosis (in some) LABORATORY ABNORMALITIES \- Methemoglobinemia MISCELLANEOUS \- Onset at birth \- Spontaneously resolves by 5 to 6 months of age MOLECULAR BASIS \- Caused by mutation in the gamma G hemoglobin gene (HBG2, 142250.0025 ) ▲ 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	CYANOSIS, TRANSIENT NEONATAL	c3151421	1,197	omim	https://www.omim.org/entry/613977	2019-09-22T15:56:58	{"omim": ["613977"], "orphanet": ["280615"], "synonyms": ["Transient neonatal cyanosis and anemia due to Toms River Hemoglobin"]}
Congenital hepatic fibrosis is a rare disease of the liver that is present at birth. Symptoms include the following: a large liver, a large spleen, gastrointestinal bleeding caused by varices, increased pressure in the blood vessels that carry blood to the liver (portal hypertension), and scar tissue in the liver (fibrosis). Isolated congenital hepatic fibrosis is rare; it usually occurs as part of a syndrome that also affects the kidneys. There is no treatment to correct the fibrosis or the specific abnormalities in the blood vessels, but complications such as bleeding and infection can be treated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	Congenital hepatic fibrosis	c0009714	1,198	gard	https://rarediseases.info.nih.gov/diseases/6168/congenital-hepatic-fibrosis	2021-01-18T18:01:08	{"mesh": ["C562378"], "synonyms": []}
For a general phenotypic description and a discussion of genetic heterogeneity of kala-azar, which is also known as visceral leishmaniasis, see 608207. Mapping A major susceptibility gene for kala-azar has been identified on chromosome 22q12 (KAZA1; 608207) in the Aringa ethnic group in eastern Sudan. Miller et al. (2007) performed a genomewide scan using 69 families from 2 adjacent villages occupied by the related Masalit ethnic group, who migrated from western Sudan to leishmaniasis-endemic eastern Sudan beginning in 1969. They identified major susceptibility loci on chromosomes 1p22 (KAZA2; 611381) and 6q27 (KAZA3) that were Y chromosome lineage- and village-specific. Neither village showed an association with chromosome 22q12. The results suggested strong lineage-specific susceptibility genes due to founder effect (10 to 15 related males for each village) and consanguinity (more than 30% consanguineous polygamous marriages) in this patriarchal society. Miller et al. (2007) noted that the chromosome 6q27 locus had also shown association with visceral leishmaniasis susceptibility in a Brazilian population (Jamieson et al., 2007). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor *[BMI]: body mass index	KALA-AZAR, SUSCEPTIBILITY TO, 3	c1969648	1,199	omim	https://www.omim.org/entry/611382	2019-09-22T16:03:21	{"omim": ["611382"], "synonyms": ["Alternative titles", "LEISHMANIASIS, VISCERAL, SUSCEPTIBILITY TO, 3"]}

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