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Congenital panfollicular nevus is a rare, benign, skin tumor disorder characterized by the presence of congenital, large (few centimeters), elevated, well-circumscribed, pink-tan, multinodular, non-ulcerative, bosselated-surface skin lesions located on the neck, scalp or hand and which enlarge with time. Histologically, hamartomatous proliferation containing irregularly arranged, malformed hair follicles in various stages of development, surrounded by fibrous tissue and densely distributed within the dermis is observed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Congenital panfollicular nevus	c4476799	2,200	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139414	2021-01-23T17:01:36	{}
Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome is a rare, genetic disorder of thiamine metabolism and transport characterized by infantile spasms progressing to symptomatic generalized or partial seizures, severe global developmental delay, progressive brain atrophy, and bilateral thalamic and basal ganglia lesions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome	None	2,201	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=263410	2021-01-23T17:49:41	{}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Cavitary pneumonia" – news · newspapers · books · scholar · JSTOR (July 2018) (Learn how and when to remove this template message) Cavitary pneumonia SpecialtyPulmonology Cavitary pneumonia is a disease in which the normal lung architecture is replaced by a cavity. In a healthy lung, oxygen transport occurs at the level of the alveoli (air spaces), each of which has an average size of 0.1 mm. These alveoli can become enlarged by a number of processes: bacterial infection (tuberculosis), fungal infection, vasculitis (granulomatosis with polyangiitis), collagen vascular disease (Sjögren's syndrome) or granulomatous disease (sarcoidosis). ## References[edit] * 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 This article about a medical condition affecting the respiratory system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Cavitary pneumonia	c0747674	2,202	wikipedia	https://en.wikipedia.org/wiki/Cavitary_pneumonia	2021-01-18T18:58:11	{"umls": ["C0747674"], "wikidata": ["Q5055162"]}
The absence of the septum pellucidum is a rare condition that affects the structure of the brain. Specifically, a thin membrane called the septum pellucidum is missing from its normal position in the middle of the brain. When it is missing, symptoms may include learning difficulties, behavioral changes, seizures, and changes in vision. Absence of the septum pellucidum is not typically seen as an isolated finding. Instead, absence of the septum pellucidum is associated with other conditions such as septo-optic dysplasia. Treatment options for the condition vary depending on the underlying disorder. Diagnosis of absence of the septum pellucidum can be made through imaging such as an MRI. Symptoms of absence of the septum pellucidum typically present during childhood, but a diagnosis can also be made before an individual is born (prenatally). If an individual is found to be missing the septum pellucidum, a search for an underlying disorder should be made. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Absence of septum pellucidum	c0431371	2,203	gard	https://rarediseases.info.nih.gov/diseases/9253/absence-of-septum-pellucidum	2021-01-18T18:02:23	{"mesh": ["C535562"], "umls": ["C0431371"], "synonyms": []}
## Clinical Features Molinari et al. (2008) reported an Australian family with nonsyndromic X-linked mental retardation. Of 5 sibs, there was 1 healthy girl, 2 girls with mild mental retardation, and 2 boys with severe mental retardation. The 2 affected males had a similar phenotype with the same degree of handicap. Both were in educational classes for the moderately handicapped and were able to hold a limited conversation; however, neither learned to read or write. Both were on disability pensions as adults. Their mother was described as slow and was found to carry the mutation. One affected sister was deceased and had been enrolled in a special class for the mildly handicapped at school, but was not as slow as the brothers. History Molinari et al. (2008) identified a mutation in the MAGT1 gene (300715.0001) in affected members of a family with MRX95. Piton et al. (2013) detected this mutation in 13 (5 male and 8 female) of 10,557 chromosomes in the NHLBI Exome Variant Server, and considered variation in the MAGT1 gene to be very unlikely to play a role in X-linked mental retardation. INHERITANCE \- X-linked dominant NEUROLOGIC Central Nervous System \- Mental retardation, severe (in males) Mental retardation, mild (in carrier females) MISCELLANEOUS \- Based on a report of an Australian family with 3 affected females and 2 affected males ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	MENTAL RETARDATION, X-LINKED 95	c2931498	2,204	omim	https://www.omim.org/entry/300716	2019-09-22T16:19:43	{"doid": ["0050776"], "mesh": ["C567906"], "omim": ["300716"], "orphanet": ["777"]}
Not to be confused with Nephritic syndrome. Nephrotic syndrome Microscopic image of diabetic glomerulosclerosis, the main cause of nephrotic syndrome in adults. SpecialtyNephrology SymptomsSwelling, weight gain, feeling tired, foamy urine[1] ComplicationsBlood clots, infections, high blood pressure[1] CausesFocal segmental glomerulosclerosis, membranous nephropathy, minimal change disease, diabetes, lupus[1][2] Diagnostic methodUrine testing, kidney biopsy[1] Differential diagnosisNephritic syndrome, cirrhosis, severe malnutrition[2] TreatmentDirected at underlying cause[1] Frequency5 per 100,000 per year[3][4] Nephrotic syndrome is a collection of symptoms due to kidney damage.[1] This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling.[1] Other symptoms may include weight gain, feeling tired, and foamy urine.[1] Complications may include blood clots, infections, and high blood pressure.[1] Causes include a number of kidney diseases such as focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease.[1][2] It may also occur as a complication of diabetes or lupus.[1] The underlying mechanism typically involves damage to the glomeruli of the kidney.[1] Diagnosis is typically based on urine testing and sometimes a kidney biopsy.[1] It differs from nephritic syndrome in that there are no red blood cells in the urine.[2] Treatment is directed at the underlying cause.[1] Other efforts include managing high blood pressure, high blood cholesterol, and infection risk.[1] A low salt diet and limiting fluids is often recommended.[1] About 5 per 100,000 people are affected per year.[3][4] The usual underlying cause varies between children and adults.[4] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 2.1 Primary glomerulonephrosis * 2.2 Secondary glomerulonephrosis * 2.2.1 By histologic pattern * 2.3 Genetics * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 4.2 Differential diagnosis * 5 Treatment * 5.1 Symptomatic * 5.2 Kidney damage * 6 Prognosis * 7 Epidemiology * 8 References * 9 External links ## Signs and symptoms[edit] Nephrotic syndrome is usually accompanied by retention of water and sodium. The degree to which this occurs can vary between slight edema in the eyelids that decreases during the day, to affecting the lower limbs, to generalized swelling, to full blown anasarca.[5] Nephrotic syndrome is characterized by large amounts of proteinuria (>3.5 g per 1.73 m2 body surface area per day,[6] or > 40 mg per square meter body surface area per hour in children), hypoalbuminemia (< 2.5 g/dl), hyperlipidaemia, and edema that begins in the face. Lipiduria (lipids in urine) can also occur, but is not essential for the diagnosis of nephrotic syndrome. Hyponatremia also occurs with a low fractional sodium excretion. Hyperlipidaemia is caused by two factors:[citation needed] * Hypoproteinemia stimulates protein synthesis in the liver, resulting in the overproduction of lipoproteins. * Lipid catabolism is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in lipoprotein breakdown.[7] Cofactors, such as apolipoprotein C2 may also be lost by increased filtration of proteins. A few other characteristics seen in nephrotic syndrome are: * The most common sign is excess fluid in the body due to the serum hypoalbuminemia. Lower serum oncotic pressure causes fluid to accumulate in the interstitial tissues. Sodium and water retention aggravates the edema. This may take several forms: * Puffiness around the eyes, characteristically in the morning. * Pitting edema over the legs. * Fluid in the pleural cavity causing pleural effusion. More commonly associated with excess fluid is pulmonary edema. * Fluid in the peritoneal cavity causing ascites. * Generalized edema throughout the body known as anasarca. * Most of the people with nephrotic syndrome are normotensive but hypertension (rarely) may also occur. * Anaemia (iron resistant microcytic hypochromic type) maybe present due to transferrin loss. * Dyspnea may be present due to pleural effusion or due to diaphragmatic compression with ascites. * Erythrocyte sedimentation rate is increased due to increased fibrinogen & other plasma contents. * Some people may notice foamy or frothy urine, due to a lowering of the surface tension by the severe proteinuria. Actual urinary complaints such as haematuria or oliguria are uncommon, though these are seen commonly in nephritic syndrome. * May have features of the underlying cause, such as the rash associated with systemic lupus erythematosus, or the neuropathy associated with diabetes. * Examination should also exclude other causes of gross edema—especially the cardiovascular and liver system. * Muehrcke's nails; white lines (leukonychia) that extend all the way across the nail and lie parallel to the lunula[8] The main signs of nephrotic syndrome are:[9] * A proteinuria of greater than 3.5 g /24 h /1.73 m2 (between 3 and 3.5 g/24 h /1.73 m2 is considered to be proteinuria in the nephrotic range) or greater than 40 mg/h/m2 in children.[10][11] The ratio between urinary concentrations of albumin and creatinine can be used in the absence of a 24-hour urine test for total protein. This coefficient will be greater than 200–400 mg/mmol in nephrotic syndrome. This pronounced loss of proteins is due to an increase in glomerular permeability that allows proteins to pass into the urine instead of being retained in the blood. Under normal conditions a 24-hour urine sample should not exceed 80 milligrams or 10 milligrams per decilitre.[12] * A hypoalbuminemia of less than 2.5 g/dL,[10] that exceeds the liver clearance level, that is, protein synthesis in the liver is insufficient to increase the low blood protein levels. * Edema is thought to be caused by two mechanisms. The first being hypoalbuminemia which lowers the oncotic pressure within vessels resulting in hypovolemia and subsequent activation of the renin–angiotensin system and thus retention of sodium and water. Additionally, it is thought that albumin causes a direct effect on the epithelial sodium channel (ENaC) on the principal cell that leads to the reabsorption of sodium and water. Nephrotic syndrome edema initially appears in parts of the lower body (such as the legs) and in the eyelids. In the advanced stages it also extends to the pleural cavity and peritoneum (ascites) and can even develop into a generalized anasarca. * Hyperlipidaemia is caused by an increase in the synthesis of low and very low-density lipoproteins in the liver that are responsible for the transport of cholesterol and triglycerides. There is also an increase in the liver synthesis of cholesterol. * Thrombophilia, or hypercoagulability, is a greater predisposition for the formation of blood clots that is caused by a decrease in the levels of antithrombin III in the blood due to its loss in urine. * Lipiduria or loss of lipids in the urine is indicative of glomerular pathology due to an increase in the filtration of lipoproteins.[13] ### Complications[edit] Nephrotic syndrome can be associated with a series of complications that can affect an individual's health and quality of life:[14] * Thromboembolic disorders: particularly those caused by a decrease in blood antithrombin III levels due to leakage. Antithrombin III counteracts the action of thrombin. Thrombosis usually occurs in the kidney veins although it can also occur in arteries. Treatment is with oral anticoagulants (not heparin as heparin acts via anti-thrombin 3 which is lost in the proteinuria so it will be ineffective.) Hypercoagulopathy due to extravasation of fluid from the blood vessels (edema) is also a risk for venous thrombosis. * Infections: The increased susceptibility of people with nephrotic syndrome to infections can be a result of the leakage of immunoglobulins from the blood, the loss of proteins in general and the presence of oedematous fluid (which acts as a breeding ground for infections). The most common infection is peritonitis, followed by lung, skin and urinary infections, meningoencephalitis and in the most serious cases septicaemia. The most notable of the causative organisms are Streptococcus pneumoniae and Haemophilus influenzae. * Spontaneous bacterial peritonitis can develop where there is ascites present. This is a frequent development in children but very rarely found in adults.[15] * Acute kidney failure due to hypovolemia: the loss of vascular fluid into the tissues (edema) produces a decreased blood supply to the kidneys that causes a loss of kidney function. Thus it is a tricky task to get rid of excess fluid in the body while maintaining circulatory euvolemia. * Pulmonary edema: the loss of proteins from blood plasma and the consequent fall in oncotic pressure causes an abnormal accumulation of liquid in the lungs causing hypoxia and dyspnoea. * Hypothyroidism: deficiency of the thyroglobulin transport protein thyroxin (a glycoprotein that is rich in iodine and is found in the thyroid gland) due to decreased thyroid binding globulin. * Vitamin D deficiency can occur. Vitamin D binding protein is lost. * Hypocalcaemia: lack of 25-hydroxycholecalciferol (the way that vitamin D is stored in the body). As vitamin D regulates the amount of calcium present in the blood, a decrease in its concentration will lead to a decrease in blood calcium levels. It may be significant enough to cause tetany. Hypocalcaemia may be relative; calcium levels should be adjusted based on the albumin level and ionized calcium levels should be checked. * Microcytic hypochromic anaemia: iron deficiency caused by the loss of ferritin (compound used to store iron in the body). It is iron-therapy resistant. * Protein malnutrition: this occurs when the amount of protein that is lost in the urine is greater than that ingested, this leads to a negative nitrogen balance.[16][17] * Growth retardation: can occur in cases of relapse or resistance to therapy. Causes of growth retardation are protein deficiency from the loss of protein in urine, anorexia (reduced protein intake), and steroid therapy (catabolism). * Cushing's syndrome ## Causes[edit] Histological image of a normal kidney glomerulus. It is possible to see a glomerulus in the centre of the image surrounded by kidney tubules. Nephrotic syndrome has many causes and may either be the result of a glomerular disease that can be either limited to the kidney, called primary nephrotic syndrome (primary glomerulonephrosis), or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome. ### Primary glomerulonephrosis[edit] Primary causes of nephrotic syndrome are usually described by their histology:[18] * Minimal change disease (MCD): is the most common cause of nephrotic syndrome in children. It owes its name to the fact that the nephrons appear normal when viewed with an optical microscope as the lesions are only visible using an electron microscope. Another symptom is a pronounced proteinuria. * Focal segmental glomerulosclerosis (FSGS): is the most common cause of nephrotic syndrome in adults.[19] It is characterized by the appearance of tissue scarring in the glomeruli. The term focal is used as some of the glomeruli have scars, while others appear intact; the term segmental refers to the fact that only part of the glomerulus suffers the damage. * Membranous glomerulonephritis (MGN): The inflammation of the glomerular membrane causes increased leaking in the kidney. It is not clear why this condition develops in most people, although an auto-immune mechanism is suspected.[19] * Membranoproliferative glomerulonephritis (MPGN): is the inflammation of the glomeruli along with the deposit of antibodies in their membranes, which makes filtration difficult. * Rapidly progressive glomerulonephritis (RPGN): (Usually presents as a nephritic syndrome) A person's glomeruli are present in a crescent moon shape. It is characterized clinically by a rapid decrease in the glomerular filtration rate (GFR) by at least 50% over a short period, usually from a few days to 3 months.[20] They are considered to be "diagnoses of exclusion", i.e. they are diagnosed only after secondary causes have been excluded. ### Secondary glomerulonephrosis[edit] Diabetic glomerulonephritis in a person with nephrotic syndrome. Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though they may exhibit some difference suggesting a secondary cause, such as inclusion bodies.[21] They are usually described by the underlying cause. * Diabetic nephropathy: is a complication that occurs in some diabetics. Excess blood sugar accumulates in the kidney causing them to become inflamed and unable to carry out their normal function. This leads to the leakage of proteins into the urine. * Systemic lupus erythematosus: this autoimmune disease can affect a number of organs, among them the kidney, due to the deposit of immunocomplexes that are typical to this disease. The disease can also cause lupus nephritis. * Sarcoidosis: This disease does not usually affect the kidney but, on occasions, the accumulation of inflammatory granulomas (collection of immune cells) in the glomeruli can lead to nephrotic syndrome. * Syphilis: kidney damage can occur during the secondary stage of this disease (between 2 and 8 weeks from onset). * Hepatitis B: certain antigens present during hepatitis can accumulate in the kidneys and damage them. * Sjögren's syndrome: this autoimmune disease causes the deposit of immunocomplexes in the glomeruli, causing them to become inflamed, this is the same mechanism as occurs in systemic lupus erythematosus. * HIV: the virus's antigens provoke an obstruction in the glomerular capillary's lumen that alters normal kidney function. * Amyloidosis: the deposit of amyloid substances (proteins with anomalous structures) in the glomeruli modifying their shape and function. * Multiple myeloma: kidney impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in kidney obstruction. In addition, myeloma light chains are also directly toxic on proximal kidney tubules, further adding to kidney dysfunction. * Vasculitis: inflammation of the blood vessels at a glomerular level impedes the normal blood flow and damages the kidney. * Cancer: as happens in myeloma, the invasion of the glomeruli by cancerous cells disturbs their normal functioning. * Genetic disorders: congenital nephrotic syndrome is a rare genetic disorder in which the protein nephrin, a component of the glomerular filtration barrier, is altered. * Drugs ( e.g. gold salts, penicillin, captopril):[22] gold salts can cause a more or less important loss of proteins in urine as a consequence of metal accumulation. Penicillin is nephrotoxic in people with kidney failure and captopril can aggravate proteinuria. #### By histologic pattern[edit] Membranous nephropathy (MN) * Sjögren's syndrome * Systemic lupus erythematosus (SLE) * Diabetes mellitus * Sarcoidosis * Drugs (such as corticosteroids, gold, intravenous heroin) * Malignancy (cancer) * Bacterial infections, e.g. leprosy & syphilis * Protozoal infections, e.g. malaria Focal segmental glomerulosclerosis (FSGS)[23] * Hypertensive nephrosclerosis * HIV[24] * Obesity[24] * Kidney loss Minimal change disease (MCD)[23] * Drugs, especially NSAIDs in the elderly * Malignancy, especially Hodgkin's lymphoma * Allergy * Bee sting Membranoproliferative Glomerulonephritis * Hepatitis C ### Genetics[edit] Over 50 mutations are known to be associated with this condition.[25] ## Pathophysiology[edit] Drawing of the kidney glomerulus. The kidney glomerulus filters the blood that arrives at the kidney. It is formed of capillaries with small pores that allow small molecules to pass through that have a molecular weight of less than 40,000 Daltons,[26] but not larger macromolecules such as proteins. In nephrotic syndrome, the glomeruli are affected by an inflammation or a hyalinization (the formation of a homogenous crystalline material within cells) that allows proteins such as albumin, antithrombin or the immunoglobulins to pass through the cell membrane and appear in urine.[14] Albumin is the main protein in the blood that is able to maintain an oncotic pressure, which prevents the leakage of fluid into the extracellular medium and the subsequent formation of edemas. As a response to hypoproteinemia the liver commences a compensatory mechanism involving the synthesis of proteins, such as alpha-2 macroglobulin and lipoproteins.[14] An increase in the latter can cause the hyperlipidemia associated with this syndrome. ## Diagnosis[edit] Urinalysis will be able to detect high levels of proteins and occasionally microscopic haematuria. Ultrasound of a kidney with nephrotic syndrome. There is a hyperechoic kidney without demarcation of the cortex and medulla.[27] Along with obtaining a complete medical history, a series of biochemical tests are required in order to arrive at an accurate diagnosis that verifies the presence of the illness. In addition, imaging of the kidneys (for structure and presence of two kidneys) is sometimes carried out, and/or a biopsy of the kidneys. The first test will be a urinalysis to test for high levels of proteins,[28] as a healthy subject excretes an insignificant amount of protein in their urine. The test will involve a 24-hour bedside urinary total protein estimation. The urine sample is tested for proteinuria (>3.5 g per 1.73 m2 per 24 hours). It is also examined for urinary casts, which are more a feature of active nephritis. Next a blood screen, comprehensive metabolic panel (CMP) will look for hypoalbuminemia: albumin levels of ≤2.5 g/dL (normal=3.5-5 g/dL). Then a Creatinine Clearance CCr test will evaluate kidney function particularly the glomerular filtration capacity.[29] Creatinine formation is a result of the breakdown of muscular tissue, it is transported in the blood and eliminated in urine. Measuring the concentration of organic compounds in both liquids evaluates the capacity of the glomeruli to filter blood. Electrolytes and urea levels may also be analysed at the same time as creatinine (EUC test) in order to evaluate kidney function. A lipid profile will also be carried out as high levels of cholesterol (hypercholesterolemia), specifically elevated LDL, usually with concomitantly elevated VLDL, is indicative of nephrotic syndrome. A kidney biopsy may also be used as a more specific and invasive test method. A study of a sample's anatomical pathology may then allow the identification of the type of glomerulonephritis involved.[28] However, this procedure is usually reserved for adults as the majority of children suffer from minimal change disease that has a remission rate of 95% with corticosteroids.[30] A biopsy is usually only indicated for children that are corticosteroid resistant as the majority suffer from focal and segmental glomeruloesclerosis.[30] Further investigations are indicated if the cause is not clear including analysis of auto-immune markers (ANA, ASOT, C3, cryoglobulins, serum electrophoresis), or ultrasound of the whole abdomen. ### Classification[edit] A broad classification of nephrotic syndrome based on underlying cause: Nephrotic syndrome PrimarySecondary Nephrotic syndrome is often classified histologically: Nephrotic syndrome MCDFSGSMGNMPGN ### Differential diagnosis[edit] Some symptoms that are present in nephrotic syndrome, such as edema and proteinuria, also appear in other illnesses. Therefore, other pathologies need to be excluded in order to arrive at a definitive diagnosis.[31] * Edema: in addition to nephrotic syndrome there are two other disorders that often present with edema; these are heart failure and liver failure.[32] Congestive heart failure can cause liquid retention in tissues as a consequence of the decrease in the strength of ventricular contractions. The liquid is initially concentrated in the ankles but it subsequently becomes generalized and is called anasarca.[33] People with congestive heart failure also experience an abnormal swelling of the heart cardiomegaly, which aids in making a correct diagnosis. Jugular venous pressure can also be elevated and it might be possible to hear heart murmurs. An echocardiogram is the preferred investigation method for these symptoms. Liver failure caused by cirrhosis, hepatitis and other conditions such as alcoholism, IV drug use or some hereditary diseases can lead to swelling in the lower extremities and the abdominal cavity. Other accompanying symptoms include jaundice, dilated veins over umbilicus (caput medusae), scratch marks (due to widespread itching, known as pruritus), enlarged spleen, spider angiomata, encephalopathy, bruising, nodular liver and anomalies in the liver function tests.[34] Less frequently symptoms associated with the administration of certain pharmaceutical drugs have to be discounted. These drugs promote the retention of liquid in the extremities such as occurs with NSAIs, some antihypertensive drugs, the adrenal corticosteroids and sex hormones.[34] Acute fluid overload can cause edema in someone with kidney failure. These people are known to have kidney failure, and have either drunk too much or missed their dialysis. In addition, when Metastatic cancer spreads to the lungs or abdomen it causes effusions and fluid accumulation due to obstruction of lymphatic vessels and veins, as well as serous exudation. * Proteinuria: the loss of proteins from the urine is caused by many pathological agents and infection by these agents has to be ruled out before it can be certain that a person has nephrotic syndrome. Multiple myeloma can cause a proteinuria that is not accompanied by hypoalbuminemia, which is an important aid in making a differential diagnosis;[35] other potential causes of proteinuria include asthenia, weight loss or bone pain. In diabetes mellitus there is an association between increases in glycated hemoglobin levels and the appearance of proteinuria.[36] Other causes are amyloidosis and certain other allergic and infectious diseases. ## Treatment[edit] The treatment of nephrotic syndrome can be symptomatic or can directly address the injuries caused to the kidney. ### Symptomatic[edit] The objective of this treatment is to treat the imbalances brought about by the illness:[37] edema, hypoalbuminemia, hyperlipemia, hypercoagulability and infectious complications. * Edema: a return to an unswollen state is the prime objective of this treatment of nephrotic syndrome. It is carried out through the combination of a number of recommendations: * Rest: depending on the seriousness of the edema and taking into account the risk of thrombosis caused by prolonged bed rest.[38] * Medical nutrition therapy: based on a diet with the correct energy intake and balance of proteins that will be used in synthesis processes and not as a source of calories. A total of 35 kcal/kg body weight/day is normally recommended.[39] This diet should also comply with two more requirements: the first is to not consume more than 1 g of protein/kg body weight/ day,[39] as a greater amount could increase the degree of proteinuria and cause a negative nitrogen balance.[17] People are usually recommended lean cuts of meat, fish, and poultry. The second guideline requires that the amount of water ingested is not greater than the level of diuresis. In order to facilitate this the consumption of salt must also be controlled, as this contributes to water retention. It is advisable to restrict the ingestion of sodium to 1 or 2 g/day, which means that salt cannot be used in cooking and salty foods should also be avoided.[40] Foods high in sodium include seasoning blends (garlic salt, Adobo, season salt, etc.) canned soups, canned vegetables containing salt, luncheon meats including turkey, ham, bologna, and salami, prepared foods, fast foods, soy sauce, ketchup, and salad dressings. On food labels, compare milligrams of sodium to calories per serving. Sodium should be less than or equal to calories per serving. * Medication: The pharmacological treatment of edema is based on diuretic medications (especially loop diuretics, such as furosemide). In severe cases of edema (or in cases with physiological repercussions, such as scrotal, preputial or urethral edema) or in peoeple with one of a number of severe infections (such as sepsis or pleural effusion), the diuretics can be administered intravenously. This occurs where the risk from plasmatic expansion[41] is considered greater than the risk of severe hypovolemia, which can be caused by the strong diuretic action of intravenous treatment. The procedure is the following: 1. Analyse haemoglobin and haematocrit levels. 2. A solution of 25% albumin is used that is administered for only 4 hours in order to avoid pulmonary edema. 3. Haemoglobin and haematocrit levels are analysed again: if the haematocrit value is less than the initial value (a sign of correct expansion) the diuretics are administered for at least 30 minutes. If the haematocrit level is greater than the initial one this is a contraindication for the use of diuretics as they would increase said value. It may be necessary to give a person potassium or require a change in dietary habits if the diuretic drug causes hypokalaemia as a side effect. * Hypoalbuminemia: is treated using the medical nutrition therapy described as a treatment for edema. It includes a moderate intake of foods rich in animal proteins.[42] * Hyperlipidaemia: depending of the seriousness of the condition it can be treated with medical nutrition therapy as the only treatment or combined with drug therapy. The ingestion of cholesterol should be less than 300 mg/day,[39] which will require a switch to foods that are low in saturated fats.[43] Avoid saturated fats such as butter, cheese, fried foods, fatty cuts of red meat, egg yolks, and poultry skin. Increase unsaturated fat intake, including olive oil, canola oil, peanut butter, avocadoes, fish and nuts. In cases of severe hyperlipidaemia that are unresponsive to nutrition therapy the use of hypolipidemic drugs, may be necessary (these include statins, fibrates and resinous sequesters of bile acids).[44] * Thrombophilia: low molecular weight heparin (LMWH) may be appropriate for use as a prophylactic in some circumstances, such as in asymptomatic people that have no history of suffering from thromboembolism.[45][46] When the thrombophilia is such that it leads to the formation of blood clots, heparin is given for at least 5 days along with oral anticoagulants (OAC). During this time and if the prothrombin time is within its therapeutic range (between 2 and 3),[47] it may be possible to suspend the LMWH while maintaining the OACs for at least 6 months.[48] * Infectious complications: an appropriate course of antibacterial drugs can be taken according to the infectious agent. In addition to these key imbalances, vitamin D and calcium are also taken orally in case the alteration of vitamin D causes a severe hypocalcaemia, this treatment has the goal of restoring physiological levels of calcium in the person.[49] * Achieving better blood glucose level control if the person is diabetic. * Blood pressure control. ACE inhibitors are the drug of choice. Independent of their blood pressure lowering effect, they have been shown to decrease protein loss. ### Kidney damage[edit] The treatment of kidney damage may reverse or delay the progression of the disease.[37] Kidney damage is treated by prescribing drugs: * Corticosteroids: the result is a decrease in the proteinuria and the risk of infection as well as a resolution of the edema.[50] Prednisone is usually prescribed at a dose of 60 mg/m2 of body surface area/day in a first treatment for 4–8 weeks. After this period the dose is reduced to 40 mg/m2 for a further 4 weeks. People suffering a relapse or children are treated with prednisolone 2 mg/kg/day till urine becomes negative for protein. Then, 1.5 mg/kg/day for 4 weeks. Frequent relapses treated by: cyclophosphamide or nitrogen mustard or ciclosporin or levamisole. People can respond to prednisone in a number of different ways: * People with Corticosteroid sensitive or early steroid-responder: the subject responds to the corticosteroids in the first 8 weeks of treatment. This is demonstrated by a strong diuresis and the disappearance of edemas, and also by a negative test for proteinuria in three urine samples taken during the night. * People with Corticosteroid resistant or late steroid-responder: the proteinuria persists after the 8-week treatment. The lack of response is indicative of the seriousness of the glomerular damage, which could develop into chronic kidney failure. * People with Corticosteroid intolerant : complications such as hypertension appear, and they gain a lot of weight and can develop aseptic or avascular necrosis of the hip or knee,[51] cataracts and thrombotic phenomena and/or embolisms. * People with Corticosteroid dependent : proteinuria appears when the dose of corticosteroid is decreased or there is a relapse in the first two weeks after treatment is completed. The susceptibility testing in vitro to glucocorticoids on the person's peripheral blood mononuclear cells is associated with the number of new cases of not optimal clinical responses: the most sensitive people in vitro have shown a higher number of cases of corticodependence, while the most resistant people in vitro showed a higher number of cases of ineffective therapy.[52] * Immunosupressors (cyclophosphamide): only indicated in recurring nephrotic syndrome in corticosteroid dependent or intolerant people. In the first two cases the proteinuria has to be negated before treatment with the immunosuppressor can begin, which involves a prolonged treatment with prednisone. The negation of the proteinuria indicates the exact moment when treatment with cyclophosphamide can begin. The treatment is continued for 8 weeks at a dose of 3 mg/kg/day, the immunosuppression is halted after this period. In order to be able to start this treatment the person should not be suffering from neutropenia nor anaemia, which would cause further complications. A possible side effect of the cyclophosphamide is alopecia. Complete blood count tests are carried out during the treatment in order to give advance warning of a possible infection. ## Prognosis[edit] The prognosis for nephrotic syndrome under treatment is generally good although this depends on the underlying cause, the age of the person and their response to treatment. It is usually good in children, because minimal change disease responds very well to steroids and does not cause chronic kidney failure. Any relapses that occur become less frequent over time;[53] the opposite occurs with mesangiocapillary glomerulonephritis, in which the kidney fails within three years of the disease developing, making dialysis necessary and subsequent kidney transplant.[53] In addition children under the age of 5 generally have a poorer prognosis than prepubescents, as do adults older than 30 years of age as they have a greater risk of kidney failure.[54] Other causes such as focal segmental glomerulosclerosis frequently lead to end stage kidney disease. Factors associated with a poorer prognosis in these cases include level of proteinuria, blood pressure control and kidney function (GFR). Without treatment nephrotic syndrome has a very bad prognosis especially rapidly progressing glomerulonephritis, which leads to acute kidney failure after a few months. ## Epidemiology[edit] Nephrotic syndrome can affect any age, although it is mainly found in adults with a ratio of adults to children of 26 to 1.[55] The syndrome presents in different ways in the two groups: the most frequent glomerulopathy in children is minimal change disease (66% of cases), followed by focal segmental glomerulosclerosis (8%) and mesangiocapillary glomerulonephritis (6%).[21] In adults the most common disease is mesangiocapillary glomerulonephritis (30-40%), followed by focal and segmental glomeruloesclerosis (15-25%) and minimal change disease (20%). The latter usually presents as secondary and not primary as occurs in children. Its main cause is diabetic nephropathy.[21] It usually presents in a person from their 40s or 50s. Of the glomerulonephritis cases approximately 60% to 80% are primary, while the remainder are secondary.[55] There are also differences in epidemiology between the sexes, the disease is more common in men than in women by a ratio of 2 to 1.[55] The epidemiological data also reveals information regarding the most common way that symptoms develop in people with nephrotic syndrome:[55] spontaneous remission occurs in up to 20% or 30% of cases during the first year of the illness. However, this improvement is not definitive as some 50% to 60% of people with Nephrotic syndrome die and / or develop chronic kidney failure 6 to 14 years after this remission. On the other hand, between 10% and 20% of people have continuous episodes of remissions and relapses without dying or jeopardizing their kidney. The main causes of death are cardiovascular, as a result of the chronicity of the syndrome, and thromboembolic accidents. ## References[edit] 1. ^ a b c d e f g h i j k l m n o p "Nephrotic Syndrome in Adults". National Institute of Diabetes and Digestive and Kidney Diseases. February 2014. Retrieved 9 November 2017. 2. ^ a b c d Ferri, Fred F. (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 889. ISBN 9780323529570. 3. ^ a b Kher, Kanwal; Schnaper, H. William; Greenbaum, Larry A. (2016). Clinical Pediatric Nephrology, Third Edition. CRC Press. p. 307. ISBN 9781482214635. 4. ^ a b c Kelly, Christopher R.; Landman, Jaime (2012). The Netter Collection of Medical Illustrations - Urinary System e-Book. Elsevier Health Sciences. p. 101. ISBN 978-1455726561. 5. ^ Behrman, Richard E.; Robert M Kliegman; Hal B. Jenson (2008). Nelson Tratado de Pediatria (in Spanish). Elsevier, España. p. 1755. ISBN 978-8481747478. 6. ^ "Electronic Learning Module for Kidney and Urinary Tract Diseases". Archived from the original on 2008-12-20. Retrieved 2015-12-25. 7. ^ "Case Based Pediatrics Chapter". Hawaii.edu. Retrieved 23 August 2018. 8. ^ Freedberg, Irwin M.; et al., eds. (2003). Fitzpatrick's dermatology in general medicine (6th ed.). New York, NY [u.a.]: McGraw-Hill. p. 659. ISBN 0-07-138076-0. 9. ^ "Manifestaciones clínicas del síndrome nefrótico" (PDF). See table 4.2. Archived from the original (PDF) on 24 September 2015. Retrieved 12 Sep 2008. 10. ^ a b García - Conde, J.; Merino Sánchez, J.; González Macías, J. (1995). "Fisiopatología glomerular". Patología General. Semiología Clínica y Fisiopatología. McGraw - Hill Interamericana. ISBN 8448600932. 11. ^ Parra Herrán, Carlos Eduardo; Castillo Londoño, Juan Sebastián; López Panqueva, Rocío del Pilar; Andrade Pérez, Rafael Enrique. "Síndrome nefrótico y proteinuria en rango no nefrótico". Retrieved 2008-09-14. 12. ^ "Valores normales de proteína en orina de 24 horas". Retrieved 24 August 2012. 13. ^ "La pérdida de lipoproteínas en la orina". Retrieved 2008-11-21.[permanent dead link] 14. ^ a b c Álvarez, Sandalio Durán (1999). "Complicaciones agudas del síndrome nefrótico" [Acute complications of nephrotic syndrome]. Revista Cubana de Pediatría (in Spanish). 7 (4). 15. ^ Ruiz, S.; Soto, S.; Rodado, R.; Alcaraz, F.; López Guillén, E. (September 2007). "Peritonitis bacteriana espontánea como forma de presentación de síndrome nefrótico idiopático en un adulto de raza negra" [Spontaneous bacterial peritonitis as form of presentation of idiophatic nephrotic syndrome in an adult black race]. Anales de Medicina Interna (in Spanish). 24 (9): 442–4. doi:10.4321/s0212-71992007000900008. PMID 18198954. 16. ^ Zollo, Anthony J (2005). "Nefrología". Medicina interna. Secretos (Cuarta ed.). Elsevier España. p. 283. ISBN 8481748862. 17. ^ a b "Balance de nitrógeno y equilibrio nitrogenado". Retrieved 8 Sep 2008. "It occurs during renal pathologies, during fasting, in eating disorders or during heavy physical exercise." 18. ^ "Descripción histológica de las glomerulonefritis ideopáticas". Retrieved 8 Sep 2008. 19. ^ a b "Patient information: The nephrotic syndrome (Beyond the Basics)". Retrieved 2013-06-28. 20. ^ James W Lohr, MD. "Rapidly progressive glomerulonephritis". Retrieved 2013-06-28. 21. ^ a b c "Frecuencia de las glomerulonefritis y causas de las glomerulonefritis secundarias". Retrieved 8 Sep 2008.[permanent dead link] 22. ^ "Fármacos que pueden producir síndrome nefrótico". Retrieved 8 Sep 2008. 23. ^ a b Fogo AB, Bruijn JA. Cohen AH, Colvin RB, Jennette JC. Fundamentals of Renal Pathology. Springer. ISBN 978-0-387-31126-5. 24. ^ a b "Nephrotic syndrome". Archived from the original on 2013-04-23. Retrieved 2016-05-21. 25. ^ Braun, Daniela A.; Lovric, Svjetlana; Schapiro, David; Schneider, Ronen; Marquez, Jonathan; Asif, Maria; Hussain, Muhammad Sajid; Daga, Ankana; Widmeier, Eugen; Rao, Jia; Ashraf, Shazia; Tan, Weizhen; Lusk, C. Patrick; Kolb, Amy; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Hoogstraten, Charlotte A.; Eddy, Kaitlyn; Kitzler, Thomas M.; Shril, Shirlee; Moawia, Abubakar; Schrage, Kathrin; Khayyat, Arwa Ishaq A.; Lawson, Jennifer A.; Gee, Heon Yung; Warejko, Jillian K.; Hermle, Tobias; Majmundar, Amar J.; Hugo, Hannah; Budde, Birgit; Motameny, Susanne; Altmüller, Janine; Noegel, Angelika Anna; Fathy, Hanan M.; Gale, Daniel P.; Waseem, Syeda Seema; Khan, Ayaz; Kerecuk, Larissa; Hashmi, Seema; Mohebbi, Nilufar; Ettenger, Robert; Serdaroğlu, Erkin; Alhasan, Khalid A.; Hashem, Mais; Goncalves, Sara; Ariceta, Gema; Ubetagoyena, Mercedes; Antonin, Wolfram; Baig, Shahid Mahmood; Alkuraya, Fowzan S.; Shen, Qian; Xu, Hong; Antignac, Corinne; Lifton, Richard P.; Mane, Shrikant; Nürnberg, Peter; Khokha, Mustafa K.; Hildebrandt, Friedhelm (4 September 2018). "Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome". Journal of Clinical Investigation. 128 (10): 4313–4328. doi:10.1172/JCI98688. PMC 6159964. PMID 30179222. 26. ^ "Apuntes de fisiopatología de sistemas". Archived from the original on 2008-09-08. Retrieved 8 Sep 2008. 27. ^ Hansen, Kristoffer; Nielsen, Michael; Ewertsen, Caroline (23 December 2015). "Ultrasonography of the Kidney: A Pictorial Review". Diagnostics. 6 (1): 2. doi:10.3390/diagnostics6010002. PMC 4808817. PMID 26838799. 28. ^ a b "Nefrología y urología". Retrieved 12 Sep 2008. 29. ^ "El diagnóstico del síndrome nefrótico". Retrieved 12 Sep 2008. 30. ^ a b Voguel S, Andrea; Azócar P, Marta; Nazal Ch, Vilma; Salas del C, Paulina. "Indicaciones de la biospsia renal en niños". Revista Chilena de Pediatría. 77 (3): 295–303. doi:10.4067/S0370-41062006000300011. Retrieved 2008-09-14. 31. ^ "Diagnóstico diferencial en el síndrome nefrótico". Archived from the original on 2009-03-06. Retrieved 2008-09-14.CS1 maint: bot: original URL status unknown (link) 32. ^ Harold Friedman, H (2001). "General problems". Problem-oriented Medical Diagnosis (Seventh ed.). Lippincott Williams & Wilkins. pp. 3 and 4. ISBN 0-7817-2909-2. 33. ^ "El edema en la insuficiencia cardíaca". Retrieved 2008-09-14. 34. ^ a b Goldman, Lee; Braunwald, Eugene (2000). "Edemas". Cardiología en atención primaria. Harcourt. pp. 114–117. ISBN 8481744328. 35. ^ Rivera, F; Egea, J.J; Jiménez del Cerro, L.A; Olivares, J. "La proteinuria en el mieloma múltiple". Retrieved 2008-09-14.[permanent dead link] 36. ^ Bustillo Solano, Emilio. "Relación de la proteinuria con el nivel de hemoglobina glicosilada en los diabéticos". Archived from the original on 2008-09-14. Retrieved 2008-09-14. 37. ^ a b Curtis, Michael J.; Page, Clive P.; Walker, Michael J.A; Hoffman, Brian B. (1998). "Fisiopatología y enfermedades renales". Farmacología integrada. Harcourt. ISBN 8481743402. 38. ^ Saz Peiro, Pablo. "El reposo prolongado" (PDF). Archived from the original (PDF) on 24 January 2009. Retrieved 8 Sep 2008. 39. ^ a b c "Dietoterapia del síndrome nefrótico". Archived from the original on 2009-01-22. Retrieved 8 Sep 2008. 40. ^ "Lista de alimentos ricos en sodio". Retrieved 8 Sep 2008. 41. ^ "Fluidoterapia: tipos de expansores" (PDF). Archived from the original (PDF) on 2008-09-20. Retrieved 8 Sep 2008. "Plasma expanders are natural or synthetic substances (dextran, albumin...), that are able to retain liquid in the vascular space." 42. ^ "Lista de alimentos ricos en proteínas". Retrieved 8 Sep 2008. "Expressed as grams per 100 g of food." 43. ^ "Sustitución de los alimentos ricos en grasas de la dieta". Archived from the original on February 12, 2008. Retrieved 8 Sep 2008. "Organizations in the US recommend that no more than 30% of total daily calorie intake is from fats." 44. ^ Martín Zurro, Armando (2005). "Hipolipemiante, diuréticos, estatina.". Compendio de atención primaria: Conceptos, organización y práctica clínica (Segunda ed.). Elsevier España. p. 794. ISBN 8481748161. 45. ^ Jiménez Alonso, Juan. "Profilaxis de los fenómenos tromboembólicos" (PDF). Retrieved 2008-09-14.[permanent dead link] 46. ^ Glassock RJ (August 2007). "Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum". J. Am. Soc. Nephrol. 18 (8): 2221–5. doi:10.1681/ASN.2006111300. PMID 17599972. 47. ^ "Rango Internacional Normalizado (INR)". Retrieved 2008-09-14. 48. ^ "Tratamiento de la hipercoagulabilidad". Archived from the original on 2008-09-15. Retrieved 2008-09-14. 49. ^ "Tratamiento de la hipocalcemia". Retrieved 2008-09-14. 50. ^ Hahn D, Hodson EM, Willis NS, Craig JC (2015). "Corticosteroid therapy for nephrotic syndrome in children". Cochrane Database of Systematic Reviews (3): CD001533. doi:10.1002/14651858.CD001533.pub5. PMC 7025788. PMID 25785660. 51. ^ According to MedlinePlus, avascular necrosis is the death of the bone caused by insufficient blood supply to the bone. 52. ^ Cuzzoni, E; De Iudicibus, S; Stocco, G; Favretto, D (2016). "In vitro sensitivity to methyl-prednisolone is associated with clinical response in pediatric idiopathic nephrotic syndrome". Clin Pharmacol Ther. 100 (3): 268–74. doi:10.1002/cpt.372. PMID 27007551. S2CID 37671642. 53. ^ a b Guerrero Fernández, J. "Pronóstico de la enfermedad". Retrieved 2016-05-21. 54. ^ "Síndrome nefrótico idiopático: diagnóstico histológico por biopsia renal percutanea". 1995. Archived from the original on 2016-03-25. Retrieved 2016-05-21. 55. ^ a b c d Borrego R., Jaime; Montero C., Orlando (2003). Nefrología: Fundamentos de medicina (Cuarta ed.). Corporación para investigaciones biológicas. p. 340. ISBN 9589400639. ## External links[edit] * Childhood Nephrotic Syndrome \- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH * Adult Nephrotic Syndrome \- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH * Clardy, Chris (May 2000) "Nephrotic Syndrome in Children" Pediatric Nephrology Handout Classification D * ICD-10: N04 * ICD-9-CM: 581 * MeSH: D009404 * DiseasesDB: 8905 External resources * MedlinePlus: 000490 * eMedicine: med/1612 ped/1564 * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy Authority control * NDL: 00568067 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Nephrotic syndrome	c0027726	2,205	wikipedia	https://en.wikipedia.org/wiki/Nephrotic_syndrome	2021-01-18T19:09:58	{"mesh": ["D009404"], "umls": ["C0027726"], "wikidata": ["Q504790"]}
Hyperferritinemia-cataract syndrome is a disorder characterized by an excess of an iron storage protein called ferritin in the blood (hyperferritinemia) and tissues of the body. A buildup of this protein begins early in life, leading to clouding of the lenses of the eyes (cataracts). In affected individuals, cataracts usually develop in infancy, rather than after age 60 as typically occurs in the general population. Cataracts that are not removed surgically cause progressive dimming and blurriness of vision because the clouded lenses reduce and distort incoming light. Although the hyperferritinemia in this disorder does not usually cause any health problems other than cataracts, the elevated ferritin levels in the blood can be mistaken for a sign of certain liver disorders. These conditions result in excess iron in the body and may be treated by blood-drawing. However, individuals with hyperferritinemia-cataract syndrome do not have an excess of iron, and with repeated blood draws will develop reduced iron levels leading to a low number of red blood cells (anemia). Therefore, correct diagnosis of hyperferritinemia-cataract syndrome is important to avoid unnecessary treatments or invasive test procedures such as liver biopsies. ## Frequency Hyperferritinemia-cataract syndrome has been estimated to occur in 1 in 200,000 individuals. ## Causes Hyperferritinemia-cataract syndrome is caused by mutations in the FTL gene. This gene provides instructions for making the ferritin light chain, which is one part (subunit) of the protein ferritin. Ferritin is made up of 24 subunits formed into a hollow spherical molecule. The 24 subunits consist of varying numbers of the ferritin light chain and another subunit called the ferritin heavy chain, which is produced from another gene. The proportion of the two subunits varies in different tissues. Ferritin stores and releases iron in cells. Each ferritin molecule can hold as many as 4,500 iron atoms inside its spherical structure. This storage capacity allows ferritin to regulate the amount of iron in cells and tissues. The mutations that cause hyperferritinemia-cataract syndrome are found in a segment of the gene called the iron responsive element (IRE). The IRE normally can attach (bind) to a protein called the iron regulatory protein (IRP). When this binding occurs, the activity (expression) of the FTL gene is stopped to prevent too much ferritin light chain from being produced. This normally occurs when iron levels are low, because under those circumstances less ferritin is needed to store the iron. Mutations in the IRE segment of the FTL gene prevent it from binding with IRP, interfering with the mechanism by which ferritin production is matched to iron levels and resulting in excess ferritin being formed. ### Learn more about the gene associated with Hyperferritinemia-cataract syndrome * FTL ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Hyperferritinemia-cataract syndrome	c1833213	2,206	medlineplus	https://medlineplus.gov/genetics/condition/hyperferritinemia-cataract-syndrome/	2021-01-27T08:25:17	{"gard": ["2806"], "mesh": ["C538137"], "omim": ["600886"], "synonyms": []}
Lentigo maligna Other namesLentiginous melanoma on sun-damaged skin' Irregular patch about 10mm square after scrape biopsy which concluded "suspicious of early malignant melanoma". Colour before scrape biopsy was light brown. Post excision pathology was "Lentigo maligna - Melanoma in situ" SpecialtyDermatology Lentigo maligna is where melanocyte cells have become malignant and grow continuously along the stratum basale of the skin,[1] but have not invaded below the epidermis.[2] Lentigo maligna is not the same as lentigo maligna melanoma, as detailed below. It typically progresses very slowly and can remain in a non-invasive form for years. It is normally found in the elderly (peak incidence in the 9th decade), on skin areas with high levels of sun exposure like the face and forearms. Incidence of evolution to lentigo maligna melanoma is low, about 2.2% to 5% in elderly patients. It is also known as "Hutchinson's melanotic freckle".[3] This is named for Jonathan Hutchinson.[4][5] The word lentiginous comes from the latin for freckle. ## Contents * 1 Relation to melanoma * 2 Signs and symptoms * 3 Diagnosis * 4 Treatment * 5 References * 6 External links * 7 External links ## Relation to melanoma[edit] Lentigo maligna is a histopathological variant of melanoma in situ.[6] Lentigo maligna is sometimes classified as a very early melanoma,[7] and sometimes as a precursor to melanoma.[8] When malignant melanocytes from a lentigo maligna have invaded below the epidermis, the condition is termed lentigo maligna melanoma.[2] ## Signs and symptoms[edit] Characteristics include a blue/black stain of skin initially. Skin is thin, about 4-5 cell layers thick, which is often related to aging. Histological features include epidermal atrophy and increased number of melanocytes. ## Diagnosis[edit] First dilemma in diagnosis is recognition. As lentigo malignas often present on severely sun-damaged skin, it is frequently found amongst numerous pigmented lesions – thin seborrheic keratoses, lentigo senilis, lentigines. It is difficult to distinguish these lesions with the naked eye alone, and even with some difficulty using dermatoscopy. As the lentigo maligna is often very large, it often merges with, or encompasses other skin tumors – such as lentigines, melanocytic nevi, and seborrheic keratosis. Second dilemma is the biopsy technique. Even though excisional biopsy (removing the entire lesion) is ideal, and advocated by pathologists; practical reason dictates that this should not be done. These tumors are often large and presenting on the facial area. Excision of such large tumor would be absolutely contraindicated if the lesion's identity is uncertain. The preferred method of diagnosis is by using a punch biopsy, allowing the physician to sample multiple full thickness pieces of the tumor at multiple sites. While one section of the tumor might show benign melanocytic nevus, another section might show features concerning for severe cellular atypia. When cellular atypia is noted, a pathologist might indicate that the entire lesion should be removed. It is at this point that one can comfortably remove the entire lesion, and thus confirm the final diagnosis of lentigo maligna. The size of the punch biopsy can vary from 1 mm to 2 mm, but it is preferable to use a punch 1.5 mm or larger. Representative samples of the most atypical parts of the nevus should be biopsied, often guided by dermatoscopy. * Light microscopy of lentigo maligna showing the characteristic atypical epidermal melanocytes. H&E stain. * Immunohistochemistry with SOX10 (staining the cell nuclei of melanocytes) facilitates diagnosis of lentigo maligna, in this case showing an increased number of melanocytes along stratum basale of the skin, and nuclear pleumorphism. The changes are continuous with the resection margin (inked in yellow, at left), conferring a diagnosis of a not radically removed lentigo maligna. ## Treatment[edit] Scar 13 days after excision of coloured patch about 10mm square with 5mm margins from 1cm to right of base of nose. Length of incision required for skin flap to cover excision site. Scar should lighten and become finer for up to further 6 months if protected from sun. The best treatment of lentigo maligna is not clear as it has not been well studied.[9] Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is high (up to 50%). This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The use of dermatoscopy can significantly improve the surgeon's ability to identify the surgical margin. The narrow surgical margin used (smaller than the standard of care of 5 mm), combined with the limitation of the standard bread loafing technique of fixed tissue histology - result in a high "false negative" error rate, and frequent recurrences. Margin controlled (peripheral margins) is necessary to eliminate the false negative errors. If breadloafing is utilized, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control. Where the lesion is on the face and either large or 5mm margins are possible, a skin flap or skin graft may be indicated/required. Grafts have their own risks of failure and poor cosmetic outcomes. Flaps can require extensive incision resulting in long scars and may be better done by plastic surgeons (and possibly better again by those with extensive LM or "suspicious of early malignant melanoma" experience. Mohs surgery has been done with cure rate reported to be 77%.[10] The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.[11] Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. In view of the very poor cure rate with standard excision, some surgeons combine the two methods: surgical excision of the lesion, then three months treatment of the area with imiquimod cream. Studies seem to conflict about the level of certainty associated with using imiquimod.[12][13] Another treatment to be considered where standard margins cannot be achieved or cosmetics are a major consideration is ultra-soft x-ray/grenz-ray radiation.[14] In the very elderly or those with otherwise limited life expectancy, the impact of major day surgery for excision with 5mm margins and large skin flap could be worse than doing nothing or the possibility of failed treatments with imiquimod or Grenz ray. ## References[edit] 1. ^ Oakley, Amanda (2011). "Lentigo maligna and lentigo maligna melanoma". DermNet NZ. 2. ^ a b Michael Xiong; Ahmad Charifa; Chih Shan J. Chen. "Cancer, Lentigo Maligna Melanoma". StatPearls, National Center for Biotechnology Information. Last Update: May 18, 2019. 3. ^ Green A, Little JH, Weedon D (January 1983). "The diagnosis of Hutchinson's melanotic freckle (lentigo maligna) in Queensland". Pathology. 15 (1): 33–5. doi:10.3109/00313028309061399. PMID 6856341. 4. ^ synd/1439 at Who Named It? 5. ^ J. Hutchinson. Senile freckle with deep staining - a superficial epithelioma of the cheek. Archives of Surgery, London, 1892, 3: 159. 6. ^ McKenna JK, Florell SR, Goldman GD, Bowen GM (April 2006). "Lentigo maligna/lentigo maligna melanoma: current state of diagnosis and treatment". Dermatol Surg. 32 (4): 493–504. doi:10.1111/j.1524-4725.2006.32102.x. PMID 16681656. 7. ^ "Precancerous conditions of the skin". Canadian Cancer Society. Retrieved 2020-02-26. 8. ^ Fleming, C. (2010). "How to manage patients with lentigo maligna". Melanoma Research. 20: e26. doi:10.1097/01.cmr.0000382797.99333.66. ISSN 0960-8931. 9. ^ Tzellos, T; Kyrgidis, A; Mocellin, S; Chan, A; Pilati, P; Apalla, Z (19 December 2014). "Interventions for melanoma in situ, including lentigo maligna". The Cochrane Database of Systematic Reviews. 12 (12): CD010308. doi:10.1002/14651858.CD010308.pub2. PMID 25526608. 10. ^ Mikhail, G. Mohs Micrographic Surgery. 1991, Saunders, pp. 13-14 11. ^ Usefulness of the Staged Excision for Lentigo Maligna and Lentigo Maligna Melanoma: The 'Square' Procedure" (J Am Acad Dermatol 1997;37:758-63) 12. ^ Li, Lena (2011). "Efficacy of Imiquimod Cream, 5%, for Lentigo Maligna After Complete Excision". Archives of Dermatology. 147 (10): 1191–5. doi:10.1001/archdermatol.2011.260. PMID 22006136. Retrieved 2 November 2011. 13. ^ Powell, A. M. (2009). "Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up". British Journal of Dermatology. 160 (5): 994–998. doi:10.1111/j.1365-2133.2009.09032.x. PMID 19222462. 14. ^ Hedblad, Mari-Anne (2012). "Grenz ray treatment of lentigo maligna and early lentigo maligna melanoma". Journal of the American Academy of Dermatology. 67 (1): 60–68. doi:10.1016/j.jaad.2011.06.029. PMID 22030019. ## External links[edit] Classification D * ICD-10: C44, D03 (ILDS D03.L10) * ICD-O: 8742/2 * MeSH: D018327 * DiseasesDB: 32059 * Media related to Lentigo maligna at Wikimedia Commons ## External links[edit] * v * t * e Skin cancer of nevi and melanomas Melanoma * Mucosal melanoma * Superficial spreading melanoma * Nodular melanoma * lentigo * Lentigo maligna/Lentigo maligna melanoma * Acral lentiginous melanoma * Amelanotic melanoma * Desmoplastic melanoma * Melanoma with features of a Spitz nevus * Melanoma with small nevus-like cells * Polypoid melanoma * Nevoid melanoma * Melanocytic tumors of uncertain malignant potential Nevus/ melanocytic nevus * Nevus of Ito/Nevus of Ota * Spitz nevus * Pigmented spindle cell nevus * Halo nevus * Pseudomelanoma * Blue nevus * of Jadassohn–Tièche * Cellular * Epithelioid * Deep penetrating * Amelanotic * Malignant * Congenital melanocytic nevus (Giant * Medium-sized * Small-sized) * Balloon cell nevus * Dysplastic nevus/Dysplastic nevus syndrome * Acral nevus * Becker's nevus * Benign melanocytic nevus * Nevus spilus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Lentigo maligna	c0149722	2,207	wikipedia	https://en.wikipedia.org/wiki/Lentigo_maligna	2021-01-18T18:53:48	{"mesh": ["D018327"], "icd-9": ["M8742/2"], "icd-10": ["C44"], "wikidata": ["Q13257137"]}
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: "Cricopharyngeal spasm" – news · newspapers · books · scholar · JSTOR (November 2009) (Learn how and when to remove this template message) Cricopharyngeal spasm SpecialtyOtorhinolaryngology Cricopharyngeal spasms occur in the cricopharyngeus muscle of the pharynx. These spasms are frequently misunderstood by the patient to be cancer due to the 'lump in the throat' feeling (Globus pharyngis) that is symptomatic of this syndrome. Cricopharyngeal spasm is an uncomfortable but harmless and temporary disorder. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Physiology * 4 Diagnosis * 5 Treatment * 6 References ## Signs and symptoms[edit] * Sensation of a 'lump' in the back of the throat * Throat feels swollen * Discomfort - Lump can often feel quite big and pain is occasional * Symptoms normally worse in the evening * Stress aggravates the symptoms * Saliva is difficult to swallow, yet food is easy to swallow - eating, in fact, often makes the tightness go away for a time * 'Lump' sensation comes and goes from day to day * Symptoms can persist for very long periods, often several months. * The symptoms can be mimicked by pushing on the cartilage in the neck, just below the Adam's apple ## Causes[edit] Causes include stress and anxiety. Other causes are not yet clear. In some cases, eating certain foods may bring on acute spasms, in susceptible individuals. Peanuts, pumpkin seeds and other nuts may trigger these spasms.[citation needed] ## Physiology[edit] There are two sphincters in the oesophagus. They are normally contracted and they relax when one swallows so that food can pass through them going to the stomach. They then squeeze closed again to prevent regurgitation of the stomach contents. If this normal contraction becomes a spasm, these symptoms begin. ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2017) ## Treatment[edit] No cure for the condition as such exists. A number of treatments may provide partial relief: * Botox injections may temporarily disable the muscle and provide relief for 3-4 months per injection[1] * Muscle relaxants * Lorazepam (Ativan), diazepam (Valium) and other benzodiazepines relax the smooth muscle in the throat, slowing or halting contractions. In some people, benzodiazepines may have addictive properties. * Stress reduction * High stress levels make these spasms more noticeable * It is advisable to take note of when your symptoms are at their worst * Warm fluids * Hot fluids may be helpful for some people with cricopharyngeal spasm (or other esophageal disorders)[2] * Tricyclic anti-depressants (Pamelor, etc.), taken in small doses, have been having positive results recently, according to the Cleveland Clinic. * Neck stretching * May provide temporary relief. Hands are placed on each clavicle as you hyperextend your neck (looking at the ceiling). Protracting the jaw with the neck extended will stretch your neck. Hold this position for 20-30 seconds. ## References[edit] 1. ^ Parameswaran MS, Soliman AM (2002). "Endoscopic botulinum toxin injection for cricopharyngeal dysphagia". The Annals of Otology, Rhinology, and Laryngology. 111 (10): 871–4. doi:10.1177/000348940211101002. PMID 12389853. S2CID 41591340. 2. ^ Triadafilopoulos, G; Tsang, HP; Segall, GM (June 1998). "Hot water swallows improve symptoms and accelerate esophageal clearance in esophageal motility disorders". Journal of Clinical Gastroenterology. 26 (4): 239–44. doi:10.1097/00004836-199806000-00003. PMID 9649001. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Cricopharyngeal spasm	c0267063	2,208	wikipedia	https://en.wikipedia.org/wiki/Cricopharyngeal_spasm	2021-01-18T18:38:17	{"umls": ["C0267063", "C0396005"], "icd-10": ["K22.4"], "wikidata": ["Q5185088"]}
Subphrenic Abscess Other namesSubdiaphragmatic Abscess [1] SpecialtyInfectious disease, gastroenterology Subphrenic abscess is a disease characterized by an accumulation of infected fluid between the diaphragm, liver, and spleen.[2] This abscess develops after surgical operations like splenectomy. Presents with cough, increased respiratory rate with shallow respiration, diminished or absent breath sounds, hiccups, dullness in percussion, tenderness over the 8th–11th ribs, fever, chills, anorexia and shoulder tip pain on the affected side. Lack of treatment or misdiagnosis could quickly lead to sepsis, septic shock, and death. Patients who develop peritonitis may get localized abscesses in the right or left subphrenic space. The right side is more common due to the high frequency of ruptured appendices and perforated duodenal ulcers. Two common approaches to draining a subphrenic abscess are 1) incision inferior to or through the bed of the 12th rib (no need to create an opening in the pleura or peritoneum) 2) an anterior subphrenic abscess is often drained through a subcostal incision located inferior and parallel to the right costal margin. [3] It is also associated with peritonitis.[4] ## References[edit] 1. ^ "MeSH Browser". meshb.nlm.nih.gov. Retrieved 15 March 2019. 2. ^ Banerjee, Arpan K. (2006). Radiology Made Easy (2nd ed.). Cambridge University Press. p. 92. ISBN 978-0-521-67635-9. Retrieved 3 February 2011. 3. ^ R.F. Dondelinger; P. Rossi; J.C. Kurdziel; S. Wallace, eds. (1990). Interventional Radiology. Thieme Publishing Group. p. 110. ISBN 978-3-13-728901-2. Retrieved 3 February 2011. 4. ^ "Subphrenic Abscess". National Library of Medicine - Medical Subject Headings. Retrieved 3 February 2011. ## External links[edit] Classification D * MeSH: D013369 * DiseasesDB: 12587 * SNOMED CT: 52478002 This article related to pathology is a stub. You can help Wikipedia by expanding it. * v * t * e This article about a medical condition affecting the respiratory system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Subphrenic abscess	c0038565	2,209	wikipedia	https://en.wikipedia.org/wiki/Subphrenic_abscess	2021-01-18T18:57:51	{"mesh": ["D013369"], "wikidata": ["Q4367483"]}
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: "Subgaleal hemorrhage" – news · newspapers · books · scholar · JSTOR (January 2014) (Learn how and when to remove this template message) Subgaleal hemorrhage Newborn scalp bleeds SpecialtyPediatrics Subgaleal hemorrhage or hematoma is bleeding in the potential space between the skull periosteum and the scalp galea aponeurosis. ## Contents * 1 Symptoms * 2 Causes * 3 Diagnosis * 4 Management * 5 See also * 6 References * 7 External links ## Symptoms[edit] The diagnosis is generally clinical, with a fluctuant boggy mass developing over the scalp (especially over the occiput) with superficial skin bruising. The swelling develops gradually 12–72 hours after delivery, although it may be noted immediately after delivery in severe cases. Subgaleal hematoma growth is insidious, as it spreads across the whole calvaria and may not be recognized for hours to days. If enough blood accumulates, a visible fluid wave may be seen. Patients may develop periorbital ecchymosis ("raccoon eyes").[citation needed] Patients with subgaleal hematoma may present with hemorrhagic shock given the volume of blood that can be lost into the potential space between the skull periosteum and the scalp galea aponeurosis, which has been found to be as high as 20-40% of the neonatal blood volume in some studies.[1] The swelling may obscure the fontanel and cross cranial suture lines, (distinguishing it from cephalohematoma).[citation needed] Patients with subgaleal hemorrhage may also have significant hyperbilirubinemia due to resorption of hemolyzed blood. Laboratory studies may demonstrate reduced hemoglobin and hematocrit due to blood loss into the subgaleal space, and coagulation studies may reflect an underlying coagulopathy. Mortality has been reported to occur in 12-14% of cases, generally as a consequence of massive blood loss presenting with shock, often in the setting of uncorrected coagulopathy. However, with early identification and prompt treatment, the prognosis is good, and there are usually no long-term consequences.[2] ## Causes[edit] The majority of neonatal cases (90%) result from applying a vacuum to the head at delivery (ventouse-assisted delivery). The vacuum assist ruptures the emissary veins (i.e., connections between dural sinus and scalp veins) leading to accumulation of blood under the aponeurosis of the scalp muscle and superficial to the periosteum.[3] Additionally, subgaleal hematoma has a high frequency of occurrence of associated head trauma (40%), such as intracranial hemorrhage or skull fracture. The occurrence of these features does not correlate significantly with the severity of subgaleal hemorrhage.[citation needed] ## Diagnosis[edit] Early recognition of this injury is crucial for survival. Infants who have experienced a difficult operative delivery or are suspected to have a SGH require ongoing monitoring including frequent vital signs (minimally every hour), and serial measurements of hematocrits and their occipital frontal circumference, which increases 1 cm with each 40 mL of blood deposited into the subgaleal space. Head imaging, using either CT or MRI, can be useful for differentiating subgaleal hemorrhage from other sources of cranial bleeding. Head ultrasound is useful for the diagnosis of SGH in the hands of an operator experienced in imaging the neonatal head and scalp, and is preferable to CT due to lack of ionizing radiation. Coagulation studies are required to detect coagulopathy that may be associated with the bleeding.[citation needed] ## Management[edit] Management consists of vigilant observation over days to detect progression and, if required, of management of complications (e.g., hemorrhagic shock, unconjugated hyperbilirubinemia and jaundice from hemolyzed red blood cells). The subgaleal space is capable of holding up to 40% of a newborn baby's blood and can therefore result in acute shock and death. Fluid bolus may be required if blood loss is significant and patient becomes tachycardic. Transfusion and phototherapy may be necessary. Investigation for coagulopathy may be indicated.[citation needed] ## See also[edit] * Caput succedaneum * Cephal * Cephalohematoma * Hematoma ## References[edit] 1. ^ Ronald S. Gibbs; David N. Danforth; Beth Y Karlan; Arthur F Haney (2008). Danforth's obstetrics and gynecology. Lippincott Williams & Wilkins. p. 470. ISBN 978-0-7817-6937-2. Retrieved 12 April 2010. 2. ^ Kilani, R.A. (2006). "Neonatal subgaleal hematoma: presentation and outcome - Radiological findings and factors associated with mortality". American Journal of Perinatology. 23 (1): 41–8. doi:10.1055/s-2005-923438. PMID 16450272. Retrieved 28 June 2019. 3. ^ AAP Textbook of Pediatrics ## External links[edit] Classification D * ICD-10: P12, S00.0 (when not due to a birth injury) * ICD-9-CM: 767.1 * v * t * e Conditions originating in the perinatal period / fetal disease Maternal factors complicating pregnancy, labour or delivery placenta * Placenta praevia * Placental insufficiency * Twin-to-twin transfusion syndrome chorion/amnion * Chorioamnionitis umbilical cord * Umbilical cord prolapse * Nuchal cord * Single umbilical artery presentation * Breech birth * Asynclitism * Shoulder presentation Growth * Small for gestational age / Large for gestational age * Preterm birth / Postterm pregnancy * Intrauterine growth restriction Birth trauma * scalp * Cephalohematoma * Chignon * Caput succedaneum * Subgaleal hemorrhage * Brachial plexus injury * Erb's palsy * Klumpke paralysis Affected systems Respiratory * Intrauterine hypoxia * Infant respiratory distress syndrome * Transient tachypnea of the newborn * Meconium aspiration syndrome * Pleural disease * Pneumothorax * Pneumomediastinum * Wilson–Mikity syndrome * Bronchopulmonary dysplasia Cardiovascular * Pneumopericardium * Persistent fetal circulation Bleeding and hematologic disease * Vitamin K deficiency bleeding * HDN * ABO * Anti-Kell * Rh c * Rh D * Rh E * Hydrops fetalis * Hyperbilirubinemia * Kernicterus * Neonatal jaundice * Velamentous cord insertion * Intraventricular hemorrhage * Germinal matrix hemorrhage * Anemia of prematurity Gastrointestinal * Ileus * Necrotizing enterocolitis * Meconium peritonitis Integument and thermoregulation * Erythema toxicum * Sclerema neonatorum Nervous system * Perinatal asphyxia * Periventricular leukomalacia Musculoskeletal * Gray baby syndrome * muscle tone * Congenital hypertonia * Congenital hypotonia Infections * Vertically transmitted infection * Neonatal infection * rubella * herpes simplex * mycoplasma hominis * ureaplasma urealyticum * Omphalitis * Neonatal sepsis * Group B streptococcal infection * Neonatal conjunctivitis Other * Miscarriage * Perinatal mortality * Stillbirth * Infant mortality * Neonatal withdrawal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Subgaleal hemorrhage	c2721649	2,210	wikipedia	https://en.wikipedia.org/wiki/Subgaleal_hemorrhage	2021-01-18T18:42:47	{"umls": ["C2721649"], "icd-9": ["767.1"], "icd-10": ["P12"], "wikidata": ["Q7631144"]}
Adult-onset Still's disease (AOSD) is an inflammatory condition that affects multiple organs. The most common symptoms are high fevers, skin rash, arthritis, and high levels of ferritin, a protein that stores iron in the blood. Other symptoms include an enlarged spleen and lymph nodes, joint pain, and sore throat. In some cases, symptoms may be severe and lead to organ and joint damage. The cause of AOSD is unknown, but genetic and other unknown factors may be involved. Diagnosis is based on the symptoms and the results of several blood tests. Other more common conditions need to be ruled out before AOSD can be diagnosed. Treatment involves multiple different types of medications and is focused on controlling the symptoms. Still's disease which occurs in children (under the age of 16) is known as systemic onset juvenile rheumatoid arthritis (JRA). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Adult-onset Still's disease	c0085253	2,211	gard	https://rarediseases.info.nih.gov/diseases/436/adult-onset-stills-disease	2021-01-18T18:02:15	{"mesh": ["D016706"], "umls": ["C0085253"], "orphanet": ["829"], "synonyms": ["Adult Still's disease", "Still's disease adult onset"]}
## Cloning and Expression A family of structurally and pharmacologically distinct peptides, the endothelins, have been identified and sequenced in humans (Inoue et al., 1989). Three isoforms of human endothelin have been identified: endothelin-1, -2, and -3. Endothelin-1 is a potent, 21-amino acid vasoconstrictor peptide produced by vascular endothelial cells. Inoue et al. (1989) cloned the full length of the human preproendothelin-1 gene and the corresponding cDNA and determined the complete nucleotide sequence. The human preproendothelin-1 mRNA consists of 2,026 nucleotides, excluding the poly(A) tail. Endothelin-1 was originally isolated from the supernatant of porcine aortic endothelial cell cultures and is the most potent vasoconstrictor known. Subsequent cloning and sequence analysis from a human placental cDNA library showed that human endothelin-1 is identical to porcine endothelin. In addition to its vasoconstrictor action, endothelin has effects on the central nervous system and on neuronal excitability. Gordon et al. (2013) stated that EDN1 is translated as a 212-amino acid preproprotein that undergoes a series of proteolytic processing events: cleavage by a signal peptidase to produce proEDN1; cleavage by furin (136950) at 2 sites in proEDN1 to liberate the 38-amino acid bigEDN1; and cleavage of bigEDN1 by ECE enzymes to produce the mature, bioactive EDN1 peptide consisting of 21 amino acids. Gene Structure Inoue et al. (1989) determined that the EDN1 gene is composed of 5 exons distributed over 6,836 bp. Benatti et al. (1993) demonstrated that at least 2 preproendothelin-1 mRNAs are produced from a single gene by use of different promoters; the 2 molecules share the same coding sequence but differ in the 5-prime untranslated region. Analysis of the tissue distribution of the 2 mRNAs showed a tissue-type specificity for one mRNA in brain and heart tissues. Biochemical Features ### Crystal Structure Shihoya et al. (2016), reported the crystal structures of human endothelin type B receptor (131244) in the ligand-free form and in complex with the endogenous agonist endothelin-1. The structures and mutation analysis revealed the mechanism for the isopeptide selectivity between endothelin-1 and -3. Transmembrane helices 1, 2, 6, and 7 move and envelop the entire endothelin peptide in a virtually irreversible manner. The agonist-induced conformational changes are propagated to the receptor core and the cytoplasmic G protein-coupling interface, and probably induce conformational flexibility in TM6. A comparison with the M2 muscarinic receptor (CHRM2; 118493) suggested a shared mechanism for signal transduction in class A G protein-coupled receptors. Mapping Bloch et al. (1989) localized the ET1 gene to human chromosome 6. By Southern blot analysis of somatic cell hybrid DNAs and by in situ hybridization, Arinami et al. (1991) confirmed the assignment of EDN1 to chromosome 6 and regionalized it to 6p24-p23. By pairwise linkage analysis, Pages et al. (1993) placed EDN1 distal to D6S89 (maximum lod = 78.98 at theta = 0.059) and proximal to F13A1 (maximum lod = 38.65 at theta = 0.113). Maemura et al. (1996) mapped the Edn1 gene to mouse chromosome 13, where the mouse mutation congenital hydrocephalus (ch) is also mapped. Gene Function Using in situ hybridization in studies of postmortem material from the spinal cord and dorsal root ganglia, Giaid et al. (1989) found evidence of expression of endothelin-1 mRNA in distinct neuronal cell types of the dorsal ganglia and spinal cord. Maemura et al. (1996) found that the highest expression of Edn1 mRNA was detected in the lung in adult mice, whereas in the embryo the gene is predominantly expressed in the epithelium and mesenchyme of the pharyngeal arches and in the endothelium of the large arteries. To investigate the influence of pregnancy-specific hormonal environment on expression of ET1 and the ET1 receptor (EDNR), Bourgeois et al. (1997) cultured and characterized vascular smooth muscle cells from stem villi vessels. They investigated whether the muscular layer of stem villi vessels could be a site of the ET1 expression described in the placenta, and they examined this expression in placental vascular smooth muscle cells (PVSMCs). Peptide precursors prepro-ET1 and prepro-ET3 mRNAs were identified in stem villi vessels, whereas only prepro-ET1 mRNA was observed in PVSMCs. The authors characterized EDNR expressed by these cells in comparison with the muscular layer of stem villi vessels. Whereas both EDNRA (131243) and EDNRB (131244) are present in stem villi vessels, they found that PVSMCs exclusively express EDNRA. They described an alternatively spliced EDNRA transcript that is generated by exclusion of exon 3 in stem villi vessels and PVSMCs. The authors concluded that alternative splicing mechanisms of EDNRA mRNA could constitute a control of the abundance of active EDNRA in terms of contractility. Maggi et al. (2000) demonstrated that in FNC-B4 cells, which are derived from a human fetal olfactory epithelium, both sex steroids and odorants regulate GnRH secretion. They found biologic activity of EDN1 in this GnRH-secreting neuronal cell. In situ hybridization and immunohistochemistry revealed gene and protein expression of EDN1 and its converting enzyme (ECE1; 600423) in both fetal olfactory mucosa and FNC-B4 cells. Experiments with radiolabeled EDN1 and EDN3 (131242) strongly indicated the presence of 2 classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies using selective analogs indicated that these 2 classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Endothelin-1 inhibits active Na-K transport by as much as 50% in the renal tubule and other tissues (Zeidel et al., 1989). Okafor and Delamere (2001) noted that the presence of low levels of ET1 in aqueous humor combined with the potential for release of ET1 from ciliary processes suggested that the crystalline lens could be exposed to ET1 in vivo. They studied the influence of ET1 on active Na-K transport in the porcine lens. Their results suggested that ET1 inhibited active lens Na-K transport by activating EDNRA and EDNRB. Activation of the ET receptors also caused an increase in cytoplasmic calcium concentration in cultured lens epithelial cells. Both responses to ET1 appear to have a tyrosine kinase step. Udono et al. (2001) explored the effects of hypoxia on the production and secretion of adrenomedullin (ADM; 103275) and endothelin in human retinal pigment epithelial (RPE) cells. They found that ADM mRNA levels and immunoreactive ADM levels in the medium were increased by hypoxia in all 3 RPE cell lines studied. Immunoreactive ET1 was detected in 2 cultured media. Hypoxia treatment for 28 hours increased immunoreactive ET1 levels approximately 1.3-fold in 1 cultured cell medium but decreased it in 2 cell lines. Treatment with ADM ameliorated the hypoxia-induced decrease in the cell number. Exogenous ET1 had no significant effect on the number of cells under normoxia or hypoxia. Udono et al. (2001) concluded that the ADM induced by hypoxia may have protective roles against hypoxic cell damage in RPE cells. Napolitano et al. (2000) investigated the interactions between ET1 and the nitric oxide (NO) system in the fetoplacental unit. They examined the mRNA expression of ET1, inducible NO synthase (iNOS; 163730), and endothelial NOS (eNOS; 163729) in human cultured placental trophoblastic cells obtained from preeclamptic (189800) and normotensive pregnancies. ET1 expression was increased in preeclampsia cells, whereas iNOS, which represents the main source of NO synthesis, was decreased; conversely, eNOS expression was increased. ET1 was able to influence its own expression as well as NOS isoform expression in normal and preeclampsia trophoblastic cultured cells. The findings suggested the existence of a functional relationship between ET(s) and NOS isoforms that could constitute the biologic mechanism leading to the reduced placental blood flow and increased resistance to flow in the fetomaternal circulation that are characteristic of the pathophysiology of preeclampsia. Pache et al. (2002) tested the hypothesis that plasma endothelin-1 would be increased in 4 patients with biopsy-proven giant cell arteritis (187360). All patients showed significantly increased plasma levels of endothelin-1, although the clinical relevance of the increase required further evaluation. Jamal and Schneider (2002) found that ultraviolet induction of EDN1 through EDNRB downregulated E-cadherin (192090) and associated catenin proteins in human melanocytes and melanoma cells. Downregulation of E-cadherin through this pathway involved the downstream activation of caspase-8 (601763), but not the distal executioner caspases, and it did not lead to apoptosis. EDN1 also induced a transient association between caspase-8 and E-cadherin/beta-catenin (116806) complexes. Jamal and Schneider (2002) concluded that inhibition of E-cadherin through this pathway would tend to promote melanoma invasion. Endothelin-1 is a pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. It is a potent vasoactive peptide and appears to be implicated in the pathogenesis of pain associated with ischemic states (such as coronary artery disease or sickle cell anemia), and inflammation (such as arthritis) in addition to cancer. Endothelin-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A receptors (EDNRA; 131243) of local nociceptors, it can coincidentally produce analgesia through endothelin-B receptors (EDNRB; 131244). Khodorova et al. (2003) mapped an endogenous analgesic circuit, in which endothelin-B receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G protein-coupled inwardly rectifying potassium channels (GIRKs, also called Kir-3) linked to opioid receptors on nociceptors. These results indicated the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and established keratinocytes as an endothelin-B receptor-operated opioid pool. Osteoblastic bone metastases are common in prostate and breast cancer patients. Yin et al. (2003) sought to determine mechanisms by which tumor cells stimulate new bone formation. They identified 3 breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulated new bone formation in vitro and osteoblastic metastases in vivo via the endothelin-A receptor. Treatment with an orally active endothelin-A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with cancer cells of a particular line. Yin et al. (2003) concluded that tumor-producing endothelin-1 may have a major role in the establishment of osteoblastic bone metastases and that endothelin-A receptor blockade (Remuzzi et al., 2002) is a promising form of therapy. Chauhan et al. (2004) described a model of chronic ET1 administration to the rat optic nerve and evaluated its effect on retinal ganglion cell and axon survival. ET1 led to a mean reduction in optic nerve blood flow of 68%. This resulted in a time-dependent loss of retinal ganglion cells and their axons without apparent change in the optic disc topography. Campia et al. (2004) examined forearm blood flow responses to intraarterial injection of an endothelin-A receptor blocker in 37 normotensive and 27 hypertensive patients. In hypertensive patients, the vasodilator effect of the blocker was significantly higher in blacks than in whites (p = 0.01), whereas blood flow was not significantly affected in black or white healthy controls. Campia et al. (2004) concluded that hypertensive blacks have enhanced EDNRA-dependent vasoconstrictor tone, which they suggested might be related to increased production of ET1. Placental growth factor (PGF; 601121) upregulates ET1 expression via HIF1-alpha (HIF1A; 603348). Using primary human endothelial cells and cell lines, Li et al. (2015) found that PGF also upregulated ET1 via a pathway involving PAX5 (167414) and microRNA-648 (MIR648; 616205). They showed that MIR648 directly targeted the 3-prime UTR of ET1 and destabilized the transcript, thereby reducing ET1 translation. Overexpression and knockdown studies revealed that PGF reduced MIR648 content indirectly by downregulating PAX5, a positive regulator of MIR648 expression. Molecular Genetics ### High Density Lipoprotein Cholesterol Pare et al. (2007) used a candidate gene approach to study the genetics of coronary artery disease (CAD) in the Saguenay-Lac-Saint-Jean (SLSJ) region of northeastern Quebec. The SLSJ region is inhabited by an archetypal 'founder effect' population of approximately 280,000 individuals, which was subjected to a first bottleneck with the establishment of New France by French settlers in the 17th-18th century and then to a second bottleneck with the founding of the SLSJ region in the 19th century. Consequently, only approximately 600 ancestors contributed up to 70% of the genetic pool (Heyer and Tremblay, 1995). It was anticipated that the population would show decrease in allelic and genetic heterogeneity, 2 phenomena that hinder dissection of the genetic architecture of complex traits. The project involved the analysis of 884 individuals from 142 families (with average sibships of 5.7) as well as 558 cases and control subjects from the SLSJ region, with the use of 1,536 SNPs in 103 candidate genes. Suggestive linkage for high density lipoprotein (HDL) cholesterol was observed on chromosome 1p36.22. Furthermore, several associations that remained significant after Bonferroni correction for multiple testing were observed with lipoprotein-related traits as well as plasma concentrations of adiponectin (605441). Of note, HDL cholesterol levels were associated with a lys198-to-asn (K198N) substitution in the EDN1 gene (rs5370; 131240.0001) in a sex-specific manner, as well as with an SNP located 7.7 kb upstream of lecithin:cholesterol acyltransferase (LCAT; 606967). Whereas the other observed associations had been previously described, these 2 were not. Using an independent validation sample of 806 individuals, Pare et al. (2007) confirmed the EDN1 association (p less than 0.005), whereas the LCAT association was nonsignificant (p = 0.12). Wiltshire et al. (2008) analyzed the K198N polymorphism of the EDN1 gene in 1,109 individuals from the general population of Western Australia and 556 patients with coronary artery disease, and found no association with hypertension, systolic blood pressure, lipid levels, insulin resistance, or metabolic syndrome in either population. ### Auriculocondylar Syndrome 3 In patients from 2 unrelated consanguineous families with auriculocondylar syndrome-3 (ARCND3; 615706), Gordon et al. (2013) identified homozygosity for missense mutations in the EDN1 gene (131240.0002 and 131240.0003) that segregated with disease in each family. ### Isolated Question Mark Ears In affected individuals from 2 unrelated families with isolated question mark ears (QME; 612798), Gordon et al. (2013) identified heterozygosity for a missense (V64D; 131240.0004) and a nonsense (Y83X; 131240.0005) mutation in the EDN1 gene, respectively. The mutations segregated with disease in each family. Gordon et al. (2013) suggested a model in which heterozygous-null EDN1 alleles result in isolated question mark ears, whereas hypomorphic alleles result in an auriculocondylar syndrome phenotype in homozygotes and no phenotype in heterozygotes. ### Exclusion Studies Berge and Berg (1992) found no relationship between a TaqI DNA polymorphism at the EDN1 locus and the level of normal blood pressure or variability in blood pressure. Pezzetti et al. (2000) examined the endothelin gene and 3 other genes in the endothelin pathway (ECE1, EDNRA, EDNRB) as possible candidates for orofacial cleft (OFC; 119530). Linkage results indicated that none of these genes is involved in the pathogenesis of OFC. Animal Model Kurihara et al. (1994) found that mice homozygous for a knockout of the endothelin-1 gene died of respiratory failure at birth and had morphologic abnormalities of the pharyngeal arch-derived craniofacial tissues and organs. Heterozygous mice produced lower levels of endothelin-1 than wildtype mice and developed elevated blood pressure. The phenotype of the homozygous ET1 deficient mice was quite similar to first pharyngeal arch syndromes, such as Pierre Robin syndrome (261800) and Treacher Collins syndrome (154500). To clarify the physiologic and pathophysiologic role of ET1, Kurihara et al. (1994) disrupted the mouse Edn1 locus by gene targeting and demonstrated that ET1 is essential to the normal development of pharyngeal arch-derived tissues and organs. In a later study, Kurihara et al. (1995) focused on the phenotypic manifestations in the cardiovascular system of homozygous deficient mice. They found cardiovascular malformations, including interrupted aortic arch (2.3%), tubular hypoplasia of the aortic arch (4.6%), aberrant right subclavian artery (12.9%), and ventricular septal defect with abnormalities of the outflow tract (48.4%). The frequency and extent of these abnormalities were increased by treatment with neutralizing monoclonal antibodies or a selective antagonist to EDNRA. At an earlier embryonic stage, formation of pharyngeal arch arteries and endocardial cushion is disturbed in homozygotes. In situ hybridization by Kurihara et al. (1995) confirmed ET1 expression in the endothelium of the arch arteries and cardiac outflow tract and the endocardial cushion, as well as in the epithelium of the pharyngeal arches. Thus, they concluded that ET1 is involved in the normal development of the heart and great vessels, and circulating ET1 and/or other ET isoforms may cause a functional redundancy, at least partly, through EDNRA. During embryogenesis, establishment of the circulatory system requires the organized development of the heart and vessels. Six pairs of branchial arch arteries appear in a rostral to caudal direction, and form the precursors of the great vessels and large arteries of the head and neck. The sequential remodeling of the arch arteries together with the regression of the right dorsal aorta results in a highly asymmetric arterial system in the mature organism. An intimate involvement of cardiac neural crest cells in arch artery remodeling is suggested by the phenotype resulting from the ablation of cardiac neural crest in chick embryos, where various types of great vessel abnormalities and septation defects of the outflow tract develop (Kirby and Waldo, 1995). Yanagisawa et al. (1998) and Clouthier et al. (1998) found that mice deficient in Ece1 (600423) or Ednra (131243) develop defects in a subset of cephalic and cardiac neural crest derivatives. The most common great vessel malformations in Ece1 -/- and Ednra -/- mice were found to be interruption of the aortic arch between the left common carotid artery and left subclavian artery (type B interruption of the aortic arch). The second most common defect was absence of the right subclavian artery. Among outflow tract abnormalities, perimembranous interventricular septal defect was observed in almost all embryos with disruption of either gene. In further studies, Yanagisawa et al. (1998) demonstrated that the defects in the mice with gene disruptions were highly similar to those seen in neural crest-ablated chick embryos and in human congenital cardiac defects. The authors demonstrated that signaling mediated by the endothelin-1/endothelin receptor-A pathway plays an essential role in the complex process of aortic arch patterning by affecting the postmigratory cardiac neural crest cell development. Endothelin-1, a potent vasoconstrictor peptide expressed by endothelium, is also produced in the heart in response to a variety of stresses. It induces hypertrophy in cultured cardiac myocytes but only at concentrations far greater than those found in plasma. Shohet et al. (2004) tested whether endothelin-1 generated by cardiomyocytes in vivo is a local signal for cardiac hypertrophy. To avoid the perinatal lethality seen in systemic Et1 null mice, they used the Cre/loxP system to generate mice with cardiac myocyte-specific disruption of the Et1 gene. They used the alpha-myosin heavy chain (160710) promoter to drive expression of Cre and obtained 75% reduction in Et1 mRNA in cardiac myocytes isolated from these mice at baseline and after stimulation, in vivo, for 24 hours with triiodothyronine (T3). Necropsy measurements of cardiac mass indexed for body weight showed a 57% reduction in cardiac hypertrophy in response to 16 days of exogenous T3 in mice homozygous for the disrupted Et1 allele compared to sibs with an intact Et1 gene. Moreover, in vivo MRI showed only a 3% increase in left ventricular mass indexed for body weight in mice with the disrupted allele after 3 weeks of T3 treatment versus a 47% increase in mice with an intact Et1 gene. Shohet et al. (2004) concluded that ET1, produced locally by cardiac myocytes, and acting in a paracrine/autocrine manner, is an important signal for myocardial hypertrophy that facilitates the response to thyroid hormone. In a study of regulators of nerve growth factor (NGFB; 162030), Ieda et al. (2004) found that EDN1 specifically upregulated NGFB expression in primary cultured cardiomyocytes. EDN1-induced NGF augmentation was mediated by EDNRA, Gi-beta-gamma (see 139310), PKC (see 176960), the Src family (see 190090), EGFR (131550), MAPK3 (601795), MAPK14 (600289), AP1 (165160), and CEBPD (116898). Either conditioned medium or coculture with EDN1-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. Edn1-deficient mice exhibited reduced NGF expression and norepinephrine concentration in the heart, reduced cardiac sympathetic innervation, excess apoptosis of sympathetic stellate ganglia, and loss of neurons at the late embryonic stage. Cardiac-specific overexpression of NGF in Edn1-deficient mice overcame the reduced sympathetic expression and loss of stellate ganglia neurons. Ieda et al. (2004) concluded that EDN1 plays a critical role in sympathetic innervation of the heart. Ahn et al. (2004) generated mice with collecting duct-specific knockout of Et1 that had no collecting duct Et1 mRNA and reduced urinary Et1 excretion. On a normal sodium diet, the mice were hypertensive, while body weight, sodium excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. On a high sodium diet, they had increased hypertension, reduced urinary sodium excretion, and excessive weight gain, but showed no difference in aldosterone excretion and plasma renin activity compared to controls. Ahn et al. (2004) concluded that collecting duct-derived ET1 is an important physiologic regulator of renal sodium excretion and systemic blood pressure. In adult transgenic mice with conditional cardiac-restricted ET1 overexpression, Yang et al. (2004) observed nuclear factor kappa-B (see 164011) translocation, cytokine expression, inflammation and hypertrophy, resulting in dilated cardiomyopathy, congestive heart failure, and death as early as 5 weeks after transgene induction. Significant prolongation of survival was observed with a combined EDNRA/EDNRB antagonist but not with an EDNRA-selective antagonist, consistent with an important role for EDNRB in this model. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	ENDOTHELIN 1	c3888126	2,212	omim	https://www.omim.org/entry/131240	2019-09-22T16:41:36	{"omim": ["131240"], "synonyms": ["Alternative titles", "ET1"]}
Polydactyly is a condition in which a person has more than five fingers per hand or five toes per foot. It is the most common birth defect of the hand and foot. Polydactyly can occur as an isolated finding such that the person has no other physical anomalies or intellectual impairment. However, it can occur in association with other birth defects and cognitive abnormalities as part of a genetic syndrome. In some cases, the extra digits may be well-formed and functional. Surgery may be considered especially for poorly formed digits or very large extra digits. Surgical management depends greatly on the complexity of the deformity. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Polydactyly	c0152427	2,213	gard	https://rarediseases.info.nih.gov/diseases/4410/polydactyly	2021-01-18T17:58:16	{"mesh": ["D017689"], "omim": ["603596"], "orphanet": ["2913"], "synonyms": ["Extra digits", "Supernumerary digits", "Polydactylia", "Hyperdactyly", "Polydactylism", "Non-syndromic polydactyly"]}
For other uses, see Psychosis (disambiguation). Not to be confused with Psychopathy. Condition of the mind that involves a loss of contact with reality Psychosis Other namesPsychotic break Van Gogh's The Starry Night, from 1889, shows changes in light and color as can appear with psychosis.[1][2][3] SpecialtyPsychiatry, clinical psychology SymptomsFalse beliefs, seeing or hearing things that others do not see or hear, incoherent speech[4] ComplicationsSelf-harm, suicide[5] CausesMental illness (schizophrenia, bipolar disorder), sleep deprivation, some medical conditions, certain medications, drugs (including alcohol and cannabis)[4] TreatmentAntipsychotics, counselling, social support[5] PrognosisDepends on cause[5] Frequency3% of people at some point in time (US)[4] Psychosis is an abnormal condition of the mind that results in difficulties determining what is real and what is not real.[4] Symptoms may include delusions and hallucinations.[4] Other symptoms may include incoherent speech and behavior that is inappropriate for the situation.[4] There may also be sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities.[4] Psychosis can have serious outcomes.[6] Psychosis has many different causes.[4] These include mental illness, such as schizophrenia or bipolar disorder, sleep deprivation, some medical conditions, certain medications, and drugs such as alcohol or cannabis.[4] One type, known as postpartum psychosis, can occur after giving birth.[7] The neurotransmitter dopamine is believed to play a role.[8] Acute psychosis is considered primary if it results from a psychiatric condition and secondary if it is caused by a medical condition.[9] The diagnosis of a mental illness requires excluding other potential causes.[10] Testing may be done to check for central nervous system diseases, toxins, or other health problems as a cause.[11] Treatment may include antipsychotic medication, counselling, and social support.[4][5] Early treatment appears to improve outcomes.[4] Medications appear to have a moderate effect.[12][13] Outcomes depend on the underlying cause.[5] In the United States about 3% of people develop psychosis at some point in their lives.[4] The condition has been described since at least the 4th century BC by Hippocrates and possibly as early as 1500 BC in the Egyptian Ebers Papyrus.[14][15] ## Contents * 1 Signs and symptoms * 1.1 Hallucinations * 1.2 Delusions * 1.3 Disorganization * 1.4 Negative symptoms * 1.5 Psychosis in adolescents * 2 Causes * 2.1 Normal states * 2.2 Trauma * 2.3 Psychiatric disorder * 2.3.1 Subtypes * 2.3.2 Cycloid psychosis * 2.4 Medical conditions * 2.5 Psychoactive drugs * 2.5.1 Alcohol * 2.5.2 Cannabis * 2.5.3 Methamphetamine * 2.6 Medication * 3 Pathophysiology * 3.1 Neuroimaging * 3.2 Hallucinations * 3.3 Delusions * 3.4 Negative symptoms * 3.5 Neurobiology * 4 Diagnosis * 5 Prevention * 6 Treatment * 6.1 Medication * 6.2 Counseling * 6.3 Early intervention * 7 History * 7.1 Etymology * 7.2 Classification * 7.3 Treatment * 7.4 Society * 8 Research * 9 See also * 10 References * 11 Further reading * 12 External links ## Signs and symptoms[edit] ### Hallucinations[edit] A hallucination is defined as sensory perception in the absence of external stimuli. Hallucinations are different from illusions and perceptual distortions, which are the misperception of external stimuli. Hallucinations may occur in any of the senses and take on almost any form. They may consist of simple sensations (such as lights, colors, sounds, tastes, or smells) or more detailed experiences (such as seeing and interacting with animals and people, hearing voices, and having complex tactile sensations). Hallucinations are generally characterized as being vivid and uncontrollable.[16] Auditory hallucinations, particularly experiences of hearing voices, are the most common and often prominent feature of psychosis. Up to 15% of the general population may experience auditory hallucinations (though not all are due to psychosis). The prevalence of auditory hallucinations in patients with schizophrenia is generally put around 70%, but may go as high as 98%. Reported prevalence in bipolar disorder ranges between 11% and 68%.[17] During the early 20th century, auditory hallucinations were second to visual hallucinations in frequency, but they are now the most common manifestation of schizophrenia, although rates vary between cultures and regions. Auditory hallucinations are most commonly intelligible voices. When voices are present, the average number has been estimated at three. Content, like frequency, differs significantly, especially across cultures and demographics. People who experience auditory hallucinations can frequently identify the loudness, location of origin, and may settle on identities for voices. Western cultures are associated with auditory experiences concerning religious content, frequently related to sin. Hallucinations may command a person to do something potentially dangerous when combined with delusions.[18] Extracampine hallucinations are perceptions outside the sensory apparatus for example a sound is perceived through the knee,[18] or a visual extracampine hallucination is seeing by sensing that somebody is near to you, that is not there.[19] Visual hallucinations occur in roughly a third of people with schizophrenia, although rates as high as 55% are reported. The prevalence in bipolar disorder is around 15%. Content frequently involves animate objects, although perceptual abnormalities such as changes in lighting, shading, streaks, or lines may be seen. Visual abnormalities may conflict with proprioceptive information, and visions may include experiences such as the ground tilting. Lilliputian hallucinations are less common in schizophrenia, and occur more frequently in various types of encephalopathy such as peduncular hallucinosis.[18] A visceral hallucination, also called a cenesthetic hallucination, is characterized by visceral sensations in the absence of stimuli. Cenesthetic hallucinations may include sensations of burning, or re-arrangement of internal organs.[18] ### Delusions[edit] Psychosis may involve delusional beliefs. A delusion is commonly defined as an unrelenting sense of certainty maintained despite strong contradictory evidence. Delusions are context- and culture-dependent: a belief which inhibits critical functioning and is widely considered delusional in one population may be common (and even adaptive) in another, or in the same population at a later time. Since normative views may themselves contradict available evidence, a belief need not contravene cultural standards in order to be considered delusional. Prevalence in schizophrenia is generally considered at least 90%, and around 50% in bipolar disorder. The DSM-5 characterizes certain delusions as "bizarre" if they are clearly implausible, or are incompatible with the surrounding cultural context. The concept of bizarre delusions has many criticisms, the most prominent being judging its presence is not highly reliable even among trained individuals.[18] A delusion may involve diverse thematic content. The most common type is a persecutory delusion, in which a person believes that some entity is attempting to harm them. Others include delusions of reference (the belief that some element of one's experience represents a deliberate and specific act by or message from some other entity), delusions of grandeur (the belief that one possesses special power or influence beyond one's actual limits), thought broadcasting (the belief that one's thoughts are audible) and thought insertion (the belief that one's thoughts are not one's own). The subject matter of delusions seems to reflect the current culture in a particular time and location. For example in the US, during the early 1900s syphilis was a common topic, during the second world war Germany, during the cold war communists, and in recent years technology has been a focus. [20] Some psychologists, such as those who practice the Open Dialogue method believe that the content of psychosis represent an underlying thought process that may, in part, be responsible for psychosis, [21] though the accepted medical position is that psychosis is due to a brain disorder. Historically, Karl Jaspers classified psychotic delusions into primary and secondary types. Primary delusions are defined as arising suddenly and not being comprehensible in terms of normal mental processes, whereas secondary delusions are typically understood as being influenced by the person's background or current situation (e.g., ethnicity; also religious, superstitious, or political beliefs).[22] ### Disorganization[edit] Disorganization is split into disorganized speech or thinking, and grossly disorganized motor behavior. Disorganized speech or thinking, also called formal thought disorder, is disorganization of thinking that is inferred from speech. Characteristics of disorganized speech include rapidly switching topics, called derailment or loose association; switching to topics that are unrelated, called tangential thinking; incomprehensible speech, called word salad or incoherence. Disorganized motor behavior includes repetitive, odd, or sometimes purposeless movement. Disorganized motor behavior rarely includes catatonia, and although it was a historically prominent symptom, it is rarely seen today. Whether this is due to historically used treatments or the lack thereof is unknown.[18][16] Catatonia describes a profoundly agitated state in which the experience of reality is generally considered impaired. There are two primary manifestations of catatonic behavior. The classic presentation is a person who does not move or interact with the world in any way while awake. This type of catatonia presents with waxy flexibility. Waxy flexibility is when someone physically moves part of a catatonic person's body and the person stays in the position even if it is bizarre and otherwise nonfunctional (such as moving a person's arm straight up in the air and the arm staying there). The other type of catatonia is more of an outward presentation of the profoundly agitated state described above. It involves excessive and purposeless motor behaviour, as well as extreme mental preoccupation that prevents an intact experience of reality. An example is someone walking very fast in circles to the exclusion of anything else with a level of mental preoccupation (meaning not focused on anything relevant to the situation) that was not typical of the person prior to the symptom onset. In both types of catatonia there is generally no reaction to anything that happens outside of them. It is important to distinguish catatonic agitation from severe bipolar mania, although someone could have both. ### Negative symptoms[edit] Negative symptoms include reduced emotional expression, decreased motivation, and reduced spontaneous speech. Afflicted individuals lack interest and spontaneity, and have the inability to feel pleasure.[23] ### Psychosis in adolescents[edit] Psychosis is rare in adolescents.[6] Young people who have psychosis may have trouble connecting with the world around them and may experience hallucinations and/or delusions.[6] Adolescents with psychosis may also have cognitive deficits that may make it harder for the youth to socialize and work.[6] Potential impairments include the speed of mental processing, ability to focus without getting distracted (attention span), and problems with their verbal memory.[6] ## Causes[edit] The symptoms of psychosis may be caused by serious psychiatric disorders such as schizophrenia, a number of medical illnesses, and trauma. Psychosis may also be temporary or transient, and be caused by medications or substance abuse (substance-induced psychosis). ### Normal states[edit] Brief hallucinations are not uncommon in those without any psychiatric disease. Causes or triggers include:[24] * Falling asleep and waking: hypnagogic and hypnopompic hallucinations, which are entirely normal[25] * Bereavement, in which hallucinations of a deceased loved one are common[24] * Severe sleep deprivation[26][27][28] * Stress[29] ### Trauma[edit] Traumatic life events have been linked with an elevated risk in developing psychotic symptoms.[30] Childhood trauma has specifically been shown to be a predictor of adolescent and adult psychosis.[31] Approximately 65% of individuals with psychotic symptoms have experienced childhood trauma (e.g., physical or sexual abuse, physical or emotional neglect).[32] Increased individual vulnerability toward psychosis may interact with traumatic experiences promoting an onset of future psychotic symptoms, particularly during sensitive developmental periods.[31] Importantly, the relationship between traumatic life events and psychotic symptoms appears to be dose-dependent in which multiple traumatic life events accumulate, compounding symptom expression and severity.[30][31] This suggests trauma prevention and early intervention may be an important target for decreasing the incidence of psychotic disorders and ameliorating its effects.[30] ### Psychiatric disorder[edit] From a diagnostic standpoint, organic disorders were believed to be caused by physical illness affecting the brain (that is, psychiatric disorders secondary to other conditions) while functional disorders were considered disorders of the functioning of the mind in the absence of physical disorders (that is, primary psychological or psychiatric disorders). Subtle physical abnormalities have been found in illnesses traditionally considered functional, such as schizophrenia. The DSM-IV-TR avoids the functional/organic distinction, and instead lists traditional psychotic illnesses, psychosis due to general medical conditions, and substance-induced psychosis. Primary psychiatric causes of psychosis include the following:[33][34][24] * schizophrenia and schizophreniform disorder * affective (mood) disorders, including major depression, and severe depression or mania in bipolar disorder (manic depression). People experiencing a psychotic episode in the context of depression may experience persecutory or self-blaming delusions or hallucinations, while people experiencing a psychotic episode in the context of mania may form grandiose delusions. * schizoaffective disorder, involving symptoms of both schizophrenia and mood disorders * brief psychotic disorder, or acute/transient psychotic disorder * delusional disorder (persistent delusional disorder) * chronic hallucinatory psychosis Psychotic symptoms may also be seen in:[24] * schizotypal personality disorder * certain personality disorders at times of stress (including paranoid personality disorder, schizoid personality disorder, and borderline personality disorder) * major depressive disorder in its severe form, although it is possible and more likely to have severe depression without psychosis * bipolar disorder in the manic and mixed episodes of bipolar I disorder and depressive episodes of both bipolar I and bipolar II; however, it is possible to experience such states without psychotic symptoms. * posttraumatic stress disorder * induced delusional disorder * Sometimes in obsessive–compulsive disorder * Juvenile‐onset affective disorder[6] * Dissociative disorders, due to many overlapping symptoms, careful differential diagnosis includes especially dissociative identity disorder.[35] Stress is known to contribute to and trigger psychotic states. A history of psychologically traumatic events, and the recent experience of a stressful event, can both contribute to the development of psychosis. Short-lived psychosis triggered by stress is known as brief reactive psychosis, and patients may spontaneously recover normal functioning within two weeks.[36] In some rare cases, individuals may remain in a state of full-blown psychosis for many years, or perhaps have attenuated psychotic symptoms (such as low intensity hallucinations) present at most times. Neuroticism is an independent predictor of the development of psychosis.[37] #### Subtypes[edit] Subtypes of psychosis include: * Menstrual psychosis, including circa-mensual (approximately monthly) periodicity, in rhythm with the menstrual cycle. * Postpartum psychosis, occurring shortly after giving birth * Monothematic delusions * Myxedematous psychosis * Stimulant psychosis * Tardive psychosis * Shared psychosis #### Cycloid psychosis[edit] Cycloid psychosis is a psychosis that progresses from normal to full-blown, usually between a few hours to days, not related to drug intake or brain injury.[38] The cycloid psychosis has a long history in European psychiatry diagnosis. The term "cycloid psychosis" was first used by Karl Kleist in 1926. Despite the significant clinical relevance, this diagnosis is neglected both in literature and in nosology. The cycloid psychosis has attracted much interest in the international literature of the past 50 years, but the number of scientific studies have greatly decreased over the past 15 years, possibly partly explained by the misconception that the diagnosis has been incorporated in current diagnostic classification systems. The cycloid psychosis is therefore only partially described in the diagnostic classification systems used. Cycloid psychosis is nevertheless its own specific disease that is distinct from both the manic-depressive disorder, and from schizophrenia, and this despite the fact that the cycloid psychosis can include both bipolar (basic mood shifts) as well as schizophrenic symptoms. The disease is an acute, usually self-limiting, functionally psychotic state, with a very diverse clinical picture that almost consistently is characterized by the existence of some degree of confusion or distressing perplexity, but above all, of the multifaceted and diverse expressions the disease takes. The main features of the disease is thus that the onset is acute, contains the multifaceted picture of symptoms and typically reverses to a normal state and that the long-term prognosis is good. In addition, diagnostic criteria include at least four of the following symptoms:[38] * Confusion * Mood-incongruent delusions * Hallucinations * Pan-anxiety, a severe anxiety not bound to particular situations or circumstances * Happiness or ecstasy of high degree * Motility disturbances of akinetic or hyperkinetic type * Concern with death * Mood swings to some degree, but less than what is needed for diagnosis of an affective disorder Cycloid psychosis occurs in people of generally 15–50 years of age.[38] ### Medical conditions[edit] A very large number of medical conditions can cause psychosis, sometimes called secondary psychosis.[24] Examples include: * disorders causing delirium (toxic psychosis), in which consciousness is disturbed * neurodevelopmental disorders and chromosomal abnormalities, including velocardiofacial syndrome * neurodegenerative disorders, such as Alzheimer's disease,[39] dementia with Lewy bodies,[40] and Parkinson's disease[41][42] * focal neurological disease, such as stroke, brain tumors,[43] multiple sclerosis,[42] and some forms of epilepsy * malignancy (typically via masses in the brain, paraneoplastic syndromes)[42] * infectious and postinfectious syndromes, including infections causing delirium, viral encephalitis, HIV/AIDS,[44] malaria,[45] syphilis[46] * endocrine disease, such as hypothyroidism, hyperthyroidism, Cushing's syndrome, hypoparathyroidism and hyperparathyroidism;[47] sex hormones also affect psychotic symptoms and sometimes giving birth can provoke psychosis, termed postpartum psychosis[48] * inborn errors of metabolism, such as Succinic semialdehyde dehydrogenase deficiency, porphyria and metachromatic leukodystrophy[49][50][51][52] * nutritional deficiency, such as vitamin B12 deficiency[9] * other acquired metabolic disorders, including electrolyte disturbances such as hypocalcemia, hypernatremia,[53] hyponatremia,[54] hypokalemia,[55] hypomagnesemia,[56] hypermagnesemia,[57] hypercalcemia,[58] and hypophosphatemia,[59] but also hypoglycemia,[60] hypoxia, and failure of the liver or kidneys * autoimmune and related disorders, such as systemic lupus erythematosus (lupus, SLE), sarcoidosis, Hashimoto's encephalopathy, anti-NMDA-receptor encephalitis, and non-celiac gluten sensitivity[49][61] * poisoning, by therapeutic drugs (see below), recreational drugs (see below), and a range of plants, fungi, metals, organic compounds, and a few animal toxins[24] * sleep disorders, such as in narcolepsy (in which REM sleep intrudes into wakefulness)[24] * parasitic diseases, such as neurocysticercosis ### Psychoactive drugs[edit] Main article: Substance-induced psychosis Various psychoactive substances (both legal and illegal) have been implicated in causing, exacerbating, or precipitating psychotic states or disorders in users, with varying levels of evidence. This may be upon intoxication for a more prolonged period after use, or upon withdrawal.[24] Individuals who have a substance induced psychosis tend to have a greater awareness of their psychosis and tend to have higher levels of suicidal thinking compared to individuals who have a primary psychotic illness.[62] Drugs commonly alleged to induce psychotic symptoms include alcohol, cannabis, cocaine, amphetamines, cathinones, psychedelic drugs (such as LSD and psilocybin), κ-opioid receptor agonists (such as enadoline and salvinorin A) and NMDA receptor antagonists (such as phencyclidine and ketamine).[24][63] Caffeine may worsen symptoms in those with schizophrenia and cause psychosis at very high doses in people without the condition.[64][65] Cannabis and other illicit recreational drugs are often associated with psychosis in adolescents and cannabis use before 15 years old may increase the risk of psychosis later in life as an adult.[6] #### Alcohol[edit] Further information: Long-term effects of alcohol consumption § Mental health effects Approximately three percent of people who are suffering from alcoholism experience psychosis during acute intoxication or withdrawal. Alcohol related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to the long-term effects of alcohol consumption resulting in distortions to neuronal membranes, gene expression, as well as thiamin deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as causing psychosocial impairments.[66] #### Cannabis[edit] Further information: Causes of schizophrenia § Cannabis, and Long-term effects of cannabis § Chronic psychosis and schizophrenia spectrum disorders According to some studies, the more often cannabis is used the more likely a person is to develop a psychotic illness,[67] with frequent use being correlated with twice the risk of psychosis and schizophrenia.[68][69] While cannabis use is accepted as a contributory cause of schizophrenia by some,[70] it remains controversial, with pre-existing vulnerability to psychosis emerging as the key factor that influences the link between cannabis use and psychosis.[71][72] Some studies indicate that the effects of two active compounds in cannabis, tetrahydrocannabinol (THC) and cannabidiol (CBD), have opposite effects with respect to psychosis. While THC can induce psychotic symptoms in healthy individuals, CBD may reduce the symptoms caused by cannabis.[73] Cannabis use has increased dramatically over the past few decades whereas the rate of psychosis has not increased. Together, these findings suggest that cannabis use may hasten the onset of psychosis in those who may already be predisposed to psychosis.[74] High-potency cannabis use indeed seems to accelerate the onset of psychosis in predisposed patients.[75] A 2012 study concluded that cannabis plays an important role in the development of psychosis in vulnerable individuals, and that cannabis use in early adolescence should be discouraged.[76] #### Methamphetamine[edit] Main article: Stimulant psychosis Methamphetamine induces a psychosis in 26–46 percent of heavy users. Some of these people develop a long-lasting psychosis that can persist for longer than six months. Those who have had a short-lived psychosis from methamphetamine can have a relapse of the methamphetamine psychosis years later after a stressful event such as severe insomnia or a period of heavy alcohol abuse despite not relapsing back to methamphetamine.[77] Individuals who have a long history of methamphetamine abuse and who have experienced psychosis in the past from methamphetamine abuse are highly likely to re-experience methamphetamine psychosis if drug use is recommenced. Methamphetamine-induced psychosis is likely gated by genetic vulnerability, which can produce long-term changes in brain neurochemistry following repetitive use.[78] ### Medication[edit] Administration, or sometimes withdrawal, of a large number of medications may provoke psychotic symptoms.[24] Drugs that can induce psychosis experimentally or in a significant proportion of people include amphetamine and other sympathomimetics, dopamine agonists, ketamine, corticosteroids (often with mood changes in addition), and some anticonvulsants such as vigabatrin.[24][79] Stimulants that may cause this include lisdexamfetamine.[80] Medication may induce psychological side effects, including depersonalization, derealization and psychotic symptoms like hallucinations as well as mood disturbances.[81] ## Pathophysiology[edit] ### Neuroimaging[edit] The first brain image of an individual with psychosis was completed as far back as 1935 using a technique called pneumoencephalography[82] (a painful and now obsolete procedure where cerebrospinal fluid is drained from around the brain and replaced with air to allow the structure of the brain to show up more clearly on an X-ray picture). Both first episode psychosis, and high risk status is associated with reductions in grey matter volume (GMV). First episode psychotic and high risk populations are associated with similar but distinct abnormalities in GMV. Reductions in the right middle temporal gyrus, right superior temporal gyrus (STG), right parahippocampus, right hippocampus, right middle frontal gyrus, and left anterior cingulate cortex (ACC) are observed in high risk populations. Reductions in first episode psychosis span a region from the right STG to the right insula, left insula, and cerebellum, and are more severe in the right ACC, right STG, insula and cerebellum.[83][84] Another meta analysis reported bilateral reductions in insula, operculum, STG, medial frontal cortex, and ACC, but also reported increased GMV in the right lingual gyrus and left precentral gyrus.[85] The Kraepelinian dichotomy is made questionable[clarification needed] by grey matter abnormalities in bipolar and schizophrenia; schizophrenia is distinguishable from bipolar in that regions of grey matter reduction are generally larger in magnitude, although adjusting for gender differences reduces the difference to the left dorsomedial prefrontal cortex, and right dorsolateral prefrontal cortex.[86] During attentional tasks, first episode psychosis is associated with hypoactivation in the right middle frontal gyrus, a region generally described as encompassing the dorsolateral prefrontal cortex (dlPFC). In congruence with studies on grey matter volume, hypoactivity in the right insula, and right inferior parietal lobe is also reported.[87] During cognitive tasks, hypoactivities in the right insula, dACC, and the left precuneus, as well as reduced deactivations in the right basal ganglia, right thalamus, right inferior frontal and left precentral gyri are observed. These results are highly consistent and replicable possibly except the abnormalities of the right inferior frontal gyrus.[88] Decreased grey matter volume in conjunction with bilateral hypoactivity is observed in anterior insula, dorsal medial frontal cortex, and dorsal ACC. Decreased grey matter volume and bilateral hyperactivity is reported in posterior insula, ventral medial frontal cortex, and ventral ACC.[89] ### Hallucinations[edit] Studies during acute experiences of hallucinations demonstrate increased activity in primary or secondary sensory cortices. As auditory hallucinations are most common in psychosis, most robust evidence exists for increased activity in the left middle temporal gyrus, left superior temporal gyrus, and left inferior frontal gyrus (i.e. Broca's area). Activity in the ventral striatum, hippocampus, and ACC are related to the lucidity of hallucinations, and indicate that activation or involvement of emotional circuitry are key to the impact of abnormal activity in sensory cortices. Together, these findings indicate abnormal processing of internally generated sensory experiences, coupled with abnormal emotional processing, results in hallucinations. One proposed model involves a failure of feedforward networks from sensory cortices to the inferior frontal cortex, which normally cancel out sensory cortex activity during internally generated speech. The resulting disruption in expected and perceived speech is thought to produce lucid hallucinatory experiences.[90] ### Delusions[edit] The two-factor model of delusions posits that dysfunction in both belief formation systems and belief evaluation systems are necessary for delusions. Dysfunction in evaluations systems localized to the right lateral prefrontal cortex, regardless of delusion content, is supported by neuroimaging studies and is congruent with its role in conflict monitoring in healthy persons. Abnormal activation and reduced volume is seen in people with delusions, as well as in disorders associated with delusions such as frontotemporal dementia, psychosis and Lewy body dementia. Furthermore, lesions to this region are associated with "jumping to conclusions", damage to this region is associated with post-stroke delusions, and hypometabolism this region associated with caudate strokes presenting with delusions. The aberrant salience model suggests that delusions are a result of people assigning excessive importance to irrelevant stimuli. In support of this hypothesis, regions normally associated with the salience network demonstrate reduced grey matter in people with delusions, and the neurotransmitter dopamine, which is widely implicated in salience processing, is also widely implicated in psychotic disorders. Specific regions have been associated with specific types of delusions. The volume of the hippocampus and parahippocampus is related to paranoid delusions in Alzheimer's disease, and has been reported to be abnormal post mortem in one person with delusions. Capgras delusions have been associated with occipito-temporal damage, and may be related to failure to elicit normal emotions or memories in response to faces.[91] ### Negative symptoms[edit] This section may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (November 2019) (Learn how and when to remove this template message) Psychosis is associated with ventral striatal hypoactivity during reward anticipation and feedback. Hypoactivity in the left ventral striatum is correlated with the severity of negative symptoms.[92] While anhedonia is a commonly reported symptom in psychosis, hedonic experiences are actually intact in most people with schizophrenia. The impairment that may present itself as anhedonia probably actually lies in the inability to identify goals, and to identify and engage in the behaviors necessary to achieve goals.[93] Studies support a deficiency in the neural representation of goals and goal directed behavior by demonstrating that receipt (not anticipation) of reward is associated with a robust response in the ventral striatum; reinforcement learning is intact when contingencies about stimulus-reward are implicit, but not when they require explicit neural processing; reward prediction errors (during functional neuroimaging studies), particularly positive PEs are abnormal. A positive prediction error response occurs when there is an increased activation in a brain region, typically the striatum, in response to unexpected rewards. A negative prediction error response occurs when there is a decreased activation in a region when predicted rewards do not occur.[93] ACC response, taken as an indicator of effort allocation, does not increase with reward or reward probability increase, and is associated with negative symptoms; deficits in dlPFC activity and failure to improve performance on cognitive tasks when offered monetary incentives are present; and dopamine mediated functions are abnormal.[93] ### Neurobiology[edit] Further information: Dopamine hypothesis of schizophrenia This section may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (November 2019) (Learn how and when to remove this template message) Psychosis has been traditionally linked to the overactivity of the neurotransmitter dopamine. In particular to its effect in the mesolimbic pathway. The two major sources of evidence given to support this theory are that dopamine receptor D2 blocking drugs (i.e., antipsychotics) tend to reduce the intensity of psychotic symptoms, and that drugs that accentuate dopamine release, or inhibit its reuptake (such as amphetamines and cocaine) can trigger psychosis in some people (see stimulant psychosis).[94] NMDA receptor dysfunction has been proposed as a mechanism in psychosis.[95] This theory is reinforced by the fact that dissociative NMDA receptor antagonists such as ketamine, PCP and dextromethorphan (at large overdoses) induce a psychotic state. The symptoms of dissociative intoxication are also considered to mirror the symptoms of schizophrenia, including negative symptoms.[96] NMDA receptor antagonism, in addition to producing symptoms reminiscent of psychosis, mimics the neurophysiological aspects, such as reduction in the amplitude of P50, P300, and MMN evoked potentials.[97] Hierarchical Bayesian neurocomputational models of sensory feedback, in agreement with neuroimaging literature, link NMDA receptor hypofunction to delusional or hallucinatory symptoms via proposing a failure of NMDA mediated top down predictions to adequately cancel out enhanced bottom up AMPA mediated predictions errors.[98] Excessive prediction errors in response to stimuli that would normally not produce such a response is thought to root from conferring excessive salience to otherwise mundane events.[99] Dysfunction higher up in the hierarchy, where representation is more abstract, could result in delusions.[100] The common finding of reduced GAD67 expression in psychotic disorders may explain enhanced AMPA mediated signaling, caused by reduced GABAergic inhibition.[101][102] The connection between dopamine and psychosis is generally believed to be complex. While dopamine receptor D2 suppresses adenylate cyclase activity, the D1 receptor increases it. If D2-blocking drugs are administered, the blocked dopamine spills over to the D1 receptors. The increased adenylate cyclase activity affects genetic expression in the nerve cell, which takes time. Hence antipsychotic drugs take a week or two to reduce the symptoms of psychosis. Moreover, newer and equally effective antipsychotic drugs actually block slightly less dopamine in the brain than older drugs whilst also blocking 5-HT2A receptors, suggesting the 'dopamine hypothesis' may be oversimplified.[103] Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis[104] and Zoldan et al. reported moderately successful use of ondansetron, a 5-HT3 receptor antagonist, in the treatment of levodopa psychosis in Parkinson's disease patients.[105] A review found an association between a first-episode of psychosis and prediabetes.[106] Prolonged or high dose use of psychostimulants can alter normal functioning, making it similar to the manic phase of bipolar disorder.[107] NMDA antagonists replicate some of the so-called "negative" symptoms like thought disorder in subanesthetic doses (doses insufficient to induce anesthesia), and catatonia in high doses). Psychostimulants, especially in one already prone to psychotic thinking, can cause some "positive" symptoms, such as delusional beliefs, particularly those persecutory in nature. ## Diagnosis[edit] To make a diagnosis of a mental illness in someone with psychosis other potential causes must be excluded.[108] An initial assessment includes a comprehensive history and physical examination by a health care provider. Tests may be done to exclude substance use, medication, toxins, surgical complications, or other medical illnesses. A person with psychosis is referred to as psychotic. Delirium should be ruled out, which can be distinguished by visual hallucinations, acute onset and fluctuating level of consciousness, indicating other underlying factors, including medical illnesses.[109] Excluding medical illnesses associated with psychosis is performed by using blood tests to measure: * Thyroid-stimulating hormone to exclude hypo- or hyperthyroidism, * Basic electrolytes and serum calcium to rule out a metabolic disturbance, * Full blood count including ESR to rule out a systemic infection or chronic disease, and * Serology to exclude syphilis or HIV infection. Other investigations include: * EEG to exclude epilepsy, and an * MRI or CT scan of the head to exclude brain lesions. Because psychosis may be precipitated or exacerbated by common classes of medications, medication-induced psychosis should be ruled out, particularly for first-episode psychosis. Both substance- and medication-induced psychosis can be excluded to a high level of certainty, using toxicology screening. Because some dietary supplements may also induce psychosis or mania, but cannot be ruled out with laboratory tests, a psychotic individual's family, partner, or friends should be asked whether the patient is currently taking any dietary supplements.[110] Common mistakes made when diagnosing people who are psychotic include:[108] * Not properly excluding delirium, * Not appreciating medical abnormalities (e.g., vital signs), * Not obtaining a medical history and family history, * Indiscriminate screening without an organizing framework, * Missing a toxic psychosis by not screening for substances and medications, * Not asking their family or others about dietary supplements, * Premature diagnostic closure, and * Not revisiting or questioning the initial diagnostic impression of primary psychiatric disorder. Only after relevant and known causes of psychosis are excluded, a mental health clinician may make a psychiatric differential diagnosis using a person's family history, incorporating information from the person with psychosis, and information from family, friends, or significant others. Types of psychosis in psychiatric disorders may be established by formal rating scales. The Brief Psychiatric Rating Scale (BPRS)[111] assesses the level of 18 symptom constructs of psychosis such as hostility, suspicion, hallucination, and grandiosity. It is based on the clinician's interview with the patient and observations of the patient's behavior over the previous 2–3 days. The patient's family can also answer questions on the behavior report. During the initial assessment and the follow-up, both positive and negative symptoms of psychosis can be assessed using the 30 item Positive and Negative Symptom Scale (PANSS).[112] The DSM-5 characterizes disorders as psychotic or on the schizophrenia spectrum if they involve hallucinations, delusions, disorganized thinking, grossly disorganized motor behavior, or negative symptoms.[16] The DSM-5 does not include psychosis as a definition in the glossary, although it defines "psychotic features", as well as "psychoticism" with respect to personality disorder. The ICD-10 has no specific definition of psychosis.[113] Factor analysis of symptoms generally regarded as psychosis frequently yields a five factor solution, albeit five factors that are distinct from the five domains defined by the DSM-5 to encompass psychotic or schizophrenia spectrum disorders. The five factors are frequently labeled as hallucinations, delusions, disorganization, excitement, and emotional distress.[113] The DSM-5 emphasizes a psychotic spectrum, wherein the low end is characterized by schizoid personality disorder, and the high end is characterized by schizophrenia.[42] ## Prevention[edit] The evidence for the effectiveness of early interventions to prevent psychosis appeared inconclusive.[114] But psychosis caused by drugs can be prevented.[115] Whilst early intervention in those with a psychotic episode might improve short-term outcomes, little benefit was seen from these measures after five years.[116] However, there is evidence that cognitive behavioral therapy (CBT) may reduce the risk of becoming psychotic in those at high risk,[117] and in 2014 the UK National Institute for Health and Care Excellence (NICE) recommended preventive CBT for people at risk of psychosis.[118][119] ## Treatment[edit] The treatment of psychosis depends on the specific diagnosis (such as schizophrenia, bipolar disorder or substance intoxication). The first-line treatment for many psychotic disorders is antipsychotic medication,[120] which can reduce the positive symptoms of psychosis in about 7 to 14 days. For youth or adolescents, treatment options include medications, psychological interventions, and social interventions.[6] ### Medication[edit] The choice of which antipsychotic to use is based on benefits, risks, and costs.[116] It is debatable whether, as a class, typical or atypical antipsychotics are better.[121][122] Tentative evidence supports that amisulpride, olanzapine, risperidone and clozapine may be more effective for positive symptoms but result in more side effects.[123] Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages.[124] There is a good response in 40–50%, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two or three different antipsychotics) in 20% of people.[125] Clozapine is an effective treatment for those who respond poorly to other drugs ("treatment-resistant" or "refractory" schizophrenia),[126] but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count) in less than 4% of people.[116][127][128] Most people on antipsychotics get side effects. People on typical antipsychotics tend to have a higher rate of extrapyramidal side effects while some atypicals are associated with considerable weight gain, diabetes and risk of metabolic syndrome; this is most pronounced with olanzapine, while risperidone and quetiapine are also associated with weight gain.[123] Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.[123] ### Counseling[edit] Psychological treatments such as acceptance and commitment therapy (ACT) are possibly useful in the treatment of psychosis, helping people to focus more on what they can do in terms of valued life directions despite challenging symptomology.[129] There are psychological interventions that seek to treat the symptoms of psychosis. In a 2019 review, nine classes of psychosocial interventions were identified: need adapted treatment, open dialogue, psychoanalysis/psychodynamic psychotherapy, major role therapy, soteria, psychosocial outpatient and inpatient treatment, milieu therapy, and CBT. This paper concluded that when on minimal or no medication "the overall evidence supporting the effectiveness of these interventions is generally weak".[130] ### Early intervention[edit] Main article: Early intervention in psychosis Early intervention in psychosis is based on the observation that identifying and treating someone in the early stages of a psychosis can improve their longer term outcome.[131] This approach advocates the use of an intensive multi-disciplinary approach during what is known as the critical period, where intervention is the most effective, and prevents the long-term morbidity associated with chronic psychotic illness. ## History[edit] ### Etymology[edit] The word psychosis was introduced to the psychiatric literature in 1841 by Karl Friedrich Canstatt in his work Handbuch der Medizinischen Klinik. He used it as a shorthand for 'psychic neurosis'. At that time neurosis meant any disease of the nervous system, and Canstatt was thus referring to what was considered a psychological manifestation of brain disease.[132] Ernst von Feuchtersleben is also widely credited as introducing the term in 1845,[133] as an alternative to insanity and mania. The term stems from Modern Latin psychosis, "a giving soul or life to, animating, quickening" and that from Ancient Greek ψυχή (psyche), "soul" and the suffix -ωσις (-osis), in this case "abnormal condition".[134][135] In its adjective form "psychotic", references to psychosis can be found in both clinical and non-clinical discussions. However, in a non-clinical context, "psychotic" is generally used as a synonym for "insane". ### Classification[edit] The word was also used to distinguish a condition considered a disorder of the mind, as opposed to neurosis, which was considered a disorder of the nervous system.[136] The psychoses thus became the modern equivalent of the old notion of madness, and hence there was much debate on whether there was only one (unitary) or many forms of the new disease.[137] One type of broad usage would later be narrowed down by Koch in 1891 to the 'psychopathic inferiorities'—later renamed abnormal personalities by Schneider.[132] The division of the major psychoses into manic depressive illness (now called bipolar disorder) and dementia praecox (now called schizophrenia) was made by Emil Kraepelin, who attempted to create a synthesis of the various mental disorders identified by 19th-century psychiatrists, by grouping diseases together based on classification of common symptoms. Kraepelin used the term 'manic depressive insanity' to describe the whole spectrum of mood disorders, in a far wider sense than it is usually used today. In Kraepelin's classification this would include 'unipolar' clinical depression, as well as bipolar disorder and other mood disorders such as cyclothymia. These are characterised by problems with mood control and the psychotic episodes appear associated with disturbances in mood, and patients often have periods of normal functioning between psychotic episodes even without medication. Schizophrenia is characterized by psychotic episodes that appear unrelated to disturbances in mood, and most non-medicated patients show signs of disturbance between psychotic episodes. ### Treatment[edit] Early civilizations considered madness a supernaturally inflicted phenomenon. Archaeologists have unearthed skulls with clearly visible drillings, some datable back to 5000 BC suggesting that trepanning was a common treatment for psychosis in ancient times.[138] Written record of supernatural causes and resultant treatments can be traced back to the New Testament. Mark 5:8–13 describes a man displaying what would today be described as psychotic symptoms. Christ cured this "demonic madness" by casting out the demons and hurling them into a herd of swine. Exorcism is still utilized in some religious circles as a treatment for psychosis presumed to be demonic possession.[139] A research study of out-patients in psychiatric clinics found that 30 percent of religious patients attributed the cause of their psychotic symptoms to evil spirits. Many of these patients underwent exorcistic healing rituals that, though largely regarded as positive experiences by the patients, had no effect on symptomology. Results did, however, show a significant worsening of psychotic symptoms associated with exclusion of medical treatment for coercive forms of exorcism.[140] The medical teachings of the fourth-century philosopher and physician Hippocrates of Cos proposed a natural, rather than supernatural, cause of human illness. In Hippocrates' work, the Hippocratic corpus, a holistic explanation for health and disease was developed to include madness and other "diseases of the mind." Hippocrates writes: > Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs and tears. Through it, in particular, we think, see, hear, and distinguish the ugly from the beautiful, the bad from the good, the pleasant from the unpleasant…. It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings sleeplessness, inopportune mistakes, aimless anxieties, absentmindedness, and acts that are contrary to habit.[141] Hippocrates espoused a theory of humoralism wherein disease is resultant of a shifting balance in bodily fluids including blood, phlegm, black bile, and yellow bile.[142] According to humoralism, each fluid or "humour" has temperamental or behavioral correlates. In the case of psychosis, symptoms are thought to be caused by an excess of both blood and yellow bile. Thus, the proposed surgical intervention for psychotic or manic behavior was bloodletting.[143] 18th-century physician, educator, and widely considered "founder of American psychiatry", Benjamin Rush, also prescribed bloodletting as a first-line treatment for psychosis. Although not a proponent of humoralism, Rush believed that active purging and bloodletting were efficacious corrections for disruptions in the circulatory system, a complication he believed was the primary cause of "insanity".[144] Although Rush's treatment modalities are now considered antiquated and brutish, his contributions to psychiatry, namely the biological underpinnings of psychiatric phenomenon including psychosis, have been invaluable to the field. In honor of such contributions, Benjamin Rush's image is in the official seal of the American Psychiatric Association. Early 20th-century treatments for severe and persisting psychosis were characterized by an emphasis on shocking the nervous system. Such therapies include insulin shock therapy, cardiazol shock therapy, and electroconvulsive therapy.[145] Despite considerable risk, shock therapy was considered highly efficacious in the treatment of psychosis including schizophrenia. The acceptance of high-risk treatments led to more invasive medical interventions including psychosurgery.[146] In 1888, Swiss psychiatrist Gottlieb Burckhardt performed the first medically sanctioned psychosurgery in which the cerebral cortex was excised. Although some patients showed improvement of symptoms and became more subdued, one patient died and several developed aphasia or seizure disorders. Burckhardt would go on to publish his clinical outcomes in a scholarly paper. This procedure was met with criticism from the medical community and his academic and surgical endeavors were largely ignored.[147] In the late 1930s, Egas Moniz conceived the leucotomy (AKA prefrontal lobotomy) in which the fibers connecting the frontal lobes to the rest of the brain were severed. Moniz's primary inspiration stemmed from a demonstration by neuroscientists John Fulton and Carlyle's 1935 experiment in which two chimpanzees were given leucotomies and pre- and post-surgical behavior was compared. Prior to the leucotomy, the chimps engaged in typical behavior including throwing feces and fighting. After the procedure, both chimps were pacified and less violent. During the Q&A, Moniz asked if such a procedure could be extended to human subjects, a question that Fulton admitted was quite startling.[148] Moniz would go on to extend the controversial practice to humans suffering from various psychotic disorders, an endeavor for which he received a Nobel Prize in 1949.[149] Between the late 1930s and early 1970s, the leucotomy was a widely accepted practice, often performed in non-sterile environments such as small outpatient clinics and patient homes.[148] Psychosurgery remained standard practice until the discovery of antipsychotic pharmacology in the 1950s.[150] The first clinical trial of antipsychotics (also commonly known as neuroleptics) for the treatment of psychosis took place in 1952. Chlorpromazine (brand name: Thorazine) passed clinical trials and became the first antipsychotic medication approved for the treatment of both acute and chronic psychosis. Although the mechanism of action was not discovered until 1963, the administration of chlorpromazine marked the advent of the dopamine antagonist, or first generation antipsychotic.[151] While clinical trials showed a high response rate for both acute psychosis and disorders with psychotic features, the side effects were particularly harsh, which included high rates of often irreversible Parkinsonian symptoms such as tardive dyskinesia. With the advent of atypical antipsychotics (also known as second generation antipsychotics) came a dopamine antagonist with a comparable response rate but a far different, though still extensive, side-effect profile that included a lower risk of Parkinsonian symptoms but a higher risk of cardiovascular disease.[152] Atypical antipsychotics remain the first-line treatment for psychosis associated with various psychiatric and neurological disorders including schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia, and some autism spectrum disorders.[153] Dopamine is now one of the primary neurotransmitters implicated in psychotic symptomology. Blocking dopamine receptors (namely, the dopamine D2 receptors) and decreasing dopaminergic activity continues to be an effective but highly unrefined effect of antipsychotics, which are commonly used to treat psychosis. Recent pharmacological research suggests that the decrease in dopaminergic activity does not eradicate psychotic delusions or hallucinations, but rather attenuates the reward mechanisms involved in the development of delusional thinking; that is, connecting or finding meaningful relationships between unrelated stimuli or ideas.[94] The author of this research paper acknowledges the importance of future investigation: > The model presented here is based on incomplete knowledge related to dopamine, schizophrenia, and antipsychotics—and as such will need to evolve as more is known about these. > > — Shitij Kapur, From dopamine to salience to psychosis—linking biology, pharmacology and phenomenology of psychosis Freud's former student Wilhelm Reich explored independent insights into the physical effects of neurotic and traumatic upbringing, and published his holistic psychoanalytic treatment with a schizophrenic. With his incorporation of breathwork and insight with the patient, a young woman, she achieved sufficient self-management skills to end the therapy.[154] Lacan extended Freud's ideas to create a psychoanalytic model of psychosis based upon the concept of " foreclosure", the rejection of the symbolic concept of the father. ### Society[edit] Psychiatrist David Healy has criticised pharmaceutical companies for promoting simplified biological theories of mental illness that seem to imply the primacy of pharmaceutical treatments while ignoring social and developmental factors that are known important influences in the etiology of psychosis.[155] ## Research[edit] Further research in the form of randomized controlled trials is needed to determine the effectiveness of treatment approaches for helping adolescents with psychosis.[6] ## See also[edit] * Open Dialogue * Metacognitive training ## References[edit] 1. ^ Kelly, Evelyn B. (2001). Coping with schizophrenia (1st ed.). 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"Schizophrenia from Hippocrates to Kraepelin". Clinical Psychology: 259–277. doi:10.1007/978-1-4757-9715-2_10. ISBN 978-1-4757-9717-6. 144. ^ Rush B (1830). Medical Inquiries and Observations upon Diseases of the Mind. Philadelphia. pp. 98–190. ISBN 978-0-559-92167-4. 145. ^ Shorter, Edward (1998). A History of Psychiatry: From the Era of the Asylum to the Age of Prozac. Hoboken, New Jersey: John Wiley & Sons. ISBN 978-0-471-24531-5. 146. ^ Stone JL (March 2001). "Dr. Gottlieb Burckhardt--the pioneer of psychosurgery". Journal of the History of the Neurosciences. 10 (1): 79–92. doi:10.1076/jhin.10.1.79.5634. PMID 11446267. S2CID 29727830. 147. ^ Gross D, Schäfer G (February 2011). "Egas Moniz (1874-1955) and the "invention" of modern psychosurgery: a historical and ethical reanalysis under special consideration of Portuguese original sources". Neurosurgical Focus. 30 (2): E8. doi:10.3171/2010.10.FOCUS10214. PMID 21284454. 148. ^ a b Pressman JD (1998). Last Resort: Psychosurgery and the Limits of Medicine. Cambridge Studies in the History of Medicine. Cambridge, UK: Cambridge University Press. pp. 18–40. ISBN 978-0-521-35371-7. OCLC 36729044. 149. ^ Berrios GE (March 1997). "The origins of psychosurgery: Shaw, Burckhardt and Moniz". History of Psychiatry. 8 (29 pt 1): 61–81. doi:10.1177/0957154X9700802905. PMID 11619209. S2CID 22225524. 150. ^ Mashour GA, Walker EE, Martuza RL (June 2005). "Psychosurgery: past, present, and future". Brain Research. Brain Research Reviews. 48 (3): 409–19. doi:10.1016/j.brainresrev.2004.09.002. PMID 15914249. S2CID 10303872. 151. ^ Stip E (May 2002). "Happy birthday neuroleptics! 50 years later: la folie du doute". European Psychiatry. 17 (3): 115–9. doi:10.1016/S0924-9338(02)00639-9. PMID 12052571. 152. ^ Crossley NA, Constante M, McGuire P, Power P (June 2010). "Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: meta-analysis". The British Journal of Psychiatry. 196 (6): 434–9. doi:10.1192/bjp.bp.109.066217. PMC 2878818. PMID 20513851. 153. ^ Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, Wang Z, Timmer M, Sultzer D, Shekelle PG (September 2011). "Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis". JAMA. 306 (12): 1359–69. doi:10.1001/jama.2011.1360. PMID 21954480. 154. ^ Reich, Wilhelm, Character Analysis, 437 155. ^ Healy D (2002). The Creation of Psychopharmacology. Cambridge: Harvard University Press. ISBN 978-0-674-00619-5. ## Further reading[edit] * Sims A (2002). Symptoms in the mind: An introduction to descriptive psychopathology (3rd ed.). Edinburgh: Elsevier Science Ltd. ISBN 978-0-7020-2627-0. * Murray ED, Buttner N, Price BH (April 2012). "Depression and Psychosis in Neurological Practice". In Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.). Neurology in Clinical Practice (6th ed.). Butterworth Heinemann. ISBN 978-1-4377-0434-1. * Williams P (2012). Rethinking Madness: Towards a Paradigm Shift In Our Understanding and Treatment of Psychosis. Sky’s Edge Publishing. ISBN 978-0-9849867-0-5. Personal accounts * Dick PK (1981). VALIS. London: Gollancz. ISBN 978-0-679-73446-8. [Semi-autobiographical] * Jamison KR (1995). An Unquiet Mind: A Memoir of Moods and Madness. London: Picador. ISBN 978-0-679-76330-7. * Schreber DP (2000). Memoirs of My Nervous Illness. New York: New York Review of Books. ISBN 978-0-940322-20-2. * Hinshaw SP (2002). The Years of Silence are Past: My Father's Life with Bipolar Disorder. Cambridge: Cambridge University Press. * McLean R (2003). Recovered Not Cured: A Journey Through Schizophrenia. Australia: Allen & Unwin. ISBN 978-1-86508-974-4. * Saks ER (2007). The Center Cannot Hold—My Journey Through Madness. New York: Hyperion. ISBN 978-1-4013-0138-5. ## External links[edit] Classification D * ICD-10: F20-F29 * ICD-9-CM: 290-299 * OMIM: 603342 * MeSH: D011618 External resources * MedlinePlus: 001553 Wikimedia Commons has media related to Psychosis. 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* Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Psychosis	c0033975	2,214	wikipedia	https://en.wikipedia.org/wiki/Psychosis	2021-01-18T18:51:57	{"mesh": ["D011618"], "umls": ["C0033975"], "icd-10": ["F23", "F28", "F22", "F29", "F20", "F27", "F25", "F24", "F21", "F26"], "wikidata": ["Q170082"]}
A number sign (#) is used with this entry because propionic acidemia is caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA (232000) or PCCB (232050). Cells from patients with mutations in the PCCA gene fall into complementation group pccA. Cells from patients with mutations in the PCCB gene fall into complementation group pccBC. Mutations in the pccB subgroup occur in the N terminus of the PCCB gene, which includes the biotin-binding site, whereas mutations in the pccC subgroup occur in the C terminus of the PCCB gene (Fenton et al., 2001). Clinical Features The features of propionic acidemia are episodic vomiting, lethargy and ketosis, neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, and intolerance to protein. Outstanding chemical features are hyperglycinemia and hyperglycinuria. This disorder is not to be confused with hereditary glycinuria (138500), which is presumably transmitted as a dominant. Soriano et al. (1967) suggested that in the disorder first described by Childs et al. (1961), a generalized defect in utilization of amino acids results in excessive deamination of certain amino acids in muscle, with consequent hyperammonemia and ketoacidosis. In a second group of patients whose disorder is also termed hyperglycinemia, ketoacidosis, neutropenia, and thrombocytopenia have not been observed and glycine is the only amino acid present in excess in serum and urine; see glycine encephalopathy (605899). Hsia et al. (1969) studied fibroblasts from a sister of the boy described by Childs et al. (1961) and demonstrated deficient propionate carboxylation as the basic defect in ketotic hyperglycinemia. Hsia et al. (1971) also showed that 'ketotic hyperglycinemia' is the same as propionic acidemia and is the result of a defect in PCC. In further studies on this patient, Brandt et al. (1974) demonstrated that with low protein diet, growth and intelligence developed normally to age 9 years; indeed, intelligence was superior. The family originally reported by Childs et al. (1961) had the pccA type of propionic acidemia (Wolf, 1986). In a male Pakistani offspring of first-cousin parents, Gompertz et al. (1970) described acidosis and ketosis due to propionic acidemia, leading to death at 8 days of age. A sib had died at 2 weeks of age with metabolic acidosis and ketonuria. The defect was found to involve mitochondrial propionyl-CoA carboxylase. The same condition was described by Hommes et al. (1968). Al Essa et al. (1998) pointed out that not only do acute intercurrent infections precipitate acidosis in propionic acidemia, but such infections are unusually frequent in propionic acidemia in Saudi Arabia. Propionic acidemia is unusually frequent in Saudi Arabia, with a frequency of 1 in 2,000 to 1 in 5,000, depending on the region. The disorder has a severe phenotype in Saudi Arabia. Al Essa et al. (1998) had information on approximately 90 patients; certain tribes accounted for almost 80% of these cases, suggesting a founder effect. The number of other cases of organic acidemias observed during the same period was 656. Longitudinal data, in some instances up to 8 years, were available for 38 patients with propionic acidemia. A high frequency of infections was observed in 80% of the patients. Most microorganisms implicated were unusual, suggesting an underlying immune deficiency. The infections occurred despite aggressive treatment with appropriate diets, carnitine, and, during acute episodes of the disease, with metronidazole, which suggested a global effect of the disease on T and B lymphocytes as well as on the bone marrow cells. In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with branched-chain organic aciduria, including isovaleric aciduria (243500), propionic aciduria, and methylmalonic aciduria (251000) can rarely have strokes. Cerebellar hemorrhage has been described in all 3 disorders, and basal ganglia ischemic stroke has been described in propionic aciduria and methylmalonic aciduria. These events may occur in the absence of metabolic decompensation. Biochemical Features Hillman et al. (1978) observed biotin-responsive propionic acidemia. Wolf and Hsia (1978) suggested that biotin-responsiveness can be tested by measuring propionyl-CoA carboxylase and beta-methylcrotonyl CoA carboxylase (see 609010 and 609014) in peripheral blood leukocytes before and after biotin. From kinetic analysis of complementations in heterokaryons of propionyl CoA carboxylase-deficient fibroblasts, Wolf et al. (1980) concluded that the 'bio' and 'pcc' mutations affect different genes; that complementation between pccA and pccB, pccC or pccBC lines is intergenic with subunit exchange and synthesis of new carboxylase molecules and that complementation between pccB and pccC mutants is interallelic. Wolf and Feldman (1982) considered it likely that the pccBC complementation group reflects mutations of the alpha subunit and the pccA group mutations of the beta subunit. Using cDNA clones coding for the alpha and beta chains as probes, Lamhonwah and Gravel (1987) found absence of alpha mRNA in 4 of 6 pccA strains and the presence of beta mRNA in all pccA mutants studied. They also found the presence of both alpha and beta mRNAs in 3 pccBC, 2 pccB, and 3 pccC mutants. Ohura et al. (1989) presented evidence from which they concluded that beta-chain subunits of propionyl-CoA carboxylase are normally synthesized and imported into the mitochondria in excess of alpha-chain subunits, but only that portion assembled with alpha subunits escapes degradation. In pccA patients, the primary defect in alpha-chain synthesis leads secondarily to degradation of normally synthesized beta chains. The differential rates of synthesis of alpha and beta chains appear to account for the finding that persons heterozygous for pccBC mutations have normal carboxylase activity in their cells. Among 15 Japanese patients with propionic acidemia, Ohura et al. (1991) found that both the alpha and beta subunits were absent in 3 and low in 3 others; according to their previous data, they concluded that these 6 patients had an alpha-subunit defect. In 8 other patients, alpha subunits were normal, but the beta subunits were aberrant; these patients were considered to have beta-subunit defects. One of the 15 patients had apparently normal alpha and beta subunits. An altered MspI restriction pattern for PCCB cDNA, consisting of a unique 2.7-kb band, was found in 3 patients with beta-subunit deficiency. Diagnosis ### Prenatal Diagnosis Buchanan et al. (1980) pointed out that propionic acidemia can be diagnosed either by an elevated quantity of the metabolite methylcitrate in amniotic fluid or by deficient activity of propionyl-CoA carboxylase in amniocytes. Contamination by maternal cells can give a normal value for the latter determination; methylcitrate assay may be the most reliable approach. Perez-Cerda et al. (1989) successfully diagnosed PCC deficiency in the first trimester of pregnancy by direct enzyme assay in uncultured chorionic villi. Muro et al. (1999) reported prenatal diagnosis of an affected fetus based on DNA analysis in chorionic villus tissue in a family where the proband had previously been shown to carry the 1170insT mutation (232050.0004) and a private leu519-to-pro (L519P) mutation in the PCCB gene. Muro et al. (1999) also assessed carrier status in this family by DNA analysis. Clinical Management The severe metabolic ketoacidosis in this disorder requires vigorous alkali therapy and protein restriction. Oral antibiotic therapy to reduce gut propionate production may also prove useful (Fenton et al., 2001). Van Calcar et al. (1992) described a 22-year-old woman whose first episode of acute acidosis occurred at age 6 months following an upper respiratory infection; diagnosis of propionic acidemia was delayed until the age of 6.5 years. They gave detailed information on her pregnancy, which resulted in the birth of a healthy infant. Molecular Genetics Ugarte et al. (1999) reviewed mutations in the PCCA and PCCB genes. A total of 24 PCCA mutations had been reported, mostly missense point mutations and a variety of splicing defects. No mutation was predominant in the Caucasian or Oriental populations studied. Among 10 patients with propionic acidemia, Desviat et al. (2006) identified 4 different PCCA splice site mutations and 3 different PCCB splice site mutations. The authors emphasized the different molecular effects of splicing mutations and the possible phenotypic consequences. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive CARDIOVASCULAR Heart \- Cardiomyopathy RESPIRATORY \- Tachypnea \- Apnea ABDOMEN Liver \- Hepatomegaly Pancreas \- Pancreatitis Gastrointestinal \- Decreased appetite \- Feeding difficulties \- Vomiting \- Dehydration SKELETAL \- Osteoporosis SKIN, NAILS, & HAIR Skin \- Dermatitis acidemica NEUROLOGIC Central Nervous System \- Acute encephalopathy \- Lethargy \- Axial hypotonia \- Limb hypertonia \- Coma \- Seizure \- Psychomotor retardation \- Cerebral atrophy \- Dystonia \- Cerebellar hemorrhage (rare) \- Ischemic stroke in the basal ganglia (rare) METABOLIC FEATURES \- Metabolic acidosis HEMATOLOGY \- Pancytopenia \- Neutropenia \- Anemia \- Thrombocytopenia LABORATORY ABNORMALITIES \- Hyperammonemia \- Lactic acidosis \- Elevated propionate \- Elevated 3-hydroxypropionic acid \- Elevated 3-methylcitric acid \- Hyperglycinemia \- Hyperglycinuria \- Serum carnitine deficiency \- Propionyl-CoA carboxylase deficiency \- Hypoglycemia MISCELLANEOUS \- Majority of patients develop symptoms within the first few weeks of life \- Two complementation groups - pccA (secondary to defects in the alpha chain of PCC, 232000 ) and pccBC (secondary to defects in the beta subunit of PCC, 232050 ) \- Course characterized by repeated relapses precipitated by excessive protein intake, intercurrent infection, or constipation MOLECULAR BASIS \- Caused by mutation in the propionyl Coenzyme A carboxylase, alpha polypeptide gene (PCCA, 232000.0001 ) \- Caused by mutation in the propionyl Coenzyme A carboxylase, beta polypeptide gene (PCCB, 232050.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PROPIONIC ACIDEMIA	c0268579	2,215	omim	https://www.omim.org/entry/606054	2019-09-22T16:10:44	{"doid": ["14701"], "mesh": ["D056693"], "omim": ["606054"], "icd-10": ["E71.121"], "orphanet": ["35"], "synonyms": ["Alternative titles", "PROPIONYL-CoA CARBOXYLASE DEFICIENCY", "PCC DEFICIENCY", "GLYCINEMIA, KETOTIC", "HYPERGLYCINEMIA WITH KETOACIDOSIS AND LEUKOPENIA", "KETOTIC HYPERGLYCINEMIA"], "genereviews": ["NBK92946"]}
A subtype of type 2 von Willebrand disease characterized by a bleeding disorder associated with a decrease in the affinity of the Willebrand factor (VWF) for platelets and the subendothelium caused by a deficiency of high molecular weight VWF multimers. The disease manifests as mucocutaneous bleeding (menorrhagia, epistaxis, gastrointestinal hemorrhage etc.). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Von Willebrand disease type 2A	c1282968	2,216	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166084	2021-01-23T19:12:46	{"mesh": ["D056728"], "omim": ["613554"], "umls": ["C1282968"], "icd-10": ["D68.0"]}
Parks et al. (1978) described this combination in 2 sisters and a brother, the only children of nonconsanguineous parents. Basal thyrotropin levels were low despite hypothyroidism, and increased little after injection of thyrotropin-releasing hormone. Stimulated growth hormone levels were less than 5 nanograms per milliliter. Treatment with both thyroxine and growth hormone was necessary for rapid growth. The findings were judged compatible with either familial neoplasia of the anterior pituitary or a regulatory defect promoting hyperplasia and inhibiting hormone release. Endocrine \- Pituitary dwarfism \- Hypothyroidism Growth \- Growth retardation Lab \- Deficient production of growth hormone and TSH \- Poor thyrotropin response to thyrotropin-releasing hormone \- Low response to growth hormone stimulation Radiology \- Large sella turcica Inheritance \- Autosomal recessive \- ? familial anterior pituitary neoplasia or a regulatory defect promoting hyperplasia and inhibiting hormone release ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PITUITARY DWARFISM WITH LARGE SELLA TURCICA	c0271575	2,217	omim	https://www.omim.org/entry/262710	2019-09-22T16:23:19	{"mesh": ["C562705"], "omim": ["262710"]}
Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin. Individuals with neuroblastoma may develop general signs and symptoms such as irritability, fever, tiredness (fatigue), pain, loss of appetite, weight loss, or diarrhea. More specific signs and symptoms depend on the location of the tumor and where it has spread. A tumor in the abdomen can cause abdominal swelling. A tumor in the chest may lead to difficulty breathing. A tumor in the neck can cause nerve damage known as Horner syndrome, which leads to drooping eyelids, small pupils, decreased sweating, and red skin. Tumor metastasis to the bone can cause bone pain, bruises, pale skin, or dark circles around the eyes. Tumors in the backbone can press on the spinal cord and cause weakness, numbness, or paralysis in the arms or legs. A rash of bluish or purplish bumps that look like blueberries indicates that the neuroblastoma has spread to the skin. In addition, neuroblastoma tumors can release hormones that may cause other signs and symptoms such as high blood pressure, rapid heartbeat, flushing of the skin, and sweating. In rare instances, individuals with neuroblastoma may develop opsoclonus myoclonus syndrome, which causes rapid eye movements and jerky muscle motions. This condition occurs when the immune system malfunctions and attacks nerve tissue. Neuroblastoma occurs most often in children before age 5 and rarely occurs in adults. ## Frequency Neuroblastoma is the most common cancer in infants younger than 1 year. It occurs in 1 in 100,000 children and is diagnosed in about 650 children each year in the United States. ## Causes Neuroblastoma and other cancers occur when a buildup of genetic mutations in critical genes—those that control cell growth and division (proliferation) or maturation (differentiation)—allow cells to grow and divide uncontrollably to form a tumor. In most cases, these genetic changes are acquired during a person's lifetime and are called somatic mutations. Somatic mutations are present only in certain cells and are not inherited. When neuroblastoma is associated with somatic mutations, it is called sporadic neuroblastoma. It is thought that somatic mutations in at least two genes are required to cause sporadic neuroblastoma. Less commonly, gene mutations that increase the risk of developing cancer can be inherited from a parent. When the mutation associated with neuroblastoma is inherited, the condition is called familial neuroblastoma. Mutations in the ALK and PHOX2B genes have been shown to increase the risk of developing sporadic and familial neuroblastoma. It is likely that there are other genes involved in the formation of neuroblastoma. Several mutations in the ALK gene are involved in the development of sporadic and familial neuroblastoma. The ALK gene provides instructions for making a protein called ALK receptor tyrosine kinase. Although the specific function of this protein is unknown, it appears to play an important role in cell proliferation. Mutations in the ALK gene result in an abnormal version of ALK receptor tyrosine kinase that is constantly turned on (constitutively activated). Constitutively active ALK receptor tyrosine kinase may induce abnormal proliferation of immature nerve cells and lead to neuroblastoma. Several mutations in the PHOX2B gene have been identified in sporadic and familial neuroblastoma. The PHOX2B gene is important for the formation and differentiation of nerve cells. Mutations in this gene are believed to interfere with the PHOX2B protein's role in promoting nerve cell differentiation. This disruption of differentiation results in an excess of immature nerve cells and leads to neuroblastoma. Deletion of certain regions of chromosome 1 and chromosome 11 are associated with neuroblastoma. Researchers believe the deleted regions in these chromosomes could contain a gene that keeps cells from growing and dividing too quickly or in an uncontrolled way, called a tumor suppressor gene. When a tumor suppressor gene is deleted, cancer can occur. The KIF1B gene is a tumor suppressor gene located in the deleted region of chromosome 1, and mutations in this gene have been identified in some people with familial neuroblastoma, indicating it is involved in neuroblastoma development or progression. There are several other possible tumor suppressor genes in the deleted region of chromosome 1. No tumor suppressor genes have been identified in the deleted region of chromosome 11. Another genetic change found in neuroblastoma is associated with the severity of the disease but not thought to cause it. About 25 percent of people with neuroblastoma have extra copies of the MYCN gene, a phenomenon called gene amplification. It is unknown how amplification of this gene contributes to the aggressive nature of neuroblastoma. ### Learn more about the genes and chromosomes associated with Neuroblastoma * ALK * KIF1B * MYCN * PHOX2B * chromosome 1 * chromosome 11 Additional Information from NCBI Gene: * BARD1 * ERBB2 * LMO1 ## Inheritance Pattern Most people with neuroblastoma have sporadic neuroblastoma, meaning the condition arose from somatic mutations in the body's cells and was not inherited. About 1 to 2 percent of affected individuals have familial neuroblastoma. This form of the condition has an autosomal dominant inheritance pattern, which means one copy of the altered gene in each cell increases the risk of developing the disorder. However, the inheritance is considered to have incomplete penetrance because not everyone who inherits the altered gene from a parent develops neuroblastoma. Having the altered gene predisposes an individual to develop neuroblastoma, but an additional somatic mutation is probably needed to cause the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Neuroblastoma	c2749485	2,218	medlineplus	https://medlineplus.gov/genetics/condition/neuroblastoma/	2021-01-27T08:25:08	{"gard": ["7185"], "omim": ["256700", "613013", "613014"], "synonyms": []}
Alphaarterivirus equid Virus classification (unranked): Virus Realm: Riboviria Kingdom: Orthornavirae Phylum: Pisuviricota Class: Pisoniviricetes Order: Nidovirales Family: Arteriviridae Subfamily: Equarterivirinae Genus: Alphaarterivirus Species: Alphaarterivirus equid Equine viral arteritis (EVA) is a disease of horses caused by a virus of the species Alphaarterivirus equid, an RNA virus.[1][2] It is the only species in the genus Alphaarterivirus, and that is the only genus in the Equarterivirinae subfamily. The virus which causes EVA was first isolated in 1953, but the disease has afflicted equine animals worldwide for centuries. It has been more common in some breeds of horses in the United States, but there is no breed "immunity". In the UK, it is a notifiable disease.[3] There is no known human hazard.[4] ## Contents * 1 Signs * 2 Cause * 3 Diagnosis * 4 Prevention * 5 Research * 6 History * 7 See also * 8 References * 9 External links ## Signs[edit] The signs shown depend on the horse's age, the strain of the infecting virus, the condition of the horse and the route by which it was infected.[5] Most horses with EVA infection do not show any signs; if a horse does show signs, these can vary greatly in severity.[6] Following infection, the first sign is fever,[7] peaking at 41 °C (106 °F),[8] followed by various signs such as lethargy,[7] nasal discharge,[8] "pink eye" (conjunctivitis),[7] swelling over the eye (supraorbital edema),[7] urticaria,[4] and swelling of the limbs and under the belly (the ventral abdomen) which may extend to the udder in mares or the scrotum of male horses.[8] More unusual signs include spontaneous abortion in pregnant mares, and, most likely in foals,[8] severe respiratory distress and death.[4] ## Cause[edit] EVA is caused by an arterivirus called equine arteritis virus (EAV). Arteriviruses are small, enveloped, animal viruses with an icosahedral core containing a positive-sense RNA genome. As well as equine arteritis virus the Arterivirus family includes porcine reproductive and respiratory syndrome virus (PRRSV), lactate dehydrogenase elevating virus (LDV) of mice and simian haemorrhagic fever virus (SHFV).[2] There are a number of routes of transmission of the virus. The most frequent is the respiratory route. Virions can also be shed into the semen, and the disease has been spread by artificial insemination. Stallions may become carriers.[1][3] ## Diagnosis[edit] Because of the variability of symptoms, diagnosis is by laboratory testing. Blood samples, nasal swabs and semen can be used for isolation of the virus, detection of the viral RNA by reverse transcriptase polymerase chain reaction and detection of antibodies by ELISA tests.[1][3][9] ## Prevention[edit] A vaccine is available in the UK and Europe, however in laboratory tests it is not possible to distinguish between antibodies produced as a result of vaccination and those produced in response to infection with the virus. Management also plays an important part in the prevention of EVA.[1][3] ## Research[edit] Zinc ionophores show antiviral activity against Equine viral arteritis.[10] ## History[edit] The virus causing EVA was first identified following an outbreak of respiratory disease and spontaneous abortion on a horse farm in Ohio in 1953.[5] The first outbreak of EVA in the UK was in 1993. The outbreak affected six premises and around 100 horses were infected. Further spread of the virus was prevented by movement restrictions.[11] ## See also[edit] * Equine arteritis virus leader TRS hairpin (LTH) * Virology * Ionophore ## References[edit] 1. ^ a b c d "Equine Viral Arteritis: Introduction". The Merck Veterinary Manual. 2006. Retrieved 2007-06-25. 2. ^ a b Balasuriya & Snijder (2008). "Arteriviruses". Animal Viruses: Molecular Biology. Caister Academic Press. ISBN 978-1-904455-22-6. 3. ^ a b c d "Defra, UK - Disease surveillance and control - Notifiable diseases - Equine Viral Arteritis". Archived from the original on 2010-11-15. 4. ^ a b c van der Kolk, JH; Veldhuis Kroeze, EJB (2013). "Equine arteritis virus". Infectious diseases of the horse diagnosis, pathology, management and public health. London: Manson Publishing Ltd. pp. 144–147. ISBN 9781840766240. 5. ^ a b Balasuriya, UB (December 2014). "Equine viral arteritis". The Veterinary Clinics of North America. Equine Practice. 30 (3): 543–60. doi:10.1016/j.cveq.2014.08.011. PMID 25441113. 6. ^ Minke, JM; Audonnet, JC; Fischer, L (2004). "Equine viral vaccines: the past, present and future". Veterinary Research. 35 (4): 425–43. doi:10.1051/vetres:2004019. PMID 15236675. 7. ^ a b c d Maclachlan, NJ; Dubovi, EJ, eds. (2010). "Equine arteritis virus". Fenner's Veterinary Virology (5th ed.). Academic Press. pp. 467–471. ISBN 9780128011706. 8. ^ a b c d Sellon, DC; Long, M (2013). "Chapter 15: Equine viral arteritis". Equine infectious diseases (2nd ed.). Elsevier Health Sciences. ISBN 9781455751150. 9. ^ "Animal Health Trust". 10. ^ te Velthuis, Aartjan J. W.; van den Worm, Sjoerd H. E.; Sims, Amy C.; Baric, Ralph S.; Snijder, Eric J.; van Hemert, Martijn J.; Andino, Raul (4 November 2010). "Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture". PLOS Pathogens. 6 (11): e1001176. doi:10.1371/journal.ppat.1001176. PMID 21079686. 11. ^ Wood JL, Chirnside ED, Mumford JA, Higgins AJ (April 1995). "First recorded outbreak of equine viral arteritis in the United Kingdom". Vet. Rec. 136 (15): 381–5. doi:10.1136/vr.136.15.381. PMID 7604517. S2CID 6648131. ## External links[edit] * The short film Equine Viral Arteritis (EVA) - A Manageable Problem is available for free download at the Internet Archive Taxon identifiers Alphaarterivirus equid * Wikidata: Q57758308 * NCBI: 2499620 Equine arteritis virus * Wikidata: Q18844364 * Wikispecies: Equine arteritis virus * EoL: 741075 * IRMNG: 11459758 * NCBI: 11047 Alphaarterivirus * Wikidata: Q57753807 * NCBI: 2499610 Equarterivirinae * Wikidata: Q57751690 * NCBI: 2499604 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Equine viral arteritis	c0276313	2,219	wikipedia	https://en.wikipedia.org/wiki/Equine_viral_arteritis	2021-01-18T18:43:01	{"wikidata": ["Q552059"]}
Tietz syndrome is a genetic hypopigmentation and deafness syndrome characterized by congenital profound bilateral sensorineural hearing loss and generalized albino-like hypopigmentation of skin, eyes and hair. ## Epidemiology Tietz syndrome has been reported in 7 families to date. ## Clinical description Affected cases have a pale skin, blue eyes and light blond to white hair with white eyebrows and eyelashes. They gradually gain some pigmentation often as freckles on sun-exposed areas. Hearing loss is always bilateral, congenital, sensorineural and profound. Psychomotor development is normal. ## Etiology The syndrome is due to a missense mutation or in-frame deletion of one amino acid in the basic domain of the MITF (3p14-p13) gene, coding a basic helix-loop-helix (bHLH) leucine zipper transcription factor, regulating melanocyte development and the biosynthetic melanin pathway. However, these types of mutations give rise to variable phenotype, ranging from Tietz syndrome to Waardenburg syndrome type 2 (see this term), with possible interactions with modifier loci. ## Genetic counseling Tietz syndrome is an autosomal dominant syndrome. Genetic counseling is recommended. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Tietz syndrome	c0391816	2,220	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=42665	2021-01-23T17:32:14	{"gard": ["7772"], "mesh": ["C536919"], "omim": ["103500"], "umls": ["C0391816"], "synonyms": ["Hypopigmentation-deafness syndrome", "Hypopigmentation-hearing loss syndrome"]}
A number sign (#) is used with this entry because of evidence that congenital muscular dystrophy with cataracts and intellectual disability (MDCCAID) is caused by homozygous or compound heterozygous mutation in the INPP5K gene (607875) on chromosome 17p13. Description MDCCAID is an autosomal recessive form of muscular dystrophy with onset of progressive muscle weakness in early childhood. Almost all patients also have early-onset cataracts, most have intellectual disability of varying severity, and some have seizures (summary by Wiessner et al., 2017 and Osborn et al., 2017). Clinical Features Wiessner et al. (2017) reported 12 patients from 8 unrelated families with congenital muscular dystrophy. The patients ranged in age from 6 to 37 years, and 5 of the families were consanguineous. Most patients presented with hypotonia at birth, although a few presented with global or motor developmental delay in the first years of life; 2 presented with early-onset cataracts. Features included delayed motor milestones, hypotonia with muscle weakness and atrophy affecting the proximal muscles more than the distal muscles, and the lower limbs more than the upper limbs, resulting in gait difficulties. The muscle weakness tended to stabilize for several years, but motor capabilities deteriorated, and most patients became wheelchair-bound in adulthood. Five patients developed respiratory compromise; none had cardiac involvement. Eight patients had mild cognitive deficits, but 4 had normal intelligence. More variable features found in some patients included contractures, scoliosis, spinal rigidity, hyperlaxity, and seizures. Laboratory studies showed increased serum creatine kinase, and muscle biopsies showed nonspecific dystrophic changes, such as increased fiber size variation, fibrosis, increased adipose tissue, and some internal nuclei. Three biopsies showed small vacuoles. Electron microscopy of 2 patient biopsies showed reduction of myofibrils and disrupted Z-lines. EMG studies in 3 patients were consistent with a myopathic process. Wiessner et al. (2017) noted the phenotypic similarities to Marinesco-Sjogren syndrome (MSS; 248800). Osborn et al. (2017) reported 5 patients, including 2 sisters born of consanguineous Arab parents, with congenital muscular dystrophy. The patients showed delayed psychomotor development in infancy with difficulty walking due to proximal muscle weakness. Three patients were wheelchair-bound at ages 13, 21, and 31 years. Four patients showed spasticity of the lower limbs, with spastic gait, hyperreflexia, pyramidal signs, and toe walking. Three patients had cataracts, and 3 had strabismus. Additional features included muscle atrophy, short stature, hyperlordosis, Gowers sign, inability to climb stairs, and hypotonia and hyporeflexia of the upper limbs; 3 patients had seizures and 4 had microcephaly. Muscle biopsies showed fiber size variability, increased connective tissue, and atrophic fibers. Muscle biopsy in 2 unrelated patients showed decreased glycosylation of alpha-DAG (128239), reminiscent of dystroglycanopathies (see, e.g., MDDGC1, 609308). Laboratory studies showed increased serum creatine kinase. Inheritance The transmission pattern of MDCCAID in the families reported by Wiessner et al. (2017) and Osborn et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 12 patients from 8 unrelated families with MDCCAID, Wiessner et al. (2017) identified homozygous or compound heterozygous mutations in the INPP5K gene (see, e.g., 607875.0001 and 607875.0002). Patients from 6 families of Bangladeshi or Pakistani origin, 5 of which were consanguineous, carried the same homozygous missense mutation (I50T; 607875.0001). The mutations in the first family were found by a combination of linkage analysis and whole-exome sequencing. Mutations in 6 additional families were found by Sanger sequencing of the INPP5K gene in 12 families with the disorder; the mutations in the last family were found by Sanger sequencing of 21 isolated cases with a similar phenotype. In vitro studies showed that all the mutations resulted in a significant decrease in enzyme activity. Patient cells did not show evidence of the endoplasmic reticulum (ER) unfolded protein response or of increased autophagy in skeletal muscle, suggesting another pathogenic mechanism. In 5 patients from 4 unrelated families with MDCCAID, Osborn et al. (2017) identified homozygous or compound heterozygous mutations in the INPP5K gene (607875.0003-607875.0007). The mutations were found by exome sequencing, and in vitro studies showed that all resulted in a significant decrease in enzyme activity. Animal Model Wiessner et al. (2017) found that morpholino knockdown of the inpp5k orthologs in zebrafish embryos resulted in curled and shortened tails, impaired swimming and touch-evoked escape responses, and smaller eyes compared to controls. Skeletal muscle morphology in mutant fish was also abnormal, including disruption of both slow- and fast-twitch fiber types. Osborn et al. (2017) found that morpholino knockdown of inpp5k orthologs in zebrafish embryos resulted in microphthalmia, microcephaly, curved and shortened body, and reduced touch-evoked motility. Morphant eyes showed disorganized lens cortex with cell nuclei present in the center of the lens nucleus. Skeletal muscle fibers were disorganized and showed reduced synaptic formation at the neuromuscular junction. Electron microscopy of morphant skeletal muscle showed undefined A- and I-bands, shortened sarcomeres with smaller sarcomeric triads, and loose myofibrils. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly (in some patients) Eyes \- Cataracts \- Strabismus RESPIRATORY \- Respiratory insufficiency (in some patients) SKELETAL Spine \- Spinal rigidity \- Scoliosis \- Hyperlordosis MUSCLE, SOFT TISSUES \- Muscle weakness, proximal greater than distal \- Hypotonia \- Gower sign \- Dystrophic changes seen on muscle biopsy \- Increased fiber size variability \- Increased adipose tissue \- Occasional small vacuoles \- Decreased myofibrils \- Disrupted Z-lines NEUROLOGIC Central Nervous System \- Global developmental delay \- Delayed motor development \- Intellectual disability (in most patients) \- Abnormal gait \- Toe walking \- Seizures (in some patients) \- Lower limb spasticity (in some patients) \- Hyperreflexia of the lower limbs (in some patients) LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Onset at birth or early infancy \- Progressive disorder \- Many patients become wheelchair-bound as adults MOLECULAR BASIS \- Caused by mutation in the inositol polyphosphate-5-phosphatase K gene (INPP5K, 607875.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	MUSCULAR DYSTROPHY, CONGENITAL, WITH CATARACTS AND INTELLECTUAL DISABILITY	c4479410	2,221	omim	https://www.omim.org/entry/617404	2019-09-22T15:45:52	{"omim": ["617404"]}
Exogenous ochronosis (EO) refers to the bluish-black discoloration of areas of the skin, especially the face, ear cartilage, the ocular (eye) tissue, and other body locations. It occurs as the result of exposure to malarial drugs, skin lightening creams and over-exposure the the sun. Other than the skin discoloration, there are no other health effects. EO does not typically appear until adulthood and may be difficult to diagnose. There is no specific treatment for this condition. Treatment options exist, and include prescription skin creams, vitamins, laser treatments and other skin treatments. Exogenous ochronosis is different from hereditary ochronosis, which is an inherited condition that occurs with alkaptonuria. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Exogenous ochronosis	c1444199	2,222	gard	https://rarediseases.info.nih.gov/diseases/10757/exogenous-ochronosis	2021-01-18T18:00:38	{"mesh": ["C531762"], "synonyms": ["Ochronosis, acquired"]}
A number sign (#) is used with this entry because of evidence that perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA) is caused by compound heterozygous mutation in the PI4KA gene (600286) on chromosome 22q11. One such family has been reported. Clinical Features Pagnamenta et al. (2015) reported a family in which 3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers. Three had micrognathia and 2 had dolichocephaly. Muscle histology was reported to be within normal limits. The fetuses were conceived by nonconsanguineous parents of European ancestry; the parents had had 3 early miscarriages in addition to the affected fetuses. Inheritance The transmission pattern of perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis in the family reported by Pagnamenta et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with PMGYCHA, Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene (R796X, 600286.0001 and D1854N, 600286.0002). The mutations, which were found by a combination of exome sequencing and linkage analysis, segregated with the disorder in the family. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The findings indicated the importance of phosphoinositide signaling in early brain development. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Dolichocephaly Face \- Micrognathia SKELETAL \- Arthrogryposis Pelvis \- Externally rotated hips Limbs \- Flexed posture Hands \- Overlapping fingers Feet \- Talipes equinovarus NEUROLOGIC Central Nervous System \- Polymicrogyria, perisylvian \- Cerebellar hypoplasia \- Cerebellar dysplasia \- Small pons (1 patient) MISCELLANEOUS \- Onset in utero \- Three fetuses from 1 family have been reported (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the phosphatidylinositol 4-kinase, catalytic, alpha gene (PI4KA, 600286.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	POLYMICROGYRIA, PERISYLVIAN, WITH CEREBELLAR HYPOPLASIA AND ARTHROGRYPOSIS	c1845668	2,223	omim	https://www.omim.org/entry/616531	2019-09-22T15:48:37	{"mesh": ["C536658"], "omim": ["616531"], "orphanet": ["268940", "98889"], "synonyms": []}
Language disorder involving inability to understand language Not to be confused with Wernicke–Korsakoff syndrome or expressive aphasia. Receptive aphasia Other namesWernicke's aphasia, fluent aphasia, sensory aphasia Broca's area and Wernicke's area SpecialtyNeurology Wernicke's aphasia, also known as receptive aphasia,[1] sensory aphasia or posterior aphasia, is a type of aphasia in which individuals have difficulty understanding written and spoken language.[2] Patients with Wernicke's aphasia demonstrate fluent speech, which is characterized by typical speech rate, intact syntactic abilities and effortless speech output.[3] Writing often reflects speech in that it tends to lack content or meaning. In most cases, motor deficits (i.e. hemiparesis) do not occur in individuals with Wernicke's aphasia.[4] Therefore, they may produce a large amount of speech without much meaning. Individuals with Wernicke's aphasia are typically unaware of their errors in speech and do not realize their speech may lack meaning.[5] They typically remain unaware of even their most profound language deficits. Like many acquired language disorders, Wernicke's aphasia can be experienced in many different ways and to many different degrees. Patients diagnosed with Wernicke's aphasia can show severe language comprehension deficits; however, this is dependent on the severity and extent of the lesion.[2] Severity levels may range from being unable to understand even the simplest spoken and/or written information to missing minor details of a conversation.[2] Many diagnosed with Wernicke's aphasia have difficulty with repetition in words and sentences and/or working memory.[5] Wernicke's aphasia was named after German physician Carl Wernicke, who is credited with discovering the area of the brain responsible for language comprehension (Wernicke's area).[6] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 4.1 Role of neuroplasticity in recovery * 4.2 Auditory comprehension treatment * 4.3 Word retrieval * 4.4 Restorative therapy approach * 4.5 Social approach to treatment * 5 Prognosis * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] The following are common symptoms seen in patients with Wernicke's aphasia: * Impaired comprehension: deficits in understanding (receptive) written and spoken language.[2] This is because Wernicke's area is responsible for assigning meaning to the language that is heard, so if it is damaged, the brain cannot comprehend the information that is being received. * Poor word retrieval: ability to retrieve target words is impaired.[2] This is also referred to as anomia. * Fluent speech: individuals with Wernicke's aphasia do not have difficulty with producing connected speech that flows.[6] Although the connection of the words may be appropriate, the words they are using may not belong together or make sense (see Production of jargon below).[7] * Production of jargon: speech that lacks content, consists of typical intonation, and is structurally intact.[8] Jargon can consist of a string of neologisms, as well as a combination of real words that do not make sense together in context. The jargon may include word salads. * Awareness: Individuals with Wernicke's aphasia are often not aware of their incorrect productions, which would further explain why they do not correct themselves when they produce jargon, paraphasias, or neologisms.[9] * Paraphasias:[2][3] * Phonemic (literal) paraphasias: involves the substitution, addition, or rearrangement of sounds so that an error can be defined as sounding like the target word. Often, half of the word is still intact which allows for easy comparison to the appropriate, original word. * E.g. "bap" for "map" * Semantic (verbal) paraphasias: saying a word that is related to the target word in meaning or category; frequently observed in Wernicke's aphasia. * E.g. "jet" for "airplane" or "knife" for "fork" * Neologisms: nonwords that have no relation to the target word.[2] * E.g. "dorflur" for "shoe" * Circumlocution: talking around the target word.[2] * E.g. "uhhh it's white... it's flat... you write on it..." (when referencing paper) * Press of speech: run-on speech.[2] * If a clinician asks, "what do you do at a supermarket?" And the individual responds with "Well, the supermarket is a place. It is a place with a lot of food. My favorite food is Italian food. At a supermarket, I buy different kinds of food. There are carts and baskets. Supermarkets have lots of customers, and workers..." * Lack of hemiparesis: typically, no motor deficits are seen with a localized lesion in Wernicke's area.[4] * Reduced retention span: reduced ability to retain information for extended periods of time.[2] * Impairments in reading and writing: impairments can be seen in both reading and writing with differing severity levels.[6] How to differentiate from other types of aphasia[2] * Expressive aphasia (non-fluent Broca's aphasia): individuals have great difficulty forming complete sentences with generally only basic content words (leaving out words like "is" and "the"). * Global aphasia: individuals have extreme difficulties with both expressive (producing language) and receptive (understanding language). * Anomic aphasia: the biggest hallmark is an individual's poor word-finding abilities; their speech is fluent and appropriate, but full of circumlocutions (evident in both writing and speech). * Conduction aphasia: individual can comprehend what is being said and is fluent in spontaneous speech, but they cannot repeat what is being said to them. ## Causes[edit] The most common cause of Wernicke's aphasia is stroke. Strokes may occur when blood flow to the brain is completely interrupted or severely reduced. This has a direct effect on the amount of oxygen and nutrients being able to supply the brain, which causes brain cells to die within minutes.[10] "The middle cerebral arteries supply blood to the cortical areas involved in speech, language and swallowing. The left middle cerebral artery provides Broca's area, Wernicke's area, Heschl's gyrus, and the angular gyrus with blood".[11] Therefore, in patients with Wernicke's aphasia, there is typically an occlusion to the left middle cerebral artery. As a result of the occlusion in the left middle cerebral artery, Wernicke's aphasia is most commonly caused by a lesion in the posterior superior temporal gyrus (Wernicke's area).[2] This area is posterior to the primary auditory cortex (PAC) which is responsible for decoding individual speech sounds. Wernicke's primary responsibility is to assign meaning to these speech sounds. The extent of the lesion will determine the severity of the patients deficits related to language. Damage to the surrounding areas (perisylvian region) may also result in Wernicke's aphasia symptoms due to variation in individual neuroanatomical structure and any co-occurring damage in adjacent areas of the brain.[2] ## Diagnosis[edit] Aphasia is usually first recognized by the physician who treats the person for his or her brain injury. Most individuals will undergo a magnetic resonance imaging (MRI) or computed tomography (CT) scan to confirm the presence of a brain injury and to identify its precise location.[12] In circumstances where a person is showing possible signs of aphasia, the physician will refer him or her to a speech-language pathologist (SLP) for a comprehensive speech and language evaluation. SLPs will examine the individual's ability to express him or herself through speech, understand language in written and spoken forms, write independently, and perform socially.[12] The American Speech, Language, Hearing Association (ASHA) states a comprehensive assessment should be conducted in order to analyze the patient's communication functioning on multiple levels; as well as the effect of possible communication deficits on activities of daily living. Typical components of an aphasia assessment include: case history, self report, oral-motor examination, language skills, identification of environmental and personal factors, and the assessment results. A comprehensive aphasia assessment includes both formal and informal measures.[13] Formal assessments include: * Boston Diagnostic Aphasia Examination (BDAE): diagnoses the presence and type of aphasia, focusing on location of lesion and the underlying linguistic processes.[14] * Western Aphasia Battery – Revised (WAB): determines the presence, severity, and type of aphasia; and can also determine baseline abilities of patient.[15] * Communication Activities of Daily Living - Second Edition (CADL-2): measures functional communication abilities; focuses on reading, writing, social interactions, and varying levels of communication.[16] * Revised Token Test (RTT): assess receptive language and auditory comprehension; focuses on patient's ability to follow directions.[17] Informal assessments, which aid in the diagnosis of patients with suspected aphasia, include:[18] * Conversational speech and language sample[18] * Family interview[18] * Case history or medical chart review[18] * Behavioral observations[18] Diagnostic information should be scored and analyzed appropriately. Treatment plans and individual goals should be developed based on diagnostic information, as well as patient and caregiver needs, desires, and priorities.[13] ## Treatment[edit] According to Bates et al. (2005), "the primary goal of rehabilitation is to prevent complications, minimize impairments, and maximize function". The topics of intensity and timing of intervention are widely debated across various fields.[19] Results are contradictory: some studies indicate better outcomes with early intervention,[20] while other studies indicate starting therapy too early may be detrimental to the patient's recovery.[21] Recent research suggests, that therapy be functional and focus on communication goals that are appropriate for the patient's individual lifestyle.[22] Specific treatment considerations for working with individuals with Wernicke's aphasia (or those who exhibit deficits in auditory comprehension) include using familiar materials, using shorter and slower utterances when speaking, giving direct instructions, and using repetition as needed.[2] ### Role of neuroplasticity in recovery[edit] Neuroplasticity is defined as the brain's ability to reorganize itself, lay new pathways, and rearrange existing ones, as a result of experience.[23] Neuronal changes after damage to the brain such as collateral sprouting, increased activation of the homologous areas, and map extension demonstrate the brain's neuroplastic abilities. According to Thomson, "Portions of the right hemisphere, extended left brain sites, or both have been shown to be recruited to perform language functions after brain damage.[24] All of the neuronal changes recruit areas not originally or directly responsible for large portions of linguistic processing.[25] Principles of neuroplasticity have been proven effective in neurorehabilitation after damage to the brain. These principles include: incorporating multiple modalities into treatment to create stronger neural connections, using stimuli that evoke positive emotion, linking concepts with simultaneous and related presentations, and finding the appropriate intensity and duration of treatment for each individual patient.[23] ### Auditory comprehension treatment[edit] Auditory comprehension is a primary focus in treatment for Wernicke's aphasia, as it is the main deficit related to this diagnosis. Therapy activities may include: * Single-word comprehension: A common treatment method used to support single-word comprehension skills is known as a pointing drill. Through this method, clinicians lay out a variety of images in front of a patient. The patient is asked to point to the image that corresponds to the word provided by the clinician.[2] * Understanding spoken sentences: "Treatment to improve comprehension of spoken sentences typically consists of drills in which patients answer questions, follow directions or verify the meaning of sentences".[2] * Understanding conversation: An effective treatment method to support comprehension of discourse includes providing a patient with a conversational sample and asking him or her questions about that sample. Individuals with less severe deficits in auditory comprehension may also be able to retell aspects of the conversation.[2] ### Word retrieval[edit] Anomia is consistently seen in aphasia, so many treatment techniques aim to help patients with word finding problems. One example of a semantic approach is referred to as semantic feature analyses. The process includes naming the target object shown in the picture and producing words that are semantically related to the target. Through production of semantically similar features, participants develop more skilled in naming stimuli due to the increase in lexical activation.[26] ### Restorative therapy approach[edit] Neuroplasticity is a central component to restorative therapy to compensate for brain damage. This approach is especially useful in Wernicke's aphasia patients that have suffered from a stroke to the left brain hemisphere.[27] Schuell's stimulation approach is a main method in traditional aphasia therapy that follows principles to retrieve function in the auditory modality of language and influence surrounding regions through stimulation. The guidelines to have the most effective stimulation are as follows: Auditory stimulation of language should be intensive and always present when other language modalities are stimulated.[27] * The stimulus should be presented at a difficulty level equal to or just below the patient's ability. * Sensory stimulation must be present and repeated throughout the treatment. * Each stimulus applied should produce a response; if there is no response more stimulation cues should be provided. * Response to stimuli should be maximized to create more opportunities for success and feedback for the speech-language pathologist. * The feedback of the speech-language pathologist should promote further success and patient and encouragement. * Therapy should follow an intensive and systemic method to create success by progressing in difficulty. * Therapies should be varied and build off of mastered therapy tasks.[27] Schuell's stimulation utilizes stimulation through therapy tasks beginning at a simplified task and progressing to become more difficult including: * Point to tasks. During these tasks the patient is directed to point to an object or multiple objects. As the skill is learned the level of complexity increases by increasing the number of objects the patient must point to.[27] * Simple: "Point to the book." * Complex: "Point to the book and then to the ceiling after touching your ear." * Following directions with objects. During these tasks the patient is instructed to follow the instruction of manually following directions that increase in complexity as the skill is learned.[27] * Simple: "Pick up the book." * Complex: "Pick up the book and put it down on the bench after I move the cup." * Yes or no questions – This task requires the patient to respond to various yes or no questions that can range from simple to complex.[27] * Paraphrasing and retelling – This task requires the patient to read a paragraph and, afterwards, paraphrase it aloud. This is the most complex of Schuell's stimulation tasks because it requires comprehension, recall, and communication.[27] ### Social approach to treatment[edit] The social approach involves a collaborative effort on behalf of patients and clinicians to determine goals and outcomes for therapy that could improve the patient's quality of life. A conversational approach is thought to provide opportunities for development and the use of strategies to overcome barriers to communication. The main goals of this treatment method are to improve the patient's conversational confidence and skills in natural contexts using conversational coaching, supported conversations, and partner training.[28] * Conversational coaching involves patients with aphasia and their speech language pathologists, who serve as a "coach" discussing strategies to approach various communicative scenarios. The "coach" will help the patient develop a script for a scenario (such as ordering food at a restaurant), and help the patient practice and perform the scenario in and out of the clinic while evaluating the outcome.[29] * Supported conversation also involves using a communicative partner who supports the patient's learning by providing contextual cues, slowing their own rate of speech, and increasing their message's redundancy to promote the patient's comprehension.[29] Additionally, it is important to include the families of patients with aphasia in treatment programs. Clinicians can teach family members how to support one another, and how to adjust their speaking patterns to facilitate their loved one's treatment and rehabilitation.[28] ## Prognosis[edit] Prognosis is strongly dependent on the location and extent of the lesion (damage) to the brain. Many personal factors also influence how a person will recover, which include age, previous medical history, level of education, gender, and motivation.[24] All of these factors influence the brain's ability to adapt to change, restore previous skills, and learn new skills. It is important to remember that all the presentations of Receptive Aphasia may vary. The presentation of symptoms and prognosis are both dependent on personal components related to the individual's neural organization before the stroke, the extent of the damage, and the influence of environmental and behavioral factors after the damage occurs.[30] The quicker a diagnosis of a stroke is made by a medical team, the more positive the patient's recovery may be. A medical team will work to control the signs and symptoms of the stroke and rehabilitation therapy will begin to manage and recover lost skills. The rehabilitation team may consist of a certified speech-language pathologist, physical therapist, occupational therapist, and the family or caregivers.[19] The length of therapy will be different for everyone, but research suggests that intense therapy over a short amount of time can improve outcomes of speech and language therapy for patients with aphasia. Research is not suggesting the only way therapy should be administered, but gives insight on how therapy affects the patient's prognosis.[21] ## See also[edit] * Agraphia * Logorrhea (psychology) * Paragrammatism ## References[edit] 1. ^ Nakai, Y; Jeong, JW; Brown, EC; Rothermel, R; Kojima, K; Kambara, T; Shah, A; Mittal, S; Sood, S; Asano, E (2017). "Three- and four-dimensional mapping of speech and language in patients with epilepsy". Brain. 140 (5): 1351–1370. doi:10.1093/brain/awx051. PMC 5405238. PMID 28334963. 2. ^ a b c d e f g h i j k l m n o p q Brookshire, Robert (2007). Introduction to neurogenic communication disorders (7th ed.). St. Louis, MO: Mosby Elsevier. 3. ^ a b Damasio, A.R. (1992). "Aphasia". The New England Journal of Medicine. 326 (8): 531–539. doi:10.1056/nejm199202203260806. PMID 1732792. 4. ^ a b Murdoch, B.E. (1990). Acquired Speech and Language Disorders: A Neuroanatomical and Functional Neurological Approach. Baltimore, MD: Chapman and Hall. pp. 73–76. 5. ^ a b "Common Classifications of Aphasia". American Speech-Language-Hearing Association. 6. ^ a b c "Wernicke's (Receptive) Aphasia". National Aphasia Association. 7. ^ "Types of Aphasia". American Stroke Association. 8. ^ "ASHA Glossary". American Speech-Language-Hearing Association. 9. ^ "Aphasia Definitions". National Aphasia Association. 10. ^ "Stroke". Mayo Clinic. Mayo Foundation for Medical Education and Research. Retrieved 14 December 2020. 11. ^ McCaffrey, P. "Medical aspects: Blood supply in the brain". 12. ^ a b "Aphasia". National Institute on Deafness and Other Communication Disorders (NIDCD). 13. ^ a b "Aphasia: Roles and responsibilities". American Speech-Language-Hearing Association. 14. ^ Goodglass, H.; Kaplan, E.; Barresi, B. (2001). Boston Diagnostic Aphasia Examination. Austin, TX: PRO-ED, Inc. 15. ^ Kereesz, A. (2006). Western Aphasia Battery. San Antonio, TX: Pearson. 16. ^ Holland, A.L.; Fromm, D.; Wozniak, L. (2018). Communication Activities in Daily Living (CADL-3) (3rd ed.). Alberta, Canada: Brijan Resources. 17. ^ McNeil, M.M.; Prescott, T.E. (1978). Revised Token Test. Austin, TX: PRO-ED, Inc. 18. ^ a b c d e "Assessment Tools, Techniques, and Data Sources". American Speech-Language-Hearing Association. 19. ^ a b Bates, B.; Choi, J.; Duncan, P.W.; Glasberg, J.J.; Graham, G.D.; Katz, R.C....; Zorowitz, R. (2005). "Veterans affairs/department of defense clinical practice guideline for the management of adult stroke rehabilitation care". Stroke. 36 (9): 2049–2056. doi:10.1161/01.STR.0000180432.73724.AD. PMID 16120847. 20. ^ Bhogal, S.K.; Teasell, R.; Speechley, M. (2003). "Intensity of aphasia therapy, impact on recovery". Stroke. 34 (4): 987–993. doi:10.1161/01.STR.0000062343.64383.D0. PMID 12649521. 21. ^ a b Nouwens, F.; Visch-Brink, E.G.; Van de Sandt-Koenderman, M.M.E.; Dippeo, D.W.J; Kaudstaal, P.J.; de Law, L.M.L. (2015). "Optimal timing for speech and language therapy after stroke: More evidence needed". Expert Review of Neurotherapeutics. 15 (8): 885–893. doi:10.1586/14737175.2015.1058161. PMID 26088694. 22. ^ "Life Participation Approach to Aphasia: A Statement of Values for the Future". American Speech-Language-Hearing Association. 23. ^ a b Bayles, K.A.; Tomodea, C.K. (2010). "Neuroplasticity: Implications for treating cognitive communication disorders". ASHA National Convention. 24. ^ a b Thomson, C.K. (2000). "Neuroplasticity: Evidence from aphasia". Journal of Communication Disorders. 33 (4): 357–366. doi:10.1016/S0021-9924(00)00031-9. PMC 3086401. PMID 11001162. 25. ^ Raymer, A.M.; Beeson, P.; Holland, A.; Kendall, D.; Maher, L.M.; Martin, M.; Gonzolez Rothi, L.J. (2008). "Transitional research in aphasia: From neuroscience to neurorehabilitation". Journal of Speech, Language, and Hearing Research. 51: 259–275. 26. ^ Boyle, M.; Coelho, C.A. (2004). "Semantic feature analysis treatment for anomia in two fluent aphasia syndromes". American Journal of Speech-Language Pathology. 13 (3): 236–249. doi:10.1044/1058-0360(2004/025). PMID 15339233. 27. ^ a b c d e f g Manasco, H. (2021). Introduction to neurogenic communication disorders. Burlington, Massachusetts: Jones & Bartlett Learning. 28. ^ a b LaPointe, L. (2005). Aphasia and Related Neurogenic Language Disorders (3rd ed.). New York, NY: Thieme Medical Publishers Inc. 29. ^ a b Davis, G.A. "Aphasia Therapy Guide". National Aphasia Association. 30. ^ Keefe, K.A. (1995). "Applying basic neuroscience to aphasia therapy: What the animals are telling us". American Journal of Speech-Language Pathology. 4 (4): 88–93. doi:10.1044/1058-0360.0404.88. ## Further reading[edit] * Klein, Stephen B., and Thorne. Biological Psychology. New York: Worth, 2007. Print. * Saladin, Kenneth S. Anatomy & Physiology: the Unity of Form and Function. New York: McGraw-Hill Higher Education, 2010. Print. ## External links[edit] Classification D * ICD-10: F80.2 * ICD-9-CM: 784.3 * MeSH: D001041 * 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 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Receptive aphasia	c0454578	2,224	wikipedia	https://en.wikipedia.org/wiki/Receptive_aphasia	2021-01-18T18:33:27	{"mesh": ["D001041"], "icd-9": ["784.3"], "icd-10": ["F80.2"], "wikidata": ["Q1741331"]}
A rare, genetic, autosomal recessive spastic ataxia disease characterized by cerebellar ataxia, spasticity, cerebellar (and in some cases cerebral) atrophy, dystonia, and leukoencephalopathy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Autosomal recessive spastic ataxia with leukoencephalopathy	c1969645	2,225	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=314603	2021-01-23T17:18:28	{"mesh": ["C566956"], "omim": ["611390"], "umls": ["C1969645"], "icd-10": ["G11.4"], "synonyms": ["ARSAL", "Autosomal recessive spastic ataxia type 3", "SPAX3"]}
Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often. Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA). During episodes of fever, people with HIDS typically have enlargement of the lymph nodes (lymphadenopathy), abdominal pain, joint pain, diarrhea, skin rashes, and headache. Occasionally they will have painful sores called aphthous ulcers around their mouth. In females, these may also occur around the vagina. Rarely, people with HIDS develop a buildup of protein deposits (amyloidosis) in the kidneys that can lead to kidney failure. Fever episodes in individuals with HIDS can be triggered by vaccinations, surgery, injury, or stress. Most people with HIDS have abnormally high levels of immune system proteins called immunoglobulin D (IgD) and immunoglobulin A (IgA) in the blood. It is unclear why some people with HIDS have high levels of IgD and IgA and some do not. Elevated levels of these immunoglobulins do not appear to cause any signs or symptoms. Individuals with HIDS do not have any signs and symptoms of the condition between fever episodes and typically have a normal life expectancy. People with MVA have signs and symptoms of the condition at all times, not just during episodes of fever. Affected children have developmental delay, problems with movement and balance (ataxia), recurrent seizures (epilepsy), progressive problems with vision, and failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MVA typically have an unusually small, elongated head. In childhood or adolescence, affected individuals may develop eye problems such as inflammation of the eye (uveitis), a blue tint in the white part of the eye (blue sclera), an eye disorder called retinitis pigmentosa that causes vision loss, or clouding of the lens of the eye (cataracts). Affected adults may have short stature and may develop muscle weakness (myopathy) later in life. During fever episodes, people with MVA may have an enlarged liver and spleen (hepatosplenomegaly), lymphadenopathy, abdominal pain, diarrhea, and skin rashes. Children with MVA who are severely affected with multiple problems may live only into early childhood; mildly affected individuals may have a normal life expectancy. ## Frequency More than 200 people with mevalonate kinase deficiency have been reported worldwide; the majority of these individuals have HIDS. ## Causes Mutations in the MVK gene cause mevalonate kinase deficiency. The MVK gene provides instructions for making the mevalonate kinase enzyme. This enzyme is involved in the production of cholesterol, which is later converted into steroid hormones and bile acids. Steroid hormones are needed for normal development and reproduction, and bile acids are used to digest fats. Mevalonate kinase also helps to produce other substances that are necessary for certain cellular functions, such as cell growth, cell maturation (differentiation), formation of the cell's structural framework (the cytoskeleton), gene activity (expression), and protein production and modification. Most MVK gene mutations that cause mevalonate kinase deficiency result in an enzyme that is unstable and folded into an incorrect 3-dimensional shape, leading to a reduction of mevalonate kinase enzyme activity. Despite this shortage (deficiency) of mevalonate kinase activity, people with mevalonate kinase deficiency typically have normal production of cholesterol, steroid hormones, and bile acids. It is unclear how a lack of mevalonate kinase activity causes the signs and symptoms of this condition. Some researchers believe the features may be due to a buildup of mevalonic acid, the substance that mevalonate kinase normally acts on. Other researchers think that a shortage of the substances produced from mevalonic acid, such as those substances necessary for certain cellular functions, causes the fever episodes and other features of this condition. The severity of the enzyme deficiency determines the severity of the condition. People who have approximately 1 to 20 percent of normal mevalonate kinase activity typically develop HIDS. Individuals who have less than 1 percent of normal enzyme activity usually develop MVA. ### Learn more about the gene associated with Mevalonate kinase deficiency * MVK ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Mevalonate kinase deficiency	c0398691	2,226	medlineplus	https://medlineplus.gov/genetics/condition/mevalonate-kinase-deficiency/	2021-01-27T08:24:50	{"gard": ["2788", "3588"], "mesh": ["D054078"], "omim": ["260920", "610377"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-3B (DFNA3B) is caused by heterozygous mutation in the connexin-30 gene (GJB6; 604418) on chromosome 13q12. One such family has been reported. See also DFNA3A (601544), which is caused by mutation in the connexin-26 gene (GJB2; 121011) on chromosome 13q12. Clinical Features Grifa et al. (1999) reported an Italian family with autosomal dominant hearing loss. The phenotype was variable, ranging from bilateral middle to high frequency hearing loss to profound sensorineural deafness. The phenotype showed linkage to chromosome 13q12, but molecular analysis excluded mutations in the GJB2 gene. Molecular Genetics In affected members of an Italian family with autosomal dominant nonsyndromic sensorineural deafness, Grifa et al. (1999) identified a heterozygous mutation in the GJB6 gene (604418.0001). INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss, bilateral (middle-to-high frequency) MISCELLANEOUS \- One Italian family has been described (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the gap junction protein, beta-6 gene (GJB6, 604418.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	DEAFNESS, AUTOSOMAL DOMINANT 3B	c2675237	2,227	omim	https://www.omim.org/entry/612643	2019-09-22T16:00:55	{"doid": ["0110565"], "mesh": ["C567215"], "omim": ["612643"], "orphanet": ["90635"], "synonyms": ["Autosomal dominant isolated neurosensory deafness type DFNA", "Autosomal dominant isolated neurosensory hearing loss type DFNA", "Autosomal dominant isolated sensorineural deafness type DFNA", "Autosomal dominant isolated sensorineural hearing loss type DFNA", "Autosomal dominant non-syndromic neurosensory deafness type DFNA", "Autosomal dominant non-syndromic neurosensory hearing loss type DFNA", "Autosomal dominant non-syndromic sensorineural hearing loss type DFNA"], "genereviews": ["NBK1434", "NBK1536"]}
Trifascicular block SpecialtyCardiology Trifascicular block is a problem with the electrical conduction of the heart, specifically the three fascicles that carry electrical signals from the atrioventricular node to the ventricles. The three fascicles include the right bundle branch, the left anterior fascicle and the left posterior fascicle. The left anterior fascicle and left posterior fascicle are together referred to as the left bundle branch. "Block" at any of these levels can cause an abnormality on an electrocardiogram The most literal meaning of trifascicular block is complete heart block: all three fascicles are blocked. A second, and clinically distinct, definition of trifascicular block is a circumstance in which right bundle branch block (RBBB) and left bundle branch block occur in the same patient, but at distinct points in time. For example, a patient that is found to have a RBBB one day and a LBBB another can be said to have "alternating bundle branch blocks". In this context, because all three fascicles show evidence of block at different points in time, the term trifascicular block is often used. Finally, the third meaning of trifascicular block refers to a specific finding on an electrocardiogram in which bifascicular block is observed in a patient with a prolonged PR interval (first degree AV block). The treatment of trifascicular block is highly dependent on which clinical entity (one of the three above) is being described. ## Contents * 1 Diagnosis * 2 Treatment * 3 See also * 4 References * 5 External links ## Diagnosis[edit] An electrophysiology study of the conduction system can help discern the severity of conduction system disease. In an electrophysiology study, trifascicular block due to AV nodal disease is represented by a prolonged AH interval (denoting prolonged time from impulse generation in the atria and conduction to the bundle of His) with a relatively preserved HV interval (denoting normal conduction from the bundle of His to the ventricles). Trifascicular block due to distal conduction system disease is represented by a normal AH interval and a prolonged HV interval. In the absence of symptoms, a prolonged AH interval is likely benign while a prolonged HV interval is almost always pathologic. ## Treatment[edit] An implantable cardiac pacemaker or permanent pacemaker is recommended in the following clinical circumstances. Class 1 recommendation is the strongest recommendation. Level A evidence is the highest level of evidence. Class I * Bifascicular block \+ complete heart block, even in the absence of symptoms (1b) * Bifascicular block \+ 2nd degree AV Block Type 2, even in the absence of symptoms (1b) * Alternating bundle branch blocks, even in the absence of symptoms (1c) Class II * Bifascicular block \+ syncope \+ alternative causes ruled out (e.g. orthostasis, arrhythmia) (2a) Class III (i.e. pacemaker not recommended) * Bifascicular block without symptoms * Bifascicular block \+ 1st degree AV Block, without symptoms ## See also[edit] * Bifascicular block ## References[edit] ## External links[edit] {Medical resources \| ICD10 = I45.3 \| ICD9 = 426.54 \| ICDO = \| OMIM = \| DiseasesDB = \| MedlinePlus = \| eMedicineSubj = \| eMedicineTopic = \| MeshID = \| GeneReviewsNBK = \| GeneReviewsName = \| NORD = \| GARDNum = \| GARDName = \| Orphanet = \| AO = \| RP = \| WO = \| OrthoInfo = \| NCI = \| Scholia = \| SNOMED CT = }} * http://library.med.utah.edu/kw/ecg/mml/ecg_0293_mod.html * http://www.ecglibrary.com/trifas.html * http://circ.ahajournals.org/content/117/21/e350 \- old guidelines, in which trifascicular block terminology is used. * http://circ.ahajournals.org/content/97/13/1325.long \- new guidelines in which trifascicular block terminology continues to be used. * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Trifascicular block	c0155707	2,228	wikipedia	https://en.wikipedia.org/wiki/Trifascicular_block	2021-01-18T19:10:10	{"umls": ["C0155707"], "icd-9": ["426.54"], "icd-10": ["I45.3"], "wikidata": ["Q3640997"]}
Congenital complete agenesis of pericardium is a rare, mostly asymptomatic, congenital heart malformation characterized by the complete absence of the entire pericardium, or by the absence of either the right (uncommon) or left pericardium. It is occasionally associated with chest pain (common), dyspnea, dizziness, bradycardia and syncope, while exertional manifestations are rare. The disease is usually incidentally diagnosed during surgery or at autopsy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Congenital complete agenesis of pericardium	None	2,229	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99129	2021-01-23T17:09:01	{"icd-10": ["Q24.8"]}
A rare genetic disease characterized by sclerosing dysplasia affecting the diaphyseal and metaphyseal regions of the long bones, as well as the skull and metacarpals, in association with skin changes like those seen in ichthyosis vulgaris and premature ovarian failure with bilateral hypoplasia of the ovaries. Patients present in adulthood, primarily with swelling of the extremities and occasional mild pain in the legs. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Osteosclerosis-ichthyosis-premature ovarian failure syndrome	c1864942	2,230	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=75325	2021-01-23T17:51:47	{"gard": ["9904"], "mesh": ["C536064"], "omim": ["609993"], "umls": ["C1864942"], "synonyms": ["Sclerosing dysplasia of bone-ichthyosis-premature ovarian failure syndrome"]}
Occlusal trauma Secondary occlusal trauma on X-ray film displays two lone-standing mandibular teeth, the lower left first premolar and canine. As the remnants of a once full complement of 16 lower teeth, these two teeth have been alone in opposing the forces associated with mastication for some time, as can be evidenced by the widened PDL surrounding the premolar. Because this trauma is occurring on teeth that have 30-50% bone loss, this would be classified as secondary. SpecialtyDentistry, ENT surgery Occlusal trauma is the damage to teeth when an excessive force is acted upon them and they do not align properly.[1] When the jaws close, for instance during chewing or at rest, the relationship between the opposing teeth is referred to as occlusion. When trauma, disease or dental treatment alters occlusion by changing the biting surface of any of the teeth, the teeth will come together differently, and their occlusion will change.[2] When that change has a negative effect on how the teeth occlude, this may cause tenderness, pain, and damage to or movement of the teeth. This is called traumatic occlusion.[1][3] Traumatic occlusion may cause a thickening of the cervical margin of the alveolar bone[4] and widening of the periodontal ligament, although the latter is can also be caused by other processes.[5] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Primary vs. secondary * 3.1 Primary * 3.2 Secondary * 4 Cause and treatment * 5 References * 6 External links ## Signs and symptoms[edit] Clinically, there is a number of physiological results that serve as evidence of occlusal trauma:,[6][7] * Tooth mobility * Fremitus * Tooth migration * Pain * Thermal sensitivity * Pain on chewing or percussion * Wear facets ## Diagnosis[edit] Microscopically, there will be a number of features that accompany occlusal trauma:[8] * Hemorrhage * Necrosis * Widening of the periodontal ligament, or PDL (also serves as a very common radiographic feature) * Bone resorption * Cementum loss and tears It was concluded that widening of the periodontal ligament was a "functional adaptation to changes in functional requirements".[9] ## Primary vs. secondary[edit] There are two types of occlusal trauma, primary and secondary. ### Primary[edit] Primary occlusal trauma occurs when greater than normal occlusal forces are placed on teeth, as in the case of parafunctional habits, such as bruxism or various chewing or biting habits, including but not limited to those involving fingernails and pencils or pens. The associated excessive forces can be grouped into three categories. Excesses of:[10] * Duration * Frequency and * Magnitude Primary occlusal trauma will occur when there is a normal periodontal attachment apparatus and, thus, no periodontal disease.[11] ### Secondary[edit] Secondary occlusal trauma occurs when normal or excessive occlusal forces are placed on teeth with compromised periodontal attachment, thus contributing harm to an already damaged system. As stated, secondary occlusal trauma occurs when there is a compromised periodontal attachment and, thus, a pre-existing periodontal condition.[11] ## Cause and treatment[edit] Teeth are constantly subject to both horizontal and vertical occlusal forces. With the center of rotation of the tooth acting as a fulcrum, the surface of bone adjacent to the pressured side of the tooth will undergo resorption and disappear, while the surface of bone adjacent to the tensioned side of the tooth will undergo apposition and increase in volume.[12] In both primary and secondary occlusal trauma, tooth mobility might develop over time, with it occurring earlier and being more prevalent in secondary occlusal trauma. To treat mobility due to primary occlusal trauma, the cause of the trauma must be eliminated. Likewise for teeth subject to secondary occlusal trauma, though these teeth may also require splinting together to the adjacent teeth so as to eliminate their mobility. In primary occlusal trauma, the cause of the mobility was the excessive force being applied to a tooth with a normal attachment apparatus, otherwise known as a periodontally-uninvolved tooth. The approach should be to eliminate the cause of the pain and mobility by determining the causes and removing them; the mobile tooth or teeth will soon cease exhibiting mobility. This could involve removing a high spot on a recently restored tooth, or even a high spot on a non-recently restored tooth that perhaps moved into hyperocclusion. It could also involve altering one's parafunctional habits, such as refraining from chewing on pens or biting one's fingernails. For a bruxer, treatment of the patient's primary occlusal trauma could involve selective grinding of certain interarch tooth contacts or perhaps employing a nightguard to protect the teeth from the greater than normal occlusal forces of the patient's parafunctional habit. For someone who is missing enough teeth in non-strategic positions so that the remaining teeth are forced to endure a greater per square inch occlusal force, treatment might include restoration with either a removable prosthesis or implant-supported crown or bridge. In secondary occlusal trauma, simply removing the "high spots" or selective grinding of the teeth will not eliminate the problem, because the teeth are already periodontally involved. After splinting the teeth to eliminate the mobility, the cause of the mobility (in other words, the loss of clinical attachment and bone) must be managed; this is achieved through surgical periodontal procedures such as soft tissue and bone grafts, as well as restoration of edentulous areas. As with primary occlusal trauma, treatment may include either a removable prosthesis or implant-supported crown or bridge. ## References[edit] 1. ^ a b Bibb, CA: Occlusal Evaluation and Therapy in the Management of Periodontal Disease. In Newman, MG; Takei, HH; Carranza, FA; editors: Carranza’s Clinical Periodontology, 9th Edition. Philadelphia: W.B. Saunders Company, 2002. pages 698-701. 2. ^ Hinrichs, JE: Occlusal The Role of Dental Calculus and Other Predisposing Factors. In Newman, MG; Takei, HH; Carranza, FA; editors: Carranza’s Clinical Periodontology, 9th Edition. Philadelphia: W.B. Saunders Company, 2002. page 192. 3. ^ traumatogenic occlusion - definition of traumatogenic occlusion in the Medical dictionary - by the Free Online Medical Dictionary, Thesaurus and Encyclopedia 4. ^ Carranza, FA: Bone Loss and Patterns of Bone Destructions. In Newman, MG; Takei, HH; Carranza, FA; editors: Carranza’s Clinical Periodontology, 9th Edition. Philadelphia: W.B. Saunders Company, 2002. page 362. 5. ^ Trauma from Occlusion Handout, Dr. Michael Deasy, Department of Periodontics, NJDS 2007. page 5 6. ^ Trauma from Occlusion Handout, Dr. Michael Deasy, Department of Periodontics, NJDS 2007. page 12 7. ^ Dave Rupprecht, "Trauma from Occlusion: a Review", Naval Postgraduate Dental School National Naval Dental Center, January 2004, Vol 26, No. 1 8. ^ Trauma from Occlusion Handout, Dr. Michael Deasy, Department of Periodontics, NJDS 2007. page 7 9. ^ Wentz et al. J Perio, 1958 10. ^ Trauma from Occlusion Handout, Dr. Michael Deasy, Department of Periodontics, NJDS 2007. page 14 11. ^ a b Carranza, FA; Bernard, GW: The Tooth-Supporting Structures. In Newman, MG; Takei, HH; Carranza, FA; editors: Carranza’s Clinical Periodontology, 9th Edition. Philadelphia: W.B. Saunders Company, 2002. page 53. 12. ^ Trauma from Occlusion Handout, Dr. Michael Deasy, Department of Periodontics, NJDS 2007. page 4 ## External links[edit] Classification D * MeSH: D003769 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Occlusal trauma	c0011385	2,231	wikipedia	https://en.wikipedia.org/wiki/Occlusal_trauma	2021-01-18T18:54:30	{"mesh": ["D003769"], "wikidata": ["Q7075713"]}
A number sign (#) is used with this entry because this form of peroxisome biogenesis disorder (PBD1B) is caused by homozygous or compound heterozygous mutation in the PEX1 gene (602136) on chromosome 7q21. Mutations in the PEX1 gene also cause Zellweger syndrome (PBD1A; 214100). Description Peroxisome biogenesis disorder-1B (PBD1B) is characterized by the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). Initial presentation and natural history varies, with many children presenting as newborns, whereas others do not come to attention until later. Most affected children have hypotonia, but unlike Zellweger syndrome (see PBD1A, 214100) there is a degree of psychomotor development, and some patients achieve head control, sit unsupported, and may even walk independently. Many can communicate, and although language is rare, there have been children who have near normal language for age. Craniofacial anomalies are similar to but less pronounced than in Zellweger syndrome. In some individuals a leukodystrophy develops, with degeneration of myelin, loss of previously acquired skills, and development of spasticity; this may stabilize, or progress and be fatal. In PBD1B, the most common manifestations that are less apparent in ZS are sensorineural hearing loss and retinitis pigmentosa (summary by Steinberg et al., 2006). While Zellweger syndrome usually results in death in the first year of life, children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). Individuals with mutations in the PEX1 gene have cells of complementation group 1 (CG1, equivalent to CGE). For information on the history of PBD complementation groups, see 214100. ### Genetic Heterogeneity of Peroxisome Biogenesis Disorder NALD/IRD The phenotypic spectrum of NALD/IRD peroxisome biogenesis disorders can be caused by mutation in members of the peroxin (PEX) gene family. The PEX genes encode proteins essential for the assembly of functional peroxisomes (summary by Distel et al., 1996). PBD1B is caused by mutation in the PEX1 gene on chromosome 7q21; PBD2B (202370) is caused by mutation in the PEX5 gene (600414) on chromosome 12p13.3; PBD3B (266510) is caused by mutation in the PEX12 gene (601758) on chromosome 17; PBD4B (614863) is caused by mutation in the PEX6 gene (601498) on chromosome 6p21.1; PBD5B (614867) is caused by mutation in the PEX2 gene (170993) on chromosome 8q21.1; PBD6B (614871) is caused by mutation in the PEX10 gene (602859) on chromosome 1p36.32; PBD7B (614873)is caused by mutation in the PEX26 gene (608666) on chromosome 22q11.21; PBD8B (614877) is caused by mutation in the PEX16 gene (603360) on chromosome 11p11; PBD10B (617370) is caused by mutation in the PEX3 gene (603164) on chromosome 6q24; and PBD11B (614885) is caused by mutation in the PEX13 gene (601789) on chromosome 2p15. See PBD1A (214100) for a phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, which is also caused by mutation in peroxin genes. The rhizomelic chondrodysplasia subtype of PBD (RCDP1, PBD9; 215100), and a mild PBD without rhizomelia (PBD9B; 614879), are caused by mutation in the PEX7 gene (601757) on chromosome 6q23. Clinical Features Benke et al. (1981) reported brother and sister with similar facial features, seizures from birth, delayed neurologic development which began to deteriorate at age 1 year, and sudden death, associated with respiratory infections, before the age of 3 years. Tanning of the skin was noted 2 months before death of the first child; in the second child, blood cortisol levels failed to increase after intravenous ACTH administration. At autopsy, both patients showed adrenal atrophy and degenerative changes of the white matter throughout the neuroaxis. One of the infants had polar cataracts at birth. The characteristic craniofacial changes were dolichocephaly, prominent and high forehead, esotropia, epicanthic folds, broad nasal bridge, high-arched palate, low-set ears, and anteverted nostrils. The female was as severely affected as the male, making X-linked inheritance unlikely. Moser (1981) suspected that the neonatal form of adrenoleukodystrophy is inherited as an autosomal recessive: the incidence and degree of affection are comparable in boys and girls. The neonatal form of ALD is clearly separate from the X-linked forms of childhood and adult ALD/AMN and also from Zellweger syndrome (214100) to which it bears many clinical and biochemical similarities including the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0). Levels are normal in parents whereas in the X-linked form they are intermediate in the heterozygous female. It also bears similarities to hyperpipecolic acidemia (239400). All are apparently disorders of the peroxisomes, which are lacking in both Zellweger syndrome and neonatal ALD and which are the main site of oxidation of very long chain fatty acids. Since 40 enzymes have been localized to the peroxisome (Tolbert, 1981), there is adequate opportunity for genetic heterogeneity among disorders with phenotypic overlap (cf., the mucopolysaccharidoses). Kelley and Moser (1984) showed that serum pipecolic acid is elevated, often markedly, in patients with NALD but in none of those with X-linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis or other neurodegenerative disorders. This finding can be added to that of elevated very long chain fatty acids to support a generalized peroxisomal dysfunction and relationship to the Zellweger syndrome. Cystic changes in the kidneys and skeletal changes (very large fontanels and cartilaginous calcifications) occur in Zellweger syndrome but not in NALD. Differentiation is confused by the fact that cases of NALD have been found to have no hepatic peroxisomes (Partin and McAdams, 1982), a finding considered virtually pathognomonic of Zellweger syndrome, whereas 2 sibs with many classic features of Zellweger syndrome and elevated VLCFA and pipecolic acid have normal hepatic peroxisomes (Burton et al., 1981). Kelley et al. (1986) presented 8 new cases and contrasted the findings with those of Zellweger syndrome. See 300100 for a discussion of the usual form of adrenoleukodystrophy. Chen et al. (1987) found that despite the absence of the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, its mRNA could be demonstrated in neonatal ALD fibroblasts. This suggested to them that the protein was rapidly degraded in the cytoplasm before its entry into peroxisomes. In Zellweger syndrome, acyl-CoA oxidase and beta-ketothiolase are also deficient. All 3 enzymes are synthesized on free polyribosomes and then transported into peroxisomes. Patients with the infantile form of phytanic acid storage disease show both clinical and biochemical differences from patients with the classic form of Refsum disease (266500). Features include early onset, mental retardation, minor facial dysmorphism, retinitis pigmentosa, sensorineural hearing deficit, hepatomegaly, osteoporosis, failure to thrive, and hypocholesterolemia. The biochemical abnormalities are not restricted to phytanic acid but also include accumulation of very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. Deficiency of peroxisomes in hepatocytes and cultured skin fibroblasts is demonstrable (Wanders et al., 1990). A relationship between the infantile form of Refsum disease and Zellweger syndrome (ZWS) was suggested by the observations of Poulos et al. (1984) in 2 patients. In the infantile form of Refsum disease, as in Zellweger syndrome, peroxisomes are deficient and peroxisomal functions are impaired (Schram et al., 1986). Clinically, infantile Refsum disease, ZWS, and adrenoleukodystrophy (300100) have several overlapping features. Biochemically, IRD patients show accumulation of phytanic acid as in the classic form of Refsum disease but in addition they show defective bile acid metabolism as in ZWS (Stokke et al., 1984). In IRD, manifestations date from birth. Features in addition to those of Refsum disease include some seen in Zellweger syndrome: delayed development, mental retardation, hepatomegaly, and skeletal changes. The levels of VLCFAs are elevated in ZWS and IRD but not in classic Refsum disease. In infantile Refsum disease, Zellweger disease, and the rhizomelic form of chondrodysplasia punctata (RCDP1; 215100), also a peroxisomal disorder, the activity of the peroxisomal enzyme acyl-CoA-dehydroxyacetonephosphate acyltransferase is low in platelets and fibroblasts, plasmalogens are deficient, and the plasma phytanic acid levels are usually elevated in patients over the age of 5 months. Wanders et al. (1986) found restoration of acyltransferase activity when RCDP cells and infantile Refsum cells were fused. When infantile Refsum cells and Zellweger cells were fused, restoration of enzyme activity was not observed. Wanders et al. (1986) felt that this did not necessarily indicate that these are allelic disorders. In 4 cases of infantile Refsum disease, Roels et al. (1986) could visualize no peroxisomes by light microscopy after cytochemical staining for catalase, a marker enzyme for this organelle. Absence of peroxisomes was confirmed by electron microscopy in 3 patients and, in the fourth, organelles of peculiar size and shape, with minimal catalase activity, were seen. Birefringent macrophages containing PAS-positive material, on light microscopy, was considered another useful finding. Poll-The et al. (1987) compared IRD with neonatal adrenoleukodystrophy (NALD) and Zellweger syndrome. The studies of Brul et al. (1988) suggested that one form of Zellweger syndrome, the infantile form of Refsum syndrome, and hyperpipecolic acidemia (239400) are allelic; they failed to show complementation after somatic cell fusion. Goez et al. (1995) described 2 IRD infants who had neonatal cholestatic jaundice as the sole initial clinical presentation of their disorder and no accompanying clinical features that would indicate peroxisomal disease. Parental consanguinity was present in both cases. The correct diagnosis was made by evaluation of plasma VLCFAs. Both families were Israeli-Arabs. The 2 parental couples met by chance in the hospital corridor and realized for the first time that all 4 were relatives. Bader et al. (2000) reported 4 Amish sibs from a consanguineous (second-cousin) marriage with clinical and biochemical findings of IRD. At least 3 of the 4 had characteristic poorly formed yellow-orange teeth. In addition, the 2 affected females had a pronounced behavior/mood problem which was most apparent after puberty. Jansen et al. (2004) pointed out that infantile Refsum disease was called such because at the time it was first described, Refsum disease was the only known disorder characterized by the accumulation of phytanic acid. Subsequent studies showed that these patients had metabolite patterns typical of generalized peroxisomal biogenesis disorders and, indeed, morphologic studies of liver showed a strong deficiency of peroxisomes. Jansen et al. (2004) concluded that infantile Refsum disease is an unfortunate name for this peroxisome biogenesis disorder, and suggested that the term be discarded. Paul et al. (1993) described affected male and female infant offspring of first-cousin Egyptian parents who presented with manifestations suggesting infantile progressive spinal muscular atrophy (253300). Moser et al. (1995) found that among the 61 patients in complementation group 1 (corresponding to Netherlands group 2 and Japan group E), 56% had the Zellweger syndrome phenotype (ZS; 214100), 26% had the phenotype of neonatal adrenoleukodystrophy (NALD), 11% had the phenotype of infantile Refsum disease (see 601539), and 43 patients (25%) had phenotype of rhizomelic chondrodysplasia (RCDP; 215100). A variant phenotype was observed in 7% of patients. One of the variant cases described by Moser et al. (1995) was a 40-year-old woman with severe hearing impairment and visual disturbances associated with pigmentary degeneration of the retina detected in early childhood. The patient received special education services, learned to read and write, became a good athlete, and in her twenties functioned well as a special education assistant. In her mid-thirties, gradually increasing impulsive and compulsive behavior developed, and by the age of 40 she had become mute and incontinent. This deterioration was attributed to an extensive and progressive leukodystrophy first demonstrated by magnetic resonance imaging (MRI) at age 37 years. The patient illustrated the wide range of both severity and clinical features in peroxisome biogenesis defects, even of the same complementation group. Of the whole group of 173 patients reported by Moser et al. (1995), 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. Using systematic clinical and biochemical investigations, Poll-The et al. (2004) delineated the natural history of 31 patients with PBDs, aged 1.2 to 24 years. They excluded classic Zellweger syndrome from the study and included all patients with biochemically confirmed generalized PBD over 1 year of age. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure. Hyperoxaluria was present in 10 patients, of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from nonverbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties. Molecular Genetics Reuber et al. (1997) identified a homozygous gly843-to-asp mutation of the PEX1 gene (G843D; 602136.0001) in at least 1 patient with neonatal adrenoleukodystrophy (NALD) and in several cases of infantile Refsum disease (IRD). Waterham and Ebberink (2012) stated that by far the most common mutation in PEX1 is the G843D mutation and that the effect of this mutation is relatively mild. ### Reviews Subramani (1997) summarized the progress in identifying PEX genes responsible for human genetic diseases. Waterham and Cregg (1997) reviewed the current understanding of peroxisome biogenesis. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Dysmorphic features \- Midface hypoplasia Ears \- Hearing impairment Eyes \- Retinitis pigmentosa \- Optic atrophy \- Epicanthal folds Nose \- Beaked nose ABDOMEN Liver \- Hepatomegaly \- Cirrhosis \- Hepatic fibrosis MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Leukodystrophy \- Developmental delay \- Psychomotor retardation \- Seizures LABORATORY ABNORMALITIES \- Peroxisome biogenesis disorder complementation group 1, CG1 \- Peroxisome biogenesis disorder complementation group E, CGE \- Increased very long chain fatty acids (VLCFAs) \- Varying degrees of catalase import into peroxisomes MISCELLANEOUS \- Survival into adulthood \- Disorder is progressive in some patients MOLECULAR BASIS \- Caused by mutation in the peroxisome biogenesis factor 1 gene (PEX1, 602136.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PEROXISOME BIOGENESIS DISORDER 1B	c0282527	2,232	omim	https://www.omim.org/entry/601539	2019-09-22T16:14:39	{"mesh": ["D052919"], "omim": ["601539"], "icd-10": ["G60.1"], "orphanet": ["772", "44"], "synonyms": ["Alternative titles", "PEROXISOME BIOGENESIS DISORDER (NEONATAL ADRENOLEUKODYSTROPHY/INFANTILE REFSUM DISEASE)", "PEROXISOME BIOGENESIS DISORDER (NALD/IRD)", "ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL", "REFSUM DISEASE, INFANTILE", "INFANTILE PHYTANIC ACID STORAGE DISEASE"]}
Localized heat contact urticaria SpecialtyDermatology Localized heat contact urticaria is a cutaneous condition, one of the rarest forms of urticaria, where within minutes of contact with heat from any source, itching and whealing occur at the precise site of contact, lasting up to 1 hour.[1] ## See also[edit] * Drug-induced urticaria * 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. 267. ISBN 978-1-4160-2999-1. * v * t * e Urticaria and erythema Urticaria (acute/chronic) Allergic urticaria * Urticarial allergic eruption Physical urticaria * Cold urticaria * Familial * Primary cold contact urticaria * Secondary cold contact urticaria * Reflex cold urticaria * Heat urticaria * Localized heat contact urticaria * Solar urticaria * Dermatographic urticaria * Vibratory angioedema * Pressure urticaria * Cholinergic urticaria * Aquagenic urticaria Other urticaria * Acquired C1 esterase inhibitor deficiency * Adrenergic urticaria * Exercise urticaria * Galvanic urticaria * Schnitzler syndrome * Urticaria-like follicular mucinosis Angioedema * Episodic angioedema with eosinophilia * Hereditary angioedema Erythema Erythema multiforme/ drug eruption * Erythema multiforme minor * Erythema multiforme major * Stevens–Johnson syndrome, Toxic epidermal necrolysis * panniculitis (Erythema nodosum) * Acute generalized exanthematous pustulosis Figurate erythema * Erythema annulare centrifugum * Erythema marginatum * Erythema migrans * Erythema gyratum repens Other erythema * Necrolytic migratory erythema * Erythema toxicum * Erythroderma * Palmar erythema * Generalized erythema This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Localized heat contact urticaria	None	2,233	wikipedia	https://en.wikipedia.org/wiki/Localized_heat_contact_urticaria	2021-01-18T18:35:12	{"wikidata": ["Q6664628"]}
A sack of "pink grain". Note the labelling in Spanish, and the grain's distinctive orange-pink colour. Images like this were suppressed in state media.[1] The 1971 Iraq poison grain disaster was a mass methylmercury poisoning incident that began in late 1971. Grain treated with a methylmercury fungicide and never intended for human consumption was imported into Iraq as seed grain from Mexico and the United States. Due to a number of factors, including foreign-language labelling and late distribution within the growing cycle, this toxic grain was consumed as food by Iraqi residents in rural areas. People suffered from paresthesia (numbness of skin), ataxia (lack of coordination of muscle movements) and vision loss, symptoms similar to those seen when Minamata disease affected Japan. The recorded death toll was 459 people, but figures at least ten times greater have been suggested. The 1971 poisoning was the largest mercury poisoning disaster when it occurred,[2] with cases peaking in January and February 1972 and stopping by the end of March. Reports after the disaster recommended tighter regulation, better labelling and handling of mercury-treated grain, and wider involvement of the World Health Organization in monitoring and preventing poisoning incidents. Investigation confirmed the particular danger posed to fetuses and young children. ## Contents * 1 Context * 2 Causes * 3 Symptoms, outbreak and treatment * 4 Effects * 5 See also * 6 References ## Context[edit] The properties of mercury make it an effective fungicide. Methylmercury had been banned in Sweden in 1966,[3] the first country to do so, and the United Kingdom followed in 1971.[4] Previous mercury-poisoning incidents had occurred in Iraq in 1956 and 1960. In 1956, there had been around 200 cases, and 70 deaths; in 1960 there had been 1000 cases and 200 deaths, in both cases due to ethylmercury compounds.[5] Among the recommendations made after the 1960 incident had been to colour any toxic grain for easy identification.[5] Before the 1971 incident, around 200–300 cases of methylmercury poisoning had been reported worldwide.[2] Drought had reduced harvests in 1969, affecting 500,000 people,[6] and in 1970. Saddam Hussein, as the government's no. 2 behind Ahmed Hassan al-Bakr, decided to import mercury-coated seed grain for the late 1971 planting season. Hussein himself may have worked in the Department of Agriculture in the aftermath of the 1960 incident.[7] ## Causes[edit] A map of Iraq (1976) showing the provinces referred to. Some 95,000 tonnes (93,000 long tons; 105,000 short tons) of grain (73,201 tonnes of wheat grain and 22,262 tonnes of barley), coloured a pink-orange hue, were shipped to Iraq from the United States and Mexico. The wheat arrived in Basra on SS Trade Carrier between 16 September and 15 October, barley between 22 October and 24 November 1971. Iraq's government chose Mexipak, a high-yield wheat seed developed in Mexico by Norman Borlaug. The seeds contained an average of 7.9 μg/g of mercury, with some samples containing up to nearly twice that. The decision to use mercury-coated grain has been reported as made by the Iraqi government, rather than the supplier, Cargill.[7] The three Northern governorates of Ninawa, Kirkuk and Erbil together received more than half the shipments. Contributing factors to the epidemic included the fact that distribution started late, and much grain arrived after the October–November planting season. Farmers holding grain ingested it instead, since their own planting had been completed. Distribution was hurried and open, with grain being distributed free of charge or with payment in kind. Some farmers sold their own grain lest this new grain devalue what they had. This left them dependent on tainted grain for the winter. Many Iraqis were either unaware of the significant health risk posed, or chose to ignore the warnings.[8] Initially, farmers were to certify with a thumbprint or signature that they understood the grain was poison, but according to some sources, distributors did not ask for such an indication.[7] Warnings on the sacks were in Spanish and English, not at all understood, or included the black-and-white skull and crossbones design, which meant nothing to Iraqis.[7] The long latent period may have granted farmers a false sense of security, when animals fed the grain appeared to be fine. The red dye washed off the grain; the mercury did not. Hence, washing may have given only the appearance of removing the poison.[2] Mercury was ingested through the consumption of homemade bread, meat and other animal products obtained from livestock given treated barley, vegetation grown from soil contaminated with mercury, game birds that had fed on the grain and fish caught in rivers, canals, and lakes into which treated grain had been dumped by the farmers. Ground seed dust inhalation was a contributing factor in farmers during sowing and grinding. Consumption of ground flour through homemade bread is thought to have been the major cause,[9] since no cases were reported in urban areas, where government flour supplies were commercially regulated.[2] ## Symptoms, outbreak and treatment[edit] The effect of mercury took some time – the latent period between ingestion and the first symptoms (typically paresthesia – numbness in the extremities) was between 16 and 38 days. Paresthesia was the predominant symptom in less serious cases. Worse cases included ataxia (typically loss of balance), blindness or reduced vision, and death resulting from central nervous system failure. Anywhere between 20 and 40 mg of mercury has been suggested as sufficient for paresthesia (between 0.5 and 0.8 mg/kg of body weight[9]). On average, individuals affected consumed 20 kg or so of bread; the 73,000 tonnes provided would have been sufficient for over 3 million cases.[2] The hospital in Kirkuk received large numbers of patients with symptoms that doctors recognised from the 1960 outbreak. The first case of alkylmercury poisoning was admitted to hospital on 21 December.[9] By 26 December, the hospital had issued a specific warning to the government. By January 1972, the government had started to strongly warn the populace about eating the grain, although dispatches did not mention the large numbers already ill. The Iraqi Army soon ordered disposal of the grain and eventually declared the death penalty for anyone found selling it.[1] Farmers dumped their supplies wherever possible, and it soon got into the water supply (particularly the River Tigris), causing further problems. The government issued a news blackout and released little information about the outbreak.[2][7] The World Health Organization assisted the Iraqi government through the supply of drugs, analytical equipment and expertise. Many new treatments were tried, since existing methods for heavy metal poisoning were not particularly effective. Dimercaprol was administered to several patients, but caused rapid deterioration of their condition. It was ruled out as a treatment for this sort of poisoning following the outbreak. Polythiol resins, penicillamine and dimercaprol sulfonate all helped, but are believed to have been largely insignificant in overall recovery and outcomes. Dialysis was tested on a few patients late in the treatment period, but they showed no clinical improvement.[9] The result of all treatments was varied, with some patients' blood mercury level being dramatically reduced, but a negligible effect in others. All patients received periods of treatment interspersed with lay periods; continuous treatment was suggested in future cases. Later treatment was less effective in reducing blood toxicity.[2] ## Effects[edit] Incidence of cases and fatalities, by age group[2] 6,530 patients were admitted to hospitals with poisoning, and 459 deaths reported.[2] Cases reached a peak of hundreds per day in January, and had largely subsided by the beginning of March. The last admittance was on 27 March; admissions represented every age and gender stratum, although those under the age of ten represented a third of admitted cases. This number is "certainly an underestimate",[9] because of the availability of hospital treatment, hospital overcrowding and lack of faith in treatment. In the most severely affected areas, prevalence was 28% and mortality was 21% of the cases.[9] Some Iraqi doctors believe both the number of cases and fatalities are at least ten times too low,[7] with perhaps 100,000 cases of brain damage. One suggested reason for the vast discrepancy between reported and estimated numbers of deaths is the Iraqi custom, common to large parts of the Middle East, for a person to die at home when possible. Home deaths would not have been recorded.[10] A large number of patients with minor symptoms recovered completely; those with more serious symptoms improved. This was in contrast to expected outcomes, largely based on analysis of Minamata disease in Japan. In boys with mercury levels below clinical poisoning, a reduction in school performance was noted, although this correlation could not be confirmed.[9] In infants, the mercury poisoning caused central nervous system damage. Relatively low doses caused slower development in children, and abnormal reflexes.[8] Different treatments for mercury poisoning have since been developed, and "quiet baby syndrome", characterised by a baby who never cries, is now a recognised symptom of methylmercury-induced brain damage.[10] Ongoing recommendations of the food regulation authorities have focused on consumption by pregnant women and infant children,[11] noting the particular susceptibility of fetuses and infants to methylmercury poisoning. Data from Iraq have confirmed that methylmercury can pass to a child in utero, and mercury levels were equal to or higher in the newborn child than in the mother.[2] In 1974, a joint Food and Agriculture Organization (FAO) and World Health Organization (WHO) meeting made several recommendations to prevent a similar outbreak. These included stressing the importance of labelling bags in the local language and with locally understood warning symbols. The possibility of an additive creating a strong bitter taste was studied.[9] The meeting urged governments to strictly regulate methyl- and ethylmercury use in their respective countries, including limiting use to where no other reasonable alternative was available. It also recommended the involvement of the FAO and WHO in assisting national governments in regulation and enforcement, and the setting up of national poison control centres. Over 9–13 November, a Conference on Intoxication due to Alkylmercury-Treated Seed was held in Baghdad. It supported the recommendations of the FAO/WHO report and further suggested that local and national media should publicise outbreaks, including size and symptoms; it considered the distribution of this information crucial. It also laid out a general plan as to the collection of relevant information from the field and potential analysis for further investigation. It called on national governments to make use of WHO involvement whenever feasible, and absolved world governments in clear terms, saying that "No country should ever feel that any blame will attach to it for allowing an outbreak to occur".[9] ## See also[edit] * Minamata disease ## References[edit] 1. ^ a b Hightower (2008). p.151 2. ^ a b c d e f g h i j Bakir F, Damluji SF, Amin-Zaki L, et al. (July 1973). "Methylmercury poisoning in Iraq" (PDF). Science. 181 (4096): 230–41. doi:10.1126/science.181.4096.230. PMID 4719063. Retrieved 11 June 2010. 3. ^ Matolcsy, György; Nádasy, Miklós; Andriska, Viktor (1988). "Mercury". Pesticide chemistry. Amsterdam: Elsevier. p. 294. ISBN 978-0-444-98903-1. 4. ^ United Kingdom Health and Safety Executive. Banned and Non-Authorised Pesticides in the United Kingdom. Retrieved on 13 June 2010. 5. ^ a b Al-Damluji SF (1976). "Organomercury poisoning in Iraq: history prior to the 1971-72 outbreak". Bull. World Health Organ. 53 suppl: 11–13. PMC 2366396. PMID 788949. 6. ^ Goodyear, EJ (2009). "The State of Disaster Risk Reduction in Iraq" (PDF). UN Inter-Agency Information and Analysis Unit: Iraq. p. 12. Archived from the original (PDF) on 2011-07-26. Retrieved 18 July 2010. 7. ^ a b c d e f Jane M. Hightower (2008). "11". Diagnosis: Mercury: Money, Politics, and Poison. Washington, DC: Island Press. pp. 141–151. ISBN 978-1-59726-395-5. 8. ^ a b Oller, J.W.; Oller, S.D. (2009). Autism: The Diagnosis, Treatment, & Etiology of the Undeniable Epidemic. Sudbury, Mass: Jones & Bartlett Publishers. p. 156. ISBN 978-0-7637-5280-4. Retrieved 24 July 2010. 9. ^ a b c d e f g h i Skerfving SB, Copplestone JF (1976). "Poisoning caused by the consumption of organomercury-dressed seed in Iraq". Bull. World Health Organ. 54 (1): 101–112. PMC 2366450. PMID 1087584. 10. ^ a b Jernelov, Arne (2003-09-09). "Iraq's Secret Environmental Disasters". Project Syndicate. Archived from the original on 15 June 2010. Retrieved 10 June 2010. 11. ^ Heller, J.L. (14 January 2010). "Methylmercury poisoning". Medical Center. University of Maryland. Archived from the original on 28 May 2010. Retrieved 14 June 2010. * v * t * e Consumer food safety Adulterants, food contaminants * 3-MCPD * Aldicarb * Antibiotic use in livestock * Cyanide * Formaldehyde * HGH controversies * Lead poisoning * Melamine * Mercury in fish * Sudan I Flavorings * Monosodium glutamate (MSG) * Salt * Sugar * High-fructose corn syrup Intestinal parasites and parasitic disease * Amoebiasis * Anisakiasis * Cryptosporidiosis * Cyclosporiasis * Diphyllobothriasis * Enterobiasis * Fasciolopsiasis * Fasciolosis * Giardiasis * Gnathostomiasis * Paragonimiasis * Toxoplasmosis * Trichinosis * Trichuriasis Microorganisms * Botulism * Campylobacter jejuni * Clostridium perfringens * Cronobacter * Enterovirus * Escherichia coli O104:H4 * Escherichia coli O157:H7 * Hepatitis A * Hepatitis E * Listeria * Norovirus * Rotavirus * Salmonella * Vibrio cholerae Pesticides * Chlorpyrifos * DDT * Lindane * Malathion * Methamidophos Preservatives * Benzoic acid * Ethylenediaminetetraacetic acid (EDTA) * Sodium benzoate Sugar substitutes * Acesulfame potassium * Aspartame * Saccharin * Sodium cyclamate * Sorbitol * Sucralose Toxins, poisons, environment pollution * Aflatoxin * Arsenic contamination of groundwater * Benzene in soft drinks * Bisphenol A * Dieldrin * Diethylstilbestrol * Dioxin * Mycotoxins * Nonylphenol * Shellfish poisoning Food contamination incidents * Devon colic * Swill milk scandal * Esing Bakery incident * 1858 Bradford sweets poisoning * 1900 English beer poisoning * Morinaga Milk arsenic poisoning incident * Minamata disease * 1971 Iraq poison grain disaster * Toxic oil syndrome * 1985 diethylene glycol wine scandal * UK mad cow disease outbreak * 1993 Jack in the Box E. coli outbreak * 1996 Odwalla E. coli outbreak * 2006 North American E. coli outbreaks * ICA meat repackaging controversy * 2008 Canada listeriosis outbreak * 2008 Chinese milk scandal * 2008 Irish pork crisis * 2008 United States salmonellosis outbreak * 2011 Germany E. coli outbreak * 2011 United States listeriosis outbreak * 2013 Bihar school meal poisoning * 2013 horse meat scandal * 2015 Mozambique beer poisoning * 2017 Brazil weak meat scandal * 2017–18 South African listeriosis outbreak * 2018 Australian rockmelon listeriosis outbreak * 2018 Australian strawberry contamination * Food safety incidents in China * Food safety incidents in Taiwan * Food safety in Australia * Foodborne illness * outbreaks * death toll * United States Regulation, standards, watchdogs * Acceptable daily intake * E number * Food labeling regulations * Food libel laws * International Food Safety Network * ISO 22000 * Nutrition facts label * Organic certification * The Non-GMO Project * Quality Assurance International * Food Standards Agency Institutions * Institute for Food Safety and Health * European Food Safety Authority * International Food Safety Network * Spanish Agency for Food Safety and Nutrition * Food Information and Control Agency (Spain) * Centre for Food Safety (Hong Kong) * Ministry of Food and Drug Safety (South Korea) * v * t * e Cargill People * Cargill family * Austen S. Cargill II * James R. Cargill * James R. Cargill II * Margaret Anne Cargill * William Wallace Cargill * Marianne Cargill Liebmann * Cargill MacMillan Jr * Cargill MacMillan Sr * Whitney MacMillan * Gwendolyn Sontheim Meyer * Gregory R. Page * Marion MacMillan Pictet * Warren Staley Subsidiaries * Cargill Ltd. * Cargill Meat Solutions * Provimi * Wilbur Chocolate Company Joint ventures * Frontier Agriculture * The Mosaic Company Products * Rebiana * Robin Hood Flour * Truvia Related articles * 1971 Iraq poison grain disaster * Alberger process * Criticisms of Cargill * 2018 Virginia strike [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	1971 Iraq poison grain disaster	None	2,234	wikipedia	https://en.wikipedia.org/wiki/1971_Iraq_poison_grain_disaster	2021-01-18T18:53:19	{"wikidata": ["Q4284220"]}
A number sign (#) is used with this entry because Bardet-Biedl syndrome-6 (BBS6) is caused by homozygous or compound heterozygous mutation in the MKKS gene (604896) on chromosome 20p12. Mutations in the MKKS gene can also cause McKusick-Kaufman syndrome (236700). Description BBS6 is an autosomal recessive disorder with cardinal features of postaxial polydactyly, retinitis pigmentosa, kidney defects, obesity, and mental retardation (Slavotinek et al., 2000). Zaghloul and Katsanis (2009) estimated that mutations in the MKKS gene account for 5.8% of the total BBS mutational load. For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). Clinical Features Slavotinek et al. (2000) described patients from 4 families with BBS6. The first was a 13-year-old Hispanic girl with severe retinitis pigmentosa, postaxial polydactyly, mental retardation, and obesity (BMI greater than 40). A second proband and her affected brother had retinitis pigmentosa, postaxial polydactyly, mild mental retardation, morbid obesity (BMI greater than 50 and 37, respectively), lobulated kidneys with prominent calyces, and diabetes mellitus. A deceased sister had similar phenotypic features and also had vaginal atresia and syndactyly of both feet. A third family included a 4-year-old male proband with reduced visual acuity, postaxial polydactyly, obesity, and cystic kidneys, and a sib with hypospadias, postaxial polydactyly, obesity, and lobular cystic kidneys who died at age 18 months. A fourth family consisted of a female proband diagnosed at age 5 years because of severe retinitis pigmentosa, postaxial polydactyly, morbid obesity, and diabetes mellitus, and a male sib with retinitis pigmentosa, postaxial polydactyly, obesity, lobulated cystic kidneys, and diabetes mellitus. Scheidecker et al. (2015) reported a 36-year-old patient with BBS6 who had moderately severe cone dystrophy with mildly decreased visual acuity and photophobia. Molecular Genetics Slavotinek et al. (2000) and Katsanis et al. (2000) identified mutations in the MKKS gene in patients with BBS. Slavotinek et al. (2000) ascertained 34 unrelated probands with classic features of BBS including retinitis pigmentosa, obesity, and polydactyly. They found MKKS mutations in 4 typical BBS probands. Three of the probands were from Newfoundland and were also included in the study of Katsanis et al. (2000). Slavotinek et al. (2000) sought mutations in the MKKS gene because of phenotypic similarities between McKusick-Kaufman syndrome and Bardet-Biedl syndrome. McKusick-Kaufman syndrome (236700) includes hydrometrocolpos, postaxial polydactyly, and congenital heart disease, with autosomal recessive inheritance. Bardet-Biedl syndrome is likewise an autosomal recessive disorder and is characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism, and renal malformations, with secondary features that include diabetes mellitus. Katsanis et al. (2000) performed a genome screen in BBS families from Newfoundland in which linkage to known BBS loci had been excluded. Fine mapping reduced the critical interval to a region including the MKKS gene. Given the mapping position and the clinical similarity between McKusick-Kaufman syndrome and Bardet-Biedl syndrome, they screened the MKKS gene and identified mutations in 5 Newfoundland and 2 European-American BBS pedigrees. Most were frameshift mutations, predicted to result in a nonfunctional protein. Beales et al. (2001) collected a cohort of 163 BBS pedigrees from diverse ethnic backgrounds and evaluated them for mutations in the MKKS gene and for potential assignment of the disorder to any of the other known BBS loci. Using a combination of mutation and haplotype analysis, they described a spectrum of BBS6 alterations that are likely to be pathogenic; proposed substantially reduced critical intervals for BBS2 (209900) on 16q21, BBS3 (608845) on 3p, and BBS5 (603650) on 2q; and presented evidence for the existence of at least one more BBS locus, bringing the total to 7. The data suggested that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype. In a population-based study including 93 BBS patients from 74 families of various ethnicities, Billingsley et al. (2010) determined that the chaperonin-like BBS6, BBS10 (610148), and BBS12 (610683) genes are a major contributor to the disorder. Biallelic mutations in these 3 genes were found in 36.5% of the families: 4 patients had mutations in BBS6, 19 had mutations in BBS10, and 10 had mutations in BBS12. Overall, 26 (68%) of 38 mutations were novel. Six patients had mutations present in more than 1 chaperonin-like BBS gene, and 1 patient with a very severe phenotype had 4 mutations in BBS10. The phenotypes observed were beyond the classic BBS phenotype and overlapped with characteristics of MKKS (236700), including congenital heart defect, vaginal atresia, hydrometrocolpos, and cryptorchidism, and with Alstrom syndrome (203800), including diabetes, hearing loss, liver abnormalities, endocrine anomalies, and cardiomyopathy. INHERITANCE \- Autosomal recessive GROWTH Weight \- Obesity HEAD & NECK Eyes \- Retinitis pigmentosa \- Retinal dystrophy GENITOURINARY External Genitalia (Male) \- Hypogenitalism \- Hypospadias Kidneys \- Structural renal abnormalities \- Lobulated kidneys \- Cystic kidneys SKELETAL Hands \- Polydactyly Feet \- Syndactyly NEUROLOGIC Central Nervous System \- Learning disabilities \- Mental retardation ENDOCRINE FEATURES \- Diabetes mellitus MOLECULAR BASIS \- Caused by mutation in the MKKS gene (MKKS, 604896.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	BARDET-BIEDL SYNDROME 6	c0752166	2,235	omim	https://www.omim.org/entry/605231	2019-09-22T16:11:28	{"doid": ["0110128"], "mesh": ["D020788"], "omim": ["605231"], "orphanet": ["110"]}
Developmental language disorder SpecialtyNeurology Developmental language disorder (DLD) is identified when a child has problems with language development that continue into school age and beyond. The language problems have a significant impact on everyday social interactions or educational progress, and occur in the absence of autism spectrum disorder, intellectual disability or a known biomedical condition. The most obvious problems are difficulties in using words and sentences to express meanings, but for many children, understanding of language (receptive language) is also a challenge, although this may not be evident unless the child is given a formal assessment. ## Contents * 1 Classification * 1.1 Terminology * 1.2 Types of language difficulty * 1.3 Relationship with speech disorders * 1.4 Relationship with other neurodevelopmental disorders * 2 Risk factors * 2.1 Associated factors * 3 Diagnosis * 3.1 Benchmarks for children with Developmental Language Disorder * 3.2 Assessment * 4 Treatment * 4.1 How to help a child with Developmental Language Disorder * 5 Outcome * 6 Prevalence * 7 Research * 7.1 Developmental learning disorder in adults * 8 See also * 9 References * 10 Further reading * 11 External links ## Classification[edit] ### Terminology[edit] The term developmental language disorder (DLD) was endorsed in a consensus study involving a panel of experts (CATALISE Consortium) in 2017.[1] The study was conducted in response to concerns that a wide range of terminology was used in this area, with the consequence that there was poor communication, lack of public recognition, and in some cases children were denied access to services. Developmental language disorder is a subset of language disorder, which is itself a subset of the broader category of speech, language and communication needs (SLCN). The terminology for children’s language disorders has been extremely wide-ranging and confusing, with many labels that have overlapping but not necessarily identical meanings.[2] In part this confusion reflected uncertainty about the boundaries of DLD, and the existence of different subtypes. Historically, the terms ‘’developmental dysphasia’’ or ‘’developmental aphasia’’ were used to describe children with the clinical picture of DLD.[3] These terms have, however, largely been abandoned, as they suggest parallels with adult acquired aphasia. This is misleading, as DLD is not caused by brain damage.[4] Although the term DLD has been used for many years, it has been less common than the term specific language impairment (SLI),[2] which has been widely adopted, especially in North America.[5] The definition of SLI overlaps with DLD, but was rejected by the CATALISE panel because it was seen as overly restrictive in implying that the child had relatively pure problems with language in the absence of any other impairments. Children with such selective problems are relatively rare, and there is no evidence that they respond differently to intervention, or have different causal factors, from other children with language problems.[6] In the UK education system the term speech, language and communication needs (SLCN) is widely used, but this is far broader than DLD, and includes children with speech, language and social communication difficulties arising from a wide range of causes.[7] The question of whether to refer to children's language problems as ‘disorder’ was a topic of debate among the CATALISE consortium, but the conclusion was that ‘disorder’ conveyed the serious nature and potential consequences of persistent language deficits. It is also parallel with other neurodevelopmental conditions and consistent with diagnostic frameworks such as DSM-5 and ICD-11.[1] Where there are milder or more transient difficulties, language difficulties may be a more appropriate term. ### Types of language difficulty[edit] DLD can affect a range of areas of language and the degree of impairment in different areas of language can vary from child to child.[8] However, although there have been attempts to define different subtypes, these have not generally resulted in robust categories.[9] The recommendation of the CATALISE panel was that the specific areas of impairment should be assessed and documented for individual children, while recognizing that different children might have different combinations of problems. The areas which can be affected are: * Grammar – This involves the ability to combine words into grammatically correct sentences (syntax) and to combine parts of words together (morphology) such as adding grammatical endings to verbs like -ing or -ed or to add prefixes and suffixes like dis- or -ation. For instance, a child may say 'me jump here', instead of 'I jumped here'.[10] Comprehension of sentences can also be affected. For instance, there may be difficulty understanding meaning expressed by word order, and so confusion about what is blue in a sentence like 'the pencil on the shoe is blue',[11] and a tendency to use general knowledge rather than linguistic cues to meaning,[12] or problems in interpreting grammatical markers of number or tense.[13] * Semantics – This refers to children’s ability to understand the meaning of words and how meanings are expressed by combining words together. Children with DLD often have limited vocabulary and may make heavy use of a small set of words with rather general meanings.[14] As children with developmental language disorder get older, they may have a hard time understanding that some words have multiple meanings, for example the word “cold,” which can mean a low temperature, a sickness, or being unfriendly.[15][14] * Word finding – Children with word finding difficulties may know a word, but have difficulty accessing it for production[16] – similar to the tip of the tongue phenomenon. * Pragmatics – Pragmatics refers to the ability to select the appropriate message, or interpret what others say, in relation to context. Pragmatic difficulties can give an impression of oddity, with the content of language not fitting the environmental or social context; comprehension may be over-literal; the child may chatter incessantly, be poor at turn-taking in conversation and maintaining a topic[17] * Discourse – Discourse refers to a level of organization of language beyond the sentence. Child with limitations in this domain may have limited ability to tell a story or describe a set of events in a logical sequence[18] * Verbal memory and learning – Problems with remembering words or sentences can affect both the learning of new vocabulary,[19] and the understanding of long or complex sentences.[20] Young children with DLD may say their first words later than other children. It may also take children with DLD longer to learn and remember novel words.[15] * Phonology – Phonology is the branch of linguistics concerned with the way sounds are combined together in words. Children with difficulties with phonology may fail to distinguish between certain speech sounds, such as 't' and 'k', so that 'cake' is produced as 'tate'. Such difficulties are not unusual as part of typical development in toddlers, but they would usually resolve by the time children are 4–5 years old.[21] Difficulties with producing some speech sounds accurately may reduce intelligibility of speech.[22] In addition, more subtle difficulties in recognising specific sounds in words (phonological awareness) can lead to literacy difficulties.[23] ### Relationship with speech disorders[edit] Speech is the act of articulating sounds, and this can be impaired for all kinds of reasons – a structural problem such as cleft lip and cleft palate, a neurological problem affecting motor control of the speech apparatus dysarthria, or inability to perceive distinctions between sounds because of hearing loss. Some distortions of speech sounds, such as a lisp, are commonly seen in young children. These misarticulations should not be confused with language problems, which involve the ability to select and combine linguistic elements to express meanings, and the ability to comprehend meanings. Although speech disorders can be distinguished from language disorders, they can also co-occur.[24] When a child fails to produce distinctions between speech sounds for no obvious reason, this is typically regarded as a language problem affecting the learning of phonological contrasts. The classification of and terminology for disorders of speech sound production is a subject of considerable debate.[25] In practice, even for those with specialist skills, it is not always easy to distinguish between phonological disorders and other types of speech production problem. Speech sound disorder (SSD) is any problem with speech production arising from any cause.[26] Speech sound disorders of unknown cause that are not accompanied by other language problems are a relatively common reason for young children to be referred to speech-language therapy (speech-language pathology).[27] These often resolve by around 4–5 years of age with specialist intervention,[28] and so would not meet criteria for DLD. Where such problems continue beyond five years of age, they are usually accompanied by problems in broader language domains and have a poorer prognosis,[29] so a diagnosis of DLD with SSD is then appropriate. Developmental language disorder impairment compared to other common language related disorders ### Relationship with other neurodevelopmental disorders[edit] DLD often co-occurs with milder neurodevelopmental disorders of unknown origin, such as attention-deficit hyperactivity disorder, developmental dyslexia or developmental co-ordination disorder.[6] These do not preclude a diagnosis of DLD, but should be noted as co-occurring conditions. ## Risk factors[edit] It is generally accepted that DLD is strongly influenced by genetic factors.[30] The best evidence comes from the twin study method. Two twins growing up together are exposed to the same home environment, yet may differ radically in their language skills. Such different outcomes are, however, much more common in fraternal (non-identical) twins, who are genetically different. Identical twins share the same genes and tend to be much more similar in language ability. There can be some variation in the severity and persistence of DLD in identical twins, indicating that non-genetic factors affect the course of disorder, but it is unusual to find a child with DLD who has an identical twin with typical language.[31] There was considerable excitement when a large, multigenerational family with a high rate of DLD were found to have a mutation of the FOXP2 gene just in the affected family members.[32] However, subsequent studies have found that, though DLD runs in families, it is not usually caused by a mutation in FOXP2 or another specific gene.[33] Current evidence suggests that there are many different genes that can influence language learning, and DLD results when a child inherits a particularly detrimental combination of risk factors, each of which may have only a small effect.[30] Nevertheless, study of the mode of action of the FOXP2 gene has helped identify other common genetic variants involved in the same neural pathways that may play a part in causing DLD.[34] Language disorders are associated with aspects of home environment, and it is often assumed that this is a causal link, with poor language stimulation leading to weak language skills. Twin studies, however, show that two children in the same home environment can have very different language outcomes, suggesting we should consider other explanations for the link. Children with DLD often grow up into adults who have relatively low educational attainments,[35] and their children may share a genetic risk for language disorder.[2] One non-genetic factor that is known to have a specific impact on language development is being a younger sibling in a large family.[36] ### Associated factors[edit] It has long been noted that males are more affected by DLD than females, with a sex ratio of affected males: females around 3 or 4:1.[37] However, the sex difference is much less striking in epidemiological samples, suggesting that similar problems may exist in females but are less likely to be detected.[38] The reason for the sex difference is not well understood. Poor motor skills are commonly found in children with DLD.[39] Standardized measures of motor ability confirm that children with DLD exhibit deficits in fine and gross motor skill, both simple and complex. These difficulties also extend to speech-motor ability, particularly with the control of their articulatory movements. Children with DLD have difficulty with motor sequence learning and may show deficits in other procedural motor processes as well.[40] Brain scans do not usually reveal any obvious abnormalities in children with DLD, although quantitative comparisons have found differences in brain size or relative proportions of white or grey matter in specific regions. In some cases, unusual brain gyri are found. To date, no consistent 'neural signature' for DLD has been found, although some studies have noted evidence for involvement of subcortical systems.[41] Differences in the brains of children with DLD vs typically developing children are subtle and may overlap with atypical patterns seen in other neurodevelopmental disorders.[42] ## Diagnosis[edit] DLD is defined purely in behavioural terms: there is no biological test. There are three points that need to be met for a diagnosis of DLD:[1] 1. The child has language difficulties that create obstacles to communication or learning in everyday life, 2. The child's language problems are unlikely to resolve by five years of age, and 3. The problems are not associated with a known biomedical condition such as brain injury, neurodegenerative conditions, genetic conditions or chromosome disorders such as Down syndrome, sensorineural hearing loss, or autism spectrum disorder or intellectual disability. For research and epidemiological purposes, specific cutoffs on language assessments have been used to document the first criterion. Tomblin et al.[43] proposed the EpiSLI criterion, based on five composite scores representing performance in three domains of language (vocabulary, grammar, and narration) and two modalities (comprehension and production). Children scoring in the lowest 10% on two or more composite scores are identified as having language disorder. The second criterion, persistence of language problems, can be difficult to judge in a young child, but longitudinal studies have shown that difficulties are less likely to resolve for children who have poor language comprehension, rather than difficulties confined to expressive language.[1] In addition, children with isolated difficulties in just one of the areas noted under 'subtypes' tend to make better progress than those whose language is impaired in several areas.[29] The third criterion specifies that DLD is used for children whose language disorder is not part of another biomedical condition, such as a genetic syndrome, a sensorineural hearing loss, neurological disease, autism spectrum disorder or intellectual disability – these were termed 'differentiating conditions' by the CATALISE panel.[1] Language disorders occurring with these conditions need to be assessed and children offered appropriate intervention, but a terminological distinction is made so that these cases would be diagnosed as language disorder associated with the main diagnosis being specified: e.g. "language disorder associated with autism spectrum disorder." The reasoning behind these diagnostic distinctions is discussed further by Bishop (2017).[44] ### Benchmarks for children with Developmental Language Disorder[edit] Common red flags at one year of age * No reaction to sound * No babbling * Difficulty feeding * No imitation * Limited use of gestures At two years of age * Makes minimal attempts to communicate with gestures or words * Has not spoken their first words * Difficulty following simple directions * Inconsistent response to "no" At three years of age * Limited use of speech * Incomprehensible speech * Limited understanding of simple questions * Difficulty naming objects * Frustration related to communication At four years of age * Uses only 3 word phrases * Speech is not understandable to parents * Takes a long time to understand others * Difficulty asking questions and finding words to express thoughts At five years of age * Speaks only in simple sentences * Speech is not understandable to teachers * Difficulty answering questions * Difficulty with complex directions * Difficulty telling stories * Difficulty with peer interactions [45] ### Assessment[edit] Assessment will usually include an interview with the child’s caregiver, observation of the child in an unstructured setting, a hearing test, and standardized tests of language.[46] There is a wide range of language assessments in English. Some are restricted for use by experts in speech-language pathology: speech and language therapists (SaLTs/SLTs) in the UK, speech-language pathologists (SLPs) in the US and Australia. A commonly used test battery for diagnosis of DLD is the Clinical Evaluation of Language Fundamentals (CELF). Assessments that can be completed by a parent or teacher can be useful to identify children who may require more in-depth evaluation. The Children’s Communication Checklist (CCC–2) is a parent questionnaire suitable for assessing everyday use of language in children aged four years and above who can speak in sentences. Informal assessments, such as language samples, are often used by speech-language therapists/pathologists to complement formal testing and give an indication of the child's language in a more naturalistic context. A language sample may be of a conversation or narrative retell. In a narrative language sample, an adult may tell the child a story using a wordless picture book (e.g. Frog Where Are You?, Mayer, 1969), then ask the child to use the pictures and tell the story back. Language samples can be transcribed using computer software such as the Systematic Analysis of Language Software, and then analyzed for a range of features: e.g., the grammatical complexity of the child's utterances, whether the child introduces characters to their story or jumps right in, whether the events follow a logical order, and whether the narrative includes a main idea or theme and supporting details. ## Treatment[edit] Treatment is usually carried out by speech and language therapists/pathologists, who use a wide range of techniques to stimulate language learning.[47] In the past, there was a vogue for drilling children in grammatical exercises, using imitation and elicitation, but such methods fell into disuse when it became apparent that there was little generalisation to everyday situations. Contemporary approaches to enhancing development of language structure, for younger children at least, are more likely to adopt 'milieu' methods, in which the intervention is interwoven into natural episodes of communication, and the therapist builds on the child's utterances, rather than dictating what will be talked about. Interventions for older children, may be more explicit, telling the children what areas are being targeted and giving explanations regarding the rules and structures they are learning, often with visual supports.[48][49] In addition, there has been a move away from a focus solely on grammar and phonology toward interventions that develop children's social use of language, often working in small groups that may include typically developing as well as language-impaired peers.[50] Another way in contemporary remediation differ from the past is that parents are more likely to be directly involved, but this approach is largely used with preschool children, rather than those whose problems persist into school age.[51][52] For school-aged children, teachers are increasingly involved in intervention, either in collaboration with speech and language therapists/pathologists, or as the main agents of delivery of the intervention. Evidence for the benefits of a collaborative approach is emerging,[53] but the benefits of asking education staff to be the main deliverers of SLT intervention (the “consultative” approach) are unclear.[54] When SLT intervention is delivered indirectly by trained SLT assistants, however, there are indications that this can be effective.[55] In this field, randomized controlled trial methodology has not been widely used, and this makes it difficult to assess clinical efficacy with confidence. Children's language will tend to improve over time, and without controlled studies, it can be hard to know how much of observed change is down to a specific treatment. There is, however, increasing evidence that direct 1:1 intervention with an SLT/P can be effective for improving vocabulary and expressive language.[56] There have been few studies of interventions that target receptive language,[57] though some positive outcomes have been reported.[58][59][60] ### How to help a child with Developmental Language Disorder[edit] * Talk to the child often to help them learn new words. * Read to them every day. Point out words you see. * Point to signs in the grocery store, at school, and outside. * Speak to the child in the language you know best. * Listen and answer when the child talks. * Get the child to ask you questions. * Give the child time to answer questions. * Keep them in school. Children who are school-refusers have poorer language skills overall, and a higher incidence of language impairments[61] ## Outcome[edit] Longitudinal studies indicate that problems are largely resolved by five years of age in around 40% of four-year-olds with early language delays who have no other presenting risk factors.[29] However, for children who still have significant language difficulties at school entry, reading problems are common, even for children who receive specialist help,[62] and educational attainments are typically poor.[63] Poor outcomes are most common in cases where comprehension as well as expressive language is affected.[64] There is also evidence that scores on tests of nonverbal ability of children with DLD decrease over the course of development.[65] DLD is associated with an elevated risk of social, emotional and mental health concerns.[66] For instance, in a UK survey, 64% of a sample of 11-year-olds with DLD scored above a clinical threshold on a questionnaire for psychiatric difficulties, and 36% were regularly bullied, compared with 12% of comparison children.[67] In the longer-term, studies of adult outcomes of children with DLD have found elevated rates of unemployment, social isolation and psychiatric disorder among those with early comprehension difficulties.[68] However, better outcomes are found for children who have milder difficulties and do not require special educational provision.[69] ## Prevalence[edit] Epidemiological surveys, in the US[70] and the UK[38] converge in estimating the prevalence of DLD in five-year-olds at around 7%. Therefore, the prevalence is one in every 15 children. By these statistics, in a classroom of 30 students, 2 would have DLD.[15] In research by Tomblin et al. prevalence of [DLD] in racial/ethnic groups was highest in Native Americans, with African Americans being the next highest, followed by Hispanics, and then Whites.[71] No students of Asian descent presented with [DLD]; however, other research does indicate that [DLD] is present in children of Asian descent). ## Research[edit] Much research has focused on trying to identify what makes language learning so hard for some children.[72] A major divide is between theories that attribute the difficulties to a low-level problem with auditory temporal processing, and those that propose there is a deficit in a specialised language-learning system.[73][74] Other accounts emphasise deficits in specific aspects of learning and memory.[75][76] It can be difficult to choose between theories because they do not always make distinctive predictions, and there is considerable heterogeneity among children with DLD. It has also been suggested that DLD may only arise when more than one underlying deficit is present.[77] ### Developmental learning disorder in adults[edit] Relatively little research has been conducted to test the outcomes of DLD in adults. In a study comparing 17 men with DLD to their non language disordered siblings, researchers found that The DLD men had normal intelligence with higher performance IQ than verbal IQ. The participants still exhibited a severe and persisting language disorder, severe literacy impairments and significant deficits in theory of mind and phonological processing. Within the DLD cohort higher childhood intelligence and language were associated with superior cognitive and language ability at final adult outcome. In their mid-thirties, the DLD cohort had significantly worse social adaptation (with prolonged unemployment and a paucity of close friendships and love relationships) compared with both their siblings and NCDS controls. Self-reports showed a higher rate of schizotypal features but not affective disorder. Four DLD adults had serious mental health problems (two had developed schizophrenia).[78] ## See also[edit] * Specific language impairment * Auditory processing disorder * Dyslexia * Language delay * Language processing * Linguistics * Origin of speech * Pragmatic language impairment ## References[edit] 1. ^ a b c d e Bishop, Dorothy V.M.; Snowling, Margaret J.; Thompson, Paul A.; Greenhalgh, Trisha (October 2017). "Phase 2 of CATALISE: a multinational and multidisciplinary Delphi consensus study of problems with language development: Terminology". Journal of Child Psychology and Psychiatry. 58 (10): 1068–1080. doi:10.1111/jcpp.12721. PMC 5638113. PMID 28369935. 2. ^ a b c Bishop, D. V. M. (July 2014). "Ten questions about terminology for children with unexplained language problems". International Journal of Language & Communication Disorders. 49 (4): 381–415. doi:10.1111/1460-6984.12101. 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PMID 15755307. 66. ^ Cohen, Nancy (2001). Language impairment and psychopathology in infants, children, and adolescents. Thousand Oaks: Sage Publications. ISBN 0-7619-2025-0. OCLC 45749780. 67. ^ Conti-Ramsden, Gina; Botting, Nicola (1 February 2004). "Social Difficulties and Victimization in Children With SLI at 11 Years of Age". Journal of Speech, Language, and Hearing Research. 47 (1): 145–161. doi:10.1044/1092-4388(2004/013). PMID 15072535. 68. ^ Clegg, J.; Hollis, C.; Mawhood, L.; Rutter, M. (February 2005). "Developmental language disorders - a follow-up in later adult life. Cognitive, language and psychosocial outcomes". Journal of Child Psychology and Psychiatry. 46 (2): 128–149. doi:10.1111/j.1469-7610.2004.00342.x. PMID 15679523. 69. ^ Snowling, Margaret J.; Bishop, D.V.M.; Stothard, Susan E.; Chipchase, Barry; Kaplan, Carole (9 June 2006). "Psychosocial outcomes at 15 years of children with a preschool history of speech-language impairment". 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"Specific Language Impairment as a Period of Extended Optional Infinitive". Journal of Speech, Language, and Hearing Research. 38 (4): 850–863. doi:10.1044/jshr.3804.850. PMID 7474978. 74. ^ van der Lely, Heather K.J. (February 2005). "Domain-specific cognitive systems: insight from Grammatical-SLI". Trends in Cognitive Sciences. 9 (2): 53–59. doi:10.1016/j.tics.2004.12.002. PMID 15668097. S2CID 54374098. 75. ^ Gathercole, Susan E; Baddeley, Alan D (1 June 1990). "Phonological memory deficits in language disordered children: Is there a causal connection?". Journal of Memory and Language. 29 (3): 336–360. doi:10.1016/0749-596X(90)90004-J. 76. ^ Ullman, Michael T.; Pierpont, Elizabeth I. (1 January 2005). "Specific Language Impairment is not Specific to Language: the Procedural Deficit Hypothesis". Cortex. 41 (3): 399–433. doi:10.1016/S0010-9452(08)70276-4. PMID 15871604. S2CID 1027740. 77. ^ Bishop, Dorothy V. M. (2006). "Developmental cognitive genetics: How psychology can inform genetics and vice versa". Quarterly Journal of Experimental Psychology. 59 (7): 1153–1168. doi:10.1080/17470210500489372. PMC 2409179. PMID 16769616. 78. ^ Clegg, J.; Hollis, C.; Mawhood, L.; Rutter, M. (February 2005). "Developmental language disorders - a follow-up in later adult life. Cognitive, language and psychosocial outcomes". Journal of Child Psychology and Psychiatry. 46 (2): 128–149. doi:10.1111/j.1469-7610.2004.00342.x. PMID 15679523. ## Further reading[edit] * Beitchman, J. H., & Brownlie, E. B. (2014). Language Disorders in Children and Adolescents Boston: Hogrefe. ISBN 9780889373389 * Paul, Rhea (2007). Language disorders from infancy through adolescence: assessment & intervention. Mosby Elsevier. ISBN 0-323-03685-6. OCLC 487807750. ## External links[edit] * Helpful article by Professor Maggie Snowling: Dyslexia and developmental language disorder: same or different? * Raising Awareness of Language Learning Impairments (RALLI): Information about DLD via YouTube and Slideshare * Talking Point: Check the progress of your child's language development * What Works: Database of evidence-based interventions [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Developmental language disorder	c0233715	2,236	wikipedia	https://en.wikipedia.org/wiki/Developmental_language_disorder	2021-01-18T18:49:38	{"mesh": ["D007805"], "umls": ["C0233715", "C0454644", "C0241210"], "icd-10": ["F80.9"], "wikidata": ["Q2313089"]}
Cryofibrinogenemic purpura SpecialtyDermatology Cryofibrinogenemic purpura is a skin condition that manifests as painful purpura with slow healing ulcerations and edema of both feet during winter months.[1]:823 ## See also[edit] * Cryofibrinogenemia * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Cryofibrinogenemic purpura	c1274291	2,237	wikipedia	https://en.wikipedia.org/wiki/Cryofibrinogenemic_purpura	2021-01-18T18:41:43	{"umls": ["C1274291"], "wikidata": ["Q5190513"]}
A rare constitutional aplastic anemia disorder characterized by severe hypo/aplastic anemia or pancytopenia associated with skeletal anomalies (such as radial/ulnar defects and hand/digit abnormalities) and an increased risk of leukemia. There have been no further descriptions in the literature since 1995. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	WT limb-blood syndrome	c1327917	2,238	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3466	2021-01-23T19:11:05	{"gard": ["39"], "mesh": ["C536751"], "omim": ["194350"], "umls": ["C1327917"], "icd-10": ["D61.0"]}
MacKinnon and Cohen (1977) concluded that total intestinal aganglionosis is distinct from Hirschsprung disease (142623) of either the long or short segment type and is inherited as an autosomal recessive. They found reports of 9 cases in 6 families. Each of 3 families had 2 affected sibs. GI \- Aganglionosis, total intestinal Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	AGANGLIONOSIS, TOTAL INTESTINAL	c0345240	2,239	omim	https://www.omim.org/entry/202550	2019-09-22T16:31:24	{"mesh": ["C538058"], "omim": ["202550"]}
A number sign (#) is used with this entry because of evidence that Ayme-Gripp syndrome (AYGRP) is caused by heterozygous mutation in the MAF gene (177075) on chromosome 16q23. Description Ayme-Gripp syndrome is a clinically homogeneous phenotype characterized by congenital cataracts, sensorineural hearing loss, intellectual disability, seizures, brachycephaly, a distinctive flat facial appearance, and reduced growth (Niceta et al., 2015). Clinical Features Gripp et al. (1996) described 2 unrelated patients, a girl and a boy, with a seemingly previously unrecognized syndrome: congenital cataracts, sensorineural deafness, distinctive facial appearance, skeletal changes, postnatal short stature, and mental retardation. The parents were nonconsanguineous in each case. The appearance of the eyes was somewhat suggestive of Down syndrome. The philtrum was long, broad, and smooth and the face was generally flat. One of the patients had bilateral radioulnar synostosis; the other had idiopathic chondrolysis. The high-resolution karyotypes of the 2 patients were 46,XX and 46,XY, respectively. In the male patient, the authors found no microdeletions associated with either Smith-Magenis syndrome (182290) or Xp22.3. Ayme and Philip (1996) observed a 20-year-old woman with a similar complex of abnormalities. They suggested that their patient had the same disorder (Fine-Lubinsky syndrome; 601353) as that reported by Fine and Lubinsky (1983). Nakane et al. (2002) reported a Japanese boy who presented at 8 months of age with dysmorphic facies and mental retardation. He was brachycephalic, with prominent frontal bones and enlarged anterior fontanel. He also exhibited a remarkably flat face with shallow orbits, hypertelorism, low-set ears, and a small nose with depressed nasal bridge. His mouth was not small, but he could not open it widely. He had gross developmental delay and did not respond to sound. Auditory evoked responses suggested severe bilateral deafness, and ophthalmologic examination showed bilateral cataract. Nakane et al. (2002) noted that many of this patient's features were similar to those seen in the patient described by Ayme and Philip (1996); because his mouth was not small, Nakane et al. (2002) concluded that this patient represented a variant of Fine-Lubinsky syndrome. Keppler-Noreuil et al. (2007) reported an unrelated boy and girl with a clinical phenotype most closely resembling that reported by Gripp et al. (1996). Common features included facial dysmorphism suggestive of Down syndrome, including flat nasal bridge, slanted palpebral fissures, epicanthal folds, low-set ears, and tented upper lip/thin vermilion border. Both patients had short stature, congenital cataracts, hearing loss, and delayed mental development. Microarray analysis in the boy revealed a subtelomeric 1.0- to 1.9-Mb deletion of chromosome 11q25; the same deletion was also found in his mother, who had short stature, mild facial dysmorphism, and mild mental retardation (IQ of 70), but no cataracts or hearing loss. The phenotype was distinct from that seen in Jacobsen syndrome (147791). Microarray analysis was normal in the girl. Keppler-Noreuil et al. (2007) postulated that patients with this novel syndrome may have a microdeletion of the chromosome 11q terminal region or haploinsufficiency of a gene within this region. Molecular Genetics In a 43-year-old woman with Ayme-Gripp syndrome, Niceta et al. (2015) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in the MAF gene (S54L; 177075.0005). Sanger sequencing confirmed the mutation, which was not found in her parents. Analysis of the MAF gene in 12 additional probands with overlapping features revealed heterozygous missense mutations (177075.0005-177075.0010) in 7, including the patients reported by Ayme and Philip (1996), Gripp et al. (1996), and Keppler-Noreuil et al. (2007). Niceta et al. (2015) noted partial overlap between the clinical presentation of this syndrome and that of Fine-Lubinsky syndrome, and suggested the designation 'Ayme-Gripp syndrome' for the MAF-associated phenotype. INHERITANCE \- Autosomal dominant GROWTH Height \- Reduced height HEAD & NECK Head \- Brachycephaly \- Widened anterior fontanel \- Delayed closure of fontanel (in some patients) Face \- High forehead \- Prominent frontal bone \- Midface hypoplasia \- Malar hypoplasia \- Craniofacial asymmetry (in some patients) \- Long philtrum \- Prognathism (in some patients) Ears \- Hearing loss, sensorineural \- Low-set ears \- Small ears (in some patients) \- Posteriorly rotated ears (in some patients) Eyes \- Congenital cataracts \- Hypertelorism \- Broad eyebrows \- Ptosis \- Downslanting palpebral fissures (in some patients) \- Upslanting palpebral fissures (in some patients) \- Hypopigmented maculae of the retina (rare) Nose \- Short nose \- Broad nasal root \- Flat nasal bridge Mouth \- Small mouth \- Thin upper lip Teeth \- Dental anomalies (rare) CARDIOVASCULAR Heart \- Pericarditis (rare) CHEST Breasts \- Hypoplastic breasts SKELETAL Skull \- Brachycephaly Pelvis \- Chondrolysis of hip (rare) Limbs \- Joint limitations (in some patients) \- Bilateral congenital dislocation of radial heads (rare) \- Radioulnar synostosis (rare) Hands \- Brachydactyly (in some patients) \- Fifth-finger clinodactyly (in some patients) \- Camptodactyly (rare) \- Tapered fingers (rare) SKIN, NAILS, & HAIR Nails \- Dystrophic nails (in some patients) Hair \- Sparse scalp hair (in some patients) NEUROLOGIC Central Nervous System \- Mental retardation, mild to severe \- Seizures \- Enlarged ventricles or hydrocephaly \- Chiari I malformation (rare) \- Cerebral atrophy (rare) MOLECULAR BASIS \- Caused by mutation in the gene encoding the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF, 177075.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	AYME-GRIPP SYNDROME	c0795941	2,240	omim	https://www.omim.org/entry/601088	2019-09-22T16:15:26	{"mesh": ["C537933"], "omim": ["601088"], "orphanet": ["1272"], "synonyms": ["Alternative titles", "CATARACTS, CONGENITAL, WITH SENSORINEURAL DEAFNESS, DOWN SYNDROME-LIKE FACIAL APPEARANCE, SHORT STATURE, AND MENTAL RETARDATION"]}
Sepiapterin reductase deficiency is a neurometabolic disorder characterized by a pattern of involuntary sustained muscle contractions known as dystonia. Other common features include axial hypotonia , oculogyric crises, and delays in motor and cognitive development. The condition is caused by mutations in the SPR gene. It is inherited in an autosomal recessive fashion. Treatment with levodopa (L-dopa) in combination with carbidopa has shown much success causing drastic improvements in motor functioning. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Sepiapterin reductase deficiency	c0268468	2,241	gard	https://rarediseases.info.nih.gov/diseases/10365/sepiapterin-reductase-deficiency	2021-01-18T17:57:46	{"mesh": ["C562657"], "omim": ["612716"], "umls": ["C0268468"], "orphanet": ["70594"], "synonyms": ["SPR deficiency", "DYT/PARK-SPR", "Dopa-responsive dystonia due to sepiapterin reductase deficiency", "SR-deficient DRD"]}
Visceral calciphylaxis is a rare, life-threatening, non-inflammatory vasculopathy disorder characterized by diffuse precipitation of calcium in viscera (mainly in the heart or lungs, but also in the stomach or kidneys) leading to fibrosis and thrombosis, which eventually cause necrotic ulcerations of the tissue. Patients may present with dyspnea, cough and respiratory failure or acute heart block and subsequent sudden cardiac death, depending on the affected organ. The disease mainly affects patients on dialysis or patients having undergone renal transplantation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Visceral calciphylaxis	None	2,242	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=280068	2021-01-23T19:13:10	{"icd-10": ["E83.5"]}
A number sign (#) is used with this entry because Rubinstein-Taybi syndrome-1 (RSTS1) is caused by heterozygous mutation in the gene encoding the transcriptional coactivator CREB-binding protein (CREBBP; 600140) on chromosome 16p13. Description Rubinstein-Taybi syndrome is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile. Affected individuals also have an increased risk of tumor formation (Rubinstein and Taybi, 1963; review by Hennekam, 2006). Floating-Harbor syndrome (136140), which shows phenotypic overlap with Rubinstein-Taybi syndrome, is caused by mutation in the SRCAP gene (611421), a coactivator for CREBBP. ### Genetic Heterogeneity of Rubinstein-Taybi Syndrome Rubinstein-Taybi syndrome-1 (RSTS1) constitutes about 50 to 70% of patients with the disorder. Rubinstein-Taybi syndrome-2 (RSTS2; 613684) comprises about 3% of patients and is primarily due to de novo heterozygous mutation in the EP300 gene (602700) on chromosome 22q13 (Bartsch et al., 2010). See also chromosome 16p13.3 deletion syndrome (610543), a severe form of Rubinstein-Taybi syndrome resulting from a contiguous gene deletion involving the CREBBP gene as well as other neighboring genes. Clinical Features Rubinstein and Taybi (1963) reported a syndrome characterized by mental retardation, broad thumbs and toes, and facial abnormalities. Rubinstein (1969) found parental age to be about average. Levy (1976) described juvenile glaucoma in RSTS and McKusick (1968) observed congenital glaucoma. Talon cusps were reported in nearly 90% of patients with Rubinstein-Taybi syndrome by Gardner and Girgis (1979) and Davis and Brook (1986). Bonioli and Bellini (1992) reported the association of RSTS with pheochromocytoma in a 7-year-old girl. Hennekam et al. (1990) reported that among 45 RSTS patients in the Netherlands, all had broad halluces but only 39 had broad thumbs. Persistent fetal pads of the fingers, shawl scrotum, and frequent fractures were found in several patients. Constipation was a problem, and easily collapsible laryngeal walls caused difficulties in sleep and anesthesia. Hennekam and Van Doorne (1990) commented on short upper lip and pouting lower lip, a feature documented in many photographs by Hennekam et al. (1990). A high, slit-like palate was also noted. Lowry (1990) discussed the phenotypic overlap with the Saethre-Chotzen syndrome (101400). Guion-Almeida and Richieri-Costa (1992) described agenesis of the corpus callosum, iris coloboma, and megacolon in a boy with RSTS. Kanjilal et al. (1992) described pulmonary hypertension, mitral valve regurgitation, and patent ductus arteriosus as well as hypoplastic right kidney in a 3-month-old child with delayed motor and mental development corresponding to that of a 1-month-old infant. Shashi and Fryburg (1995) described mediastinal vascular ring causing tracheoesophageal obstruction with respiratory symptoms and dysphagia in a child with RSTS. The patient had a remarkable improvement in swallowing ability after surgery and some decrease in the frequency of respiratory infections. Chun et al. (1992) had reported 1 case of RSTS among their large series of cases of vascular rings at Johns Hopkins. Stevens and Bhakta (1995) evaluated cardiac abnormalities with a questionnaire survey. Of 138 patients in the study, 45 (32.6%) had a known cardiac abnormality; 27 patients had single defects, including atrial septal defect, ventricular septal defect, patent ductus arteriosus (see 607411), coarctation of the aorta, pulmonic stenosis, or bicuspid aortic valve. In 8 of these individuals the problem resolved spontaneously, while 8 required surgery. Complex congenital heart defects of 2 or more abnormalities were present in 16 patients; 2 of these patients had spontaneous resolution, while 7 required surgery. Surgery was planned in 5 additional patients. It is noteworthy that pulmonic stenosis was present in only 1 patient as an isolated finding. Miller and Rubinstein (1995) noted that patients with RSTS have an increased risk of tumor formation. Among over 700 patients, 17 had malignant tumors and 19 had benign tumors. Twelve of the tumors were located in the nervous system, including oligodendroglioma, medulloblastoma, neuroblastoma, and meningioma. Other tumor types included rhabdomyosarcoma and leukemias, among others. Miller and Rubinstein (1995) suggested that about 5% of RSTS patients develop a neoplasm, which is similar to the frequency of neoplasm in neurofibromatosis type I (162200). Bonioli et al. (1993) described the association of RSTS with slipped capital femoral epiphysis in a 10-year-old girl. Stevens (1997) described 11 patients with RSTS and patellar dislocation. The age at diagnosis of patellar dislocation ranged from birth to 16 years. Chronic dislocations were present in 10 patients, and 8 of 11 had bilateral patellar dislocation. Surgical stabilization of the patella was required in 8 patients; most achieved a good outcome with surgical repair. All families reported that the patellar dislocations impaired developmental skills, which improved after surgery. Other joint abnormalities, including congenital dislocations and laxity of joints, were described in 7 of the 11 patients. Ihara et al. (1999) suggested that premature thelarche (breast development) may not be uncommon in girls with RSTS. They reported breast development at age 6 years in a girl who had been found at the age of 6 months to have a neuroblastoma on a nationwide neuroblastoma screening program and had been surgically treated with a favorable clinical course. Among 12 girls with RSTS, Kurosawa et al. (2002) observed 2 with premature thelarche, and a third with premature thelarche and genital bleeding. Naimi et al. (2006) reported 3 unrelated patients with RSTS who had recurrent upper and lower respiratory infections and otitis media associated with defective antibody response to polysaccharide antigens. One of the 3 also had decreased numbers of T cells. One patient responded well to IgG therapy. The authors suggested that some patients with RSTS may have a primary immunodeficiency, which may explain the increased rate of respiratory infections in these patients. Bloch-Zupan et al. (2007) reported detailed orodental features of 40 patients with RSTS ranging in age from 4 to 30 years. Nondental oral findings included small mouth, thin upper lip, micrognathia, retrognathia, narrow maxilla, high-arched and narrow palate, wide alveolar ridges, and enlarged tonsils. Dental anomalies included anomalies of tooth number, talon cusps, screwdriver permanent incisors, enamel hypoplasia/discoloration, enamel wear, tooth crowding, and crossbite. Many patients had gastroesophageal reflux, which may have contributed to enamel wear. Timing of tooth eruption was usually normal. Bloch-Zupan et al. (2007) noted that dental anomalies may aid in the diagnosis of RSTS. Caksen et al. (2009) reported an 8-month-old boy with genetically confirmed RSTS who presented with varicella meningoencephalitis. The authors postulated a primary immune deficiency in this child. Stevens et al. (2011) reported the results of a questionnaire-based study of 61 adults with RSTS ranging in age from 18 to 67 years (average, 28.5 years). The average height in men was 158.5 cm and in women 150.1 cm. Many were overweight (25%), obese (33%), or morbidly obese (8%). The most commonly reported medical problems were visual difficulties (79%), including need for glasses (80%), strabismus (33%), glaucoma (11%), and cataracts (7%). Other problems included keloids (57%), eating problems (53%), spinal curvature (49%), joint laxity (46%), and dental problems (80%). All had moderate mental retardation, but most achieved some independence for self-care and many were in supported work situations. Most (69%) lived with their parents, but others lived in group homes (21%) or supervised apartments (5%). Many had behavioral problems, such as poor attention span and autistic features, and worsening of behavior over time was reported in about 37%. Very few of the participants were seeing a geneticist as an adult. Beets et al. (2014) provided growth charts for individuals with Rubinstein-Taybi syndrome, which were based on individuals with a molecularly proven diagnosis. ### Incomplete Rubinstein-Taybi Syndrome Cotsirilos et al. (1987) described 2 sibs and their mother with a syndrome that they reported as similar to Rubinstein-Taybi syndrome. All 3 individuals, who appeared to be of normal intelligence, had broad terminal phalanges of the thumbs and the great toes, antimongoloid slant of the palpebral fissures, and characteristic facial appearance with beaked nose. Four sibs of the mother as well as 2 other members of the kindred were said to have broad thumbs. There were no instances of male-to-male transmission. Autosomal or X-linked dominant inheritance was suggested. Bonioli and Bellini (1989) reported a family in which 4 relatives of a full-blown case of Rubinstein-Taybi syndrome had broad thumbs, apparently inherited as a dominant trait with incomplete penetrance. Bartsch et al. (2002) reported a girl with a mild variant of RSTS. Her face was round and slightly dysmorphic with intermittent exotropia, subtle ptosis, a beaked nose, and dorsally rotated ears. Her hands showed broad thumbs with brachytelephalangism, and her feet had broad big toes. Although she had low intellectual function, she was not mentally retarded. Genetic analysis revealed a missense mutation in the CREBBP gene (600140.0005), confirming that the phenotype is consistent with 'incomplete' RSTS. Bartsch et al. (2002) concluded that mild alleles or modifying factors can lead to incomplete RSTS, and suggested that the Rubinstein-like syndrome described by Cotsirilos et al. (1987) and Bonioli and Bellini (1989) can be equated with incomplete RSTS. Bartsch et al. (2010) reported a 3-generation German family with incomplete RSTS, including a 12-year-old female proband, her mother, and the maternal grandmother. The proband had mild dysmorphic features, such as high-arched eyebrows, elongated face, prominent nose, high-arched palate, short broad thumbs, and broad halluces. She had a short attention span, dyslexia, dyscalculia, reading difficulties, and needed special teaching in language and mathematics. Her mother had similar facial features, was mildly obese, and had normal intelligence. The grandmother reportedly had a similar appearance and had not finished school. Inheritance The vast majority (about 99%) of cases of Rubinstein-Taybi syndrome occur sporadically resulting from de novo heterozygous mutations; vertical transmission is extremely rare but has been reported (summary by Bartsch et al., 2010). Padfield et al. (1968) studied 17 patients with RSTS and found none of 50 sibs affected. Pfeifer (1968) described the syndrome in only 1 of presumably monozygotic twins. Baraitser and Preece (1983), on the other hand, reported the Rubinstein syndrome in all 4 members of 2 pairs of monozygotic twins. Der Kaloustian et al. (1972) described affected brother and sister from consanguineous parents. However, whereas the facies was characteristic, broad first digits were absent clinically and questionable radiographically. Gillies and Roussounis (1985) reported 2 families: in one, 2 sibs were affected; in the other, the uncle of the index case was affected and other members of the family were judged to show varying degrees of expression of the disorder. Stevens et al. (1990) found no second cases among the 91 sibs of 50 probands. Hennekam et al. (1989) described this disorder in mother and son, consistent with autosomal dominant inheritance. The mother's IQ was estimated to be about 65. Garcia et al. (1992) and Marion et al. (1993) reported 2 different cases of mother and daughter with RSTS. In one of these families, the mother had attended special education classes and had dropped out of school in the eleventh grade. Hennekam et al. (1990) reviewed data on 502 cases. In 12 of 13 proven or possible monozygotic twins, both children were affected. Two patients had reproduced, with 1 affected and 2 normal offspring. They found 1 recurrence among 708 sibs of 502 probands. From this information and the scarcity of affected sibs reported in the literature, they suggested that the recurrence risk figure for sibs is on the order of 0.1%, lower than the figure of 1.0% suggested by Berry (1987) for use in genetic counseling. The recurrence risk for offspring of affected persons may be 50%. Hennekam et al. (1990) favored an autosomal dominant mutation as the most likely cause. Robinson et al. (1993) reported another set of monozygotic twins concordant for RSTS. Preis and Majewski (1995) reported monozygotic twin sisters concordant for RSTS diagnosed at the age of 10 weeks. They commented that the typical features of the syndrome increasingly developed in early infancy toward the total 'Gestalt' by the age of 2 years. Bartsch et al. (2010) reported a German family in which the female proband, her mother, and her maternal grandmother all had incomplete RSTS associated with a heterozygous mutation in the CREBBP gene (T910A; 600140.0008). The 12-year-old proband had a more severe phenotype despite her mother and maternal grandmother carrying the same mutation. The findings were consistent with autosomal dominant inheritance of RSTS and indicated that in cases of inherited RSTS, affected children tend to have a more severe phenotype. Bartsch et al. (2010) reported a second German family in which 3 sisters had RSTS with facial abnormalities, broad thumbs and great toes, and developmental delay. They were diagnosed at ages 11, 6, and 5 years, respectively. One developed a slow growing ganglioglioma of the brain at age 2. The father had broad thumbs and attended basic secondary school and worked as an unskilled laborer; he was clinically suspected of having mild or incomplete RSTS. Genetic analysis identified a heterozygous splice site mutation in the CREBBP gene in the 3 girls, and somatic mosaicism for the mutation in the father. Based on their patients and a review of the literature of familial occurrence of RSTS, Bartsch et al. (2010) estimated a recurrence risk of 0.5 to 1.0% for parents of an affected child. Cytogenetics The dermatoglyphic changes described by Giroux and Miller (1967) suggested a chromosomal abnormality. In 8 cases of RSTS, Wulfsberg et al. (1983) could demonstrate no abnormality by high resolution cytogenetics, but Berry (1987) reviewed the etiogenetic basis and concluded that microdeletion is most likely. Imaizumi and Kuroki (1991) observed a sporadic case of Rubinstein-Taybi syndrome with de novo reciprocal translocation t(2;16)(p13.3;p13.3). Noting that Bazacliu et al. (1973) had reported a patient with RSTS and a deletion of chromosome 2, Imaizumi and Kuroki (1991) suggested that the RSTS gene may be at 2p13.3 rather than at 16p13.3. During a systematic chromosomal survey of 7 unrelated patients with Rubinstein-Taybi syndrome, Tommerup et al. (1991, 1992) found an apparently balanced de novo reciprocal translocation, t(7;16)(q34;p13.3), in an affected boy. The breakpoint in chromosome 16 involved the same subband p13.3 as was observed in a 2;16 translocation by Imaizumi and Kuroki (1991). Lacombe et al. (1992) provided confirmation for the assignment of the RSTS gene to 16p13.3. A 2-month-old girl with typical features showed a de novo pericentric inversion of one chromosome 16; her karyotype was 46,XX,inv(16)(p13.3;q13). In a large collaborative study, Breuning et al. (1993) investigated the region of 16p13.3 where 2 distinct reciprocal translocations occurred in patients with a clinical diagnosis of RSTS. The breakpoints lay between the cosmids N2 and RT1. Using 2-color fluorescence in situ hybridization, Breuning et al. (1993) demonstrated that the signal from RT1 was missing from 1 chromosome 16 in 6 of 24 patients with RSTS. The parents of 5 of these patients did not show a deletion of RT1, indicating a de novo rearrangement. They estimated that RSTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately one-fourth of patients. By molecular studies, Hennekam et al. (1993) found a copy of chromosome 16 from each parent in all 19 patients with RSTS studied. Uniparental disomy was also excluded for 5 other chromosome arms known to be imprinted in mice. Clinical features were essentially the same in patients with or without visible deletions, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces ('big toes'). Masuno et al. (1994) screened 25 Japanese patients with RSTS for microdeletions using high-resolution GTG banding and fluorescence in situ hybridization with a cosmid probe (RT1, D16S237). In 1 patient, a microdeletion was demonstrated by in situ hybridization, but none was detected by high-resolution banding. Diagnosis Wallerstein et al. (1997) used the RT1 probe to screen 64 patients with clinical evidence of RSTS; 7 (11%) had a deletion. Another patient had a translocation involving the region without evidence of deletion. The features of coloboma, growth retardation, nevus flammeus, and hypotonia had a positive predictive value for the presence of an RT1 deletion. The authors commented that because of the relatively low frequency of deletions in RSTS, the RT1 probe is useful in diagnostic confirmation but has limited use as a screening tool. Petrij et al. (2000) reported diagnostic analysis of 194 patients with RSTS. Of these, 86 had previously been reported. A total of 157 individuals were tested by FISH, 23 by protein truncation test and 14 by both methods for microdeletions and truncating mutations in CBP. Fourteen of 171 (8.2%) patients had microdeletions, and truncating mutations were found in 4 of 37 (10.8%) cases. Eighty-nine of the 171 were tested using 5 cosmid probes: RT1, RT100, RT102, RT191, RT203 and RT166. Eight microdeletions were found in this group, of which 4 were not deleted for RT1/RT100. Petrij et al. (2000) concluded that the use of all 5 probes is essential to detect all microdeletions in patients with clinical features of RSTS, and stated that microdeletions and truncating mutations in CBP account for approximately 20% of mutations in individuals with the RSTS phenotype. In 6 (28.6%) of 21 RSTS patients in whom no point mutations had been identified, Stef et al. (2007) used comparative genomic hybridization on microarrays and quantitative multiplex fluorescent-PCR to identify deletions involving the CREBBP gene. The deletions ranged in size from 3.3 kb to 6.5 Mb; 1 patient had a deleterious duplication containing exon 16. No phenotypic differences were observed, except for 1 patient with a 6.5-Mb deletion, who had a severe phenotype and died at 34 days of life. Stef et al. (2007) concluded that CREBBP dosage anomalies constitute a common cause of the disorder and recommended high-resolution gene dosage studies of the CREBBP gene in candidate patients. Gervasini et al. (2007) used FISH and microsatellite analysis to screen 42 Italian RSTS patients, and identified deletions ranging in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors stated that the clinical presentation was typical in all cases, but more severe in the 3 patients with constitutional deletions, and suggested that there may be underdiagnosis of a few cases of mild RSTS. Clinical Management Stirt (1982) warned of the risk of cardiac arrhythmia with use of succinylcholine in the Rubinstein-Taybi syndrome. Wiley et al. (2003) provided recommendations for specific surveillance and interventions to guide clinicians caring for individuals with RSTS. Hennekam (2006) provided a review of RSTS, including a diagnostic strategy, clinical management, and genetic counseling. Molecular Genetics Petrij et al. (1995) showed that the breakpoints at 16p13.3 demonstrated in patients with RSTS are all restricted to a region that contains the gene for the human CREB-binding protein (CREBBP; 600140), a nuclear protein participating as a coactivator in cAMP-regulated gene expression. In patients with RSTS, Petrij et al. (1995) identified heterozygous point mutations in the CREBBP gene (600140.0001, 600140.0002), suggesting that the loss of one functional copy of the CREBBP gene underlies the developmental abnormalities in RSTS. Petrij et al. (1995) suggested that the unusual incidence of neoplasms in RSTS, as well as the propensity to form keloids, may be explained by the role proposed for CREBBP in cAMP-regulated cell immortalization. The X-linked alpha-thalassemia/mental retardation syndrome (301040) is another example of multiple congenital malformations with mental retardation caused by a generalized dysregulation of gene expression. In that case, the mutation is located in the gene encoding X-linked helicase-2 (300032). Roelfsema et al. (2005) screened the entire CREBBP gene for mutations in 92 patients with RSTS and found 36 mutations. By using multiple ligation-dependent probe amplification, they found not only several deletions but also the first reported intragenic duplication in a patient with RSTS. Both CREBBP and EP300 (602700) function as transcriptional coactivators in the regulation of gene expression through various signal transduction pathways. Both are potent histone acetyltransferases. A certain level of CREBBP is essential for normal development, as indicated by the fact that inactivation of 1 allele causes RSTS. There is a direct link between loss of acetyltransferase activity and RSTS, which indicates that the disorder is caused by aberrant chromatin regulation. Roelfsema et al. (2005) searched for mutations in the EP300 gene in patients with RSTS, identified 3 mutations (602700.0003-602700.0005), and stated that these were the first mutations found in EP300 as the basis of a congenital disorder. Using high resolution array comparative genomic hybridization (array CGH) targeting exons, Tsai et al. (2011) identified a de novo 5- to 6-kb deletion on chromosome 16p13.3 encompassing exons 27 and 28 of the CREBBP gene in a male infant with classic clinical features of RSTS. Genotype/Phenotype Correlations Using FISH and 3 cosmid probes, Bartsch et al. (1999) studied 45 Rubinstein-Taybi syndrome patients from Germany, the Czech Republic, Austria, and Turkey and found 4 deletions. This gave a frequency of deletions of 8.9%; when pooled with the data from previous studies, a frequency of 11% was found. All deletions were interstitial; 3 spanned the CREB-binding protein gene and 1 was smaller. The findings of Bartsch et al. (1999) suggested a more severe phenotype in these deletion cases. The mean age at presentation was 0.96 years in patients with a deletion as opposed to 11.12 years in those without. Bartsch et al. (1999) suggested that the 2 patients who died in infancy had a contiguous gene deletion syndrome. Using a combination of FISH and multiple ligation-dependent probe amplification (MLPA) analysis, Rusconi et al. (2015) identified 14 different and novel CREBBP deletions in 14 of 171 patients with a clinical diagnosis of RSTS. The deletions, which accounted for 23% of detected CREBBP mutations in this cohort, ranged in size from 930 bp encompassing single exons to 1.35 Mb encompassing the whole gene and neighboring genes. Genotype/phenotype correlations indicated that patients with larger deletions did not always have a more severe phenotype than those with smaller deletions or point mutations, suggesting that the idea of a contiguous gene deletion syndrome in such patients, as proposed by Bartsch et al. (2006) (see 610543), may not be accurate. Hendrich and Bickmore (2001) reviewed human disorders which share in common defects of chromatin structure or modification, including the ATR-X spectrum of disorders (301040), ICF syndrome (242860), Rett syndrome (312750), Rubinstein-Taybi syndrome, and Coffin-Lowry syndrome (303600). Schorry et al. (2008) identified pathogenic mutations in the CREBBP gene in 52 (56%) of 93 patients meeting clinical diagnostic criteria for RSTS. Ten patients had single amino acid changes, 36 had truncating or splice site mutations, and 6 had microdeletions. The mutations were distributed throughout the gene. There were few phenotypic differences observed between patients grouped by different types of mutations, other than a trend toward increased severity of cognitive impairment and autistic features in patients with larger deletions. Population Genetics Padfield et al. (1968) estimated that the frequency of Rubinstein syndrome was 1 per 300-500 in institutionalized patients with mental retardation over age 5 years. Beets et al. (2014) stated that the birth prevalence of Rubinstein-Taybi syndrome is 1 in 100,000-125,000. Nomenclature Although the acronym RTS is sometimes used for Rubinstein-Taybi syndrome, the use of this acronym for 2 other syndromes, Rothmund-Thomson syndrome (268400) and Rett syndrome, may lead to confusion; hence, use of the symbol RSTS is recommended. Animal Model Oike et al. (1999) generated a mouse model of RSTS by an insertional mutation in the Cbp gene. Heterozygous mice that had truncated Cbp protein (residues 1 to 1084) containing the CREB-binding domain showed clinical features of RSTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%), and skeletal abnormalities (7%). The authors concluded that the mutant truncated Cbp protein acted in a dominant-negative fashion to generate the RSTS phenotype in mice. Mutant mice performed poorly in passive avoidance and fear-conditioning tests, suggesting deficiency in long-term memory. Short-term memory appeared to be normal. History Roy et al. (1968) suggested multifactorial inheritance in RSTS. Since the CREB-binding protein is a critical coactivator for thyroid hormone receptors, Olson and Koenig (1997) hypothesized that thyroid hormone resistance might occur in RSTS. To assess the function of the thyroid axis in RSTS, they measured free thyroxine (T4) and thyroid-stimulating hormone (TSH; see 188540) in 12 affected subjects. Free T4 and TSH levels were normal in all 12 subjects, indicating that overt thyroid hormone resistance is not a typical feature of RSTS. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature \- Average adult male height 153 cm \- Average adult female height 147 cm Weight \- Obesity after puberty Other \- Postnatal growth retardation HEAD & NECK Head \- Microcephaly \- Large anterior fontanel \- Late closure of fontanel \- Frontal bossing Face \- Low anterior hairline \- Hypoplastic maxilla \- Micrognathia \- Retrognathia \- Grimacing or unusual smile with almost closing of the eyes Ears \- Low-set ears \- Hearing loss \- Recurrent otitis Eyes \- Heavy eyebrows \- High-arched eyebrows \- Long eyelashes \- Ptosis \- Epicanthal folds \- Strabismus \- Nasolacrimal duct obstruction \- Cataracts \- Glaucoma \- Coloboma \- Downslanting palpebral fissures Nose \- Beaked nose \- Deviated nasal septum \- Broad nasal bridge Mouth \- Small opening of the mouth \- Narrow palate \- High-arched palate Teeth \- Dental crowding \- Talon cusps \- Crossbite \- Screwdriver permanent incisors \- Enamel hypoplasia \- Enamel discoloration CARDIOVASCULAR Heart \- Atrial septal defects \- Ventricular septal defects Vascular \- Patent ductus arteriosus \- Capillary hemangiomas RESPIRATORY \- Recurrent respiratory infections CHEST Ribs Sternum Clavicles & Scapulae \- Sternal anomalies ABDOMEN Gastrointestinal \- Constipation GENITOURINARY External Genitalia (Male) \- Hypospadias \- Shawl scrotum Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Delayed skeletal maturation \- Joint hypermobility Skull \- Large foramen magnum \- Parietal foramina Spine \- Scoliosis \- Spina bifida occulta Pelvis \- Small, flared iliac wings Limbs \- Patellar dislocation Hands \- Broad thumbs with radial angulation \- Fifth finger clinodactyly \- Persistent fetal fingertip pads \- Syndactyly \- Polydactyly \- Single transverse palmar creases Feet \- Broad great toes \- Plantar crease between first and second toes \- Pes planus SKIN, NAILS, & HAIR Skin \- Single transverse palmar creases \- Keloid formation in surgical scars \- Capillary hemangiomas \- Cafe-au-lait spots Hair \- Hirsutism NEUROLOGIC Central Nervous System \- Mental retardation (average IQ 51) \- Agenesis of corpus callosum \- Severe expressive speech delay \- Poor coordination \- EEG abnormalities \- Seizures \- Hypotonia \- Hyperreflexia Behavioral Psychiatric Manifestations \- Good social contacts \- Short attention span \- Labile mood IMMUNOLOGY \- Recurrent infections \- Polysaccharide antibody response defect NEOPLASIA \- Increased risk of tumor formation, especially of the head \- Increased risk of leukemia LABORATORY ABNORMALITIES \- Ten percent of cases are secondary to submicroscopic deletions of 16p13.3 detectable by FISH \- A small minority of patients have translocations and inversions involving 16p13.3 MISCELLANEOUS \- Incidence of 1 in 100,000 to 125,000 at birth \- De novo mutation in most cases \- Variable severity \- Truncating mutations in CREBBP found in 10% of patients MOLECULAR BASIS \- Caused by mutation in the CREB-binding protein gene (CREBBP, 600140.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	RUBINSTEIN-TAYBI SYNDROME 1	c0035934	2,243	omim	https://www.omim.org/entry/180849	2019-09-22T16:35:06	{"doid": ["1933"], "mesh": ["D012415"], "omim": ["180849"], "orphanet": ["353277", "783"], "synonyms": ["RSTS", "Alternative titles", "BROAD THUMB-HALLUX SYNDROME", "BROAD THUMBS AND GREAT TOES, CHARACTERISTIC FACIES, AND MENTAL RETARDATION", "RUBINSTEIN SYNDROME"], "genereviews": ["NBK1526"]}
A rare, genetic skin disease characterized by the ocular, cutaneous, and central nervous system anomalies. Typical clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas, leading sometimes to seizures, spasticity, and intellectual disability. Nevus psiloliparus, focal dermal hypo- or aplasia, eyelid skin tags, colobomas, abnormal intracranial vessels, hemispheric atrophy, porencephalic cyst, and hydrocephalus have also been associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Encephalocraniocutaneous lipomatosis	c0406612	2,244	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2396	2021-01-23T18:50:57	{"gard": ["2108"], "mesh": ["C535736"], "omim": ["613001"], "umls": ["C0406612"], "icd-10": ["E88.2"], "synonyms": ["Haberland syndrome"]}
Epilepsy syndrome characterised by seizures preceded by isolated disturbances of a cerebral function 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: "Focal seizure" – news · newspapers · books · scholar · JSTOR (February 2013) (Learn how and when to remove this template message) Focal seizure Other namesPartial seizures, localized seizures SpecialtyNeurology Focal seizures (also called partial seizures[1] and localized seizures) are seizures which affect initially only one hemisphere of the brain.[2][3] The brain is divided into two hemispheres, each consisting of four lobes – the frontal, temporal, parietal and occipital lobes. A focal seizure is generated in and affects just one part of the brain – a whole hemisphere or part of a lobe. Symptoms will vary according to where the seizure occurs. When seizures occur in the frontal lobe the patient may experience a wave-like sensation in the head. When seizures occur in the temporal lobe, a feeling of déjà vu may be experienced. When seizures are localized to the parietal lobe, a numbness or tingling may occur. With seizures occurring in the occipital lobe, visual disturbance or hallucination have been reported.[4] ## Contents * 1 Types * 1.1 Simple partial seizures * 1.2 Complex partial seizures * 2 Eponym * 3 References * 4 External links ## Types[edit] As of 2017, focal seizures are split into two main categories, focal onset aware, and focal onset impaired awareness.[5][6] What was previously termed a secondary generalised seizure is now termed a focal to bilateral seizure.[6] In focal onset aware seizures, a small part of one of the lobes may be affected and the person remains conscious. This can often be a precursor to a larger focal onset impaired awareness seizure. When this is the case, the focal aware seizure is usually called an aura. A focal impaired awareness seizure affects a larger part of the hemisphere and the person may lose consciousness. If a focal seizure spreads from one hemisphere to the other side of the brain, this will give rise to a focal to bilateral seizure.[5][6] The person will become unconscious and may experience a tonic clonic seizure. When people have multiple focal seizures they generally have a condition known as temporal lobe epilepsy. (A generalized seizure is one that involves both sides of the brain from the onset).[6] ### Simple partial seizures[edit] Simple partial seizures are seizures which affect only a small region of the brain, often the temporal lobes or structures found there, such as the hippocampi. People who have focal aware seizures remain conscious.[7] Focal aware seizures often precede larger focal impaired awareness seizures, where the abnormal electrical activity spreads to a larger area of the brain. This can result in a tonic-clonic seizure.[8] Presentation Simple partial seizures are a very subjective experience, and the symptoms vary greatly between people. Since symptoms can be subtle, diagnosis can be delayed by months or years.[9] The symptoms of these seizures can also be misconstrued as auras, especially for epilepsy patients with multiple types of seizure diagnosis. This is due to the varying locations of the brain in which the seizures originate (e.g., Rolandic). A Simple partial seizure may go unnoticed by others or shrugged off by the sufferer as merely a "funny turn." Focal aware seizures usually start suddenly and are very brief, typically lasting 60 to 120 seconds.[10] Some common symptoms of a Simple partial seizure, when the person is awake, are:[7] * preserved consciousness * sudden and inexplicable feelings of fear, anger, sadness, happiness or nausea * sensations of falling or movement * experiencing of unusual feelings or sensations * altered sense of hearing, smelling, tasting, seeing, and tactile perception (sensory illusions or hallucinations), or feeling as though the environment is not real (derealization) or dissociation from the environment or self (depersonalization) * a sense of spatial distortion—things close by may appear to be at a distance * déjà vu (familiarity) or jamais vu (unfamiliarity) * laboured speech or inability to speak at all * usually the event is remembered in detail When a seizure occurs during sleep, the person will often become semi-conscious and act out a dream they were having while engaging with the real environment as normal. Objects and people usually appear normal or only slightly distorted to them, and will be able to communicate with them on an otherwise normal level. However, since the person is still acting in a dream-like state, they will assimilate any hallucinations or delusions into their communication, often speaking to a hallucinatory person or speaking of events or thoughts pertaining to their dream or a hallucination. While-asleep symptoms include: * onset usually in REM sleep * dream-like state * appearance of full consciousness * hallucinations or delusions * behavior or visions typical in dreams * ability to engage with the environment and other people as in full consciousness, though often behaving abnormally, erratically, or failing to be coherent * complete amnesia or assimilating the memory as though it was a normal dream on regaining full consciousness * dreams of daily life that appear as if they happened in reality, and can cause disorientation upon awakening Although hallucinations may occur during focal aware seizures they are differentiated from psychotic symptoms by the fact that the person is usually aware that the hallucinations are not real.[10] Jacksonian march Jacksonian march or Jacksonian seizure is a phenomenon where a simple partial seizure spreads from the distal part of the limb toward the ipsilateral face (on same side of body). They involve a progression of the location of the seizure in the brain, which leads to a "march" of the motor presentation of symptoms.[11][citation needed] Jacksonian seizures are initiated with abnormal electrical activity within the primary motor cortex. They are unique in that they travel through the primary motor cortex in succession, affecting the corresponding muscles, often beginning with the fingers. This is felt as a tingling sensation, or a feeling of waves through the fingers when touched together. It then affects the hand and moves on to more proximal areas on the same side of body. Symptoms often associated with a Jacksonian seizure are sudden head and eye movements, tingling, numbness, smacking of the lips, and sudden muscle contractions. Most of the time any one of these actions can be seen as normal movements, without being associated with the seizure occurring[citation needed]. They occur at no particular moment and last only briefly. They may result in secondary generalized seizure involving both hemispheres. They can also start at the feet, manifesting as tingling or pins and needles, and there are painful cramps in the foot muscles, due to the signals from the brain. Because it is a partial seizure, the postictal state is of normal consciousness[citation needed]. ### Complex partial seizures[edit] A Complex partial seizure is a seizure that is associated with unilateral cerebral hemisphere involvement and causes impairment of awareness or responsiveness, i.e. alteration of consciousness.[12][6] Presentation Complex partial seizures are often preceded by an aura.[13] The seizure aura is a focal aware seizure.[13] The aura may manifest itself as a feeling of déjà vu, jamais vu, fear, euphoria or depersonalization.[14][better source needed] The aura might also occur as a visual disturbance, such as tunnel vision or a change in the perceived size of objects.[15] Once consciousness is impaired, the person may display automatisms, such as lip smacking, chewing or swallowing.[14] There may also be loss of memory (amnesia) surrounding the seizural event.[13] The person may still be able to perform routine tasks such as walking, although such movements are not purposeful or planned. Witnesses may not recognize that anything is wrong. The person may or may not even realize that they experienced a seizure. Complex partial seizures might arise from any lobe of the brain.[13] They most commonly arise from the mesial temporal lobe, particularly the amygdala, hippocampus, and neocortical regions.[16] A common associated brain abnormality is mesial temporal sclerosis.[14] Mesial temporal sclerosis is a specific pattern of hippocampal neuronal loss accompanied by hippocampal gliosis and atrophy.[17] Complex partial seizures occur when excessive and synchronous electrical brain activity causes the impaired awareness and responsiveness.[18] The abnormal electrical activity might spread to the rest of the brain and cause a focal to bilateral seizure or a generalized tonic–clonic seizure.[19] The newer classification of 2017 groups only focal and generalized seizures, and generalized seizures are those that involve both sides of the brain from the onset.[6][5] ## Eponym[edit] Jacksonian seizures are named after their discoverer, John Hughlings Jackson, an English neurologist, whose studies led to the discovery of the seizures' initiation point (in the primary motor cortex) in 1863.[20] ## References[edit] 1. ^ "Partial (Focal) Seizures". Johns Hopkins Medicine. The Johns Hopkins University. Retrieved 1 September 2016. 2. ^ Bradley, Walter G. (2012). "67". Bradley's neurology in clinical practice (6th ed.). Philadelphia, PA: Elsevier/Saunders. ISBN 978-1437704341. 3. ^ "partial seizure" at Dorland's Medical Dictionary 4. ^ [1] Archived 2013-08-09 at the Wayback Machine, Epilepsy Society - Are all seizures the same. 5. ^ a b c "2017 Revised Classification of Seizures". Epilepsy Foundation. 6. ^ a b c d e f "Types of Seizures". Epilepsy Foundation. 7. ^ a b Steven C. Schachter, MD; Joseph I. Sirven, MD (July 2013). "Simple Focal Seizures". Epilepsy Foundation. Retrieved 31 August 2016. 8. ^ Amit M. Shelat (27 February 2016). "Partial (focal) seizure". MedlinePlus. Retrieved 31 August 2016. 9. ^ Pellinen, Jacob; Tafuro, Erica; Yang, Annie; Price, Dana; Friedman, Daniel; Holmes, Manisha; Barnard, Sarah; Detyniecki, Kamil; Hegde, Manu; Hixson, John; Haut, Sheryl. "Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy". Epilepsia. n/a (n/a). doi:10.1111/epi.16707. ISSN 1528-1167. 10. ^ a b Hart, YM (2007). Epilepsy Questions and Answers. Merit Publishing. ISBN 978-1873413876. 11. ^ "Dorlands Medical Dictionary:jacksonian epilepsy".[permanent dead link] 12. ^ Trescher, William H., and Ronald P. Lescher 2000, p. 1748. 13. ^ a b c d Trescher, William H., and Ronald P. Lescher 2000, p. 1749. 14. ^ a b c Murro, Anthony M. 2006. 15. ^ Engelsen, B A., C Tzoulis, B Karlsen, A Lillebø, L M 2008. 16. ^ Trescher, William H., and Ronald P. Lescher 2000, p. 1750. 17. ^ Trepeta, Scott 2007. 18. ^ "International League Against Epilepsy." 2008. 19. ^ Trescher, William H., and Ronald P. Lescher 2000, p. 1747. 20. ^ synd/3332 at Who Named It? ## External links[edit] Classification D * ICD-10: G40.0-G40.2 * ICD-9-CM: 345.4-345.5 * MeSH: D004828 External resources * MedlinePlus: 000697 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Seizures and epilepsy Basics * Seizure types * Aura (warning sign) * Postictal state * Epileptogenesis * Neonatal seizure * Epilepsy in children Management * Anticonvulsants * Investigations * Electroencephalography * Epileptologist Personal issues * Epilepsy and driving * Epilepsy and employment Seizure types Focal Seizures Simple partial Complex partial Gelastic seizure Epilepsy Temporal lobe epilepsy Frontal lobe epilepsy Rolandic epilepsy Nocturnal epilepsy Panayiotopoulos syndrome Vertiginous epilepsy Generalised * Tonic–clonic * Absence seizure * Atonic seizure * Automatism * Benign familial neonatal seizures * Lennox–Gastaut syndrome * Myoclonic astatic epilepsy * Epileptic spasms Status epilepticus * Epilepsia partialis continua * Complex partial status epilepticus Myoclonic epilepsy * Progressive myoclonus epilepsy * Dentatorubral–pallidoluysian atrophy * Unverricht–Lundborg disease * MERRF syndrome * Lafora disease * Juvenile myoclonic epilepsy Non-epileptic seizure * Febrile seizure * Psychogenic non-epileptic seizure Related disorders * Sudden unexpected death in epilepsy * Todd's paresis * Landau–Kleffner syndrome * Epilepsy in animals Organizations * Citizens United for Research in Epilepsy (US) * Epilepsy Action (UK) * Epilepsy Action Australia * Epilepsy Foundation (US) * Epilepsy Outlook (UK) * Epilepsy Research UK * Epilepsy Society (UK) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Focal seizure	c0014547	2,245	wikipedia	https://en.wikipedia.org/wiki/Focal_seizure	2021-01-18T18:54:08	{"mesh": ["D004828"], "umls": ["C0014547", "C0234974"], "icd-9": ["345.5", "345.4"], "icd-10": ["G40.2", "G40.0"], "wikidata": ["Q7140388"]}
A number sign (#) is used with this entry because of evidence that susceptibility to prostate cancer/brain cancer is associated with somatic mutation in the EPHB2 gene (600997) on chromosome 1p36. Mapping Because an excess of cases of primary brain cancer has been observed in some studies of families with a high risk of prostate cancer, and because loss of heterozygosity at 1p36 is frequently observed in brain cancer, Gibbs et al. (1999) evaluated 12 families with both a history of prostate cancer and a blood relative with primary brain cancer. The overall lod score in these 12 families was 3.22 at a recombination fraction (theta) of 0.06 with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of prostate cancer. In the younger age group (mean age at diagnosis less than 66 years), a maximum 2-point lod score of 3.65 at theta = 0.0 was observed with marker D1S407. This linkage was rejected in both early- and late-onset families without a history of brain cancer. After exclusion of 3 of the 12 families that had better evidence of linkage to previously described prostate cancer susceptibility loci, linkage to the 1p36 region was suggested by a 2-point lod score of 4.74 at theta = 0.0 with marker D1S407. Gibbs et al. (1999) concluded that a significant proportion of these families with a high risk for prostate cancer and a family member with brain cancer show linkage to the 1p36 region. Badzioch et al. (2000) reported genotype analysis of 207 multiple-case prostate cancer families including 9 families with prostate and brain cancer. They found no evidence of linkage to 1p36 in the total set of families with prostate and brain cancer, but did find suggestive evidence (maximum lod 0.48) of linkage in those families with early onset (earlier than 66 years). Badzioch et al. (2000) concluded that linkage to this region may be a feature of early-onset prostate cancer rather than of the brain/prostate cancer phenotype. Cancel-Tassin et al. (2001) examined evidence for linkage to the CAPB locus in 64 (37 previously reported and 27 newly identified) families from southern and western Europe with at least 3 affected individuals with prostate cancer and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, no significant evidence of linkage was observed. A subset of 6 pedigrees with 1 case of brain cancer also showed negative lod scores. Even when heterogeneity was assumed, multipoint hlod scores remained negative across the entire interval. The findings suggested that the CAPB locus is not the only one responsible for susceptibility to brain and prostate cancer. Molecular Genetics Huusko et al. (2004) sought tumor-suppressor genes in solid tumors by combined nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization, looking for genes with biallelic inactivation involving nonsense mutations in one allele and loss of the other, wildtype, allele. This approach enabled them to identify previously unknown mutations in the receptor tyrosine kinase gene EPHB2 (600997). In DU 145, a prostate cancer cell line originating from a brain metastasis, Huusko et al. (2004) found a truncating mutation of EPHB2 (Q723X; 600997.0001) and a deletion of the remaining allele. In other prostate cancer samples, frameshift, splice site, missense, and nonsense mutations were found (see, e.g., 600997.0002-600997.0003). Kittles et al. (2006) demonstrated association between a somatic nonsense mutation (K1019X; 600997.0004) in the EPHB2 gene and prostate cancer in African Americans. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PROSTATE CANCER/BRAIN CANCER SUSCEPTIBILITY	c2931456	2,246	omim	https://www.omim.org/entry/603688	2019-09-22T16:12:45	{"mesh": ["C537243"], "omim": ["603688"], "orphanet": ["1331"], "synonyms": ["Alternative titles", "PCBC", "CAPB"]}
A number sign (#) is used with this entry because of evidence that susceptibility to Hirschsprung disease (HSCR4) is associated with variation in the EDN3 gene (131242) on chromosome 20q13. Description The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid. Total colonic aganglionosis and total intestinal HSCR also occur (Amiel et al., 2008). Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance (Amiel et al., 2008). For a discussion of genetic heterogeneity of susceptibility to Hirschsprung disease, see 142623. Molecular Genetics Bidaud et al. (1997) reported a sporadic case of isolated Hirschsprung disease with a heterozygous EDN3 missense mutation (131242.0004). The findings gave support to the role of the endothelin-signaling pathway in the development of neural crest-derived enteric neurons. They also suggested the possibility that either recessive or weakly penetrant dominant alleles can occur at the EDN3 locus, depending on the nature of the mutation. In a patient with short-segment Hirschsprung disease without any Waardenburg features, Svensson et al. (1999) found a novel heterozygous frameshift mutation (131242.0006), which was predicted to result in haploinsufficiency. Sanchez-Mejias et al. (2010) screened the EDN3 and EDNRB (131244) genes in 196 patients with Hirschsprung disease from Spain using high performance liquid chromatography. They detected 11 sequence variants in the EDN3 gene among the patients, including 4 novel variants. They also found novel mutations in the EDNRB gene, including a truncating mutation (see 131244.0009) in an alternative isoform. INHERITANCE \- Autosomal dominant ABDOMEN Gastrointestinal \- Hirschsprung disease \- Short aganglionic segment (sigmoidal, 1 patient) MISCELLANEOUS \- Based on 3 patients with little to no clinical details (last curated January 2011) MOLECULAR BASIS \- Susceptibility conferred by mutation in the endothelin 3 gene (EDN3, 131242.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	HIRSCHSPRUNG DISEASE, SUSCEPTIBILITY TO, 4	c0019569	2,247	omim	https://www.omim.org/entry/613712	2019-09-22T15:57:46	{"mesh": ["D006627"], "omim": ["613712"], "orphanet": ["388"]}
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay with mild intellectual disability, short stature, facial dysmorphism (such as sparse hair, high forehead, deep-set eyes, short and upslanting palpebral fissures, short nose, anteverted nares, wide nasal base with broad nasal tip and broad columella, long philtrum, thin upper lip, and low-set, posteriorly rotated ears), and variable onset of sensorineural hearing loss and retinitis pigmentosa. Additional features are other ocular anomalies, abnormalities of the fingers, hypothyroidism, and signs of premature aging. Brain imaging shows cerebellar atrophy and dysmyelination. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome	c4540367	2,248	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=494439	2021-01-23T17:13:45	{"omim": ["617763"], "synonyms": ["Retinitis pigmentosa-deafness-premature aging-short stature-facial dysmorphism syndrome"]}
For a discussion of genetic heterogeneity of X-linked spinocerebellar ataxia (SCAX), see SCAX1 (302500). Clinical Features Schmidley et al. (1987) described an X-linked disorder of the central nervous system characterized by onset in infancy of hypotonia, ataxia, sensorineural deafness, developmental delay, esotropia, and optic atrophy, and by a progressive course leading to death in childhood. Histopathologically, a neuron loss and gliosis of the dentate nucleus and inferior olive were conspicuous; involvement of the cerebellar cortex was less prominent. In the proband, the red nucleus, dorsal motor nucleus of the vagus, and central auditory pathways were severely affected. The mother of the proband, aged 33 years, had self-limiting episodes of ataxia as well as cerebellar atrophy for which no other cause was apparent. The pedigree contained at least 6 affected males in 5 different sibships connected through carrier females in 3 successive generations. No report of a precisely similar disorder was discovered. See also Arts syndrome (301835), which has similar features. INHERITANCE \- X-linked recessive HEAD & NECK Ears \- Sensorineural hearing loss Eyes \- Esotropia \- Pale optic discs \- Optic atrophy \- Strabismus RESPIRATORY \- Respiratory distress, episodic \- Hypoventilation, episodic \- Respiratory infections Larynx \- Unilateral paralysis of the vocal cord ABDOMEN Gastrointestinal \- Vomiting, episodic \- Dysphagia, episodic \- Choking, episodic \- Gastroesophageal reflux NEUROLOGIC Central Nervous System \- Developmental delay \- Cerebellar dysfunction, progressive \- Cerebellar ataxia \- Intermittent, transient episodes of worsening of ataxia \- Intermittent episodes associated with lethargy, vomiting \- Dysmetria \- Intention tremor \- Head titubation \- Incoordination \- Lethargy \- Hypotonia \- Weakness \- Seizures \- Dementia \- Spasticity (later onset) \- Neuronal loss and gliosis in the dentate nucleus \- Neuronal loss and gliosis in the inferior olives \- Cerebellar atrophy Peripheral Nervous System \- Hyporeflexia \- Areflexia MISCELLANEOUS \- Onset in infancy \- Death in early childhood ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	SPINOCEREBELLAR ATAXIA, X-LINKED 3	c1844936	2,249	omim	https://www.omim.org/entry/301790	2019-09-22T16:18:46	{"mesh": ["C537315"], "omim": ["301790"], "orphanet": ["85297"], "synonyms": ["Alternative titles", "SCAX3", "ATAXIA-DEAFNESS SYNDROME, X-LINKED"]}
Abnormal form of pregnancy (human disorder) Molar pregnancy Other namesVesicular mole, Hydatid mole, Hydatidiform mole Histopathologic image of hydatidiform mole (complete type). H & E stain. SpecialtyObstetrics Molar pregnancy is an abnormal form of pregnancy in which a non-viable fertilized egg implants in the uterus and will fail to come to term. A molar pregnancy is a gestational trophoblastic disease[1] which grows into a mass in the uterus that has swollen chorionic villi. These villi grow in clusters that resemble grapes.[2] A molar pregnancy can develop when a fertilized egg does not contain an original maternal nucleus. The products of conception may or may not contain fetal tissue. It is characterized by the presence of a hydatidiform mole (or hydatid mole, mola hydatidosa).[3] Molar pregnancies are categorized as partial moles or complete moles, with the word mole being used to denote simply a clump of growing tissue, or a growth. A complete mole is caused by a single sperm (90% of the time) or two (10% of the time) sperm combining with an egg which has lost its DNA. In the first case, the sperm then reduplicates, forming a "complete" 46 chromosome set.[4] The genotype is typically 46,XX (diploid) due to the subsequent mitosis of the fertilizing sperm but can also be 46,XY (diploid).[4] 46,YY (diploid) is not observed. In contrast, a partial mole occurs when a normal egg is fertilized by one or two sperm which then reduplicates itself, yielding the genotypes of 69,XXY (triploid) or 92,XXXY (tetraploid).[4] Complete hydatidiform moles have a 2–4% risk of developing into choriocarcinoma in Western countries and 10–15% in Eastern countries and also a 15% risk of becoming an invasive mole. Incomplete moles can become invasive (<5% risk) but are not associated with choriocarcinoma.[4] Complete hydatidiform moles account for 50% of all cases of choriocarcinoma. Molar pregnancies are a relatively rare complication of pregnancy, making up 1 in 1,000 pregnancies in the US, with much higher rates in Asia (e.g. up to 1 in 100 pregnancies in Indonesia).[5] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 3.1 Parental origin * 4 Diagnosis * 5 Treatment * 5.1 Anesthesia * 6 Prognosis * 7 Epidemiology * 8 Etymology * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Vesicular mole Molar pregnancies usually present with painless vaginal bleeding in the fourth to fifth months of pregnancy.[3] The uterus may be larger than expected, or the ovaries may be enlarged. There may also be more vomiting than would be expected (hyperemesis). Sometimes there is an increase in blood pressure along with protein in the urine. Blood tests will show very high levels of human chorionic gonadotropin (hCG).[6] ## Cause[edit] The cause of this condition is not completely understood. Potential risk factors may include defects in the egg, abnormalities within the uterus, or nutritional deficiencies. Women under 20 or over 40 years of age have a higher risk. Other risk factors include diets low in protein, folic acid, and carotene.[7] The diploid set of sperm-only DNA means that all chromosomes have sperm-patterned methylation suppression of genes. This leads to overgrowth of the syncytiotrophoblast whereas dual egg-patterned methylation leads to a devotion of resources to the embryo, with an underdeveloped syncytiotrophoblast. This is considered to be the result of evolutionary competition, with male genes driving for high investment into the fetus versus female genes driving for resource restriction to maximise the number of children.[8] ## Pathophysiology[edit] A hydatidiform mole is a pregnancy/conceptus in which the placenta contains grapelike vesicles (small sacs) that are usually visible to the naked eye. The vesicles arise by distention of the chorionic villi by fluid. When inspected under the microscope, hyperplasia of the trophoblastic tissue is noted. If left untreated, a hydatidiform mole will almost always end as a spontaneous abortion (miscarriage). Based on morphology, hydatidiform moles can be divided into two types: in complete moles, all the chorionic villi are vesicular, and no sign of embryonic or fetal development is present. In partial moles some villi are vesicular, whereas others appear more normal, and embryonic/fetal development may be seen but the fetus is always malformed and is never viable. Uterus with complete hydatidiform mole In rare cases a hydatidiform mole co-exists in the uterus with a normal, viable fetus. These cases are due to twinning. The uterus contains the products of two conceptions: one with an abnormal placenta and no viable fetus (the mole), and one with a normal placenta and a viable fetus. Under careful surveillance it is often possible for the woman to give birth to the normal child and to be cured of the mole.[9] ### Parental origin[edit] In most complete moles, all nuclear genes are inherited from the father only (androgenesis). In approximately 80% of these androgenetic moles, the most probable mechanism is that an empty egg is fertilized by a single sperm, followed by a duplication of all chromosomes/genes (a process called "endoreduplication"). In approximately 20% of complete moles, the most probable mechanism is that an empty egg is fertilized by two sperm. In both cases, the moles are diploid (i.e. there are two copies of every chromosome). In all these cases, the mitochondrial genes are inherited from the mother, as usual. Most partial moles are triploid (three chromosome sets). The nucleus contains one maternal set of genes and two paternal sets. The mechanism is usually the reduplication of the paternal haploid set from a single sperm, but may also be the consequence of dispermic (two sperm) fertilization of the egg.[10] In rare cases, hydatidiform moles are tetraploid (four chromosome sets) or have other chromosome abnormalities. A small percentage of hydatidiform moles have biparental diploid genomes, as in normal living persons; they have two sets of chromosomes, one inherited from each biological parent. Some of these moles occur in women who carry mutations in the gene NLRP7, predisposing them towards molar pregnancy. These rare variants of hydatidiform mole may be complete or partial.[11][12][13] ## Diagnosis[edit] Transvaginal ultrasonography showing a molar pregnancy. Molar pregnancy in ultrasound Hydatidiform mole on CT, sagittal view Hydatidiform mole on CT, axial view The diagnosis is strongly suggested by ultrasound (sonogram), but definitive diagnosis requires histopathological examination. On ultrasound, the mole resembles a bunch of grapes ("cluster of grapes" or "honeycombed uterus" or "snow-storm").[14] There is increased trophoblast proliferation and enlarging of the chorionic villi, and angiogenesis in the trophoblasts is impaired.[15] Sometimes symptoms of hyperthyroidism are seen, due to the extremely high levels of hCG, which can mimic the effects of thyroid-stimulating hormone.[15] Complete Mole Partial Mole Karyotype 46,XX (46,XY) 69,XXY hCG ↑↑↑↑ ↑ Uterine Size ↑ –[clarification needed] Convert to Choriocarcinoma 2% Rare Fetal Parts No Yes Components 2 sperm + empty egg 2 sperm + 1 egg Risk of Complications 15-20% malignant trophoblastic disease Low risk of malignancy (<5%) ## Treatment[edit] Hydatidiform moles should be treated by evacuating the uterus by uterine suction or by surgical curettage as soon as possible after diagnosis, in order to avoid the risks of choriocarcinoma.[16] Patients are followed up until their serum human chorionic gonadotrophin (hCG) level has fallen to an undetectable level. Invasive or metastatic moles (cancer) may require chemotherapy and often respond well to methotrexate. As they contain paternal antigens, the response to treatment is nearly 100%. Patients are advised not to conceive for half a year after hCG levels have normalized. The chances of having another molar pregnancy are approximately 1%. Management is more complicated when the mole occurs together with one or more normal fetuses. In some women, the growth can develop into gestational trophoblastic neoplasia. For women who have complete hydatidiform mole and are at high risk of this progression, evidence suggests giving prophylactic chemotherapy (known as P-chem) may reduce the risk of this happening.[17] However P-chem may also increase toxic side effects, so more research is needed to explore its effects.[17] ### Anesthesia[edit] The uterine curettage is generally done under the effect of anesthesia, preferably spinal anesthesia in hemodynamically stable patients. The advantages of spinal anesthesia over general anesthesia include ease of technique, favorable effects on the pulmonary system, safety in patients with hyperthyroidism and non-tocolytic pharmacological properties. Additionally, by maintaining patient's consciousness one can diagnose the complications like uterine perforation, cardiopulmonary distress and thyroid storm at an earlier stage than when the patient is sedated or is under general anesthesia.[18] ## Prognosis[edit] More than 80% of hydatidiform moles are benign. The outcome after treatment is usually excellent. Close follow-up is essential to ensure that treatment has been successful.[19] Highly effective means of contraception are recommended to avoid pregnancy for at least 6 to 12 months. Women who have had a prior partial or complete mole, have a slightly increased risk of a second hydatidiform mole in a subsequent pregnancy, meaning a future pregnancy will require an earlier ultrasound scan.[19] In 10 to 15% of cases, hydatidiform moles may develop into invasive moles. This condition is named persistent trophoblastic disease (PTD). The moles may intrude so far into the uterine wall that hemorrhage or other complications develop. It is for this reason that a post-operative full abdominal and chest x-ray will often be requested. In 2 to 3% of cases, hydatidiform moles may develop into choriocarcinoma, which is a malignant, rapidly growing, and metastatic (spreading) form of cancer. Despite these factors which normally indicate a poor prognosis, the rate of cure after treatment with chemotherapy is high. Over 90% of women with malignant, non-spreading cancer are able to survive and retain their ability to conceive and bear children. In those with metastatic (spreading) cancer, remission remains at 75 to 85%, although their childbearing ability is usually lost. ## Epidemiology[edit] Hydatidiform moles are a rare complication of pregnancy, occurring once in every 1,000 pregnancies in the US, with much higher rates in Asia (e.g. up to one in 100 pregnancies in Indonesia).[5] ## Etymology[edit] The etymology is derived from hydatisia (Greek "a drop of water"), referring to the watery contents of the cysts, and mole (from Latin mola = millstone/false conception).[20] The term, however, comes from the similar appearance of the cyst to a hydatid cyst in an Echinococcosis.[21] ## See also[edit] * Echinococcosis * Gestational trophoblastic disease ## References[edit] 1. ^ "Gestational Trophoblastic Disease". American Cancer Society. 14 April 2011. 2. ^ "hydatidiform mole". Merriam Webster. Retrieved May 7, 2012. 3. ^ a b Cotran RS, Kumar V, Fausto N, Nelso F, Robbins SL, Abbas AK (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. p. 1110. ISBN 0-7216-0187-1. 4. ^ a b c d Kumar, Vinay, ed. (2010). Pathologic Basis of Disease (8th ed.). Saunders Elsevier. pp. 1057–1058. ISBN 978-1-4377-0792-2. 5. ^ a b Di Cintio E, Parazzini F, Rosa C, Chatenoud L, Benzi G (November 1997). "The epidemiology of gestational trophoblastic disease". General & Diagnostic Pathology. 143 (2–3): 103–8. PMID 9443567. 6. ^ Ganong WF, McPhee SJ, Lingappa VR (2005). Pathophysiology of Disease: An Introduction to Clinical Medicine (Lange). McGraw-Hill Medical. p. 639. ISBN 0-07-144159-X. 7. ^ MedlinePlus Encyclopedia: Hydatidiform mole 8. ^ Paoloni-Giacobino A (May 2007). "Epigenetics in reproductive medicine". Pediatric Research. 61 (5 Pt 2): 51R–57R. doi:10.1203/pdr.0b013e318039d978. PMID 17413849. 9. ^ Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D, et al. (June 2002). "Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin". Lancet. 359 (9324): 2165–6. doi:10.1016/S0140-6736(02)09085-2. PMID 12090984. S2CID 33752037. 10. ^ Monga, Ash, ed. (2006). Gynaecology by Ten Teachers (18th ed.). Hodder Arnold. pp. 99–101. ISBN 0-340-81662-7. 11. ^ Lawler SD, Fisher RA, Dent J (May 1991). "A prospective genetic study of complete and partial hydatidiform moles". American Journal of Obstetrics and Gynecology. 164 (5 Pt 1): 1270–7. doi:10.1016/0002-9378(91)90698-q. PMID 1674641. 12. ^ Wallace DC, Surti U, Adams CW, Szulman AE (1982). "Complete moles have paternal chromosomes but maternal mitochondrial DNA". Human Genetics. 61 (2): 145–7. doi:10.1007/BF00274205. PMID 6290372. S2CID 1417706. 13. ^ Slim R, Mehio A (January 2007). "The genetics of hydatidiform moles: new lights on an ancient disease". Clinical Genetics. 71 (1): 25–34. doi:10.1111/j.1399-0004.2006.00697.x. PMID 17204043. S2CID 32421323. Review. 14. ^ Woo JS, Hsu C, Fung LL, Ma HK (May 1983). "Partial hydatidiform mole: ultrasonographic features". The Australian & New Zealand Journal of Obstetrics & Gynaecology. 23 (2): 103–7. doi:10.1111/j.1479-828X.1983.tb00174.x. PMID 6578773. S2CID 6572375. 15. ^ a b "The 6 questions that pregnant women should be ask to the doctor". HealthGuru. 15 March 2019. 16. ^ Cotran RS, Kumar V, Fausto N, Nelso F, Robbins SL, Abbas AK (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. p. 1112. ISBN 0-7216-0187-1. 17. ^ a b Wang Q, Fu J, Hu L, Fang F, Xie L, Chen H, et al. (September 2017). "Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia". The Cochrane Database of Systematic Reviews. 9: CD007289. doi:10.1002/14651858.cd007289.pub3. PMC 6483742. PMID 28892119. 18. ^ Biyani G, Bhatia P (November 2011). "Mortality in hydatidiform mole: Should we blame thyroid?". Indian Journal of Anaesthesia. 55 (6): 628–9. doi:10.4103/0019-5049.90629. PMC 3249877. PMID 22223914. 19. ^ a b Cavaliere A, Ermito S, Dinatale A, Pedata R (January 2009). "Management of molar pregnancy". Journal of Prenatal Medicine. 3 (1): 15–7. PMC 3279094. PMID 22439034. 20. ^ Entries HYDATID n. (a.) and MOLE, n.6 in the Oxford English Dictionary online. (http://dictionary.oed.com/ — subscription required.) 21. ^ "Hydatidiform". ## External links[edit] * Humpath #3186 (Pathology images) * Clinically reviewed molar pregnancy and choriocarcinoma information for patients from Cancer Research UK * MyMolarPregnancy.com: Resource for those diagnosed with molar pregnancy. Links, personal stories, and support groups. Classification D * ICD-10: O01, D39.2 * ICD-9-CM: 630 * ICD-O: M9100/0 * OMIM: 231090 * MeSH: D006828 * DiseasesDB: 6097 External resources * MedlinePlus: 000909 * eMedicine: med/1047 med/866 * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category * v * t * e Germ cell tumors Germinomatous * Germinoma * Seminoma * Dysgerminoma Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor/Yolk sac tumor * Teratoma: Fetus in fetu * Dermoid cyst * Struma ovarii * Strumal carcinoid * Trophoblastic neoplasm: Gestational trophoblastic disease * Hydatidiform mole * Choriocarcinoma * Placental site trophoblastic tumor * Polyembryoma * Gonadoblastoma Authority control * NDL: 00563569 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Molar pregnancy	c1135868	2,250	wikipedia	https://en.wikipedia.org/wiki/Molar_pregnancy	2021-01-18T18:37:35	{"gard": ["10263"], "mesh": ["D006828", "D031901"], "umls": ["C0278796", "C1135868", "C0020217"], "orphanet": ["99927"], "wikidata": ["Q881855"]}
1q21.1 microdeletion syndrome is a newly described recurrent deletion syndrome with variable clinical manifestations but without the clinical picture of thrombocytopenia - absent radius (TAR) syndrome. ## Epidemiology It has been described in 46 patients to date. ## Clinical description The clinical phenotype is extremely variable; the most common but non-constant clinical findings include microcephaly, developmental delay or mild intellectual deficit, slight facial dysmorphic features and eye abnormalities. Congenital malformations are not common. Autism spectrum disorders, schizophrenia or attention deficit hyperactivity disorder have been noted occasionally. ## Etiology This syndrome is caused by a recurrent 1.35Mb deletion in the distal 1q21.1 region distinct from the deletion region implicated in TAR syndrome (see this term). ## Diagnostic methods This microdeletion was identified by comparative genomic hybridization (CGH) microarray and is only diagnosed by molecular cytogenetics. It cannot be identified by routine chromosome analysis. ## Genetic counseling The underlying mechanism is non-allelic homologous recombination (NAHR). Deletions appear de novo or can be inherited in an autosomal dominant manner from mildly affected or completely normal parents. This suggests that the distal 1q21.1 microdeletion has incomplete penetrance and variable expressivity. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	1q21.1 microdeletion syndrome	c2675897	2,251	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=250989	2021-01-23T19:10:01	{"gard": ["10813"], "mesh": ["C567291"], "omim": ["612474"], "umls": ["C2675897"], "icd-10": ["Q93.5"], "synonyms": ["Del(1)(q21)", "Monosomy 1q21.1"]}
Inflammatory pseudotumor (IPT) of the liver is a rare benign tumor-like lesion. ## Epidemiology Approximately 140 cases have been reported worldwide, with a higher prevalence for male adults of Asian origin and subjects affected by systemic diseases such as rheumatoid arthritis. Some cases of IPT of the liver have been associated with extrahepatic malignant tumors. ## Clinical description There are two clinical presentations. The active form most commonly manifests with abdominal pain, fever and loss of body weight. Laboratory findings include an increased erythrocyte sedimentation rate (ESR) and increases levels of C-reactive protein (CRP), leukocytosis, slightly elevated aminotransferase activity, increased bilirubin levels and variable alterations of the electrophoretic pattern. Histologically, ITP of the liver is characterized by a large population of polyclonal plasma cells with a variable amount of fibrosis, foamy histiocytes and other chronic inflammatory cells. On imaging, the lesion is often large and mimics malignant liver tumors. The second form (also described as solitary necrotic tumor) is usually clinically silent. Blood liver tests are normal and there are no remarkable laboratory findings. On imaging, the lesion is well-limited and may be surrounded by a capsule. The etiopathogenesis of IPT of the liver remains unclear. Recent publications suggested either a post-inflammatory regenerative process (caused by bacteria from food, chronic appendicitis or cholecystitis, or Epstein-Barr virus infection) or a primary neoplastic process. The clinical picture, imaging and macroscopic appearance of IPT of the liver are similar to those of other hepatic pathologies, including malignant liver tumors: granulomatous hepatitis, liver abscess, sarcoidosis (see this term), hepatic tuberculosis, hepatocellular carcinoma (see this term), cholangiocellular carcinoma (see this term), and metastatic liver tumor. ## Diagnostic methods Diagnosis is important to avoid surgery and requires a histological confirmation (percutaneous biopsy). ## Management and treatment There is no standardized optimum management. Surgical resection (partial hepatic resection) was usually performed because the diagnosis was rarely made prior the surgery. However, regression is the rule with antibiotics. Spontaneous regression has also been described. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Inflammatory pseudotumor of the liver	c1333967	2,252	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90003	2021-01-23T17:45:46	{"icd-10": ["K75.8"]}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Mesothelial hyperplasia" – news · newspapers · books · scholar · JSTOR (February 2014) (Learn how and when to remove this template message) Mesothelial hyperplasia is a hyperplasia of mesothelial cells in serous membranes (pleura, pericardium, peritoneum). Mesothelial hyperplasia is usually an incidental finding during peritoneal examination during laparotomy or laparoscopy. Grossly, mesothelial hyperplasia is characterized by the presence of small white nodules or flat plaques on the serous surface. ## Types[edit] * Reactive mesothelial hyperplasia * It is associated with a variety of chronic and acute injuries to the mesothelial surface. The inciting injury can be of inflammatory, infectious or toxic. * Peritoneal mesothelial hyperplasia can be encountered in inflammatory pelvic disease with tubo-ovarian abscess, ovarian neoplasms (malignant or benign), and peritoneal effusions. * Atypical mesothelial hyperplasia ## References[edit] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Mesothelial hyperplasia	c0333987	2,253	wikipedia	https://en.wikipedia.org/wiki/Mesothelial_hyperplasia	2021-01-18T18:50:15	{"umls": ["C0333987"], "wikidata": ["Q16963363"]}
A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 7 (DA7), also known as trismus-pseudocamptodactyly syndrome, is caused by heterozygous mutation in the MYH8 gene (160741) on chromosome 17p13. For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120). Description The trismus-pseudocamptodactyly syndrome is a distal arthrogryposis characterized by an inability to open the mouth fully (trismus) and pseudocamptodactyly in which wrist dorsiflexion, but not volar flexion, produces involuntary flexion contracture of distal and proximal interphalangeal joints. In these patients, trismus complicates dental care, feeding during infancy, and intubation for anesthesia, and the pseudocamptodactyly impairs manual dexterity, with consequent occupational and social disability (summary by Veugelers et al., 2004). Clinical Features Hecht and Beals (1969) described father and 4 children (2 sons, 2 daughters) with inability to open the mouth completely with resulting problems in mastication, short finger-flexor tendons such that dorsiflexion of the wrist resulted in camptodactyly, and short leg muscles resulting in foot deformity. The father's mother was probably also affected. Wilson et al. (1969) described the same syndrome in 9 persons in 4 generations. They ascribed the finger peculiarity to shortening of the flexor profundus muscle-tendon unit. De Jong (1971) described a Dutch family with many affected members. Ter Haar and Van Hoof (1974) examined 24 affected and 19 unaffected members of a large Dutch kindred with trismus and pseudocamptodactyly inherited in an autosomal dominant pattern. A connection between 2 apparently unrelated propositi with trismus and the same rare last name had been sought, and it was established that they had common ancestors 5 generations earlier, at the end of the 18th century. Ter Haar and Van Hoof (1974) found that measuring mouth opening and wrist angles was sufficient to divide family members into affected and unaffected groups and noted that although affected individuals were not under the 10th centile for height in the Dutch population, their height was less than that of unaffected sibs of the same sex. Mabry et al. (1974) described an extensively affected kindred. Since it was traced to a Dutch girl who migrated to the United States and to Tennessee soon after the American Revolution, the possibility that all cases reported to date are related is strong. Yamashita and Arnet (1980) reported a 4-generation family with multiple affected members showing variable presentation of hip problems, limited oral opening, micrognathia, and pseudocamptodactyly; only the proband had all of the features of the syndrome. Robertson et al. (1982) examined 31 of 53 affected members and 77 unaffected members of a 6-generation pedigree with trismus and pseudocamptodactyly originally reported by Yamashita and Arnet (1980). Expressivity was highly variable, but there was no evidence of reduced penetrance. Robertson et al. (1982) noted that foot deformities had been described in all reports, including shortness of the Achilles tendon, hammertoe, talipes equinovarus, and metatarsus varus, and suggested that shortness of flexor muscle-tendon units could account for the mouth, hand, and foot deformities. There was no short stature in this family, and the authors stated that they could not verify any Dutch ancestry. No linkage was found with 16 markers studied. Hall et al. (1982) reviewed published cases. Tsukahara et al. (1985) reported 5 affected members of a 3-generation Japanese family. The proband had both trismus and pseudocamptodactyly, whereas the other 4 affected family members had only pseudocamptodactyly, indicating variable expressivity of the syndrome. Dutch ancestry, which had predominated in earlier reports, was considered unlikely. Chen et al. (1992) reported a 6-year-old boy and his 29-year-old mother who both had inability to open their mouths fully, pseudocamptodactyly, foot deformities, and mild short stature. The mother's brother and his son were also affected but primarily with tightness of the Achilles tendon and muscle cramps. There were at least 3 generations of affected individuals in this kindred. The mother also had abnormal swallowing demonstrated by manometry and marked interphalangeal webbing; noting that the proband reported by Tsukahara et al. (1985) had soft tissue syndactyly of the toes, Chen et al. (1992) suggested that dysphagia and cutaneous syndactyly are part of the clinical spectrum. Minzer-Conzetti et al. (2008) described a 20-year-old man with genetically confirmed trismus-pseudocamptodactyly, who had mild facial dysmorphism with macrocephaly, facial asymmetry, ptosis and downslanting palpebral features, deep philtrum, and a long chin. He also had widespread joint involvement with congenital hip dysplasia and reduced movement of the left hip, reduced elbow supination, and vertical tali and talipes. Minzer-Conzetti et al. (2008) stated that the findings in this patient broadened the phenotype. Inheritance The trismus-pseudocamptodactyly syndrome is an autosomal dominant trait with variable expressivity but high penetrance (summary by Veugelers et al., 2004). Molecular Genetics In affected members of 2 families with trismus-pseudocamptodactyly syndrome (Mabry et al., 1974; Lefaivre and Aitchison, 2003), Veugelers et al. (2004) identified an arg674-to-gln mutation in the MYH8 gene (R674Q; 160741.0001). The R674Q mutation was also identified in affected members of a large Caucasian Belgian family with Carney complex variant (608837), which is associated with trismus-pseudocamptodactyly syndrome. Toydemir et al. (2006) identified the R674Q mutation in the MYH8 gene in all affected members of 4 families with trismus-pseudocamptodactyly syndrome, including descendants of the Dutch family reported by Ter Haar and Van Hoof (1974) and 3 kindreds ascertained in the United States, 1 originally reported by Chen et al. (1992). Analysis of haplotype sharing revealed that while each of the U.S. pedigrees shared the same MYH8 haplotype, this haplotype was not shared by the Dutch kindred. None of the affected individuals had multiple hyperpigmented macules or cardiac myxomas, and the R674Q mutation was not found in 49 unrelated cases of Carney complex who were negative for mutation in the PRKAR1A gene (188830). Toydemir et al. (2006) concluded that Dutch and U.S. pedigrees with trismus-pseudocamptodactyly syndrome do not share a founder mutation, and that R674Q rarely, if ever, causes Carney complex. In 2 brothers with trismus-pseudocamptodactyly, Bonapace et al. (2010) identified heterozygosity for the R674Q mutation in the MYH8 gene. The mutation was not found in their unaffected parents or sister; the authors stated that their findings were most consistent with germline mosaicism, although a recurrent de novo mutation could not be excluded. Both patients had reduced oral opening and camptodactyly of the hands with flexion of the fingers upon extension of the wrist. They also had reduced bilateral hip flexion and flexion of the toes upon foot dorsiflexion. Nomenclature In a revised and extended classification scheme of the distal arthrogryposes, Bamshad et al. (1996) referred to this disorder as distal arthrogryposis type 7 (DA7). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (3rd-25th percentile) HEAD & NECK Head \- Macrocephaly (rare) Face \- Micrognathia \- Facial asymmetry, mild \- Deep philtrum (rare) \- Long chin (rare) Eyes \- Ptosis Mouth \- Limited mouth opening (trismus) ABDOMEN Gastrointestinal \- Feeding problems \- Dysphagia SKELETAL Skull \- Enlarged coronoid process Pelvis \- Hip dislocation Limbs \- Short gastrocnemius \- Reduced elbow supination Hands \- Interphalangeal webbing \- Flexion of fingers when hand dorsiflexed (pseudocamptodactyly) Feet \- Soft tissue syndactyly of toes \- Metatarsus adductus \- Downturning toes \- Talipes equinovarus \- Hammer toes \- Vertical tali \- Vertical talipes MUSCLE, SOFT TISSUES \- Shortening of flexor profundus muscle-tendon unit \- Shortening of various muscle-tendon groups in legs \- Shortening of various muscle-tendon groups in feet MISCELLANEOUS \- More common in females \- Hands clenched at birth but loosen in infancy MOLECULAR BASIS \- Caused by mutation in the myosin, heavy polypeptide-8 gene (MYH8, 160741.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	ARTHROGRYPOSIS, DISTAL, TYPE 7	c0265226	2,254	omim	https://www.omim.org/entry/158300	2019-09-22T16:37:59	{"doid": ["0050646"], "mesh": ["C535857"], "omim": ["158300"], "orphanet": ["3377"], "synonyms": ["Alternative titles", "TRISMUS-PSEUDOCAMPTODACTYLY SYNDROME", "MOUTH, INABILITY TO OPEN COMPLETELY, AND SHORT FINGER-FLEXOR TENDONS", "HECHT SYNDROME"]}
A number sign (#) is used with this entry because of evidence that patent ductus arteriosus-2 (PDA2) is caused by heterozygous mutation in the TFAP2B gene (601601) on chromosome 6p12. Mutation in TFAP2B also causes Char syndrome (CHAR; 169100), in which affected individuals exhibit facial dysmorphism and hand abnormalities in addition to patent ductus arteriosus (PDA). Description The ductus arteriosus is a muscular artery connecting the pulmonary artery and the aorta during fetal life, shunting blood away from the lungs. It normally occludes shortly after birth. Failure of ductal closure results in PDA, one of the most common congenital heart defects, affecting 1 in 2,000 to 1 in 5,000 full-term infants and constituting 5% to 7% of all congenital heart defects (summary by Mani et al., 2005). PDA can be an isolated anomaly or occur in association with other congenital anomalies (summary by Khetyar et al., 2008). For a discussion of genetic heterogeneity of isolated PDA, see PDA1 (607411). Clinical Features Khetyar et al. (2008) studied a consanguineous Kuwaiti family segregating autosomal dominant PDA, with 6 affected family members over 2 generations. Clinical history and physical examination confirmed that no affected individuals exhibited the characteristic craniofacial or fifth finger anomalies of Char syndrome. Chen et al. (2011) reported 2 Chinese families segregating autosomal dominant isolated PDA. The first family consisted of 2 affected sisters with 3 affected offspring, and the second involved an affected mother and daughter. None of the patients exhibited features of Char syndrome. Molecular Genetics In 6 affected members of a consanguineous Kuwaiti family segregating autosomal dominant PDA, Khetyar et al. (2008) sequenced the TFAP2B gene and identified heterozygosity for a splice site mutation (601601.0008) that was not found in 6 unaffected family members. In 5 affected members of a Chinese family with isolated PDA, Chen et al. (2011) identified heterozygosity for a splice site mutation (601601.0007) in the TFAP2B gene. The authors noted that the same splice site mutation had previously been reported in a large family with Char syndrome (Mani et al., 2005), and stated that the reasons for differences in expression patterns remained unclear. In a mother and daughter from an unrelated Chinese family, Chen et al. (2011) identified heterozygosity for a 4-bp deletion in TFAP2B (601601.0009). Both mutations segregated fully with disease in the respective families, and neither was found in 100 ethnically matched controls. Chen et al. (2011) also analyzed the TFAP2B gene in 100 unrelated Chinese children with isolated PDA and 100 healthy unrelated Chinese children (controls) and identified a novel SNP 34 bp upstream of the TFAP2B transcription initiation site (c.1-34G-A). The A allele was found significantly more frequently among affected individuals than among controls (p = 0.012). The AA genotype was found in 8 affected individuals and in no controls. The authors suggested that this variant should be considered as a potential risk factor for PDA. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Patent ductus arteriosus MOLECULAR BASIS \- Caused by mutation in the transcription factor AP2-beta gene (TFAP2B, 601601.0007 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PATENT DUCTUS ARTERIOSUS 2	c4284595	2,255	omim	https://www.omim.org/entry/617035	2019-09-22T15:47:09	{"omim": ["617035"], "orphanet": ["466729"], "synonyms": []}
IVIC syndrome is a very rare genetic malformation syndrome characterized by upper limb anomalies (radial ray defects, carpal bone fusion), extraocular motor disturbances, and congenital bilateral non-progressive mixed hearing loss. ## Epidemiology Prevalence of IVIC is not known. To date, four affected families from Venezuela, Italy, Hungary, and Turkey (discordant monozygotic twins) have been described. ## Clinical description Asymmetrical upper limbs are a characteristic clinical manifestation. Thumb involvement is the most typical clinical manifestation and can range from absence or hypoplasia to the presence of a triphalangic thumb. Other upper limb anomalies include radial ray defects and carpal bone fusion. Upper limbs may be severely malformed. Extraocular motor disturbances and hearing loss of variable severity have also been reported. Some affected individuals have been reported to have mild thrombocytopenia, leukocytosis, shoulder girdle hypoplasia, cardiac involvement, kidney malrotation, intermediate anorectal malformation (see this term), or rectovaginal fistula. The clinical presentation is highly variable but lower limbs are normal. There have been reports of sudden death. ## Etiology The syndrome has been linked to mutations in the SALL4 gene (20q13.2) encoding a transcription factor involved in the maintenance and self-renewal of embryonic and hematopoietic stem cells. Okihiro syndrome (see this term) is a disorder allelic to IVIC syndrome. ## Genetic counseling IVIC syndrome is inherited in an autosomal dominant manner. Genetic counseling should be offered to affected families, informing them of the 50% risk of offspring inheriting the disease-causing mutation and therefore being affected with the syndrome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	IVIC syndrome	c1327918	2,256	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2307	2021-01-23T18:22:10	{"gard": ["269"], "mesh": ["C535544"], "omim": ["147750"], "umls": ["C1327918"], "icd-10": ["Q71.8"], "synonyms": ["Oculo-oto-radial syndrome", "Radial ray defects, hearing impairment, external ophthalmoplegia, and thrombocytopenia"]}
For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see ARMD1 (603075). Mapping Majewski et al. (2003) studied 70 families with age-related macular degeneration (ARMD), ranging from small nuclear families to extended multigenerational pedigrees, with 344 affected and 217 unaffected members. Both parametric and allele-sharing models were used and analyses were performed not only on complete pedigrees but also on subdivisions of the pedigrees into nuclear families. To dissect potential genetic factors responsible for differences in disease manifestation, Majewski et al. (2003) stratified the sample by 2 major phenotypes, neovascular ARMD and geographic atrophy, and by age of affected family members at the time of evaluation. They observed a peak at chromosome 9q33 in the initial sample, the expanded sample, and in both parametric and nonparametric analyses, as well as after subdivision of the pedigrees into nuclear families. A lod score of 2.01 was achieved for marker D9S934 using the allele-sharing approach in entire pedigrees. Iyengar et al. (2004) conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease of the retina or geographic atrophy. They observed a total of 13 regions on 11 chromosomes with a nominal multipoint significance level of P equal to or less than 0.01 or lod equal to or more than 1.18. At marker D9S930 on chromosome 9q32 a P value of 0.0038 was obtained. Molecular Genetics Because of its role as a key mediator of inflammatory signaling pathways and its link to regulation of cholesterol efflux, and its position in a region of chromosome 9q32-q33 showing evidence of linkage to ARMD (Majewski et al., 2003; Iyengar et al., 2004), Zareparsi et al. (2005) examined toll-like receptor-4 (TLR4; 603030) as a candidate gene in ARMD. They screened a cohort of 667 unrelated Caucasian ARMD patients and 439 controls for the D299G (603030.0001) variant of TLR4, which has shown an association with atherosclerosis, and the T399I variant (603030.0002). Multiple logistic regression demonstrated an increased risk of ARMD in carriers of the G allele at TLR4 residue 299 (odds ratio = 2.65, P = 0.025), but lack of an independent effect by T399I variant. TLR4 D299G showed an additive effect on ARMD risk (odds ratio = 4.13, P = 0.002) with allelic variants of apolipoprotein E (APOE; 107741) and ATP-binding cassette transporter-1 (ABCA1; 600046), 2 genes involved in cholesterol efflux. The effect of the TLR4, APOE, and ABCA1 variants on ARMD susceptibility was opposite to that of association with atherosclerosis risk. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	MACULAR DEGENERATION, AGE-RELATED, 10	c1969108	2,257	omim	https://www.omim.org/entry/611488	2019-09-22T16:03:18	{"mesh": ["C566935"], "omim": ["611488"]}
X-linked (XR) Mendelian susceptibility to mycobacterial diseases (MSMD; see this term) describes a rare group of immunodeficiencies due to specific mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) or the cytochrome b-245, beta polypeptide (CYBB) genes. They are characterized by mycobacterial infections, occuring in males. ## Epidemiology The prevalence is unknown. Six male patients have been reported with XR-MSMD deficiency due to IKBKG mutations and seven male patients have been reported with XR-MSMD deficiency due to CYBB mutations. ## Clinical description XR-MSMD due to IKBKG deficiency affects otherwise healthy male patients. The most common infections seen are Mycobacterium avium, Mycobacterium bovis BCG and Mycobacterium tuberculosis. An invasive Haemophilus influenza type b infection was reported in one patient. In two cases, mild signs of anhidrotic ectodermal dysplasia (AED; see this term), limited to conical deciduous incisors, were observed. Patients with XR-MSMD due to CYBB deficiency present with disseminated tuberculosis mycobacterial disease (such as BCG or M. tuberculosis). They do not suffer from any other infectious diseases. ## Etiology XR-MSMD is due to hemizygous mutations in the IKBKG or CYBB genes. IKBKG (Xq28) encodes the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma. This mutation causes defects in T-cell dependant IL-12 production and consequently IFN-gamma production. The mutations disturb the plasticity of the leucine zipper domain (LDZ) helix of IKBKG interfering selectively with the CD40-NEMO-NFkB signaling pathway. These hypomorphic mutations are associated with impaired NF-kB activation of c-Rel containing proteins in response to CD40. The CYBB gene (Xp21.1) encodes the gp91-phox subunit of the phagocyte NADPH oxydase. These mutations do not impair the respiratory burst in granulocytes and monocytes, but they impair macrophages and B-cell lines selectively. ## Diagnostic methods Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA. Low levels of IFN-gamma and IL-12 production by the patients' mononuclear cells upon phytohemagglutinin (PHA) are detected in those with an IKBKG mutation. In addition, an impaired IL-12 production by monocytes upon PHA stimulation by activated T cells is shown. Impaired NADPH activity is demonstrated in vitro in macrophages and B-cell lines in those with a CYBB mutation. A mutational analysis is necessary to identify the exact causative genes involved allowing for the implementation of a specific treatment plan. ## Differential diagnosis Differential diagnoses include other diseases caused by IKBKG mutations such as EDA with immunodeficiency (see this term). It is important to exclude the diagnosis of chronic granulomatous disease (CGD; see this term) caused by CYBB mutations. Other genetic forms of MSMD should also be excluded. ## Antenatal diagnosis This immunodeficiency is not severe and antenatal diagnosis is not necessary. ## Genetic counseling The occurrence of mycobacterial diseases in maternally-related males suggests an X-linked recessive form of MSMD. Genetic counseling is possible when a known mutation is present in the family. ## Management and treatment BCG vaccination should be avoided in those with a known XR-MSMD mutation. Treatment usually involves IFN-gamma therapy in addition to antibiotics. ## Prognosis The prognosis is good. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	X-linked mendelian susceptibility to mycobacterial diseases	c1970879	2,258	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319605	2021-01-23T19:11:19	{"mesh": ["C567070"], "omim": ["300636", "300645"], "icd-10": ["D84.8"], "synonyms": ["X-linked MSMD"]}
Ski sickness or Häusler's disease is a form of motion sickness which is suffered by some skiers when weather conditions are bad. Poor visibility in heavy fog can bring on the condition as well as psychological factors such as fear of heights or fear of mountains. High speed and falling may also contribute as when descending rapidly atmospheric pressure changes in the ear from high to low altitude.[1] Symptoms are similar to other sicknesses brought about by motion and include: dizziness, headaches and nausea and in more extreme cases vomiting.[2] In whiteout conditions, the brain is unable to determine orientation or movement accurately. The condition is caused by the rhythmic turning motion of skiing and other effects such as a reduction in sensory feedback from constrained feet.[3] In 1995 Rudolf Häusler of the University of Berne was the first described to suffer from this disease. [4] Ski sickness could affect up to 10% of skiers.[2] Professor Häusler found that over-the-counter prescription medicines for motion sickness relieved the symptoms for most sufferers. ## References[edit] 1. ^ Häusler R (January 1995). "Ski sickness". Acta Otolaryngol. 115 (1): 1–2. doi:10.3109/00016489509133337. PMID 7762376. 2. ^ a b "Slope motion: Professor identifies ski sickness". SwissInfo. March 31, 2002. Retrieved 2007-03-03. 3. ^ Duncan Graham-Rowe (9 February 2002). "Sickly slopes". New Scientist. Retrieved 2007-03-03. 4. ^ "Ski Sickness", Acta Otolaryngol (Stockh) 1995; 115: 1-2, 1995 Scandinavian University Press * v * t * e Motion sickness Types * Airsickness * Seasickness * Simulator sickness * Ski sickness * Space adaptation syndrome * Virtual reality sickness Medicine treatment * Bonine * Cinnarizine * Dramamine * Marezine * Promethazine * Transdermscop Related * Bárány chair * Sickness bag [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Ski sickness	None	2,259	wikipedia	https://en.wikipedia.org/wiki/Ski_sickness	2021-01-18T19:04:59	{"wikidata": ["Q7534959"]}
Farsightedness, also known as hyperopia, is an eye condition that causes blurry near vision. People who are farsighted have more trouble seeing things that are close up (such as when reading or using a computer) than things that are far away (such as when driving). For normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. Some people who are farsighted have eyeballs that are too short from front to back. Others have a cornea or lens that is abnormally shaped. These changes cause light entering the eye to be focused too far back, behind the retina instead of on its surface. It is this difference that causes nearby objects to appear blurry. In a person with this condition, one eye may be more farsighted than the other. If it is not treated with corrective lenses or surgery, farsightedness can lead to eye strain, excess tearing, squinting, frequent blinking, headaches, difficulty reading, and problems with hand-eye coordination. However, some children with the eye changes characteristic of farsightedness do not notice any blurring of their vision or related signs and symptoms early in life. Other parts of the visual system are able to compensate, at least temporarily, for the changes that would otherwise cause light to be focused in the wrong place. Most infants are born with a mild degree of farsightedness, which goes away on its own as the eyes grow. In some children, farsightedness persists or is more severe. Children with a severe degree of farsightedness, described as high hyperopia, are at an increased risk of developing other eye conditions, particularly "lazy eye" (amblyopia) and eyes that do not look in the same direction (strabismus). These conditions can cause significant visual impairment. In general, older adults also have difficulty seeing things close up; this condition is known as presbyopia. Presbyopia develops as the lens of the eye becomes thicker and less flexible with age and the muscles surrounding the lens weaken. Although it is sometimes described as "farsightedness," presbyopia is caused by a different mechanism than hyperopia and is considered a separate condition. ## Frequency Farsightedness is a relatively common vision abnormality, although it is much less common than nearsightedness (myopia) or presbyopia. The prevalence of hyperopia decreases with age: most infants are farsighted at birth, but less than 4 percent of children have the condition at age 1. The prevalence continues to decrease into adulthood. Most cases are mild. For unknown reasons, farsightedness is reported more frequently among Native Americans, African Americans, and Pacific Islanders than in people of other backgrounds. ## Causes Farsightedness is a complex condition. Multiple genetic variations, each with a small effect, likely influence whether a person is farsighted. Few genes associated with the condition have been identified, and none of the identified genes appears to play a major role in the development of farsightedness. At least some of the genes that influence farsightedness play roles in eye development, particularly in determining the length of the eyeball from front to back (also known as the axial length). It is possible that environmental factors also contribute to a person's risk of being farsighted, but these have not been well-studied. In many farsighted people, this vision problem is not part of a larger genetic syndrome. However, farsightedness (especially high hyperopia) can be a feature of other disorders with a genetic cause. Genetic conditions with farsightedness as a characteristic feature include microphthalmia, achromatopsia, aniridia, Leber congenital amaurosis, X-linked juvenile retinoschisis, Senior-Løken syndrome, Gorlin-Chaudhry-Moss syndrome, Down syndrome, and fragile X syndrome. ## Inheritance Pattern Farsightedness is a complex condition that usually does not have a clear pattern of inheritance. The risk of developing this condition is greater for first-degree relatives of affected individuals (such as siblings or children) as compared to the general public. When farsightedness is a feature of a genetic syndrome, it follows the inheritance pattern of that syndrome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Farsightedness	c1855925	2,260	medlineplus	https://medlineplus.gov/genetics/condition/farsightedness/	2021-01-27T08:24:56	{"mesh": ["C565497"], "omim": ["238950"], "synonyms": []}
A rare drug-induced, immune-mediated prothrombotic disorder associated with thrombocytopenia and venous and/or arterial thrombosis. ## Epidemiology Approximately 1% of patients exposed to heparin for at least one week develop HIT, and approximately 50% of them will have thrombosis. HIT is slightly more common in females. ## Clinical description HIT may develop at any age (>3 months) but pediatric cases are rare. Moderate thrombocytopenia begins typically 5- 10 days after heparin administration. If the patient had already been exposed to heparin within the last 100 days, rapid-onset is possible, with the platelet count drop occurring within minutes or hours after heparin administration. Delayed-onset HIT is also possible with thrombocytopenia beginning after heparin has already been discontinued. Thrombocytopenia is usually asymptomatic; bleeding is rare. HIT is associated with a high risk of thrombotic complications (e.g. pulmonary embolism, myocardial infarction, thrombotic stroke), with a strong predilection for arterial thrombosis involving limb arteries and deep vein thrombosis. Additional microvascular thrombosis can lead to venous limb gangrene/amputation. Other complications include skin necrosis at heparin injection sites and anaphylactoid reactions (e.g. fever, hypotension, chest pain, dyspnea, cardiorespiratory arrest) that could be secondary to post-intravenous heparin bolus. ## Etiology HIT results from a humoral immune reaction directed against a complex involving endogenous platelet factor 4 (PF4) and exogenous heparin: auto-antibodies recognize PF4 only when it is complexed with heparin. This immune complex activates the circulating platelets via their FcγRIIA surface receptors, leading to consumptive thrombocytopenia and hypercoagulability. The source of heparin (bovine >porcine), its formulation (unfractionated >low molecular weight >fondaparinux), the dose (prophylactic >therapeutic >heparin flushes), route of administration (subcutaneous >intravenous) and duration of administration (over 4 days >4 days or less) are determining factors. ## Diagnostic methods Diagnosis of HIT is suspected from the clinical picture based on the ''4 T's'' (Thrombocytopenia, Timing, Thrombosis, no oTher cause of platelet fall) or the HIT Expert Probability (HEP) scoring system. It is supported by detection of anti-PF4/heparin antibodies, most often by ELISA (although 50% of ELISA-positive patients do not have HIT), and confirmed by detection of pathologic platelet-activating antibodies with the serotonin-release assay or the heparin-induced platelet activation test. ## Differential diagnosis Differential diagnosis includes nonimmune heparin-associated thrombocytopenia (due to the direct interaction of heparin with circulating platelets, occurring during the first days of heparin administration), as well as postoperative hemodilution, sepsis, non-HIT drug-induced thrombocytopenia, disseminated intravascular coagulation, and multiorgan system failure. ## Management and treatment For certain patient populations receiving heparin, a regular monitoring of platelet counts is recommended. In case of strongly-suspected or confirmed HIT, treatment consists of stopping heparin and initiating alternative anticoagulant treatment, either with non-heparin anti-factor Xa therapies (danaparoid, fondaparinux), or with direct thrombin inhibitors (e.g., argatroban, bivalirudin). Warfarin is contraindicated during the acute thrombocytopenic phase as it can cause microvascular thrombosis, with potential for ischemic limb necrosis (venous limb gangrene syndrome). Thrombocytopenia generally resolves to greater than 150 x 109/L at a median of 4 days, although 1 week to 1 month can be required in some cases. ## Prognosis The prognosis for platelet count recovery is excellent; however, long-term post-thrombotic sequelae (e.g. limb amputation in 5-10% of HIT patients, disabling stroke, bilateral adrenal hemorrhagic necrosis with adrenal failure) can occur. HIT-related mortality (e.g. fatal pulmonary embolism) is observed in 5-10% of 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Heparin-induced thrombocytopenia	c0272285	2,261	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3325	2021-01-23T18:30:55	{"gard": ["2650"], "umls": ["C0272285"], "icd-10": ["D69.5"], "synonyms": ["HAT", "HIT", "Heparin-associated thrombocytopenia", "Heparin-induced thrombocytopenia type 2"]}
Ethylmalonic encephalopathy Ethylmalonic encephalopathy has an autosomal recessive pattern of inheritance. SpecialtyMedical genetics Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. Patients affected with EE are typically identified shortly after birth, with symptoms including diarrhea, petechiae and seizures.[1][2] The genetic defect in EE is thought to involve an impairment in the degradation of sulfide intermediates in the body. Hydrogen sulfide then builds up to toxic levels.[3] EE was initially described in 1994.[4] Most cases of EE have been described in individuals of Mediterranean or Arabic origin.[3] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Neurologic signs and symptoms include progressively delayed development, weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels is also affected. Children with this disorder may experience rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy.[3] EE is often identified by urine organic acid analysis, the excretion of ethylmalonic acid, methylsuccinic acid, isobutyrylglycine and isovalerylglucine. Patients will also often have elevated thiosulphate concentration in their urine.[5] The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood. A few children with a milder, chronic form of this disorder have been reported, and there can be considerable phenotypic variation, even within families.[6] The life expectancy of individuals with EE is less than ten years.[3] ## Pathophysiology[edit] Mutations in the ETHE1 gene cause ethylmalonic encephalopathy.[7] The ETHE1 gene makes an enzyme that plays an important role in energy production. It is active in mitochondria, which are the energy-producing centers within cells. Little is known about its exact function, however. Mutations in the ETHE1 gene lead to the production of a defective version of the enzyme or prevents the enzyme from being made. A lack of the ETHE1 enzyme impairs the ability to make energy in mitochondria. Additionally, a loss of this enzyme allows potentially toxic compounds, including ethylmalonic acid and lactic acid, to build up in the body. Excess amounts of these compounds can be detected in urine. It remains unclear how a loss of the ETHE1 enzyme leads to progressive brain dysfunction and the other features of ethylmalonic encephalopathy. Ethylmalonic encephalopathy is an autosomal recessive disorder, which means the defective gene is located on an autosome, and both parents must carry one copy of the defective gene in order to have a child born with the disorder. The parents of a child with an autosomal recessive disorder are usually not affected by the disorder. ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (December 2017) ## References[edit] 1. ^ Zafeiriou DI, Augoustide-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Seweil AC, Vianey-Saban C, Gregersen N (2007). "Ethylmalonic encephalopathy: clinical and biochemical observations". Neuropediatrics. 38 (2): 78–82. doi:10.1055/s-2007-984447. PMID 17712735. 2. ^ Tiranti, V.; Viscomi, C.; Hildebrandt, T.; Di Meo, I.; Mineri, R.; Tiveron, C.; Levitt, M.; Prelle, A.; Fagiolari, G.; Rimoldi, M.; Zeviani, M. (2009). "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy". Nature Medicine. 15 (2): 200–205. doi:10.1038/nm.1907. PMID 19136963. 3. ^ a b c d "Encephalopathy, Ethylmalonic". Johns Hopkins University. Retrieved 2012-05-12. 4. ^ Burlina, A. B.; Dionisi-Vici, C.; Bennett, M. J.; Gibson, K. M.; Servidei, S.; Bertini, E.; Hale, D. E.; Schmidt-Sommerfeld, E.; Sabetta, G.; Zacchello, F.; Rinaldo, P. (1994). "A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts". The Journal of Pediatrics. 124 (1): 79–86. doi:10.1016/S0022-3476(94)70257-8. PMID 8283379. 5. ^ Drousiotou, A.; Dimeo, I.; Mineri, R.; Georgiou, T.; Stylianidou, G.; Tiranti, V. (2011). "Ethylmalonic encephalopathy: Application of improved biochemical and molecular diagnostic approaches". Clinical Genetics. 79 (4): 385–390. doi:10.1111/j.1399-0004.2010.01457.x. PMID 20528888. 6. ^ Pigeon, N.; Campeau, P. M.; Cyr, D.; Lemieux, B.; Clarke, J. T. R. (2009). "Clinical Heterogeneity in Ethylmalonic Encephalopathy". Journal of Child Neurology. 24 (8): 991–996. doi:10.1177/0883073808331359. PMID 19289697. 7. ^ Mineri R, Rimoldi M, Burlina AB, Koskull S, Perletti C, Heese B, Von Döbeln U, Mereghetti P, Di Meo I, Invernizzi F, Zeviani M, Uziel G, Tiranti V (Jul 2008). "Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy". Journal of Medical Genetics. 45 (7): 473–8. doi:10.1136/jmg.2008.058271. PMID 18593870. ## External links[edit] Classification D * OMIM: 602473 * MeSH: C535737 C535737, C535737 * SNOMED CT: 723307008 External resources * Orphanet: 51188 * Ethylmalonic encephalopathy at NLM Genetics Home Reference * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Ethylmalonic encephalopathy	c1865349	2,262	wikipedia	https://en.wikipedia.org/wiki/Ethylmalonic_encephalopathy	2021-01-18T18:58:09	{"gard": ["2198"], "mesh": ["C535737"], "umls": ["C1865349"], "orphanet": ["51188"], "wikidata": ["Q17119115"]}
Laubry-Pezzi syndrome is a rare, non-syndromic, congenital heart malformation characterized by the prolapse of an aortic valve cusp into a subjacent ventricular septal defect due to Venturi effect, resulting in aortic regurgitation. Patients typically present with symptoms of progressive aortic valve insufficiency, such as shortness of breath, heart palpitations, chest pain and exercise intolerance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Laubry-Pezzi syndrome	c4707235	2,263	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99094	2021-01-23T18:14:51	{"icd-10": ["Q21.0"], "synonyms": ["VSD with aortic insufficiency", "Ventricular septal defect with aortic insufficiency"]}
A number sign (#) is used with this entry because of evidence that congenital stationary night blindness type 1I (CSNB1I)is caused by compound heterozygous mutation in the GUCY2D gene (600179) on chromosome 17p13. Description Congenital stationary night blindness type 1I (CSNB1I) is characterized by night blindness from infancy or early childhood. Visual acuity is preserved, but some patients have color vision and/or visual field defects. Older patients may show retinitis pigmentosa-like retinal degeneration (Stunkel et al., 2018). Clinical Features Stunkel et al. (2018) reported 5 patients from 4 families with night blindness, which began in infancy in 4 patients and was noted at age 12 years in 1 patient (patient 4), whose older brother (patient 1) had onset of night blindness in infancy. Visual acuity was normal and did not change over time, and there was no nystagmus or high refractive error. Two patients exhibited tritanopia on color vision testing. Electroretinography (ERG) showed rod and cone dysfunction, with absent responses to dark-adapted rod-isolating flash stimulus; low-amplitude a- and b-wave responses, but not electronegative responses (Riggs-type ERG), to the dark-adapted bright flash maximal combined response; low-amplitude but recordable light-adapted bright flash responses; and relatively preserved 30-Hz flicker (pure cone) responses. Full-field stimulus testing revealed markedly decreased retinal sensitivity to light, and dark adaptation showed lack of a rod-cone break, indicating that no rod vision was used. No progression of disease was observed in 3 of the 5 patients; however, during 5 to 6 years of follow-up, 2 unrelated boys (patients 1 and 2) showed some reduction in ERG amplitudes over time. Spectral-domain optical coherence tomography was performed in 4 of the patients, with patients 1 and 4 showing normal lamination, whereas patient 2 showed thinning of the outer nuclear layer in the foveal area, and patient 3 showed flattening of the foveal umbo. In addition, the oldest patient, a 52-year-old woman (patient 5), experienced increasing nyctalopia at age 44, and examination revealed visual field constriction and sparse bone spicule-like pigmentation in the periphery with mild arteriolar narrowing. Noting that 2 of the 5 patients showed progression of disease, and that the oldest patient developed retinitis pigmentosa-like retinal degeneration, the authors suggested that 'congenital night blindness (CNB)' might be a better designation for this disorder than CSNB. Molecular Genetics In 5 patients from 4 families with congenital night blindness, Stunkel et al. (2018) identified compound heterozygosity for mutations in the GUCY2D gene (see, e.g., 600179.0012-600179.0016). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Night blindness \- Tritanopia (in some patients) \- Visual field defects (in some patients) \- Bone spicule-like pigmentation in retinal periphery (in older patient) \- Arteriolar narrowing (in older patient) \- Absent rod responses \- Reduced but relatively preserved cone responses \- Thinning of outer nuclear layer seen on optical coherence tomography (OCT) (in 1 patient) \- Flattening of foveal umbo seen on OCT (in 1 patient) MISCELLANEOUS \- Onset of night blindness in infancy or childhood \- Intra- and interfamilial phenotypic variability \- Progressive reduction in ERG responses (in some patients) \- Development of retinitis pigmentosa-like retinal degeneration in sixth decade of life (in 1 patient) MOLECULAR BASIS \- Caused by mutation in the membrane guanylate cyclase-2D gene (GUCY2D, 600179.0012 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	NIGHT BLINDNESS, CONGENITAL STATIONARY, TYPE1I	None	2,264	omim	https://www.omim.org/entry/618555	2019-09-22T15:41:25	{"omim": ["618555"]}
For a general phenotypic description and a discussion of genetic heterogeneity of vesicoureteral reflux, see VUR1 (193000). Clinical Features Briggs et al. (2010) ascertained a large sample of children with vesicoureteral reflux, including 151 girls and 70 boys from 98 Caucasian families. Among the 98 probands, urinary tract infection was the most common presentation (75%), occurring predominantly in girls (90%). Prenatal hydronephrosis was the mode of presentation in 13% of probands, occurring more commonly in boys (69%). Four percent of patients presented with voiding problems or abdominal pain, and 8% had a parental history of the disorder. Most were younger than 5 years of age. Mapping By genomewide linkage analysis of 98 Caucasian families with 2 or more children with vesicoureteral reflux, including 150 affected sib pairs, Briggs et al. (2010) found significant linkage to chromosome 18, with a lod score of 3.71 at 65.28 cM from pter (nearest marker, SNP rs1054986). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	VESICOURETERAL REFLUX 6	c3280441	2,265	omim	https://www.omim.org/entry/614319	2019-09-22T15:55:42	{"doid": ["9620"], "omim": ["614319"], "orphanet": ["289365"], "synonyms": ["Familial VUR"]}
The recommended dosage of Benadryl tablets for adults is 1 to 2 tablets every 4 to 6 hours,[1] and only 1 tablet every 4 to 6 hours for children under the age of 12.[2] The Benadryl challenge is an internet challenge which emerged in 2020, and revolves around the deliberate consumption, abuse and overdose of the antihistamine medicine diphenhydramine, commonly sold in the United States under the brand name Benadryl.[3][1] The challenge, which spread via the social media platform TikTok, instructs participants to film themselves consuming large doses of Benadryl for the purpose of 'tripping', or hallucinating. The recreational use of diphenhydramine and its associated abuse and addiction is well-reported in medical literature, and overdoses are treatable with correct intervention. In addition, its psychoactive effects at high dosages, which are a symptom of anticholinergic poisoning, are also well documented. In severe cases, the overdose of diphenhydramine and other anticholinergic medicines can lead to a phenomenon referred to as an 'anticholinergic toxidrome',[4] which can affect organ systems throughout the body, including the nervous system and cardiovascular system. Numerous authorities have advised against the challenge, as deliberate overconsumption of diphenhydramine can lead to adverse effects, including confusion, delirium, psychosis, organ damage, hyperthermia, convulsions, coma and death, among others. On September 24, 2020, the FDA formally released a statement advising parents and medical practitioners to be aware of the challenge's prevalence and its risks.[5] Several participants have been hospitalised as a result of the challenge, including three teenagers admitted to the Cook Children's Medical Center after consuming at least 14 diphenhydramine tablets,[6] and 15-year-old Chloe Marie Phillips, an Oklahoma teen that died from an overdose after attempting to take part.[7][8][9] ## See also[edit] * Consumption of Tide Pods ## Notes[edit] 1.^ In other countries, products sold under the brand name Benadryl may contain a different antihistamine; in the United Kingdom, this is the second-generation antihistamines acrivastine or cetirizine. ## References[edit] 1. ^ "Dosing Guide". Benadryl.com. Retrieved 10 October 2020. 2. ^ "The New TikTok 'Benadryl Challenge' is Being Blamed for a Teenage Girl's Death—Here's Why It's So Dangerous". Health.com. Retrieved 2020-10-10. 3. ^ Krstic, Zee (2020-09-09). "What Parents Needs to Know About the Potentially Deadly Benadryl TikTok Challenge". Good Housekeeping. Retrieved 2020-10-09. 4. ^ Broderick, Erin D.; Metheny, Heidi; Crosby, Brianna (2020), "Anticholinergic Toxicity", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30521219, retrieved 2020-10-10 5. ^ "FDA warns about serious problems with high doses of the allergy medicine diphenhydramine (Benadryl)". Food and Drug Administration. 6. ^ "TikTok Videos Encourage Viewers to Overdose on Benadryl". Cook Children's Checkup Newsroom. Retrieved 2020-10-09. 7. ^ "Dangerous 'Benadryl Challenge' on Tik Tok may be to blame for the death of Oklahoma teen". KFOR.com Oklahoma City. 2020-08-28. Retrieved 2020-10-09. 8. ^ "Teen's Death Prompts Warning on 'Benadryl Challenge'". www.medpagetoday.com. 2020-09-25. Retrieved 2020-10-09. 9. ^ "Viral TikTok Challenge Turns Deadly After Encouraging Teens To Take Drugs". talentrecap.com. 2020-09-04. Retrieved 2021-01-11. * v * t * e Internet challenges and dares Charity * Book bucket * Food stamp * Ice bucket * Rice bucket Food and drink * Bottle flipping * Cinnamon * Chubby Bunny * Gallon smashing * Hot pepper * Milk chugging * Neknominate * Saltine cracker Health * 22 Pushup * Safe Hands Suicide games * Blue Whale * Momo hoax Other * 24 Hour Fort * Benadryl * Bird Box * Charlie Charlie * Condom * Destroy Dick December * Dolly Parton * Fire * Knife game * Mannequin * Merry-go-round * No Nut November * Planking * Running Man * Salt and ice * Tide Pods See also * Urban legend * Folklore studies [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Benadryl challenge	None	2,266	wikipedia	https://en.wikipedia.org/wiki/Benadryl_challenge	2021-01-18T18:43:11	{"wikidata": ["Q100270830"]}
Carcinoma of the penis SpecialtyOncology Frequency93,850 in 2018 [1] Deaths15,138 (2018) [1] Penile cancer is cancer that develops in the skin or tissues of the penis. Symptoms may include abnormal growth, an ulcer or sore on the skin of the penis, and bleeding or foul smelling discharge.[2] Risk factors include phimosis (inability to retract foreskin of the penis), chronic inflammation, smoking, HPV infection, condylomata acuminate, having multiple sexual partners and early age of sexual intercourse.[3] Around 95% of penile cancers are squamous cell carcinomas. Other types of penile cancer such as Merkel cell carcinoma, small cell carcinoma and melanoma are generally rare.[4] In 2018, it occurred in 34,000 men and caused 15,000 deaths.[1] ## Contents * 1 Signs and symptoms * 2 Risk factors * 2.1 Infections * 2.2 Hygiene and injury * 2.3 Other * 3 Pathogenesis * 4 Diagnosis * 4.1 Classification * 4.1.1 Staging * 4.1.2 HPV positive tumors * 5 Prevention * 6 Treatment * 7 Prognosis * 8 Epidemiology * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Penile cancer can present as redness and irritation on the penis with a skin thickening on the glans or inner foreskin or an ulcerative, outward growing (exophytic) or “finger-like” (papillary) growth.[5][6] Penile cancer may accompany penile discharge with or without difficulty or burning or tingling while urinating (dysuria) and bleeding from the penis.[5][6] ## Risk factors[edit] ### Infections[edit] * HIV infection—HIV-positive men have eight-fold increased risk of developing penile cancer than HIV-negative men.[7][8] * Human papillomavirus—HPV is a risk factor in the development of penile cancer.[9] According to the Center for Disease Control and Prevention (CDC), HPV is responsible for about 800 (about 40%) of 1,570 cases of penile cancer diagnosed annually in the United States.[10][11] There are more than 120 types of HPV.[12] * Genital warts—Genital or perianal warts increase the risk of invasive penile cancer by about 3.7 times if they occurred more than two years before the reference date.[9] About half of men with penile cancer also have genital warts, which are caused by HPV.[13] ### Hygiene and injury[edit] * Poor hygiene—Poor hygiene can increase a man's risk of penile cancer.[14][15] * Smegma—Smegma, a whitish substance that can accumulate beneath the foreskin, is associated with greater risk of penile cancer.[7][16] The American Cancer Society suggests that smegma may not be carcinogenic, but may increase the risk by causing irritation and inflammation of the penis.[7] * Balanitis and penile injury—Inflammation of the foreskin and/or the glans penis (balanitis) is associated with about 3.1 times increased risk of penile cancer.[9] It is usually caused by poor hygiene, allergic reactions to certain soaps, or an underlying health condition such as reactive arthritis, infection, or diabetes.[17] Small tears and abrasions of the penis are associated with about 3.9 times increased risk of cancer. * Phimosis—Phimosis is a medical condition where the foreskin cannot be fully retracted over the glans. It is considered a significant risk factor in the development of penile cancer (odds ratio of 38–65).[9] Phimosis may also be a symptom of penile cancer.[18] * Paraphimosis—Paraphimosis is a medical condition where the foreskin becomes trapped behind the glans. It is considered a risk factor for the development of penile cancer.[7] * Circumcision—Some studies show that circumcision during infancy or in childhood may provide partial protection against penile cancer, but this is not the case when performed in adulthood.[19] It has been suggested that the reduction in risk may be due to reduced risk of phimosis;[7][19] other possible mechanisms include reduction in risk of smegma and HPV infection.[7] ### Other[edit] * Age—Penile cancer is rarely seen in men under the age of 50. About 4 out of 5 men diagnosed with penile cancer are over the age of 55.[7] * Lichen sclerosus—Lichen sclerosus is a disease causing white patches on the skin. Lichen sclerosus increases the risk of penile cancer.[14][20] As the exact cause of lichen sclerosus is unknown, there is no known way to prevent it.[14] * Tobacco—Chewing or smoking tobacco increases the risk of penile cancer by 1.5–6 times depending on the duration smoking and daily number of cigarettes.[4][9][14] * Ultraviolet light—Men with psoriasis who have been treated using UV light and a drug known as psoralen have an increased risk of penile cancer.[7][14] ## Pathogenesis[edit] Penile cancer arises from precursor lesions, which generally progress from low-grade to high-grade lesions. For HPV related penile cancers this sequence is as follows:[4] 1. Squamous hyperplasia; 2. Low-grade penile intraepithelial neoplasia (PIN); 3. High-grade PIN (carcinoma in situ—Bowen's disease, Erythroplasia of Queyrat and bowenoid papulosis (BP)); 4. Invasive carcinoma of the penis. However, in some cases non-dysplastic or mildly dysplastic lesions may progress directly into cancer. Examples include flat penile lesions (FPL) and condylomata acuminata.[4] In HPV negative cancers the most common precursor lesion is lichen sclerosus (LS).[4] ## Diagnosis[edit] The International Society of Urological Pathology (ISUP) recommends the use of p16INK4A immunostaining for the diagnosis and classification of HPV-related penile cancer.[21] ### Classification[edit] Around 95% of penile cancers are squamous cell carcinomas. They are classified into the following types: * basaloid (4%) * warty (6%) * mixed warty-basaloid (17%) * verrucous (8%) * papillary (7%) * other SCC mixed (7%) * sarcomatoid carcinomas (1%) * not otherwise specified (49%) Other types of carcinomas are rare and may include small cell, Merkel cell, clear cell, sebaceous cell or basal cell tumors. Non-epithelial malignancies such as melanomas and sarcomas are even more rare.[4] #### Staging[edit] Like many malignancies, penile cancer can spread to other parts of the body. It is usually a primary malignancy, the initial place from which a cancer spreads in the body. Much less often it is a secondary malignancy, one in which the cancer has spread to the penis from elsewhere. The staging of penile cancer is determined by the extent of tumor invasion, nodal metastasis, and distant metastasis.[22] The T portion of the AJCC TNM staging guidelines are for the primary tumor as follows:[22] * TX: Primary tumor cannot be assessed. * T0: No evidence of primary tumor. * Tis: Carcinoma in situ. * Ta: Noninvasive verrucous carcinoma. * T1a: Tumor invades subepithelial connective tissue without lymph vascular invasion and is not poorly differentiated (i.e., grade 3–4). * T1b: Tumor invades subepithelial connective tissue with lymph vascular invasion or is poorly differentiated. * T2: Tumor invades the corpus spongiosum or cavernosum. * T3: Tumor invades the urethra or prostate. * T4: Tumor invades other adjacent structures. Anatomic Stage or Prognostic Groups of penile cancer are as follows:[22] * Stage 0—Carcinoma in situ. * Stage I—The cancer is moderately or well differentiated and only affects the subepithelial connective tissue. * Stage II—The cancer is poorly differentiated, affects lymphatics, or invades the corpora or urethra. * Stage IIIa—There is deep invasion into the penis and metastasis in one lymph node. * Stage IIIb—There is deep invasion into the penis and metastasis into multiple inguinal lymph nodes. * Stage IV—The cancer has invaded into structures adjacent to the penis, metastasized to pelvic nodes, or distant metastasis is present. #### HPV positive tumors[edit] Human papillomavirus prevalence in penile cancers is high at about 40%. HPV16 is the predominant genotype accounting for approximately 63% of HPV-positive tumors. Among warty/basaloid cancers the HPV prevalence is 70–100% while in other types it is around 30%.[4] ## Prevention[edit] * HPV vaccines such as Gardasil or Cervarix may reduce the risk of HPV and, consequently, penile cancer.[4][14] * The use of condoms is thought to be protective against the HPV associated penile cancer.[4] * Good genital hygiene, which involves washing the penis, the scrotum, and the foreskin daily with water, may prevent balanitis and penile cancer. However, soaps with harsh ingredients should be avoided. * Cessation of smoking may reduce the risk of penile cancer.[9] * Circumcision during infancy or in childhood may provide partial protection against penile cancer. Several authors have proposed circumcision as a possible strategy for penile cancer prevention;[4][14][23] however, the American Cancer Society points to the rarity of the disease and notes that neither the American Academy of Pediatrics nor the Canadian Academy of Pediatrics recommend routine neonatal circumcision.[7] * Phimosis can be prevented by practising proper hygiene and by retracting the foreskin on a regular basis.[medical citation needed] * Paraphimosis can be prevented by not leaving the foreskin retracted for prolonged periods of time.[medical citation needed] ## Treatment[edit] Treatment of penile cancer will vary depending on the clinical stage of the tumor at the time of diagnosis.[24] There are several treatment options for penile cancer, depending on staging. They include surgery, radiation therapy, chemotherapy, and biological therapy. The most common treatment is one of five types of surgery: * Wide local excision—the tumor and some surrounding healthy tissue are removed * Microsurgery—surgery performed with a microscope is used to remove the tumor and as little healthy tissue as possible * Laser surgery—laser light is used to burn or cut away cancerous cells * Circumcision—cancerous foreskin is removed * Amputation (penectomy)—a partial or total removal of the penis, and possibly the associated lymph nodes. The role of radiation therapy includes an organ-sparing approach for early-stage penile cancer at specialized centres. Furthermore, adjuvant therapy is used for patients with locally advanced disease or for symptom management.[25] ## Prognosis[edit] Prognosis can range considerably for patients, depending where on the scale they have been staged. Generally speaking, the earlier the cancer is diagnosed, the better the prognosis. The overall 5-year survival rate for all stages of penile cancer is about 50%.[22] ## Epidemiology[edit] Penile cancer is a rare cancer in developed nations with annual incidence varying from 0.3 to 1 per 100,000 per year accounting for around 0.4–0.6% of all malignancies.[4] The annual incidence is approximately 1 in 100,000 men in the United States,[26] 1 in 250,000 in Australia,[27] and 0.82 per 100,000 in Denmark.[28] In the United Kingdom, fewer than 500 men are diagnosed with penile cancer every year.[13][29] However, in the developing world penile cancer is much more common. For instance, in Paraguay, Uruguay, Uganda and Brazil the incidence is 4.2, 4.4, 2.8 and 1.5–3.7 per 100,000, respectively.[4][9] In some South American countries, Africa, and Asia, this cancer type constitutes up to 10% of malignant diseases in men.[4] The lifetime risk has been estimated as 1 in 1,437 in the United States and 1 in 1,694 in Denmark.[30] ## See also[edit] * Testicular cancer * Urethral cancer * Male breast cancer ## References[edit] 1. ^ a b c "Penile Cancer Factsheet" (PDF). Global Cancer Observatory. Retrieved 8 November 2019. 2. ^ "Signs and Symptoms of Penile Cancer \| Signs Of Penile Cancer". www.cancer.org. Retrieved 2019-12-18. 3. ^ Sumedia-Online. "EAU Guidelines: Penile Cancer". Uroweb. Retrieved 2019-12-18. 4. ^ a b c d e f g h i j k l m Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ (April 2009). "Penile cancer: epidemiology, pathogenesis and prevention". World Journal of Urology. 27 (2): 141–50. doi:10.1007/s00345-008-0302-z. PMID 18607597. 5. ^ a b Turner, Bruce; Drudge-Coates, Lawrence; Henderson, Sarah (2013-03-20). "Penile cancer: diagnosis, clinical features and management". Nursing Standard. 27 (29): 50–57. doi:10.7748/ns2013.03.27.29.50.e6135. ISSN 0029-6570. 6. ^ a b "Signs and Symptoms of Penile Cancer \| Signs Of Penile Cancer". www.cancer.org. Retrieved 2020-12-08. 7. ^ a b c d e f g h i "What Are the Risk Factors for Penile Cancer?". www.cancer.org. Retrieved 2 April 2018. 8. ^ Bleeker MC, Heideman DL, Snijders PJ, Horenblas S, Meijer CJ (2011). "Epidemiology and Etiology of Penile Cancer". Textbook of Penile Cancer. p. 1. doi:10.1007/978-1-84882-879-7_1. ISBN 978-1-84882-878-0. 9. ^ a b c d e f g Pow-Sang MR, Ferreira U, Pow-Sang JM, Nardi AC, Destefano V (August 2010). "Epidemiology and natural history of penile cancer". Urology. 76 (2 Suppl 1): S2-6. doi:10.1016/j.urology.2010.03.003. PMID 20691882. 10. ^ "Penile Cancer". National Cancer Institute. 1980-01-01. Retrieved 2 April 2018. 11. ^ https://www.cdc.gov/cancer/hpv/statistics/penile.htm HPV-Associated Penile Cancer Rates by Race and Ethnicity] Center for Disease Control and Prevention 12. ^ de Bravo BF, DeSoto M, Seu K (April 2009). "HPV: Q&A". Cancer Prevention and Treatment Fund. Retrieved August 13, 2013. 13. ^ a b "Risks and causes - Penile cancer - Cancer Research UK". cancerhelp.cancerresearchuk.org. 2017-08-30. Retrieved 2 April 2018. 14. ^ a b c d e f g Minhas S, Manseck A, Watya S, Hegarty PK (August 2010). "Penile cancer--prevention and premalignant conditions". Urology. 76 (2 Suppl 1): S24-35. doi:10.1016/j.urology.2010.04.007. PMID 20691883. 15. ^ Reis AA, Paula LB, Paula AA, Saddi VA, Cruz AD (June 2010). "[Clinico-epidemiological aspects associated with penile cancer]". Ciencia & Saude Coletiva (in Portuguese). 15 Suppl 1: 1105–11. doi:10.1590/s1413-81232010000700018. PMID 20640268. 16. ^ Morris BJ, Gray RH, Castellsague X, Bosch FX, Halperin DT, Waskett JH, Hankins CA (2011). "The Strong Protective Effect of Circumcision against Cancer of the Penis". Advances in Urology. 2011: 812368. doi:10.1155/2011/812368. PMC 3113366. PMID 21687572. 17. ^ PubMed Health PubMed, Last Reviewed: September 16, 2011 18. ^ "Symptoms of penile cancer - Penile cancer - Cancer Research UK". cancerhelp.cancerresearchuk.org. 2017-08-30. Retrieved 2 April 2018. 19. ^ a b Larke NL, Thomas SL, dos Santos Silva I, Weiss HA (August 2011). "Male circumcision and penile cancer: a systematic review and meta-analysis". Cancer Causes & Control. 22 (8): 1097–110. doi:10.1007/s10552-011-9785-9. PMC 3139859. PMID 21695385. 20. ^ Micali G, Nasca MR, Innocenzi D, Schwartz RA (March 2006). "Penile cancer". Journal of the American Academy of Dermatology. 54 (3): 369–91, quiz 391–4. doi:10.1016/j.jaad.2005.05.007. PMID 16488287. 21. ^ Canete-Portillo S, Velazquez EF, Kristiansen G, Egevad L, Grignon D, Chaux A, Cubilla AL (July 2020). "Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers V: Recommendations on the Use of Immunohistochemical and Molecular Biomarkers in Penile Cancer". The American Journal of Surgical Pathology. 44 (7): e80–e86. doi:10.1097/PAS.0000000000001477. PMID 32235153. 22. ^ a b c d "Stage Information for Penile Cancer". National Cancer Institute. 1980-01-01. Retrieved 3 November 2013. 23. ^ de Souza KW, dos Reis PE, Gomes IP, de Carvalho EC (March 2011). "[Prevention strategies for testicular and penile cancer: an integrative review]". Revista Da Escola De Enfermagem Da U S P (in Portuguese). 45 (1): 277–82. doi:10.1590/s0080-62342011000100039. PMID 21445520. 24. ^ Engelsgjerd JS, LaGrange CA (2020). Penile Cancer. StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 29763105. Retrieved 2020-12-07. 25. ^ Hakenberg OW, Dräger DL, Erbersdobler A, Naumann CM, Jünemann KP, Protzel C (September 2018). "The Diagnosis and Treatment of Penile Cancer". Deutsches Ärzteblatt International. 115 (39): 646–652. doi:10.3238/arztebl.2018.0646. PMC 6224543. PMID 30375327. 26. ^ The American Cancer Society: Penile Cancer: What is penile cancer? American Cancer Society, Last revised: January 8, 2012 27. ^ The Official Website of the Royal Australasian College of Physicians, Published September 2010 28. ^ Frisch M, Friis S, Kjaer SK, Melbye M (December 1995). "Falling incidence of penis cancer in an uncircumcised population (Denmark 1943-90)". BMJ (Clinical Research Ed.). 311 (7018): 1471. doi:10.1136/bmj.311.7018.1471. PMC 2543732. PMID 8520335. 29. ^ The American Cancer Society: Penile Cancer: What are the key statistics about penile cancer American Cancer Society, Last revised: January 18, 2012 30. ^ Cold CJ, Storms MR, Van Howe RS (April 1997). "Carcinoma in situ of the penis in a 76-year-old circumcised man". The Journal of Family Practice. 44 (4): 407–10. PMID 9108839. ## External links[edit] Classification D * ICD-10: C60 * ICD-9-CM: 187 * MeSH: D010412 * DiseasesDB: 29392 External resources * MedlinePlus: 001276 * v * t * e Human papillomavirus Related diseases Cancers * Cervical cancer * cancers * Anal * Vaginal * Vulvar * Penile * Head and neck cancer (HPV-positive oropharyngeal cancer) Warts * * genital * plantar * flat * Laryngeal papillomatosis * Epidermodysplasia verruciformis * Focal epithelial hyperplasia * Papilloma Others Acrochordon (skin tags) Vaccine * HPV vaccines * Cervarix * Gardasil Screening * Pap test: * stain * Bethesda system * Cytopathology * Cytotechnology * Experimental techniques: * Speculoscopy * Cervicography Colposcopy Biopsy histology * Cervical intraepithelial neoplasia (CIN) * Koilocyte * Vaginal intraepithelial neoplasia (VAIN) * Vulvar intraepithelial neoplasia (VIN) Treatment * Cervical conization * Loop electrical excision procedure (LEEP) History * Georgios Papanikolaou * Harald zur Hausen * v * t * e * Tumors of the male urogenital system Testicles Sex cord– gonadal stromal * Sertoli–Leydig cell tumour * Sertoli cell tumour * Leydig cell tumour Germ cell G * Seminoma * Spermatocytic tumor * Germ cell neoplasia in situ NG * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma * Choriocarcinoma * Embryoma Prostate * Adenocarcinoma * High-grade prostatic intraepithelial neoplasia * HGPIN * Small-cell carcinoma * Transitional cell carcinoma Penis * Carcinoma * Extramammary Paget's disease * Bowen's disease * Bowenoid papulosis * Erythroplasia of Queyrat * Hirsuties coronae glandis * v * t * e Sexually transmitted infections (STI) Bacterial * Chancroid (Haemophilus ducreyi) * Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) * Donovanosis (Klebsiella granulomatis) * Gonorrhea (Neisseria gonorrhoeae) * Mycoplasma hominis infection (Mycoplasma hominis) * Syphilis (Treponema pallidum) * Ureaplasma infection (Ureaplasma urealyticum) Protozoal * Trichomoniasis (Trichomonas vaginalis) Parasitic * Crab louse * Scabies Viral * AIDS (HIV-1/HIV-2) * Cancer * cervical * vulvar * penile * anal * Human papillomavirus (HPV) * Genital warts (condyloma) * Hepatitis B (Hepatitis B virus) * Herpes simplex * HSV-1 & HSV-2 * Molluscum contagiosum (MCV) General inflammation female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Penile cancer	c0153601	2,267	wikipedia	https://en.wikipedia.org/wiki/Penile_cancer	2021-01-18T18:45:09	{"mesh": ["D010412"], "umls": ["C0153601", "C0153600"], "orphanet": ["398043"], "wikidata": ["Q1342955"]}
A number sign (#) is used with this entry because of evidence that distal myopathy with anterior tibial onset is caused by homozygous mutation in the gene encoding dysferlin (DYSF; 603009) on chromosome 2p13. Mutations in the DYSF gene also cause Miyoshi myopathy (254130) and limb-girdle muscular dystrophy type 2B (see 253601). Clinical Features Liu et al. (1998) and Illa et al. (2001) described a novel form of autosomal recessive distal myopathy in a consanguineous Spanish family. Onset of the disorder is between 14 and 28 years of age and the anterior tibial muscles are the first muscle group to be involved. The disorder has a rapidly progressive course successively involving the lower and upper proximal muscles, with patients being confined to a wheelchair 11 to 22 years from onset. The cranial muscles are spared. Serum creatine kinase level is increased 20 to 70 times the normal value and muscle histopathologic studies show moderate myopathic changes without vacuoles. The disorder is similar to Nonaka myopathy (605820) in that onset occurs in the anterior tibial muscles, but is distinguished clinically from that disorder by the high creatine kinase levels and the absence of vacuoles in the muscle biopsies. Molecular Genetics In a Spanish family with distal myopathy with anterior tibial onset, Liu et al. (1998) identified a 5966delG mutation in the DYSF gene (603009.0002). This mutation yields an absence of dysferlin on the sarcolemma of muscle fibers in affected patients. INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Biopsy shows myopathy without vacuoles \- Anterior tibial muscles first involved \- Involves upper and lower proximal muscles \- Cranial muscles spared LABORATORY ABNORMALITIES \- Serum creatine kinase 20-70 times normal MISCELLANEOUS \- Onset age 14-28 years \- Rapidly progressive MOLECULAR BASIS \- Caused by mutation in the dysferlin gene (DYSF, 603009.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET	c1847532	2,268	omim	https://www.omim.org/entry/606768	2019-09-22T16:10:03	{"doid": ["0111187"], "mesh": ["C564664"], "omim": ["606768"], "orphanet": ["178400"]}
Familial papillary or follicular thyroid carcinoma is a rare, hereditary nonmedullary thyroid carcinoma characterized by the presence of differentiated thyroid cancer of follicular cell origin in two or more first-degree relatives, in the absence of other familial tumor syndromes or radiation exposure. Frequent capsular invasion is observed. Biopsy reveals multicentric tumors with multiple adenomatous nodules with or without oxyphilia and follicular or papillary carcinoma histology. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Familial papillary or follicular thyroid carcinoma	c4225426	2,269	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319487	2021-01-23T18:45:40	{"gard": ["8488"], "omim": ["188470", "188550", "603386", "603744", "606240", "616534", "616535"], "icd-10": ["C73"], "synonyms": ["FNMTC", "Familial pure nonmedullary thyroid carcinoma"]}
A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-16 (HLD16) is caused by heterozygous mutation in the TMEM106B gene (613413) on chromosome 7p21. Description Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum (summary by Simons et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080. Clinical Features Simons et al. (2017) reported 4 unrelated probands with hypomyelinating leukodystrophy. The patients had onset of nystagmus and hypotonia in the first days or weeks of life, but were alive at ages 19, 5, 38, and 26 years, respectively. Features apparent in early childhood included delayed motor development, mildly increased tone and reflexes, and poor feeding in some. Later examinations showed dystonia, wide-based or ataxic gait, dysarthria, dysmetria, saccadic pursuit, tremor, and mild pyramidal signs. The most severely affected individual (patient 1) achieved walking at age 13 years and was non-verbal at age 19, whereas the other 3 patients walked between 3 and 5 years. Cognitive function was variable: patient 2 had mild language delay, patient 3 had an IQ of 76 and could live on her own with support, and patient 4 had an IQ of 50. Only 1 patient had seizures with onset at age 4 months and was treated for 3 years. Brain imaging showed hypomyelination, with thin corpus callosum in the older patients. The 65-year-old father of 1 of the patients (patient 3) was mosaic for the mutation (about 25% levels in leukocytes), and had normal cognition and no obvious neurologic abnormalities as an adult, but reportedly had nystagmus and mild developmental delay in infancy. Overall, the phenotype was less severe than that observed in other forms of HLD. Yan et al. (2018) reported a 4-year-old Chinese girl with HLD16. She presented in infancy with mixed horizontal, vertical, and rotary nystagmus and mild developmental delay affecting the gross and fine motor domains. Cognition and social interactions were spared. She had normal muscle strength, tone, hearing, and sight. Brain MRI indicated continuous and diffuse hypomyelination. Molecular Genetics In 4 unrelated patients with HLD16, Simons et al. (2017) identified a heterozygous missense mutation in the TMEM106B gene (D252N; 613413.0001). The mutation, which was identified by trio-based whole-exome or whole-genome sequencing, was not found in the dbSNP, ExAC, or gnomAD databases. The mutation occurred de novo in 3 patients, but the mildly affected father of 1 of the patients (patient 3) was mosaic for the mutation. The most severely affected individual (patient 1) also carried a potentially damaging de novo missense variant in the USP7 gene (602519), which may have contributed to his phenotype. Functional studies of the TMEM106B variant and studies of patient cells were not performed, but the findings suggested a link between TMEM106B and lysosomes to oligodendrocytes and myelination. Yan et al. (2018) identified a de novo heterozygous D252N mutation in the TMEM106B gene in a 3-year-old girl of Chinese descent with HLD16. The mutation was found by trio whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but Yan et al. (2018) noted that the mutation occurred at a CpG dinucleotide, suggesting that it is a recurrent mutation due to a hotspot within the gene. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus (horizontal, vertical, rotary) \- Saccadic pursuit ABDOMEN Gastrointestinal \- Poor feeding (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia \- Hypertonia NEUROLOGIC Central Nervous System \- Delayed development, primarily motor \- Intellectual disability (in some patients) \- Learning disabilities \- Speech delay \- Seizures (rare) \- Gait ataxia \- Wide-based gait \- Intention tremor \- Dysarthria \- Dystonia \- Dysmetria \- Hyperreflexia \- Pyramidal signs, mild \- Hypomyelinating leukodystrophy \- Thin corpus callosum MISCELLANEOUS \- Onset in the first days or weeks of life \- Variable severity \- Some patients may have normal cognitive development \- De novo mutation (in most patients) MOLECULAR BASIS \- Caused by mutation in the transmembrane protein 106B gene (TMEM106B, 613413.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	LEUKODYSTROPHY, HYPOMYELINATING, 16	c4693779	2,270	omim	https://www.omim.org/entry/617964	2019-09-22T15:44:12	{"omim": ["617964"]}
Malignant Sertoli-Leydig cell tumor of ovary is a rare malignant sex cord stromal tumor of ovary (see this term) occuring typically in young women and characterized by manifestations of androgen excess (hirsutism, hair loss, amenorrhea, or oligomenorrhea), when functional. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Malignant Sertoli-Leydig cell tumor of the ovary	c0036769	2,271	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99916	2021-01-23T18:13:45	{"gard": ["5495"], "mesh": ["D012707"], "umls": ["C0003810", "C0036769", "C0206723"], "icd-10": ["C56"], "synonyms": ["Androblastoma", "Arrhenoblastoma", "Ovarian Sertoli-Leydig cell cancer", "Ovarian malignant Sertoli-Leydig cell tumor", "Virilizing ovarian tumor"]}
This article is about the infection by the adult worms. For the organism, see Taenia (genus). Parasitic disease due to infection with tapeworms belonging to the genus Taenia Taeniasis The life cycle of Taenia saginata, the beef tapeworm SpecialtyInfectious disease SymptomsNone, weight loss, abdominal pain[1] ComplicationsPork tapeworm: cysticercosis[1] TypesTaenia solium (pork tapeworm), Taenia saginata (beef tapeworm), Taenia asiatica (Asian tapeworm)[2] CausesInfection with adult tapeworms[2][3] Risk factorsEating contaminated undercooked pork or beef[1] Diagnostic methodExamination of stool samples[4] PreventionProperly cooking meat[1] TreatmentPraziquantel, niclosamide[1] Frequency50 million (with cysticercosis)[5] Taeniasis is an infection within the intestines by adult tapeworms belonging to the genus Taenia.[2][3] There are generally no or only mild symptoms.[2] Symptoms may occasionally include weight loss or abdominal pain.[1] Segments of tapeworm may be seen in the stool.[1] Complications of pork tapeworm may include cysticercosis.[1] Types of Taenia that cause infections in humans include Taenia solium (pork tapeworm), Taenia saginata (beef tapeworm), and Taenia asiatica (Asian tapeworm).[2] Taenia saginata is due to eating contaminated undercooked beef while Taenia solium and Taenia asiatica is from contaminated undercooked pork.[2] Diagnosis is by examination of stool samples.[4] Prevention is by properly cooking meat.[1] Treatment is generally with praziquantel, though niclosamide may also be used.[1] Together with cysticercosis, infections affect about 50 million people globally.[5] The disease is most common in the developing world.[1] In the United States less than 1,000 cases occur a year.[1] ## Contents * 1 Signs and symptoms * 1.1 Pork tapeworm * 1.2 Beef tapeworm * 1.3 Asian tapeworm * 2 Transmission * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 6.1 Regions * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Taeniasis generally has few or no symptoms.[6] It takes about 8 weeks from infection for adult worms to form and can last for years without treatment.[6] Infection may be suspected when a portion of the worm is passed in the stool.[4] It is not generally fatal.[7][8][9] ### Pork tapeworm[edit] Taenia solium adult Infection in the intestines by the adult T. solium worms is normally asymptomatic. Heavy infection can result in anaemia and indigestion.[citation needed] A complication, known as cysticercosis, may occur if the eggs of the pork tapeworm are eaten. This typically occurs from vegetables or water contaminated by feces from someone with pork tapeworm taeniasis. The eggs enter the intestine where they develop into larvae which then enter the bloodstream and invade host tissues. This is the most frequent and severe disease caused by any tapeworm. It can lead to headaches, dizziness, seizures, dementia, hypertension, lesions in the brain, blindness, tumor-like growths, and low eosinophil levels. It is a cause of major neurological problems, such as hydrocephalus, paraplegy, meningitis, and death.[10] ### Beef tapeworm[edit] Taenia saginata infection is asymptomatic, but heavy infection causes weight loss, dizziness, abdominal pain, diarrhea, headaches, nausea, constipation, chronic indigestion, and loss of appetite. It can cause antigen reaction that induce allergic reaction.[11] It is also a rare cause of ileus, pancreatitis, cholecystitis, and cholangitis.[12] ### Asian tapeworm[edit] Taenia asiatica is also usually asymptomatic. It is unclear if T. asiatica can cause cysticercosis.[1] In pigs, the cysticercus can produce cysticercosis. Cysts develop in liver and lungs. (T. saginata does not cause cysticercosis.)[13] ## Transmission[edit] Taeniasis is contracted after eating undercooked pork or beef that contain the larvae. The adult worms develop and live in the lumen of the intestine. They acquire nutrients from the intestine. The gravid proglottids, body segments containing fertilised eggs, are released in the faeces.[citation needed] If consumed by an intermediate host such as a cow or pig, they hatch within the duodenum to become larvae, penetrate through the intestinal wall into nearby blood vessels, and enter the bloodstream. Once they reach organs such as the skeletal muscles, liver or lungs, the larvae then develop into a cyst, a fluid-filled cysticercus. These contaminated tissues are then consumed through raw or undercooked meat.[7] Cysticercosis occurs when contaminated food, water, or soil that contain T. solium eggs is eaten.[14][15] ## Diagnosis[edit] Egg of T. solium Diagnosis of taeniasis is mainly using stool sample, particularly by identifying the eggs. However, this has limitation at the species level because tapeworms basically have similar eggs. Examination of the scolex or the gravid proglottids can resolve the exact species.[16] But body segments are not often available, therefore, laborious histological observation of the uterine branches and PCR detection of ribosomal 5.8S gene are sometimes necessary.[17][18] Ziehl–Neelsen stain is also used for T. saginata and T. solium, in most cases only the former will stain, but the method is not entirely reliable.[19] Loop-mediated isothermal amplification (LAMP) is highly sensitive (~2.5 times that of multiplex PCR), without false positives, for differentiating the taenid species from faecal samples.[20] To date the most relevant test for T. asiatica is by enzyme-linked immunoelectrotransfer blot (EITB). EITB can effectively identify asiatica from other taenid infections since the serological test indicates an immunoblot band of 21.5 kDa exhibited specifically by T. asiatica.[21] Even though it gives 100% sensitivity, it has not been tested with human sera for cross-reactivity, and it may show a high false positive result.[citation needed] ## Prevention[edit] Prevention efforts include properly cooking meat, treating active cases in humans, vaccinating and treating pigs against the disease, stricter meat-inspection standards, health education, improved sanitation, and improved pig raising practices.[1][6] Preventing human faeces from contaminating pig feeds also plays a role. Infection can be prevented with proper disposal of human faeces around pigs, cooking meat thoroughly and/or freezing the meat at −10 °C for 5 days. For human cysticercosis, contaminated hands are the primary cause, and especially concerning among food handlers.[7] Proper cooking of meat is an effective prevention. For example, cooking (56 °C for 5 minutes) of beef viscera destroys cysticerci. Refrigeration, freezing (−10 °C for 9 days) or long periods of salting is also lethal to cysticerci.[11] ## Treatment[edit] Praziquantel is the treatment of choice.[22] Usual treatments are with praziquantel (5–10 mg/kg, single-administration) or niclosamide (adults and children over 6 years: 2 g, single-administration after a light breakfast, followed after 2 hours by a laxative; children aged 2–6 years: 1 g; children under 2 years: 500 mg).[11] Albendazole is also highly effective.[23] Mepacrine is quite effective but has adverse effects in humans.[24] ## Epidemiology[edit] The total global infection is estimated to be between 40 and 60 million people.[25] In the US, the incidence of infection is low, but 25% of cattle sold are still infected.[16] ### Regions[edit] Taeniasis is predominantly found in Asia, Africa, Latin America, particularly on farms in which pigs are exposed to human excrement. It occurs everywhere though where beef and pork are eaten, even in countries such as the United States, with strict federal sanitation policies. Taenia saginata is relatively common in Africa, some parts of Eastern Europe,[26] the Philippines, and Latin America.[27] It is most prevalent in Sub-Saharan Africa and the Middle East.[28] Taenia asiatica is restricted to East Asia, including Taiwan, Korea, Indonesia, Nepal, Thailand and China.[29][30] ## See also[edit] * Tapeworm infection ## References[edit] 1. ^ a b c d e f g h i j k l m n "CDC - Taeniasis - General Information - Frequently Asked Questions (FAQs)". www.cdc.gov. 24 April 2019. Retrieved 16 December 2019. 2. ^ a b c d e f "CDC - Taeniasis". www.cdc.gov. 24 April 2019. Retrieved 16 December 2019. 3. ^ a b "CDC - Taeniasis - Biology". www.cdc.gov. 24 April 2019. Retrieved 16 December 2019. 4. ^ a b c "CDC - Taeniasis - Diagnosis". www.cdc.gov. 24 April 2019. Retrieved 17 December 2019. 5. ^ a b Griffiths, Jeffrey; Maguire, James H.; Heggenhougen, Kristian; Quah, Stella R. (2010). Public Health and Infectious Diseases. Elsevier. p. 216. ISBN 978-0-12-381507-1. 6. ^ a b c "Taeniasis/Cysticercosis". www.who.int. Retrieved 17 December 2019. 7. ^ a b c Garcia, Oscar H. Del Brutto, Hector H. (2014). "Taenia solium: Biological Characteristics and Life Cycle". Cysticercosis of the Human Nervous System (1., 2014 ed.). Berlin: Springer-Verlag Berlin and Heidelberg GmbH & Co. KG. pp. 11–21. ISBN 978-3-642-39021-0. 8. ^ "About Taeniasis/cysticercosis". Retrieved 13 March 2014. 9. ^ "Signs, symptoms and treatment of taeniasis/cysticercosis". Retrieved 13 March 2014. 10. ^ Flisser, A.; Avila G; Maravilla P; Mendlovic F; León-Cabrera S; Cruz-Rivera M; Garza A; Gómez B; Aguilar L; Terán N; Velasco S; Benítez M; Jimenez-Gonzalez DE (2010). "Taenia solium: current understanding of laboratory animal models of taeniosis". Parasitology. 137 (3): 347–57. doi:10.1017/S0031182010000272. PMID 20188011. 11. ^ a b c "Taeniasis/Cysticercosis". WHO Fact sheet N°376. World Health Organization. 2013. Retrieved 7 February 2014. 12. ^ Uygur-Bayramiçli, O; Ak, O; Dabak, R; Demirhan, G; Ozer, S (2012). "Taenia saginata a rare cause of acute cholangitis: a case report". Acta Clinica Belgica. 67 (6): 436–7. doi:10.1179/ACB.67.6.2062709. PMID 23340150. 13. ^ Galán-Puchades, M.T.; Fuentes, M.V. (2008). "Taenia asiatica and pig cysticercosis". Veterinary Parasitology. 157 (1–2): 160–161. doi:10.1016/j.vetpar.2008.07.008. PMID 18752896. 14. ^ Roberts, Larry S.; Janovy, Jr., John (2009). Gerald D. Schmidt & Larry S. Roberts' Foundations of Parasitology (8 ed.). Boston: McGraw-Hill Higher Education. pp. 348–351. ISBN 978-0-07-302827-9. 15. ^ "Transmission of taeniasis/cysticercosis". Retrieved 13 March 2014. 16. ^ a b Jr, Larry S. Roberts, John Janovy (2009). Gerald D. Schmidt & Larry S. Roberts' Foundations of parasitology (8th ed.). Boston: McGraw-Hill. ISBN 978-0-07-128458-5. 17. ^ González LM, Montero E, Harrison LJ, Parkhouse RM, Garate T (2000). "Differential diagnosis of Taenia saginata and Taenia solium infection by PCR". J Clin Microbiol. 38 (2): 737–744. doi:10.1128/JCM.38.2.737-744.2000. PMC 86191. PMID 10655377. 18. ^ Zarlenga DS. (1991). "The differentiation of a newly described Asian taeniid from Taenia saginata using enzymatically amplified non-transcribed ribosomal DNA repeat sequences". Southeast Asian J Trop Med Public Health. 22 (suppl): 251–255. PMID 1822899. 19. ^ Jimenez JA, Rodriguez S, Moyano LM, Castillo Y, García HH (2010). "Differentiating Taenia eggs found in human stools - Does Ziehl Neelsen staining help?". Tropical Medicine & International Health. 15 (9): 1077–1081. doi:10.1111/j.1365-3156.2010.02579.x. PMC 3428859. PMID 20579318. 20. ^ Nkouawa, A; Sako, Y; Li, T; Chen, X; Wandra, T; Swastika, IK; Nakao, M; Yanagida, T; Nakaya, K; Qiu, D; Ito, A (2010). "Evaluation of a loop-mediated isothermal amplification method using fecal specimens for differential detection of Taenia species from humans". Journal of Clinical Microbiology. 48 (9): 3350–2. doi:10.1128/JCM.00697-10. PMC 2937673. PMID 20631114. 21. ^ Jeon, Hyeong-Kyu; Eom, Keeseon S. (2009). "Immunoblot Patterns of Taenia asiatica Taeniasis". The Korean Journal of Parasitology. 47 (1): 73–7. doi:10.3347/kjp.2009.47.1.73. PMC 2655338. PMID 19290097. 22. ^ "CDC - DPDX Homepage". 2019-05-14. 23. ^ Lopes WD, Cruz BC, Soares VE, Nunes JL, Teixeira WF, Maciel WG, Buzzulini C, Pereira JC, Felippelli G, Soccol VT, de Oliveira GP, da Costa AJ (2014). "Historic of therapeutic efficacy of albendazol sulphoxide administered in different routes, dosages and treatment schemes, against Taenia saginata cysticercus in cattle experimentally infected". Experimental Parasitology. 137 (1): 14–20. doi:10.1016/j.exppara.2013.11.007. PMID 24309372. 24. ^ Ooi, Hong Kean; Ho, Chau-Mei; Chung, Wen-Cheng (2013). "Historical overview of Taenia asiatica in Taiwan". The Korean Journal of Parasitology. 51 (1): 31–6. doi:10.3347/kjp.2013.51.1.31. PMC 3587746. PMID 23467308. 25. ^ Eckert, J. (2005). "Helminths". In Kayser, F.H.; Bienz, K.A.; Eckert, J.; Zinkernagel, R.M. (eds.). Medical Microbiology. Stuttgart: Thieme. pp. 560–562. ISBN 9781588902450. 26. ^ Trevisan, C.; Sotiraki, S.; Laranjo-González, M.; Dermauw, V.; Wang, Z.; Kärssin, A.; Cvetkovikj, A.; Winkler, A.S.; Abraham, A.; Bobić, B.; Lassen, B.; Cretu, C.M.; Vasile, C.; Arvanitis, D.; Deksne, G.; Boro, I.; Kucsera, I.; Karamon, J.; Stefanovska, J.; Koudela, B.; Pavlova, M.J.; Varady, V.; Pavlak, M.; Šarkūnas, M.; Kaminski, M.; Djurković-Djaković, O.; Jokelainen, P.; Jan, D.S.; Schmidt, V.; Dakić, Z.; Gabriël, S.; Dorny, P.; Devleesschauwer, B. (2018). "Epidemiology of taeniosis/cysticercosis in Europe, a systematic review: eastern Europe" (PDF). Parasit Vectors. 11 (1): 569. doi:10.1186/s13071-018-3153-5. PMC 6208121. PMID 30376899. 27. ^ Somers, Kenneth D.; Morse, Stephen A. (2010). Lange Microbiology and Infectious Diseases Flash Cards (2nd ed.). New York: Lange Medical Books/ McGraw-Hill. pp. 184–186. ISBN 9780071628792. 28. ^ Ortega, Ynes R. (2006). Foodborne parasites. New York: Springer. pp. 207–210. ISBN 9780387311975. 29. ^ Eom, Keeseon S.; Jeon, Hyeong-Kyu; Rim, Han-Jong (2009). "Geographical distribution of Taenia asiatica and related species". The Korean Journal of Parasitology. 47 (Suppl): S115–24. doi:10.3347/kjp.2009.47.S.S115. PMC 2769216. PMID 19885327. 30. ^ Ale, Anita; Victor, Bjorn; Praet, Nicolas; Gabriël, Sarah; Speybroeck, Niko; Dorny, Pierre; Devleesschauwer, Brecht (2014). "Epidemiology and genetic diversity of Taenia asiatica: a systematic review". Parasites & Vectors. 7 (1): 45. doi:10.1186/1756-3305-7-45. PMC 3900737. PMID 24450957. ## External links[edit] Classification D * ICD-10: B68 * ICD-9-CM: 123.3 * MeSH: D013622 * DiseasesDB: 12875 External resources * MedlinePlus: 001391 * eMedicine: ped/2201 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Taeniasis	c0152073	2,272	wikipedia	https://en.wikipedia.org/wiki/Taeniasis	2021-01-18T18:46:59	{"mesh": ["D013622"], "umls": ["C0152073"], "wikidata": ["Q1475667"]}
Spot blotch Causal agentsCochliobolus sativus HostsBarley EPPO CodeCOCHSA Spot blotch is a disease of barley caused by Cochliobolus sativus. The disease is found everywhere that barley is grown, but only causes significant yield losses in warm, humid climates.[1][2] ## Contents * 1 Symptoms * 2 Disease cycle * 3 Yield loss * 4 Management * 5 External links * 5.1 Extension publications * 6 References ## Symptoms[edit] Infections appear as dark, chocolate-colored blotches. The spots merge, eventually forming irregular necrotic patches on the leaves. Leaf spots may be surrounded by a zone of yellow leaf tissue of varying width. Spot may also appear on the leaf sheaths, necks and heads of the plant. Heavily infected leaves dry up completely, and infections on the flag leaf during kernel filling are the most serious. ## Disease cycle[edit] The fungus overwinters in barley straw and stubble, in the soil, or on the seed. Spores are produced on barley debris in the spring and are dispersed by wind and rain. Barley seedlings may become infected from inoculum on the seed or in the soil. Temperatures above 20°C and moist humid conditions within the crop canopy favour spot blotch development. Conducive weather conditions may favour successive production of new spores and lesions leading to rapid disease development during the growing season. ## Yield loss[edit] The disease may be particularly damaging in the Upper Midwest of the United States. Yield losses of 10-30% may be occur when weather conditions are conducive to disease development.[1] ## Management[edit] The disease is managed by using resistant varieties, clean seed, seed treatments, foliar fungicide and rotation to non-cereal crops. ## External links[edit] ### Extension publications[edit] * Spot blotch (Canada: Alberta) * Spot blotch (Denmark) * Spot blotch (US: North Dakota) * Spot blotch (US: Oregon)[permanent dead link] ## References[edit] 1. ^ a b Mathre, D.E. (1997). Compendium of barley diseases. American Phytopathological Society. pp. 120 pp. ISBN 0-89054-180-9. 2. ^ Martens, J.W.; W.L. Seaman; T.G. Atkinson (1984). Diseases of field crops in Canada. Canadian Phytopathological Society. pp. 160 pp. ISBN 0-9691627-0-7. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Spot blotch (barley)	None	2,273	wikipedia	https://en.wikipedia.org/wiki/Spot_blotch_(barley)	2021-01-18T19:01:32	{"wikidata": ["Q7580044"]}
## Summary ### Clinical characteristics. GARS1-associated axonal neuropathy (Charcot-Marie-Tooth neuropathy type 2D / distal spinal muscular atrophy V [CMT2D/dSMA-V]) is characterized by adolescent or early-adult onset of weakness in the hands that may be preceded by transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. This is followed by progressive weakness and atrophy of thenar and first dorsal interosseus muscles; hypothenar eminence is spared until later in the course of illness. The lower limbs are involved in about half of affected individuals, with severity varying from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop. The phenotype is considered the CMT2D subtype when sensory deficits (reduction of pinprick, temperature, touch, and vibration perception in a stocking and [less often] glove pattern) are present and dSMA-V when sensory deficits are absent. ### Diagnosis/testing. The diagnosis of GARS1-associated axonal neuropathy is established in a proband with typical clinical findings and a heterozygous pathogenic variant in GARS1 identified by molecular genetic testing. ### Management. Treatment of manifestations: Assistive devices for weak hands; ankle support, toe-up braces, ankle-foot orthotics as necessary to improve gait. Surveillance: Assessment every six months by a neurologist and/or neuromuscular disorders specialist to assess progression of weakness in the limbs and determine the need for prosthetic or assistive devices. ### Genetic counseling. GARS1-associated axonal neuropathy is inherited in an autosomal dominant manner. Most individuals diagnosed with the disorder have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with GARS1-associated axonal neuropathy has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member. ## Diagnosis Charcot-Marie-Tooth neuropathy type 2D (CMT2D) characterized by distal motor and sensory neuropathy [Ionasescu et al 1996] and distal spinal muscular atrophy V (dSMA-V) with exclusively motor distal involvement [Christodoulou et al 1995] were originally thought to be distinct entities, but family studies [Sambuughin et al 1998, Ellsworth et al 1999] and later molecular genetic studies [Antonellis et al 2003] determined that they represent the clinical spectrum associated with pathogenic variants in GARS1. In this GeneReview the term "GARS1-associated axonal neuropathy" comprises both allelic disorders. ### Suggestive Findings GARS1-associated axonal neuropathy should be suspected in individuals with the following findings: * Adolescent or early-adult onset of bilateral weakness and atrophy of thenar and first dorsal interosseus muscles with progression to involve hypothenar, foot, and peroneal muscles in many individuals and mild to moderate impairment of vibration sense developing in advanced illness in some individuals (dSMA-V phenotype) * Presence of sensory deficits including reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern (CMT2D phenotype) * Chronic denervation on EMG in distal muscles with reduced compound motor action potentials at near-normal or normal motor conduction velocities and preserved sensory nerve action potentials (SNAPs), including the sural response. See Electrophysiologic Studies. * Family history consistent with autosomal dominant inheritance Note: Individuals with a negative family history and a more severe, early-onset phenotype have been described [Eskuri et al 2012]. #### Electrophysiologic Studies EMG shows denervation predominantly in the distal muscle groups at normal motor distal latencies and conduction velocities (see Table 1): * Absent or markedly reduced (frequently <1 mV) compound muscle action potentials (CMAPs) are recorded from the abductor pollicis brevis (APB) by median nerve stimulation [Sivakumar et al 2005]. * Preserved CMAPs are recorded from the abductor digiti minimi (ADM) by ulnar nerve stimulation. * CMAP amplitude recorded by stimulation of the peroneal nerve is <2 mV in most individuals and <1 mV in individuals having clinically evident leg atrophy. * Normal median SNAP amplitudes and conduction velocities are seen in most individuals, even those with mildly prolonged distal motor latency. * In individuals with advanced disease, needle EMG shows no voluntary motor activity in the abductor pollicis and first dorsal interossei because of marked atrophy. Spontaneous activity is often seen in these muscles. * The elicited sural SNAPs are preserved but with a reduced amplitude, despite sensory axonal loss identified histopathologically on examination of a sensory nerve from an individual with the CMT2D subtype; similar but milder changes were seen in individuals with dSMA-V. Note: EMG is more widely available than nerve biopsy, which can be used in a single individual in a family or in diagnostically difficult cases. See Nerve Biopsy. ### Table 1. Results of Electrophysiologic Studies in GARS1-Associated Axonal Neuropathy by Subtype View in own window Results of Electrophysiologic StudiesSubtype CMT2D (%)dSMA-V (%) Motor nerve conductionCompound muscle action potentialMedian-APB <4.5 mV100100 Ulnar-ADM <3.5 mV00 Peroneal-EDB <2 mV10062.5 Tibial-AH <2.5 mV050 Distal motor latencyMedian <5.6 ms00 Ulnar <4.5 ms011 Peroneal & tibial <7.5 ms00 Nerve conduction velocityMedian & ulnar <39 m/s00 Peroneal & tibial <29 m/s00 Sensory nerve conduction: sensory nerve action potentialMedian <10 µV; ulnar <8 µV012 Sural <6 µV1729 ADM = abductor digiti minimi; AH = adductor halluces; APB = abductor pollicis brevis; EDB = extensor digitorum brevis ### Establishing the Diagnosis The diagnosis of GARS1-associated axonal neuropathy is established in a proband with typical clinical findings and a heterozygous pathogenic variant in GARS1 identified by molecular genetic testing (see Table 2). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GARS1-associated axonal neuropathy is potentially broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from other inherited disorders with neuromuscular weakness or sensory deficits in whom the diagnosis of GARS1-associated axonal neuropathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When phenotypic and laboratory findings suggest the diagnosis of GARS1-associated axonal neuropathy, molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of GARS1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes GARS1 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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the phenotype is indistinguishable from other inherited disorders characterized by neuromuscular weakness or sensory deficits or when the diagnosis of GARS1-associated axonal neuropathy is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 2. Molecular Genetic Testing Used in GARS1-Associated Axonal Neuropathy View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method GARS1Sequence analysis 3100% 4 Gene-targeted deletion/duplication analysis 5Unknown 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\. Antonellis et al [2003], James et al [2006], Lee et al [2012], DiVincenzo et al [2014], Antoniadi et al [2015] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics ### Clinical Description In this GeneReview the term "GARS1-associated axonal neuropathy" includes both Charcot-Marie-Tooth neuropathy type 2D (CMT2D), characterized by distal motor and sensory neuropathy, and distal spinal muscular atrophy V (dSMA-V), with exclusively motor distal involvement. Onset. Both disease subtypes, CMT2D and dSMA-V, are characterized by adolescent or early-adult onset of unique patterns of motor and sensory manifestations. Age of onset ranges from eight to 36 years, with most individuals (75%) developing symptoms during the second decade of life [Sivakumar et al 2005, James et al 2006]. However, infantile onset has also been reported in individuals who have de novo GARS1 pathogenic variants [Eskuri et al 2012]. Presentation. The presenting symptom is typically muscle weakness in the hands. The earliest elicited manifestations of illness in many individuals are transient cramping and pain in the hands on exposure to cold and cramping in calf muscles on exertion. Progressive weakness and atrophy of the thenar and first dorsal interosseus muscles are the major complaints in affected individuals (Figure 1, Table 3). The hypothenar eminence is spared until later in the course of illness. #### Figure 1. Distribution of muscle weakness and atrophy in individuals with two major clinical subtypes of GARS1-associated disease A. Thenar and first dorsal interosseus muscle wasting with relatively preserved hypothenar in an individual with dSMA-V phenotype The lower limbs are involved in about half of affected individuals. Lower extremity involvement, when present, varies in severity from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop. Peroneal muscles are affected earlier and more severely than the calf muscles. If peroneal muscular atrophy develops, it is associated with pes cavus and moderate sensory abnormalities in stocking distribution and (less often) glove distribution. Individuals with lower-leg involvement have a high steppage gait. Reflexes at the ankles are diminished or absent in individuals with leg muscle weakness and sensory deficits. Sensory examination is either normal or shows mild to moderate impairment of vibration sense in the hands and feet; in individuals with the CMT2D subtype, reduction of pinprick, temperature, touch, and vibration perception in a stocking and (less often) glove pattern is observed (Table 3). In individuals with the dSMA-V subtype, sensory deficits are absent. Proximal limb muscle weakness is not observed in the upper or lower extremities. ### Table 3. Phenotypic Features of GARS1-Associated Axonal Neuropathy by Subtype View in own window Symptoms and SignsSubtype CMT2D (%)dSMA-V (%) Progressive bilateral weakness and wasting of thenar and FDI muscles100100 Peroneal weakness with atrophy and pes cavus10057.5 Pyramidal dysfunction012.5 Reduced sensation for touch, pain, and temperature1000 Reduced vibration sense10037.5 Sivakumar et al [2005] FDI = first dorsal interosseus #### Nerve Biopsy The dSMA-V subtype shows clear signs of axonal pathology with two or more regenerative clusters per fascicle (Figure 2A). No evidence of active degeneration and no obvious signs of demyelination or typical onion bulb formation are present. Myelin structures appear normal. Overall myelinated fiber density is normal (Figure 2B). Fibers >7 mm in diameter represent 52% of the overall number of fibers in the affected individual compared to 65% in control specimens. Electron microscopy (EM) shows denervated Schwann cell subunits as indicated by an increased number of profiles, suggesting damage to small unmyelinated nerve fibers (UMNFs) (Figure 2C). The UMNF density is at the low normal level. #### Figure 2. Sural nerve morphology in GARS1-related dSMA-V and CMT2D phenotypes A. dSMA-V. Pathologic changes are minimal with a near-normal myelinated nerve fiber density. The CMT2D subtype shows clear evidence of axonal pathology in nerve biopsy in one individual. Axonal swelling with filamentous accumulations (Figure 2D) and four to eight regenerative clusters per fascicle are observed (Figure 2E). Pseudo-onion bulb formations and a few thinly myelinated fibers are seen. Myelin structures appear intact. Overall myelinated fiber density is reduced. The proportion of fibers <7 mm in diameter is only 46%. Denervation of Schwann cell subunits as indicated by an increased number of profiles is seen on EM. ### Genotype-Phenotype Correlations The GARS1 variants p.Leu183Pro and p.His472Arg are exclusively associated with the dSMA-V clinical subtype; p.Gly294Arg, p.Ile334Phe, and p.Gly580Arg are associated with the CMT2D subtype. The variants p.Glu125Gly, p.Pro298Leu, and p.Asp554Asn are identified in families with both subtypes. Finally, the variant p.Gly652Ala has been associated with infantile-onset GARS1-associated axonal neuropathy [Eskuri et al 2012] (see Table 4). ### Penetrance Penetrance is incomplete in this disorder, although specific data are not available. ### Nomenclature The term "GARS1-associated axonal neuropathy" includes an axonal form of CMT type 2 and a similar group of clinical syndromes classified as distal hereditary motor neuropathy or distal spinal muscular atrophy (dSMA-V). GARS1-associated axonal neuropathy is considered the CMT2D subtype when sensory deficits (reduction of pinprick, temperature, touch, and vibration perception in a stocking and [less often] glove pattern) are present, and dSMA-V when sensation is normal or a sensory response is present on nerve conduction studies alone. Using the classification system (based on the results of molecular genetic testing in the context of inheritance, neurologic examination, and gene) proposed by Magy et al [2018], CMT2D would be referred to as AD-CMTAx-GARS1. ### Prevalence Disease prevalence is unknown; GARS1-associated axonal neuropathy is likely very rare. For example, fewer than 25 disease-associated GARS1 alleles have been described and the vast majority are specific to individual pedigrees [Meyer-Schuman & Antonellis 2017]. ## Differential Diagnosis GARS1-associated axonal neuropathy needs to be distinguished from other forms of CMT, spinal muscular atrophy (SMA), and unrelated but similar neurologic conditions. Charcot-Marie-Tooth disease type 2 (CMT2). Other subtypes of CMT2 have a wide range of onset age and diverse manifestations (see Charcot-Marie-Tooth Hereditary Neuropathy Overview). Generally, individuals with CMT2 present with distal muscular atrophy, loss of reflexes, sensory deficits, reduced sensory nerve action potentials (SNAPs), and normal or mildly slowed motor nerve conduction velocity. The unique pattern of hand involvement before leg involvement and preserved SNAPs helps distinguish CMT2D from other CMT2 subtypes. Distal spinal muscular atrophy (dSMA). Other types of dSMA (also referred to as distal hereditary motor neuropathy [dHMN]) – a genetically heterogeneous group of disorders [Irobi et al 2004a, Irobi et al 2004b] caused by progressive degeneration of anterior horn neurons – are characterized by slowly progressive muscle weakness and atrophy in the distal limbs without sensory deficits. SNAPs are preserved and motor conduction velocities are nearly normal. A separate set of genes is associated with dHMN-V subtypes [Irobi et al 2004a, Irobi et al 2004b]. The pattern of hand involvement before leg involvement distinguishes dHMN-V from other dHMN subtypes. Silver syndrome is associated with spasticity in the legs and amyotrophy in the hands. Caused by pathogenic variants in BSCL2, Silver syndrome is part of the spectrum of the BSCL2-related neurologic disorders. In contrast to Silver syndrome, in which most individuals have spasticity, only a minority of individuals with GARS1-associated axonal neuropathy show mild pyramidal signs and spasticity (Table 3) [Christodoulou et al 1995, Sivakumar et al 2005, Dubourg et al 2006]. Other neurologic disorders. The clinical pattern of disease onset with hand weakness and atrophy rather than foot involvement and absent sensory deficits in the early stages of the illness should raise a suspicion of carpal tunnel syndrome, neurogenic thoracic outlet syndrome, or multifocal motor neuropathy: * In the absence of family history, paresthesia, and pain, the clinical pattern of median nerve dysfunction at the wrist in individuals with carpal tunnel syndrome may be similar to that seen in the early stages of GARS1-associated axonal neuropathy. Carpal tunnel syndrome is usually asymmetric and limited to median nerve. * Compression of the lower cervical and T1 roots caused by a cervical rib may result in neurogenic thoracic outlet syndrome. In this condition, thenar, hypothenar, and interossei weakness/atrophy is associated with ulnar and medial antebrachial cutaneous hypesthesia that could be validated by nerve conduction studies showing reduced SNAP amplitudes in the medial antebrachial cutaneous and ulnar nerves. * Multifocal motor neuropathy is a sporadic autoimmune demyelinating disease causing slowly progressing motor disturbances in peripheral nerve distributions, predominantly in the distal upper extremities. It is often asymmetric and eventually involves hand muscles innervated by two or more motor nerves. Electrophysiologic conduction block can be demonstrated in the motor nerves, and anti-GM1 antibody titers are often elevated. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GARS1-associated axonal neuropathy, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Nerve conduction studies and EMG of arms and legs * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Appropriate treatment includes the following: * Prosthetic and adaptive devices for weak hands. Numerous devices are available for various activities of daily living. * Ankle support, toe-up braces, and ankle-foot orthotics as necessary to improve gait ### Prevention of Secondary Complications Stretching exercises, finger splints, and ankle braces to prevent contractures and deformities are appropriate. ### Surveillance Surveillance includes assessment every six months by a neurologist and/or a neuromuscular disorders specialist to assess progression of weakness in the limbs and determine the need for use of prosthetic and assistive devices. ### Agents/Circumstances to Avoid Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and severely worsen CMT [Nishikawa et al 2008]. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### 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. In a mouse model of GARS1-associated axonal neuropathy, reduced acetylated α-tubulin levels were found in primary dorsal root ganglion neurons [Benoy et al 2018]. Selective HDAC6 inhibition increased α-tubulin acetylation in peripheral nerves and partially restored nerve conduction, indicating possible therapeutic potential. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	GARS1-Associated Axonal Neuropathy	None	2,274	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1242/	2021-01-18T21:24:55	{"synonyms": []}
A rare eyelid malposition disorder characterized by congenital abnormal inversion of the eyelid towards the globe, potentially causing mechanical irritation of the ocular surface by the eyelashes, which may lead to corneal abrasion and scarring with visual impairment. Typical initial symptoms are foreign body sensation, redness, tearing, and ocular discharge. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Isolated congenital entropion	None	2,275	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=519386	2021-01-23T17:24:23	{}
Idiopathic scrotal calcinosis Other namesIdiopathic calcified nodules of the scrotum[1] SpecialtyDermatology Idiopathic scrotal calcinosis is a cutaneous condition characterized by calcification of the skin resulting from the deposition of calcium and phosphorus occurring on the scrotum.[2]:528 However, the levels of calcium and phosphate in the blood are normal.[3] Idiopathic scrotal calcinosis typically affects young males, with an onset between adolescence and early adulthood.[3] The scrotal calcinosis appears, without any symptoms, as yellowish nodules that range in size from 1 mm to several centimeters.[4] ## Contents * 1 Presentation * 2 Etiology * 3 Diagnostic * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 History * 8 See also * 9 References ## Presentation[edit] * Single or multiple hard, marble-like nodules of varying size affecting scrotal skin. * Nodules vary in size from a few millimeters to a few centimeters. * Usually start to appear in childhood or early adult life * Over time, nodules increase in number and size * Nodules may break down and discharge chalky material * Rarely, lesions may be polypoid * Usually asymptomatic ## Etiology[edit] The cause is not well defined.[4][5] Originally considered idiopathic condition. Now accepted that majority of cases develop from dystrophic calcification of cyst contents. ## Diagnostic[edit] * Clinically Relevant Pathologic Features * Lesions slowly progress throughout life * They slowly increase in number and size * Nodules are mobile and do not attach to underlying structures Pathologic Interpretation Pearls * Globular and granular purple deposits within dermis surrounded by giant cell granulomatous reaction * Sometimes remnants of cystic lesion can be identified * Very distinctive appearance with almost no histologic differential diagnosis. ## Treatment[edit] Treatment may involve surgery,[6] which is currently the only recommended intervention.[4] Surgery should include the removal of even small nodules, to prevent the recurrence of the scrotal calcinosis.[4] ## Prognosis[edit] * Benign condition * Slow progression throughout life * Lesions remain discrete and do not become confluent ## Epidemiology[edit] * Incidence: uncommon * Age: children and young adults ## History[edit] Scrotal calcinosis was first described in 1883 by Lewinski.[4] ## See also[edit] * Calcinosis cutis * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 3. ^ a b Grenader, Tal; Shavit, Linda (Aug 18, 2011). "Scrotal Calcinosis". New England Journal of Medicine. 365 (7): 647. doi:10.1056/NEJMicm1013803. PMID 21848465. 4. ^ a b c d e Khallouk A, Yazami OE, Mellas S, Tazi MF, El Fassi J, Farih MH (2011). "Idiopathic scrotal calcinosis: a non-elucidated pathogenesis and its surgical treatment". Reviews in Urology. 13 (2): 95–7. PMC 3176555. PMID 21935341. 5. ^ Dubey S, Sharma R, Maheshwari V (2010). "Scrotal calcinosis: idiopathic or dystrophic?". Dermatol. Online J. 16 (2): 5. PMID 20178701. 6. ^ Karaca M, Taylan G, Akan M, Eker G, Gideroglu K, Gul AE (April 2010). "Idiopathic Scrotal Calcinosis: Surgical Treatment and Histopathologic Evaluation of Etiology". Urology. 76 (6): 1493–1495. doi:10.1016/j.urology.2010.02.001. PMID 20381842. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Idiopathic scrotal calcinosis	c1274902	2,276	wikipedia	https://en.wikipedia.org/wiki/Idiopathic_scrotal_calcinosis	2021-01-18T18:32:52	{"umls": ["C1274902"], "wikidata": ["Q17140373"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (January 2020) (Learn how and when to remove this template message) Metagonimiasis SpecialtyInfectious disease Metagonimiasis is a disease caused by an intestinal trematode, most commonly Metagonimus yokagawai, but sometimes by M. takashii or M. miyatai. The metagonimiasis-causing flukes are one of two minute flukes called the heterophyids. Metagonimiasis was described by Katsurasa in 1911–1913 when he first observed eggs of M. yokagawai in feces (date is disputed in various studies). M. takahashii was described later first by Suzuki in 1930 and then M. miyatai was described in 1984 by Saito. ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Transmission * 2.2 Reservoirs * 2.3 Incubation period * 2.4 Morphology * 2.4.1 Eggs * 2.4.2 Adult flukes * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 6.1 Korea * 6.2 Japan * 6.3 India * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] The main symptoms are diarrhea and colicky abdominal pain. Because symptoms are often mild, infections can often be easily overlooked but diagnosis is important. Flukes attach to the wall of the small intestine, but are often asymptomatic unless in large numbers. Infection can occur from eating a single infected fish source. Peripheral eosinophilia is associated especially in early phase. When present in large numbers, can cause chronic intermittent diarrhea, nausea, and vague abdominal pains. Clinical complaints can also include lethargy and anorexia. In acute metagonimiasis, clinical manifestations are developed only 5–7 days after infection. Heavy infection has also been associated with epigastric distress, fatigue, and malaise. Occasionally, flukes invade the mucosa and eggs deposited in tissue may gain access to circulation. This can then lead to eggs embolizing in the brain, spinal cord, or heart. Granulomas may form around eggs and can cause seizures, neurologic deficits, or cardiac insufficiency. An interesting case in Japan found diabetes mellitus (DM) to be a sign of chronic infection with intracerebral hemorrhages as the acute sign of aggravation{{citation needed}}. Two months after administering praziquantel, the hemorrhages were gone, as was the diabetes. This unique case shows the potential of additional symptoms associated with metagonimiasis that are still unknown. ## Cause[edit] Metagonimiasis is most commonly caused by one of the two smallest flukes known to infect man, Metagonimus yokagawai, also called the Japanese fluke. More rarely, metagonimiasis can arise from infection with M. takahashii or M. miyatai. Recent studies analyzing the DNA of the three agents causing metagonimiasis found that DNA sequencing supports M. yokagawai and M. takahashii be placed in the same clade, and phylogenic tree analysis supports their genetic similarity. M. miyatai, however, was found to be more genetically distinct, and the authors concluded it should be nominated as a separate species. An additional study examining karyotype data on the three disease-causing agents also supported the nomination of M. miyatai as a separate species. Trematodes are one class of phylum Platyhelminthes from the order Digenia and are generally referred to as flukes. Metagonimiasis is of the family Herterophyidae. ### Transmission[edit] Transmission requires two intermediate hosts, the first of which is snails, most commonly of species Semisucospira libertina, Semiculcospira coreana, and Thiara granifera. Infection is acquired through the secondary intermediate host, fish, that have not been thoroughly cooked. Metacercariae encyst under the scales or in the flesh of fish from fresh or brackish water. Sweetfish (Pecoglossus altevelis) is one of the most common fish species infected, but others include the golden carp (Carassius auratus), common carp (Cyprinus carpio), Zacco temminckii, Protimus steindachneri, Acheilognathus lancedata, and Pseudorashora parva. Definitive hosts include humans and various fish-eating mammals, primarily dogs, cats, and pigs. Fish-eating birds may also be infected with metagonimiasis. ### Reservoirs[edit] Reservoirs include fish-eating mammals such as dogs, cats and pigs as well as fish-eating birds. The presence of heterophyid infection in humans is generally caused by a lack of host specificity by the parasites, as seen in the many non-human reservoirs for metagonimiasis. The many reservoirs also have negative implications on the efficacy of prevention and eradication efforts of the disease. ### Incubation period[edit] The incubation period is around 14 days and infestation may persist for more than one year. ### Morphology[edit] Main articles: Metagonimus, Metagonimus yokogawai, Metagonimus takahashii, and Metagonimus miyatai Adult Fluke (from CDC) Life cycle of Metagonimus yokogawai. #### Eggs[edit] The morphology of the eggs is very important for diagnosis, but is difficult as eggs are very small. Eggs have a smooth, hard shell that is transparent and yellow-brown with a more conventional, ovoid egg shape. They are about the same size as those of Heterophyes and Clonorchis, usually measuring 26-28 μm length and 15-17μm width. The egg also has a very slight opercular shoulder, marking the line of cleavage between the shell and operculum, an "escape hatch" for the mircidium. The Clonorchis has more distinctive tapering and a seated operculum that help distinguish it more readily from Metagonimus species. #### Adult flukes[edit] The body of the adult disease-causing agent of metagonimiasis is often described as leaf-shaped, similar to most trematodes. It is one of the smallest intestinal flukes, and is only slightly larger than Heteropheres. The most prominent feature is that its ventral sucker is deflected to the right of its midline and is closely associated with the opening of the genital pore. The testes are large and diagonal to each other while the smaller ovary is anterior to the testes and the uterus is filled with eggs. The uterus winds forward to the genital pore and is the largest organ in the body. The size of the adult fluke does not exceed 2.5 mm length by .75 mm width. ## Diagnosis[edit] Metagonimiasis is diagnosed by eggs seen in feces. Only after antihelminthic treatment will adult worms be seen in the feces, and then can be used as part of a diagnostic procedure. A 1993 analysis of the efficacy of ELISA tests to diagnose metagonimiasis implied that simultaneous screening of specific antibodies to several parasite agents are important in serological diagnosis of acute parasitic disease and more research should be done on the efficacy of these methods of diagnosis. Diagnosis may be difficult because the egg-laying capacity of heterophyids is limited, and therefore sedimentation concentration procedures may be needed to demonstrate eggs in lighter infections. Accurate species identification is also difficult because eggs of most flukes are similar in size and morphology, especially those of Heterophyes heterophyes, Clonorchis and Opisthorchis. It is important to ask where the person may have contracted the disease, find out if they have been to en endemic area, and check for signs and symptoms that would lead to metagonimiasis. ## Prevention[edit] Several public health prevention strategies could help lower the rates of metagonimiasis. One is to control the intermediate host (snails). This can be done through use of molluscidals. Another is to use education to ensure all people, especially in areas were the disease regularly occurs, fully cook all fish. This could potentially be problematic and not as effective as hoped as many of the people affected by metagonimiasis eat raw or pickled fish as part of a traditional, long-seated dietary practice. Additionally, implementing more sanitary water conditions would reduce the continual reintroduction of eggs to water sources, thus restarting the lifecycle. Complete control of metagonimiasis presents several potential problems because it does have several reservoir hosts, thus eradication is unlikely. ## Treatment[edit] Praziquantel is recommended in both adult and pediatric cases with dosages of 75 mg/kg/d in 3 doses for 1 day. Praziquantel is a Praziniozoquinoline derivative that alters the calcium flux through the parasite tectum and causes muscular paralysis and detachment of the fluke. Prizaquantel should be taken with liquids during a meal and as provided commercially as Biltricide. Praziquantel is not approved by the U.S. Food and Drug Administration (FDA) for treatment of metagonimiasis, but is approved for use on other parasitic infections. Praziquantel has some side effects but they are generally relatively mild and transient and a review of evidence shows it overall a well-tolerated drug. Possible side effects include abdominal pain, allergy, diarrhea, headache, liver problems, nausea or vomiting, exacerbation of porphyries, pruritus, rash, somnolence, vertigo, or dizziness. In fact, in 2002, the World Health Organization recommended the use of Praziquantel in pregnant and lactating women, though controlled trials are still needed to verify this. Another possible drug option is Tetrachloroethylene, a chlorinated hydrocarbon, but its use has been superseded by new antihelminthic drugs (like Praziquantel). A 1978 study also looked at the efficacy of several drugs on metagonimiasis infection, including bithionol, niclosamide, nicoflan, and Praziquantel. All drugs showed lower prevalence of eggs in feces, however only Praziquantel showed complete radical cure. Therefore, the authors concluded Praziquantel was the most highly effective, was very well tolerated, and was the most promising drug against metagonimiasis. ## Epidemiology[edit] Metagonimiasis infections are endemic or potentially endemic in 19 countries including Japan, Korea, China, Taiwan, the Balkans, Spain, Indonesia, the Philippines and Russia. Human infections outside endemic areas may result from ingesting pickled fish or sushi made from fish imported from endemic areas. ### Korea[edit] Food-borne trematodes are currently the most important parasitic infections in Korea and approximately 240,000 Koreans are believed to be currently infected. Of the 240,000 estimated to be infected, 120,000 are caused by M. yokagawai, 20,000 by M. takahashii, and 100,000 by M. miyatai. The national rate of infections among randomly selected people was 1.2% in 1981, 1.0% in 1986, and down to 0.5% in 2004. M. yokagawai infections are found mostly around the large and small streams where sweetfish live and have been identified as endemic foci. M. miyatai and M. takahashii are prevalent along the upper reaches of the big rivers where minnows and carps are caught for eating raw. ### Japan[edit] Metagonimiasis is also common in Japan, with 10-15% prevalence rates in populations bordering major rivers and 150,000 estimated infected. Food-borne trematodes are most common in rural areas where traditional food habits are more preserved and raw freshwater fishes are incorporated into the diet. Both clonorchiasis and metagonimiasis have become infections of higher social classes in Hong Kong and Japan, owing to their frequent consumption of raw fish. ### India[edit] There have also recently been two reported cases in India, a location in which occurrence of infection is almost unknown. The second case, in 2005, was in a 6-year-old female patient presenting with loose watery stools for four days (however more details were not obtained as the patient was both deaf and dumb since birth). Upon examination, M. yokagawai eggs were found in stool, but the patient left and further analysis and treatment could not be completed. ## See also[edit] * List of parasites (human) ## References[edit] Ahn, Yung-Kyum. "Intestinal flukes of genus Metagonimus and their second intermediate hosts in Kangwon-do." Korean Journal of Parasitology. Vol. 31: 331–340. 1993. Ash, Lawrence; Orihel, Thomas. Atlas of Human Parasitology. Fourth Edition. American Society of Clinical Pathologists. 1997. Chai, Jong-Yil et al. "An epidemiological study of metagonimiasis along the upper reaches of the Namham River." Korean Journal of Parasitology. Vol. 31: 99–108. 1993. Chi, Je G. et al. "Intestinal Pathology in Human Metagonimiasis with Ultrastructural Observation of Parasites." Journal of Korean Medical Science. Vol. 3: 171–177. 1998. Despommier D.; Gwadz R.; Hotez P.; Knirsch C. Parasitic Diseases. Fifth Edition. New York: Apple Trees Productions. 2006. Doenhoff, M. J., D. Cioli, and J. Utzinger. "Praziquantel: mechanisms for action, resistance, and new derivatives for schistosomiasis." Current Opinion in Infectious Diseases. Vol 21:659-667. 2008. FAO/NACA/WHO. "Food Safety Issues Associated with Products from Aquaculture." WHO Technical Report Series. Geneva, 1999. Han, In-Soo et al. "An Epidemiologic Study on Clonorchiasis and Metagonimiasis in Riverside Areas in Korea." Korean Journal of Parasitology. Vol. 19: 137–150. 1981. Lee, Jin-Ju, et al. "Decrease of Metagonimus yokogawai Endemicity along the Tamjin River Basin." Korean Journal of Parasitology. Vol. 46: 269–291. 2008. Lee, Gye-Sung et al. "Epidemiological study of clonorchiasis and metagonimiasis along the Geum-gang in Okcheon-gun, Korea." Korean Journal of Parasitology. Vol. 40: 9–16. 2002. Lee, Seoung Cheol et al. "Antigenti c protein fractions of Metagonimus yokogawai reacting with patient sera." Korean Journal of Parasitology. Vol. 31: 43–48. 1993. Lee, Soo-ung et al. "Sequence comparisons of 28S ribosomal DNA and mitochondrial cytochrome c oxidase subunit I of Metgonimus yokogawai, M. takahashii, and M. miyatai." Korean Journal of Parasitology. Vol. 24: 129–135. 2004. Lee, Soo-ung et al. "A cytogenetic study on human intestinal trematodes of the genus Metagonimus in Korea." Korean Journal of Parasitology. Vol. 37: 237–241. 1999. Markell, EK; John, DT; Krotoski, WA. Markell and Voge's Medical Parasitology. Ninth Edition. Philadelphia: W.B. Saunders Company. 2006. Mehlhorn, Heinz. Encyclopedic Reference of Parasitology. Second Edition. Germany: Springer. 2001. Pawlowski, Zbigniew S. "Intestinal Helminthiases and Human Health: Recent Advances and Future Needs." Parasitic Disease Programme, WHO. 1987. Rim, Han-Jong et al. "Antihelminthic Effects of Various Drugs against Metagonimiasis." Korean Journal of Parasitology. Vol. 16: 117–122. 1978. Rim, Han-Jong. "Classification and host specificity of Metagonimus spp. from Korean freshwater fish." Korean Journal of Parasitology. Vol. 34: 7-14. 1996. Shin, Eun-Hee et al. "Trends in parasitic diseases in the Republic of Korea." Trends in Parasitology. Vol. 24: 143–150. 2008. "The Medical Letter." Drugs for Parasitic Infections. 2005. www.medicalletter.org/parasitic_cdc. Uppal, B. and V. Wadhwal. "Rare Case of Metagonimus Yokogawai." Indian Journal of Medical Microbiology. Vol. 23: 61–62. 2005. WHO/FAO. "Food-Borne Trematode Infections in Asia." Ha Noi, Vietnam, 2002. WHO. "Integrated Guide to Sanitary Parasitology." Jordan, 2004. WHO. "Review on the Epidemiological Profile of Helminthes and their Control in the Western Pacific region, 1997-2008." 2006. Yamada, Shoko Merrit et al. "A Case of Metagonimiasis Complicated with Multiple Intracerbral Hemorrhages and Diabetes Mellitus." Journal of Nippon Medical School. 2008. ## External links[edit] Classification D * ICD-10: B66.8 * ICD-9-CM: 121.5 * Metagonimiasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Metagonimiasis	c0025530	2,277	wikipedia	https://en.wikipedia.org/wiki/Metagonimiasis	2021-01-18T18:57:57	{"gard": ["9745"], "mesh": ["D014201"], "umls": ["C0025530"], "wikidata": ["Q11542703"]}
Antley Bixler syndrome is a rare condition that is primarily characterized by craniofacial abnormalities and other skeletal problems. The signs and symptoms vary significantly from person to person but may include craniosynostosis; midface hypoplasia (underdeveloped middle region of the face); frontal bossing; protruding eyes; low-set, unusually-formed ears; choanal atresia or stenosis (narrowing); fusion of adjacent arm bones (synostosis); joint contractures; arachnodactyly; bowing of the thigh bones; and/or urogenital (urinary tract and genital) abnormalities. The exact underlying cause of Antley Bixler syndrome is unknown in many cases; however, some are due to changes (mutations) in the FGFR2 gene or the POR gene. There appear to be autosomal dominant and autosomal recessive forms of the condition. Treatment is based on the signs and symptoms present in each person. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Antley Bixler syndrome	c2936791	2,278	gard	https://rarediseases.info.nih.gov/diseases/5826/antley-bixler-syndrome	2021-01-18T18:02:05	{"mesh": ["D054882"], "omim": ["201750", "207410"], "orphanet": ["83"], "synonyms": ["Trapezoidocephaly synostosis syndrome", "Multisynostotic osteodysgenesis with long bone fractures", "Osteodysgenesis, multisynostotic with fractures"]}
A number sign (#) is used with this entry because Pallister-Killian syndrome (PKS) is a dysmorphic condition caused by mosaicism for tetrasomy of chromosome 12p. Description Pallister-Killian syndrome is a dysmorphic condition involving most organ systems, but also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987). Clinical Features Schinzel (1991) reviewed the clinical and cytogenetic features of the Pallister-Killian syndrome. Clinical features include profound mental retardation, seizures, streaks of hypo- or hyper-pigmentation, and facial anomalies, including prominent forehead with sparse anterior scalp hair, flat occiput, hypertelorism, short nose with anteverted nostrils, flat nasal bridge, and short neck. At birth, affected the infants have temporofrontal balding or sparseness, which, together with the abundant hair over the top of the head, gives a pattern like that of Iroquois Indians. This pattern disappears later if the child continues to have abnormal hair. Zakowski et al. (1992) described absence of the pericardium and focal aplasia cutis in the axillary area in PKS. Mauceri et al. (2000) reported a 15-year-old girl with Pallister-Killian syndrome and pineal tumor. They pointed out that isochromosome 12p is a frequent cytogenetic marker of germ cell tumors (testicular and ovarian) and has been observed in pineal germ cell tumors (de Bruin et al., 1994). Genevieve et al. (2003) described an unusual case of i(12p) in a 15-year-old boy who had mild mental retardation, minor facial features, normal weight, length, and cranial measurements, as well as hyperpigmented streaks. The boy attended normal school until the age of 14 years. Because of the hyperpigmented streaks, chromosome analysis was performed on skin fibroblasts, which showed 37% of cells had an additional isochromosome for the short arm of chromosome 12. Yeung et al. (2009) reported a girl with PKS who was referred at age 7 months for developmental delay and dysmorphic features. She had temporal alopecia, periorbital fullness, ptosis, nystagmus, wide mouth, long philtrum, and cleft palate. Other features included single palmar creases, bilateral accessory nipples, small hands and feet with dorsal edema, and hypoplasia of the labia with a common anal and vaginal opening. She had delayed growth parameters, moderate hypotonia, and global developmental delay. Although considerable developmental progress was achieved over the ensuing year, including gross motor skills and ability to stand and vocalize, this progression did not continue after 2 years. FISH analysis detected a supernumerary ring chromosome in 38% of buccal mucosa cells and 41% of skin fibroblasts, but did not detect the abnormality in blood cells. In this patient, tetrasomy 12p resulted from a ring chromosome containing 2 copies of chromosome 12p13-cen, not the usual i(12p). Yeung et al. (2009) postulated that the more advanced developmental progress in this patient compared to patients with typical PKS may have resulted from a smaller tetrasomic segment or different tissue distribution of the ring chromosome. Tissue distribution would be expected to differ if the ring chromosome arose during a postzygotic mitotic division, rather than at meiosis, as is typical for isochromosome PKS. Blyth et al. (2015) reported the clinical features of 22 living patients with Pallister-Killian syndrome in a population-based study in Great Britain. The patients ranged in age from 4 months to 31 years, although half were under 5 years of age. There was a statistically significant increase in the risk of the disorder with increasing parental age. There was not an excess of high birth weights, and all patients were within 2.67 SD of the mean. All patients except the 4-month-old baby showed some degree of global developmental delay, and most were unable to communicate verbally. However, 27.3% had only mild or moderate intellectual disability. Common features included neonatal hypotonia with feeding difficulties, scoliosis, early-onset seizures, hearing impairment, and visual anomalies, such as myopia or strabismus. As babies, all had absent frontotemporal hair which gradually improved with age. Most continued to have areas of alopecia or other hair abnormalities, such as sparse or thick eyebrows. Dysmorphic facial features were common but variable, and included slanted palpebral fissures, short nose with anteverted nares, long philtrum, tented lip, low-set ears, micrognathia, prognathia, delayed tooth eruption, and overall coarse facial features. Additional features included accessory nipples (43%), short broad hands (57%), pigmentary skin lesions (67%), limb shortening (24%), anhidrosis or hypohidrosis (40%), hyperventilation (23%), and autistic features (27%). There was no suggestion of a genotype/phenotype correlation on any tissue examined. Two individuals (9.1%) had hexasomy of chromosome 12p. ### Pallister-Killian Syndrome Due to Hexasomy of Chromosome 12p Vogel et al. (2009) reported a 5-year-old girl with PKS resulting from mosaicism for 2 supernumerary isochromosomes, or hexasomy 12p. Polyhydramnios, preaxial polydactyly, and congenital heart disease were detected at 36 weeks' gestation. After birth, she was noted to have a large nuchal fold, sparse woolly hair, frontal bossing, micrognathia, hypertelorism, large low-set ears, broad nose, anteverted nostrils, long philtrum, high palate, nail hypoplasia, and atypical palmar creases. She also had hearing deficit and hypermetropia. She was hypotonic, and motor skills were delayed, and she was not able to stand at age 24 months due to hip dystrophy. At 4 months of age, she had poor growth parameters, hypertrophic cardiomyopathy with an ejection fraction of 30%, bilateral inguinal hernias, and hypopigmented streaks with dry skin. By 5 years of age she had only a mild developmental delay, with an IQ of 81. Analysis of cultured skin fibroblasts with FISH and comparative genomic hybridization showed hexasomy 12p in 18% of cells. Vogel et al. (2009) noted that this was the second second live case of mosaicism for hexasomy 12p to be reported; the first being that of Choo et al. (2002) in a 2-year-old girl with coarse facies, mental and motor retardation, cleft palate, rhizomelic shortening of limbs, and a diaphragmatic hernia, due to 35% tetrasomy and 15% hexasomy 12p. Vogel et al. (2009) suggested that phenotypic variation in PKS is most likely a result of which tissue types carry the mosaic cell line more than the percentage of mosaic cells or gene-dosage effects. Cytogenetics Peltomaki et al. (1987) used a probe of the KRAS2 gene (190070) to confirm that the extra chromosome in Pallister-Killian syndrome is composed of 2 short arms of chromosome 12. Hunter et al. (1985) used LDHB (150100) for the same purpose. Peltomaki et al. (1987) showed that the 2 short arms are identical, thus indicating that it represents an isochromosome 12p. Peltomaki et al. (1987) reported findings that may explain the mechanism of origin of the tissue-limited mosaicism: the proportion of abnormal mitoses fell dramatically during long-term culture of fibroblasts. See also Zhang et al. (1989). Wenger et al. (1990) concluded that the tissue-specific mosaicism in the 12p isochromosome syndrome is best explained by in vivo and perhaps also in vitro loss of the isochromosome from 47,XY (or XX), plus i(12p) cells. Cormier-Daire et al. (1997) used microsatellite DNA markers on 12p alleles of maternal origin in cultured skin fibroblasts of a case of PKS. The findings suggested that the tetrasomy 12p was the result of a prezygotic event, with a nondisjunction event during maternal meiosis. Schubert et al. (1997) reported 2 cases of Pallister-Killian syndrome in which the distribution of the additional isochromosome of 12p was analyzed in various tissues. One case, diagnosed prenatally, showed mosaicism for i(12p) in chorionic villi and in amniocytes but the isochromosome was absent in cultured lymphocytes of fetal blood taken at 21 weeks. Long-term culture of umbilical cord showed the isochromosome in 100% of metaphases. In the second case of a term infant, the i(12p) was diagnosed in cultured lymphocytes (4%) and fibroblasts (93%). Secondary loss of the isochromosome was demonstrated in the second case by analyzing metaphases and interphases of fibroblasts in the first, fourth, and fifth subculture using fluorescence in situ hybridization. The proportion of cells with the isochromosome decreased from 93% to 40% and then to 28%, respectively. DNA analysis in case 1 showed a maternal meiotic origin of the i(12p). In case 1, the mother was 44 and the father was 54 years old. Ultrasonography showed flat profile, diaphragmatic hernia, and enlargement of the fourth cerebral ventricle. The infant was stillborn at 27 weeks. Diagnosis Speleman et al. (1991) used fluorescence in situ hybridization with chromosome 12-specific DNA probes for the rapid and reliable detection of the i(12p) chromosome. Detection was possible also in interphase cells. Ohashi et al. (1993) used interphase fluorescence in situ hybridization with a chromosome 12-specific alpha satellite probe for diagnosis of PKS in buccal mucosal cells. Isochromosome 12p-positive cells showed 3 signals over the nucleus, while diploid cells had 2 signals. ### Prenatal Diagnosis Soukup and Neidich (1990) made the diagnosis of Pallister-Killian syndrome on routine amniocentesis. In the aborted fetus, various degrees of mosaicism were found in 4 tissues. Thakur et al. (2019) reviewed the prenatal findings associated with Pallister-Killian syndrome. Prenatal diagnosis was usually incidentally made by karyotyping and performed because of advanced maternal age, increased nuchal translucency thickness, or fetal anomaly. The most frequent and distinctive prenatal findings were rhizomelic limb shortening, diaphragmatic hernia, thickened nuchal fold, increased prenasal thickness, postaxial polydactyly, and polyhydramnios. Other findings included a flat facial profile, congenital diaphragmatic hernia, cardiac malformations, and intrauterine growth retardation. Gestational age at diagnosis varied from 13 to 32 weeks. Cytogenetic studies most commonly showed a supernumerary marker isochromosome 12p in a mosaic state, with maternal meiosis II nondisjunction as a mechanism. The recommended sample for testing prenatally is amniotic fluid, since cytogenetic diagnosis on chorionic villi can be misleading. The authors recommended a microarray on uncultured amniocytes, with a karyotype on amniotic fluid. All reported cases have been sporadic. Population Genetics In a population-based study in Great Britain, Blyth et al. (2015) estimated the birth incidence of Pallister-Killian syndrome to be 5.1 per million live births. History This syndrome was independently reported by Pallister et al. (1977) and Teschler-Nicola and Killian (1981) because of the characteristic combination of clinical manifestations, especially the combination of coarse face, pigmentary skin anomalies, localized alopecia, profound mental retardation and seizures, and the relatively frequent occurrence of diaphragmatic defects and supernumerary nipples. The presence of tetrasomy 12p was not recognized because chromosomal studies of fibroblasts were not done. In fact, according to Pallister (2003), chromosome studies of fibroblasts were performed by his colleague Lorraine Meisner, but the anonymous chromosome was misinterpreted. INHERITANCE \- Somatic mosaicism GROWTH Height \- Normal to increased birth length \- Postnatal deceleration of length Weight \- Normal to increased birth weight \- Obesity HEAD & NECK Head \- Normal to increased head circumference \- Postnatal deceleration of head circumference \- Prominent forehead Face \- Coarse facial features over time \- Full cheeks \- Long philtrum \- Micrognathia Ears \- Deafness \- Large ears \- Protruding lobules \- External auditory canal stenosis Eyes \- Sparse eyebrows \- Sparse eyelashes \- Upslanting palpebral fissures \- Hypertelorism \- Ptosis \- Strabismus \- Myopia \- Epicanthal folds \- Cataracts \- Exophthalmos Nose \- Flat, broad nasal root \- Short nose \- Anteverted nostrils Mouth \- Thin upper lip \- 'Cupid-bow' lip \- Protruding lower lip \- Macroglossia \- Prominent lateral palatine ridges \- Cleft palate \- Bifid uvula Teeth \- Delayed dental eruption Neck \- Short neck \- Webbed neck CARDIOVASCULAR Heart \- Pericardial agenesis \- Aortic stenosis \- Ventricular septal defect \- Atrial septal defect \- Hypertrophic cardiomyopathy Vascular \- Patent ductus arteriosus \- Coarctation of the aorta RESPIRATORY \- Hyperventilation Lung \- Lung hypoplasia CHEST Breasts \- Accessory nipples Diaphragm \- Diaphragmatic hernia ABDOMEN External Features \- Umbilical hernia \- Omphalocele Gastrointestinal \- Feeding difficulties \- Intestinal malrotation \- Imperforate anus \- Anal atresia \- Anal stenosis \- Anteriorly placed anus GENITOURINARY \- Persistence of urogenital sinus/cloaca External Genitalia (Male) \- Inguinal hernia \- Small scrotum \- Hypospadias External Genitalia (Female) \- Hypoplasia of labia majora Internal Genitalia (Male) \- Cryptorchidism Internal Genitalia (Female) \- Absent upper vagina \- Absent uterus Kidneys \- Cystic kidneys \- Dysplastic kidneys SKELETAL Spine \- Kyphoscoliosis \- Sacral appendage Pelvis \- Congenital hip dislocation Limbs \- Hypermobile joints \- Contractures develop with age \- Mesomelic/rhizomelic limb shortening Hands \- Broad hands \- Fifth finger clinodactyly \- Short fingers \- Distal digital hypoplasia \- Postaxial polydactyly \- Transverse palmar creases Feet \- Broad feet \- Postaxial polydactyly \- Short toes SKIN, NAILS, & HAIR Skin \- Hypopigmented streaks \- Hyperpigmented streaks \- Transverse palmar creases \- Hypohidrosis \- Anhidrosis Hair \- Sparse anterior scalp hair \- Sparse eyebrows \- Sparse eyelashes NEUROLOGIC Central Nervous System \- Profound mental retardation (in some patients) \- Intellectual disability \- Seizures \- Hypotonia (newborn) \- Hypertonia (older children and adolescents) \- Contractures (older children and adolescents) LABORATORY ABNORMALITIES \- Mosaic tetrasomy 12p in skin fibroblasts \- Isochromosome often missing in lymphocyte MISCELLANEOUS \- Significant number of patients are stillborn or die in neonatal period \- Birth incidence approximately 5.1 per million live births MOLECULAR BASIS \- Contiguous gene syndrome caused by mosaicism for tetrasomy of chromosome 12p ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PALLISTER-KILLIAN SYNDROME	c0265449	2,279	omim	https://www.omim.org/entry/601803	2019-09-22T16:14:21	{"mesh": ["C538105"], "omim": ["601803"], "orphanet": ["884"], "synonyms": ["Alternative titles", "TETRASOMY 12p, MOSAIC", "ISOCHROMOSOME 12p SYNDROME"]}
Congenital muscular dystrophy (CMD) refers to a group of inherited conditions that affect the muscles and are present at birth or in early infancy. The severity of the condition, the associated signs and symptoms and the disease progression vary significantly by type. Common features include hypotonia; progressive muscle weakness and degeneration (atrophy); joint contractures; and delayed motor milestones (i.e. sitting up, walking, etc). CMD can be caused by a variety of different genes. Most forms are inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each person. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Congenital muscular dystrophy	c0699743	2,280	gard	https://rarediseases.info.nih.gov/diseases/9138/congenital-muscular-dystrophy	2021-01-18T18:01:08	{"umls": ["C0699743"], "orphanet": ["97242"], "synonyms": ["Congenital MD", "CMD", "MDC"]}
A number sign (#) is used with this entry because Lesch-Nyhan syndrome is caused by mutation in the HPRT gene (308000), encoding hypoxanthine guanine phosphoribosyltransferase, on chromosome Xq26. Clinical Features The features of the Lesch-Nyhan syndrome are mental retardation, spastic cerebral palsy, choreoathetosis, uric acid urinary stones, and self-destructive biting of fingers and lips. Megaloblastic anemia has been found in some patients (van der Zee et al., 1968). Virtually complete deficiency of HPRT residual activity (less than 1.5%) is associated with the Lesch-Nyhan syndrome, whereas partial deficiency (at least 8%) is associated with the Kelley-Seegmiller syndrome (300323). LNS is characterized by abnormal metabolic and neurologic manifestations. In contrast, Kelley-Seegmiller syndrome is usually associated only with the clinical manifestations of excessive purine production. Renal stones, uric acid nephropathy, and renal obstruction are often the presenting symptoms of Kelley-Seegmiller syndrome, but rarely of LNS. After puberty, the hyperuricemia in Kelley-Seegmiller syndrome may cause gout. A third group of patients, with 1.5 to 8% of HPRT activity, is associated with a neurologic variant of LNS, with uric acid overproduction and neurologic disability that varies from minor clumsiness to debilitating extrapyramidal and pyramidal motor dysfunction (Jinnah and Friedmann, 2001). Bakay et al. (1979) restudied a patient with HPRT deficiency, choreoathetosis, spasticity, dysarthria, and hyperuricemia, but normal intelligence and no self-mutilation. (A maternal uncle had been identically affected.) Although HPRT deficiency seemed to be complete, cultured fibroblasts had some capacity for metabolism of hypoxanthine and guanine. Page et al. (1987) described 2 brothers and 2 of their maternal uncles who had HPRT deficiency as the cause of mild mental retardation, spastic gait, and pyramidal tract sign. They were, furthermore, short of stature with proximally placed thumbs and fifth finger clinodactyly. Activity of the enzyme was virtually zero in lysates of red cells or hair roots, but in intact fibroblasts the level of activity was 7.5% of normal. Kinetic studies also demonstrated differences. A sister of the brothers was, by enzyme assay, heterozygous. One of the affected uncles had advanced tophaceous gout by age 32 years. ### Clinical Variability Hladnik et al. (2008) reported a family in which 5 individuals carrying the same splice site mutation in the HPRT gene showed marked phenotypic variability resulting from HPRT deficiency. One patient had classic Lesch-Nyhan syndrome with delayed development, spasticity, dystonia, and self-injurious behavior. Two patients had an intermediate phenotype with mild cognitive and learning difficulties, dystonia, and increased uric acid, but no self-injurious behavior, and 2 had mild spasticity, gout, and normal IQ. Hladnik et al. (2008) postulated that each individual had various expression of the mutant and wildtype transcript, and emphasized that individuals with the same genotype may not necessarily have the identical phenotype. Sarafoglou et al. (2010) reported a 3-generation family in which 3 individuals carrying the same missense mutation in the HPRT1 gene showed phenotypic variability. The proband presented at age 14.5 months with increased uric acid levels and later showed mildly delayed development. His cousin was diagnosed at age 26 months, and had mild generalized hypotonia, delayed motor development, focal dystonia of the lower limbs, and mild developmental impairment with speech delay. The boys' 65-year-old grandfather was more severely affected, with borderline cognitive function, severe dyslexia, spasticity, and flexion contractures leading to motor impairment. He had a long history of gout, nephrolithiasis, and progressive renal dysfunction. Medical history revealed that his symptoms had been attributed to cerebral palsy due to perinatal asphyxia. Enzymatic studies of cultured fibroblasts showed decreased activity in the proband, more severely decreased activity in the cousin, and the most severely decreased activity in the grandfather, consistent with their phenotypes. Cells from the grandfather grew more slowly than those from the grandchildren and appeared less robust. Biochemical Features A 200-fold increase in the conversion of C(14)-labeled glycine to uric acid was observed by Nyhan et al. (1965). Seegmiller et al. (1967) demonstrated deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). That the enzyme deficiency resulted in excessive purine synthesis suggested that the enzyme (or the product of its function) normally plays a controlling role in purine metabolism. Resistance to 8-azaguanine in cultured diploid human fibroblasts was induced by x-ray in pioneer experiments (Albertini and DeMars, 1973). Mutation in the HPRT gene is the basis for this resistance. Lesch-Nyhan cells are resistant to 8-azaguanine. Upchurch et al. (1975) found a normal amount of cross-reacting material in 1 of 12 patients with HPRT deficiency. The others had less than 3% of the normal amount. Ghangas and Milman (1975) confirmed this by another method. Wilson et al. (1986) analyzed cell lines of 24 patients with HPRT deficiency at the levels of residual protein, mRNA, and DNA. At least 16 patients had unique mutations of the HPRT gene. Most cell lines had normal quantities of mRNA but undetectable quantities of enzyme. Eight of the patients retained significant quantities of structurally altered but functionally abnormal HPRT enzyme variants. A minority of patients lacked both enzyme and mRNA. Fu et al. (2015) created fibroblast cultures for 21 healthy controls and 36 patients with a broad spectrum of disease severity, including Lesch-Nyhan syndrome, related to HGPRT deficiency. The authors assessed hypoxanthine recycling, guanine recycling, steady-state purine pools, and de novo purine synthesis. There was a strong correlation between disease severity and either hypoxanthine or guanine recycling. Intracellular purines were normal in the HGPRT-deficient fibroblasts, but purine wasting was evident as increased purine metabolites excreted from cells. The normal intracellular purines in the HGPRT-deficient fibroblasts were likely due in part to a compensatory increase in purine synthesis, as demonstrated by a significant increase in purinosomes. However, the increase in purine synthesis did not appear to correlate with disease severity. Inheritance X-linkage was first suggested by Hoefnagel et al. (1965) and was supported by a rapidly accumulated series of families with deficiency of HPRT. Rosenbloom et al. (1967) and Migeon et al. (1968) demonstrated 2 populations of fibroblasts, as regards the relevant enzyme activity, in heterozygous females, thus providing support both for X-linkage and for the Lyon hypothesis. Studies using human-mouse somatic cell hybrids indicate, by reasoning similar to that used for locating the thymidine kinase locus to chromosome 17 (188300), that the HPRT locus is on the X chromosome (Nabholz et al., 1969). Mosaicism can be demonstrated by study of hair roots in women heterozygous for the Lesch-Nyhan syndrome (Silvers et al., 1972). Francke et al. (1976) studied the frequency of new mutations among affected males. The Lesch-Nyhan syndrome is particularly favorable for this purpose because no affected males reproduce, the diagnosis is unequivocal and cases come readily to attention, and particularly because heterozygosity can be demonstrated in females by the existence of 2 populations of cultured fibroblasts. There were few new mutations, contrary to the expected one-third. On the other hand, about one-half of heterozygous females were new mutations, as is predicted by theory. The finding may indicate a higher frequency of mutation in males than in females. Another possibility is the role of somatic and half-chromatid mutations (Gartler and Francke, 1975). New mutation cases of heterozygous females had elevated parental age. Vogel (1977) reviewed the evidence concerning hemophilia and the Lesch-Nyhan syndrome leading to the conclusion that the mutation rate is higher in males than in females. Evidence that the mutation rate for the Lesch-Nyhan disease may be higher in males than in females was reviewed by Francke et al. (1976) and criticized by Morton and Lalouel (1977). Francke et al. (1977) answered the criticism. Strauss et al. (1980) showed that females heterozygous for the Lesch-Nyhan mutation have 2 populations of peripheral blood lymphocytes with regard to sensitivity to 6-thioguanine inhibition of tritiated thymidine incorporation following phytohemagglutinin stimulation. Henderson et al. (1969) concluded that the locus for HPRT is closely linked to the Xg (314700) locus; Greene et al. (1970) concluded, however, that the HPRT and Xg loci 'are sufficient distance from each other on the human X chromosome that linkage cannot be detected.' Nyhan et al. (1970) observed a sibship in which both HPRT deficiency and G6PD deficiency (300908) were segregating and found 2 of 4 recombinants. Nyhan et al. (1970) also found that heterozygotes had normal levels of HPRT in red cells. They interpreted this as indicating a selective advantage of G6PD-normal over G6PD-deficient cells. (In adrenoleukodystrophy (300100), it is the mutant cell that enjoys the selective advantage.) Yukawa et al. (1992) described a seemingly typical case of Lesch-Nyhan syndrome in a female with a normal karyotype. The parents were nonconsanguineous. In addition to unusual lyonization, uniparental disomy is a possible explanation. Pathogenesis ### Pathogenesis of Mental Retardation and Self-injurious Behavior Wong et al. (1996) discussed 3 lines of evidence that had suggested that HPRT deficiency is associated with abnormal dopamine (DA) function in LNS: (1) an autopsy study of 3 LNS subjects demonstrated a marked reduction in the DA content and in the activity of DNA-synthesizing enzymes in the caudate and putamen (Lloyd et al., 1981); (2) when neonatal rats are depleted of DA with the neurotoxin 6-hydroxydopamine, self-injurious behavior, similar to that seen in LNS, occurred when the rats were challenged with 3,4-dihydroxyphenylalanine (L-DOPA) as adults (Breese et al., 1990); and (3) in an HPRT-deficient mutant mouse strain, there is a reduction of striatal tyrosine hydroxylase and in the number of striatal dopamine transporters (Jinnah et al., 1994). To establish that DA deficiency is present in LNS, Wong et al. (1996) used a ligand that binds to DA transporters to estimate the density of DA-containing neurons in the caudate and putamen of 6 subjects with classic LNS. They made comparisons with 10 control subjects and 3 patients with Rett syndrome (312750). Depending on the method of analysis, a 50 to 63% reduction of the binding to DA transporters in the caudate and a 64 to 75% reduction in the putamen of LNS patients was observed compared to the normal control group; similar reductions were found between Rett syndrome and LNS patients. Volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LNS patients. To ensure that a reduction in the caudate volume would not confound the results, Wong et al. (1996) performed a rigorous partial volume correction of the caudate time activity curve. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LNS patients when contrasted to controls. Ernst et al. (1996) concluded that patients with Lesch-Nyhan disease have abnormally few dopaminergic nerve terminals and cell bodies. The abnormality involves all dopaminergic pathways and is not restricted to the basal ganglia. These dopaminergic deficits are pervasive and appear to be developmental in origin, which suggested that they contribute to the characteristic neuropsychiatric manifestations of the disease. These studies were done with positron-emission tomography (PET) with the tracer fluorodopa-F18. This tracer, an analog of dopa, is a large, neutral amino acid that is transported into presynaptic neurons, where it is converted by the enzyme dopa decarboxylase (107930) into fluorodopamine F18, which subsequently enters catecholamine-storage vesicles. Hence, data obtained with the use of fluorodopa-F18 and PET reflect dopa decarboxylase activity and dopamine-storage processes. In an accompanying editorial, Nyhan and Wong (1996) commented on the new findings and reviewed the normal function of HPRT with a diagram. Ceballos-Picot et al. (2009) demonstrated that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient sublines derived from the hybrid MN9D cell line, derived from somatic fusion of embryonic mouse primary midbrain dopaminergic neurons with a mouse neuroblastoma line. There were consistent increases in mRNAs for engrailed-1 (EN1; 131290) and -2 (EN2; 131310), transcription factors known to play a role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels. The functional relevance of the abnormal developmental molecular signature of the HPRT-deficient MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. These abnormalities were also seen in HPRT-deficient sublines from the SK-N-BE(2)-M17 human neuroblastoma line, and overexpression of engrailed was documented in primary fibroblasts from patients with Lesch-Nyhan disease. Ceballos-Picot et al. (2009) concluded that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms. Cristini et al. (2010) examined the effect of HPRT deficiency on the differentiation of neurons in human neural stem cells (NSCs) isolated from human Lesch-Nyhan disease fetal brain. LNS NSCs demonstrated aberrant expression of several transcription factors and DA markers, and HPRT-deficient dopaminergic neurons demonstrated a striking deficit in neurite outgrowth. Exposure of the LNS NSCs to retinoic acid medium elicited the generation of dopaminergic neurons. The authors concluded that neurogenesis is aberrant in LNS NSCs and suggested a role for HPRT in neurodevelopment. Diagnosis ### Prenatal Diagnosis Fujimoto et al. (1968) presented evidence that the disease can be recognized in the fetus well before 20 weeks, i.e., within the limit for elective abortion. The method used was an autoradiographic test for HPRT activity, applied to cells obtained by amniocentesis. Boyle et al. (1970) made the prenatal diagnosis and performed therapeutic abortion. Gibbs et al. (1984) showed that by ultramicroassay of HPRT it is possible to diagnose the Lesch-Nyhan syndrome on the basis of chorionic villi sampled at 8-9 weeks of gestation. Graham et al. (1996) investigated 15 pregnancies at risk for Lesch-Nyhan syndrome between 8 and 17 weeks' gestation by measurement of HPRT and APRT (102600) enzyme activities in chorionic villus samples (cultured and uncultured) or in cultured amniotic fluid cells. Ten pregnancies had normal enzyme levels and a normal outcome, while a further 2 predicted to be normal miscarried later in the pregnancy. Three pregnancies had low levels of residual HPRT activity in chorionic villi. Comparable levels of residual activity in the index case in 2 pregnancies and in cells from the abortus in the third case confirmed that the pregnancies were indeed affected. Molecular Genetics For a discussion of the molecular defects involved in Lesch-Nyhan syndrome, see the HPRT1 gene (308000). Genotype/Phenotype Correlations There is variable disease severity in patients with Lesch-Nyhan syndrome, with an inverse relationship between HPRT1 enzyme activity measured in intact cells and clinical severity. Patients with classic Lesch-Nyhan disease, the most severe and frequent form, have the lowest HPRT enzyme activity (less than 1.5% of normal) in intact cultured fibroblasts. Patients with partial HPRT deficiency, designated as Lesch-Nyhan variants, have HPRT1 enzyme activity ranging from 1.5 to 8.0%. Individuals with an intermediate variant form known as the 'neurologic variant' are neurologically indistinguishable from patients with Lesch-Nyhan disease, but they do not have self-injurious behaviors and intelligence is normal or near-normal. The least-affected patients with the variant form have residual HPRT1 enzyme activity exceeding 8%; their only manifestations are attributed to hyperuricemia, and include gout, hematuria, and nephrolithiasis (summary by Sarafoglou et al., 2010). History Lesch and Nyhan (1964) described the disorder that bears their names on the basis of 2 brothers. Nyhan (1997) gave an account of the recognition of the syndrome as an inborn error of purine metabolism. Preston (2007) provided a popular description of the discovery of the disorder and what the study of a rare disorder such as this can tell us about human behavior. INHERITANCE \- X-linked recessive GROWTH Height \- Short stature Other \- Growth retardation ABDOMEN Gastrointestinal \- Vomiting GENITOURINARY External Genitalia (Male) \- Testicular atrophy Kidneys \- Nephrolithiasis SKELETAL Feet \- Gout SKIN, NAILS, & HAIR Skin \- Uric acid tophi NEUROLOGIC Central Nervous System \- Motor delay \- Hypotonia \- Self-injurious behavior, median onset age 2 years \- Extrapyramidal signs \- Choreoathetosis \- Dystonia \- Basal ganglia dysfunction \- Spasticity, hyperreflexia \- Opisthotonus \- Dysarthria \- Dysphagia \- Mental retardation (IQ 45-75) HEMATOLOGY \- Anemia \- Megaloblastic anemia LABORATORY ABNORMALITIES \- Hyperuricemia \- Hyperuricosuria MISCELLANEOUS \- Classic Lesch-Nyhan, < 1.5% hypoxanthine phosphoribosyltransferase (HPRT) activity \- Variant Lesch-Nyhan, 1.5-8% HPRT activity with neurologic abnormalities, but no self-injurious behavior MOLECULAR BASIS \- Caused by mutation in the hypoxanthine phosphoribosyltransferase gene (HPRT1, 308000.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	LESCH-NYHAN SYNDROME	c0023374	2,281	omim	https://www.omim.org/entry/300322	2019-09-22T16:20:36	{"doid": ["1919"], "mesh": ["D007926"], "omim": ["300322"], "icd-10": ["E79.1"], "orphanet": ["510"], "synonyms": ["Alternative titles", "HYPOXANTHINE GUANINE PHOSPHORIBOSYLTRANSFERASE 1 DEFICIENCY", "HPRT1 DEFICIENCY", "HPRT DEFICIENCY", "HPRT DEFICIENCY, COMPLETE"], "genereviews": ["NBK1149"]}
Autosomal dominant craniometaphyseal dysplasia is a genetic skeletal condition characterized by progressive thickening of bones in the skull (cranium) and abnormalities at the ends of long bones in the limbs (metaphyseal dysplasia). The overgrowth of bones in the head can lead to distinctive facial features and delayed tooth eruption, as well as compression of the cranial nerves. If untreated, compression of the cranial nerves can be disabling. The condition is caused by mutations in the ANKH gene. As the name suggests, it is inherited in an autosomal dominant manner. Treatment may include surgery to reduce compression of cranial nerves and recontouring of the facial bones. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Craniometaphyseal dysplasia, autosomal dominant	c1852502	2,282	gard	https://rarediseases.info.nih.gov/diseases/1581/craniometaphyseal-dysplasia-autosomal-dominant	2021-01-18T18:01:04	{"mesh": ["C565145"], "omim": ["123000"], "orphanet": ["1522"], "synonyms": ["CMDJ", "CMDD", "Craniometaphyseal dysplasia Jackson type", "CMD"]}
A genodermatosis characterized by the presence of multiple hamartomas in various tissues and an increased risk for malignancies of the breast, thyroid, endometrium, kidney and colorectum. When CS is accompanied by germline PTEN mutations, it belongs to the PTEN hamartoma tumor syndrome (PHTS) group. ## Epidemiology Cowden syndrome (CS) CS has been described in many ancestral groups. The prevalence is unknown but is estimated at 1/200,000. ## Clinical description Disease manifestations usually occur between the second and third decades of life but can appear at any age. The most commonly, but not uniformly, reported manifestations are macrocephaly (specifically, megencephaly), mucocutaneous lesions, thyroid abnormalities, fibrocystic disease and carcinoma of the breast, gastrointestinal hamartomas, multiple early onset uterine leiomyomas, and developmental delay. Macrocephaly and rarely dysmorphic facies, if present, are evident at birth. Malignancies such as breast cancer (with an 85% lifetime risk), epithelial thyroid cancer, renal cancer and endometrial carcinoma often appear later in life. Clinicians should consider other red flags of a CS diagnosis which includes; Lhermitte‐Duclos disease (dysplastic cerebellar gangliocytoma), pathognomonic of CS. Mucocutaneous stigmata such as trichilemmomas and papillomatous papules (believed to exist in 100% of CS patients by age 30). Ganglioneuromatous gastrointestinal polyps. Glycogenic acanthosis.Pediatric differentiated (non-medullary) thyroid cancer and endometrial cancer diagnosed relatively early. ## Etiology It is now believed that 25% of CS and CS-like cases are caused by germline mutations in PTEN (10q23), which encodes a dual-specificity phosphatase. Patients with CS/CS-like phenotypes that do not have PTEN involvement have been found to have germline promoter methylation of KLLN (up to 30%), germline variations in SDHB-D (10%), or germline mutations in AKT1 and PIK3CA (10%). More recently, germline SEC23B and USF3 were identified in PTEN wildtype CS/CS-like patients with differentiated thyroid cancer as a predominant phenotype. ## Diagnostic methods The International Cowden Consortium for CS lists the pathognomonic (mucocutaneous lesions, LDD), major (breast cancer, macrocephaly, thyroid cancer and endometrial cancer), and minor criteria used to diagnose this disease. An operational diagnosis is given if a patient displays the pathognomonic skin lesions, two or more major, one major and 3 or more minor, or 4 or more minor criteria. A quantitative scoring system for adults and a separate pediatric criteria system have now been created to aid clinicians at the point of care. Finding germline mutations in PTEN or other causal genes confirms diagnosis. ## Differential diagnosis Juvenile-polyposis syndrome, Peutz-Jeghers syndrome, Birt-Hogg-Dubé syndrome, Gorlin syndrome and neurofibromatosis type 1. ## Antenatal diagnosis Antenatal diagnosis is possible for at-risk pregnancies if the disease-causing mutation is discovered in an affected family member. ## Genetic counseling CS is inherited autosomal dominantly. Genetic counseling can be offered to patients with germline PTEN mutations and asymptomatic family members should also be tested so that those with a mutation can be monitored before symptom onset. ## Management and treatment Management and treatment are multidisciplinary and based on genotype. Once a PTEN germline mutation is identified, surveillance guidelines should be followed. Thyroid ultrasound should begin once a mutation is identified, starting at the age of 7. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35. ## Prognosis The pinpointing of the diagnosis (especially by gene) and instituting organ-specific surveillance at the right time results in a good prognosis. When advanced cancers occur before diagnosis is made, a poor outcome is common. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Cowden syndrome	c0018553	2,283	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=201	2021-01-23T17:01:47	{"gard": ["6202"], "mesh": ["D006223"], "omim": ["158350", "612359", "615106", "615107", "615108", "615109", "616858"], "umls": ["C0018553"], "icd-10": ["Q85.8"], "synonyms": ["Cowden disease", "Multiple hamartoma syndrome"]}
A rare skin disease belonging to the spectrum of autoinflammatory syndromes characterized by the triad of pyoderma gangrenosum (PG), suppurative hidradenitis (SH) and acne. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Pyoderma gangrenosum-acne-suppurative hidradenitis syndrome	None	2,284	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=289478	2021-01-23T17:22:42	{"synonyms": ["PASH syndrome"]}
A number sign (#) is used with this entry because of evidence that familial cylindromatosis is caused by heterozygous mutation in the CYLD gene (605018) on chromosome 16q12. See also Brooke-Spiegler syndrome (BRSS; 605041) and multiple familial trichoepithelioma-1 (MFT1; 601606), which are allelic disorders with overlapping phenotypes. Description The disorders classically referred to as familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepithelioma were originally described as distinct clinical entities. Patients with BRSS develop multiple skin appendage tumors including cylindromas, trichoepitheliomas, and spiradenomas. Patients with familial cylindromatosis have only cylindromas, and those with MFT1 have only trichoepitheliomas. However, because these disorders show overlapping phenotypic features, and because different manifestations of each have been described within a single family, many consider these disorders to represent a phenotypic spectrum of a single disease entity (Guggenheim and Schnyder, 1961; Welch et al., 1968; Gerretsen et al., 1995; Lee et al., 2005; Bowen et al., 2005; Young et al., 2006; Saggar et al., 2008). Van Balkom and Hennekam (1994), who preferred the designation 'dermal eccrine cylindromatosis' for familial cylindromatosis, provided a review. 'Eccrine' referred to histologic evidence that the tumors may originate from the eccrine sweat glands. Blake and Toro (2009) provided a detailed review of the spectrum of disorders associated with CYLD mutations. Clinical Features Ancell (1842) and Spiegler (1899) described a familial syndrome characterized by tumors of skin appendages, now known as cylindromas (Lee et al., 2005). Baden (1962) noted that cylindromatosis can clinically resemble neurofibromatosis (NF1; 162200). Welch et al. (1968) presented family data supporting the view that 'Ancell-Spiegler' cylindromas and 'Brooke-Fordyce' trichoepitheliomas were manifestations of a single entity. Harper (1971) provided a dramatic example of cylindromatosis that developed into a 'turban tumor,' covering the scalp. Vernon et al. (1988) described a solitary, apparently benign lung cylindroma in a 42-year-old woman with multiple cutaneous cylindromas. She died from coronary occlusion which occurred precociously in other members of her family, suggesting no connection between the coronary artery disease and the cylindromas. Gerretsen et al. (1995) described a large family in which cutaneous cylindromas occurred in members of 5 generations with 30 affected persons (11 male, 19 female). Trichoepitheliomas and milia were also observed. Female-to-female, female-to-male, male-to-female, and male-to-male inheritance was observed. Penetrance reached 100% in adult life. Poblete Gutierrez et al. (2002) reported a 4-generation German family in which 4 individuals had skin appendage tumors inherited in an autosomal dominant pattern. The eldest affected member, deceased at the time of the report, had turban tumor-like cylindromas of the scalp and nasolabial region confirmed by histologic examination. Small nasolabial tumors from a woman in the third generation showed cylindromas on histology. The youngest family member, in the fourth generation, had cylindromas of the nasolabial region and trichoepitheliomas of the nose and scalp. Poblete Gutierrez et al. (2002) commented on the intrafamilial as well as intraindividual phenotypic variability. Stoll et al. (2004) reported a mother and daughter with familial cylindromatosis. The dermal eccrine cylindroma arose as small solitary lesions in the mother at age 28 years. Other tumors arose, and she had surgery multiple times. The daughter developed lesions on the frontal part of the scalp at age 23 years. Family history revealed that the mother's sister was also affected. Mapping Studying 2 families with cylindromatosis, Biggs et al. (1995) found strong evidence for linkage to chromosome 16q12-q13. There was consistent loss of the wildtype allele near these markers in 19 tumors from 4 individuals, suggesting that the gene was a tumor suppressor gene. Verhoef et al. (1998) studied a large Dutch family in which affected members had originally been given the diagnosis of tuberous sclerosis. Linkage was excluded from both of 2 chromosomal regions involved in tuberous sclerosis complex on 9q34 (TSC1; 191100) and 16p13 (TSC2; 613254). Reevaluation of the clinical and pathologic data led to a change of the working diagnosis to autosomal dominant cylindromatosis. Subsequent linkage analysis showed a lod score of 3.02 with marker D16S308 at chromosome 16q12-q13. Biggs et al. (1996) examined polymorphic markers on each chromosome, some of which are close to known tumor suppressor genes, in 25 tumors from 4 individuals with familial cylindromatosis. No loss of heterozygosity (LOH) was detected other than that at loci on chromosome 16q. They suggested that the candidate gene, which they symbolized CYLD1, may be the only tumor suppressor gene implicated in the development of cylindromas. They also demonstrated LOH using markers on chromosome 16q in 8 of 14 (57%) sporadic cylindromas, indicating that the CYLD gene is probably involved in the genesis of both familial and sporadic cylindromas. Takahashi et al. (2000) evaluated 19 families with this disorder by a combination of genetic linkage analysis and LOH in cylindromas from affected persons. All 15 informative families showed linkage to 16q12-q13, thus providing no evidence for genetic heterogeneity. Recombinant mapping placed the gene in an interval of approximately 1 Mb. There was no evidence of haplotype sharing between families. Molecular Genetics Bignell et al. (2000) identified 21 different germline mutations in the CYLD gene in affected members of 21 families with cylindromatosis. Six somatic mutations were identified in 1 patient with sporadic disease and 5 patients with familial disease. All mutations predicted truncation or absence of the encoded protein (see, e.g., 605018.0001-605018.0002). In affected members of a German family with cylindromas, including 1 patient who also had trichoepitheliomas, suggesting BRSS, Poblete Gutierrez et al. (2002) identified a heterozygous truncating mutation in the CYLD gene (605018.0003). The results indicated that a single CYLD mutation can result in phenotypically different tumor types, indicating that cylindromas and trichoepitheliomas are allelic disorders. Young et al. (2006) identified a heterozygous mutation in the CYLD gene (605018.0008) in a 73-year-old man with cylindromatosis and turban tumor syndrome and in his 2 children with multiple familial trichoepitheliomas without cylindromas. The findings suggested that the 2 disorders represent phenotypic variation of a single genetic defect. Saggar et al. (2008) performed genetic analysis of 25 probands with familial skin appendage tumors. In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BRSS, 100% for FC, and 44% for MFT1. The majority of the mutations resulted in truncated proteins. There were no apparent genotype-phenotype correlations. Saggar et al. (2008) concluded that mutations in the CYLD gene underlie all 3 disorders, but that the reasons for phenotypic variability remain to be explored. History Schmidt-Baumler (1931) raised the question of X-linked dominant inheritance. The pedigree of Blandy et al. (1961) showed an affected male who had all daughters affected and all sons unaffected. Up to the end of 1954, Evans et al. (1966) found 47 reported cases of cylindroma, of which 30 were female. The authors noted that the term cylindroma had also been applied by Billroth (1859) to a type of adenocarcinoma arising in salivary gland tissue. Hart (1973) suggested that the lesions of hereditary multiple benign cystic epithelioma could be discerned in ancient Parthian coins. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Cylindromas, multiple (face, trunk and extremities) \- Cylindromas usually occur on the scalp may coalesce into large 'turban tumors' Skin Histology \- Mosaic-like masses of epithelial cells surrounded by thin layers of PAS-positive stroma \- Cells appear to be of glandular origin NEOPLASIA \- Cylindromas may show malignant transformation MISCELLANEOUS \- Onset in early adulthood \- Allelic disorder to multiple familial trichoepithelioma 1 (MFT1, 601606 ) and Brooke-Spiegler syndrome (BSS, 605041 ) MOLECULAR BASIS \- Caused by mutation in the CYLD gene ( 605018.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	CYLINDROMATOSIS, FAMILIAL	c1851526	2,285	omim	https://www.omim.org/entry/132700	2019-09-22T16:41:30	{"omim": ["132700"], "orphanet": ["211", "79493"], "synonyms": ["Alternative titles", "ANCELL-SPIEGLER CYLINDROMAS", "'TURBAN TUMOR' SYNDROME", "CYLINDROMAS, DERMAL ECCRINE"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive cutis laxa type IC (ARCL1C) is caused by homozygous or compound heterozygous mutation in the LTBP4 gene (604710) on chromosome 19q13. Description Cutis laxa is a collection of disorders that are typified by loose and/or wrinkled skin that imparts a prematurely aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The skin lacks elastic recoil, in marked contrast to the hyperelasticity apparent in classic Ehlers-Danlos syndrome (see 130000). These properties are nearly always attributable to loss, fragmentation, or severe disorganization of dermal elastic fibers (summary by Davidson and Giro, 2002). Patients with autosomal recessive cutis laxa type IC exhibit generalized cutis laxa in association with impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development (summary by Callewaert et al., 2013). For general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100). Clinical Features Urban et al. (2009) described 4 unrelated patients with a syndrome that disrupted pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the 4 patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis and enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Urban et al. (2009) proposed the name Urban-Rifkin-Davis syndrome (URDS) for this disorder. Callewaert et al. (2013) studied affected individuals from 9 families with cutis laxa and mutations in the LTB4 gene (see MOLECULAR GENETICS). Involvement of facial skin, resulting in a coarse and aged appearance, was present in most probands, but varied in severity. In some individuals, the skin was hyperextensible or appeared translucent with a prominent venous pattern. A few patients had thin and slowly growing hair. Inguinal and diaphragmatic hernias were frequent and the latter often required surgical correction. Pulmonary involvement with emphysema was universally present, and the emphysematous changes were severe in most cases. Upper airway involvement with tracheomalacia aggravated respiratory symptoms. In the majority of patients, cardiovascular involvement was limited to peripheral pulmonary artery stenosis. Bladder diverticula occurred in more than half of all patients and caused inadequate voiding with urinary tract infections. Fragility of gastrointestinal tissues was demonstrated by diverticula and rectal prolapse. Craniofacial dysmorphism included sloping forehead, sparse hair temporally, large ears, hypertelorism, low nasal bridge, beaked nose, sagging cheeks, and retrognathia. Neurologic status seemed normal, although assessment was complicated because many patients were very young and critically ill. Overall the prognosis was poor, with a mortality rate over 80%; mean age at death was 4 years, and most succumbed to respiratory failure. Inheritance Urban et al. (2009) confirmed autosomal recessive inheritance of this disorder by the finding of causative homozygous and compound heterozygous mutations in the LTBP4 gene. Molecular Genetics In 4 of 6 unrelated patients with cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities, Urban et al. (2009) identified homozygous or compound heterozygous mutations in the LTBP4 gene (604710.0001-604710.0005). Four of the 5 identified mutations were predicted to lead to premature termination codons and one was a missense mutation. Four of the mutations were located in a hybrid or an 8-cysteine domain, domains known to have long-range effects on fibrillin and LTBP conformation. Two of the 6 patients studied were negative for LTBP4 mutations, indicating genetic heterogeneity. Callewaert et al. (2013) analyzed the FBLN4 (604633), FBLN5 (604580), and LTBP4 genes in 12 families with type I ARCL and identified homozygous or compound heterozygous mutations in the LTBP4 gene in 9 families (see, e.g., 604710.0005-604710.0008). Homozygous mutations in FLBN5 were identified in 2 families (604580.0010 and 604580.0011). No mutations were found in the FBLN4 gene, and no mutations were detected in 1 family in which the proband had cutis laxa and bladder diverticula without obvious emphysema. Callewaert et al. (2013) noted that the FBLN5 and LTBP4 mutations caused a very similar phenotype associated with severe pulmonary emphysema in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seemed to be more severe in patients with LTBP4 mutations. Pathogenesis Urban et al. (2009) demonstrated that impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased TGF-beta activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by this disorder. The LTBP4 defects were associated with blocked alveolarization and airway collapse in the lung. Urban et al. (2009) suggested that coupling of TGF-beta signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems, including the lung, intestines, and urinary tract, by multifunctional proteins such as LTBP4. They also suggested that given the potential similarities in disease mechanisms between this syndrome and the Marfan syndrome (154700), pharmacologic intervention for normalization of TGF-beta signaling may be a treatment option. INHERITANCE \- Autosomal recessive GROWTH Other \- Postnatal growth delay HEAD & NECK Head \- Wide fontanels Face \- Micrognathia \- Flat midface \- Receding forehead Eyes \- Periorbital swelling \- Hypertelorism Nose \- Wide nasal bridge Mouth \- Long philtrum \- Retrognathia CARDIOVASCULAR Heart \- Pulmonary artery stenosis \- Patent foramen ovale RESPIRATORY Larynx \- Laryngomalacia \- Tracheomalacia \- Bronchomalacia Lung \- Emphysema \- Hypoplastic lung CHEST Diaphragm \- Diaphragm hernia or eventration ABDOMEN External Features \- Umbilical hernia Gastrointestinal \- Gastroesophageal reflux \- Diverticula \- Pyloric stenosis \- Intestinal dilatation, tortuosity \- Rectal prolapsed GENITOURINARY External Genitalia (Male) \- Inguinal hernia Kidneys \- Hydronephrosis Bladder \- Bladder diverticula SKELETAL \- Joint laxity Skull \- Wide sutures Feet \- Widely spaced first and second toes \- Plantar crease SKIN, NAILS, & HAIR Skin \- Cutis laxa MUSCLE, SOFT TISSUES \- Low muscle tone MOLECULAR BASIS \- Caused by mutation in the latent transforming growth factor-beta binding protein 4 gene (LTBP4, 604710.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IC	c2750804	2,286	omim	https://www.omim.org/entry/613177	2019-09-22T15:59:23	{"doid": ["0070139"], "mesh": ["C567716"], "omim": ["613177"], "orphanet": ["221145"], "synonyms": ["Alternative titles", "CUTIS LAXA WITH SEVERE PULMONARY, GASTROINTESTINAL, AND URINARY ABNORMALITIES", "URBAN-RIFKIN-DAVIS SYNDROME"], "genereviews": ["NBK343782"]}
A number sign (#) is used with this entry because of evidence that susceptibility to paroxysmal nocturnal hemoglobinuria-2 (PNH2) can be conferred by heterozygous mutation in the PIGT gene (610272) on chromosome 20q13. A somatic mutation in the PIGT gene in addition to the germline mutation appears to be necessary for development of the phenotype. One such patient has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of PNH, see PNH1 (300818). Clinical Features Krawitz et al. (2013) reported a Caucasian woman who was diagnosed with hemolytic anemia with a negative direct antiglobulin test at age 44 years. She experienced frequent hemolytic crises, abdominal pain, diarrhea, headache, arthralgia, dyspnea, and fatigue for several year thereafter. Flow cytometric analysis of the patient at age 49 years showed reduced expression of GPI-anchored proteins on blood cells. She was treated with the complement inhibitor eculizumab with improvement of the clinical features. Medical history revealed that she had cold-induced urticaria in childhood and later had episodic urticaria without exposure to cold, which was sometimes accompanied by systemic symptoms. Molecular Genetics In a woman with paroxysmal nocturnal hemoglobinuria, Krawitz et al. (2013) identified a heterozygous germline splice site mutation in the PIGT gene (610272.0002). The mutation was found by targeted enrichment of all exons of genes involved in GPI anchor synthesis followed by deep sequencing, and it was confirmed by Sanger sequencing. Array CGH on patient peripheral cells showed that a large proportion of granulocytes also carried a somatic heterozygous 8-Mb deletion of chromosome 20q11.23-q13.12, including the PIGT gene. Transfection of the splice site mutation into Pigt-null CHO cells caused only a minor increase in CD55 (125240) surface expression but almost no CD59 (107271) expression, suggesting a loss of function. The findings suggested that 2 hits in the PIGT gene, 1 germline and 1 somatic in hematopoietic stem cells, are necessary for development of the disorder. INHERITANCE \- Autosomal dominant \- Somatic mutation RESPIRATORY \- Dyspnea ABDOMEN \- Abdominal pain Gastrointestinal \- Diarrhea SKELETAL \- Arthralgia SKIN, NAILS, & HAIR Skin \- Urticaria NEUROLOGIC Central Nervous System \- Headache \- Fatigue HEMATOLOGY \- Hemolytic anemia LABORATORY ABNORMALITIES \- Decreased expression of GPI-anchored proteins on blood cells MISCELLANEOUS \- One patient has been reported (last curated September 2013) \- Features occur episodically \- Caused by heterozygous germline mutation and second-hit somatic mutation MOLECULAR BASIS \- Susceptibility conferred by mutation in the phosphatidylinositol glycan, class T gene (PIGT, 610272.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	PAROXYSMAL NOCTURNAL HEMOGLOBINURIA 2	c0024790	2,287	omim	https://www.omim.org/entry/615399	2019-09-22T15:52:14	{"doid": ["0060284"], "mesh": ["D006457"], "omim": ["615399"], "orphanet": ["447"]}
Microscopic polyangiitis Other namesMicropolyangiitis SpecialtyImmunology, rheumatology Microscopic polyangiitis is an ill-defined autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Clinical features may include constitutional symptoms like fever, loss of appetite, weight loss, fatigue, and kidney failure.[1] A majority of patients may have blood in the urine and protein in the urine. Rapidly progressive glomerulonephritis may occur. Because many different organ systems may be involved, a wide range of symptoms are possible in MPA.[citation needed]Purpura and livedo racemosa may be present.[2] ## Cause[edit] While the mechanism of disease has yet to be fully elucidated, the leading hypothesis is that the process is begun with an autoimmune process of unknown cause that triggers production of p-ANCA. These antibodies will circulate at low levels until a pro-inflammatory trigger — such as infection, malignancy, or drug therapy. The trigger upregulates production of p-ANCA. Then, the large number of antibodies make it more likely that they will bind a neutrophil. Once bound, the neutrophil degranulates. The degranulation releases toxins that cause endothelial injury.[3] Most recently, two different groups of investigators have demonstrated that anti-MPO antibodies alone can cause necrotizing and crescentic glomerulonephritis.[4] ## Diagnosis[edit] Laboratory tests may reveal an increased sedimentation rate, elevated CRP, anemia and elevated creatinine due to kidney impairment. An important diagnostic test is the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) with myeloperoxidase specificity[5] (a constituent of neutrophil granules), and protein and red blood cells in the urine. In patients with neuropathy, electromyography may reveal a sensorimotor peripheral neuropathy.[citation needed] ### Differential diagnosis[edit] The signs and symptoms of microscopic polyangiitis may resemble those of granulomatosis with polyangiitis (GPA) (another form of small-vessel vasculitis) but typically lacks the significant upper respiratory tract involvement (e.g., sinusitis) frequently seen in people affected by GPA.[citation needed] ## Treatment[edit] The customary treatment involves long term dosage of prednisone, alternated or combined with cytotoxic drugs, such as cyclophosphamide or azathioprine.Plasmapheresis may also be indicated in the acute setting to remove ANCA antibodies.[citation needed] Rituximab has been investigated,[6] and in April 2011 approved by the FDA when used in combination with glucocorticoids in adult patients.[7] ## See also[edit] * ANCA-associated vasculitides * Polyarteritis nodosa * List of cutaneous conditions ## References[edit] 1. ^ Altaie R, Ditizio F, Fahy GT (March 2005). "Microscopic polyangitis presenting with sub-acute reversible optic neuropathy". Eye (Lond). 19 (3): 363–5. doi:10.1038/sj.eye.6701479. PMID 15272290. 2. ^ Nagai Y, Hasegawa M, Igarashi N, Tanaka S, Yamanaka M, Ishikawa O (December 2008). "Cutaneous manifestations and histological features of microscopic polyangiitis". Eur J Dermatol. 19 (1): 57–60. doi:10.1684/ejd.2008.0566. PMID 19059827. 3. ^ Xiao H, Heeringa P, Hu P, et al. (October 2002). "Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice". J. Clin. Invest. 110 (7): 955–63. doi:10.1172/JCI15918. PMC 151154. PMID 12370273. 4. ^ Falk RJ, Jennette JC (July 2002). "ANCA are pathogenic—oh yes they are!". J. Am. Soc. Nephrol. 13 (7): 1977–9. PMID 12089397. 5. ^ Seishima M, Oyama Z, Oda M (2004). "Skin eruptions associated with microscopic polyangiitis". Eur J Dermatol. 14 (4): 255–8. PMID 15319159. 6. ^ Jayne D (January 2008). "Challenges in the management of microscopic polyangiitis: past, present and future". Curr Opin Rheumatol. 20 (1): 3–9. doi:10.1097/BOR.0b013e3282f370d1. PMID 18281850. 7. ^ Sources: * "FDA approves Rituxan to treat two rare disorders" (Press release). Food and Drug Administration. 19 April 2011. Retrieved 20 April 2011. * "RITUXAN (rituximab) injection, solution". Daily Med. U.S. National Library of Medicine. ## External links[edit] Classification D * ICD-10: M31.7 * ICD-9-CM: 446.0 * MeSH: D055953 * DiseasesDB: 8193 External resources * eMedicine: med/2931 * v * t * e Systemic vasculitis Large vessel * Takayasu's arteritis * Giant cell arteritis Medium vessel * Polyarteritis nodosa * Kawasaki disease * Thromboangiitis obliterans Small vessel Pauci-immune * c-ANCA * Granulomatosis with polyangiitis * p-ANCA * Eosinophilic granulomatosis with polyangiitis * Microscopic polyangiitis Type III hypersensitivity * Cutaneous small-vessel vasculitis * IgA vasculitis Ungrouped * Acute hemorrhagic edema of infancy * Cryoglobulinemic vasculitis * Bullous small vessel vasculitis * Cutaneous small-vessel vasculitis Other * Goodpasture syndrome * Sneddon's syndrome * v * t * e Disease of the kidney glomerules Primarily nephrotic Non-proliferative * Minimal change * Focal segmental * Membranous Proliferative * Mesangial proliferative * Endocapillary proliferative * Membranoproliferative/mesangiocapillary By condition * Diabetic * Amyloidosis Primarily nephritic, RPG Type I RPG/Type II hypersensitivity * Goodpasture syndrome Type II RPG/Type III hypersensitivity * Post-streptococcal * Lupus * diffuse proliferative * IgA Type III RPG/Pauci-immune * Granulomatosis with polyangiitis * Microscopic polyangiitis * Eosinophilic granulomatosis with polyangiitis General * glomerulonephritis * glomerulonephrosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Microscopic polyangiitis	c2347126	2,288	wikipedia	https://en.wikipedia.org/wiki/Microscopic_polyangiitis	2021-01-18T19:04:41	{"gard": ["3652"], "mesh": ["D055953"], "umls": ["C0343192"], "icd-9": ["446.0"], "icd-10": ["M31.7"], "orphanet": ["727"], "synonyms": ["MPA", "Micropolyangiitis", "Microscopic polyarteritis"], "wikidata": ["Q1934069"]}
Type of urinary tract infection Ureaplasma urealyticum infection Typesinfectious disease Ureaplasma urealyticum infection is a type of urinary tract infection that can be sexually transmitted. It can also be passed from mother to infant during birth.[1] It is caused by the bacterium Ureaplasma urealyticum,which can found in a majority of sexually active people,[citation needed] most of whom are asymptomatic.[2] It can also be found in cultures in cases of pelvic inflammatory disease. It is not a commensal of the healthy uterine or amniotic microbiome. Infection with U. urealyticum can contribute to neonatal infection and negative birth outcomes. ## Contents * 1 Presentation * 1.1 Men * 1.2 Women and infants * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Presentation[edit] ### Men[edit] It had also been associated with a number of diseases in humans, including nonspecific urethritis, and infertility.[3][4] ### Women and infants[edit] Infection in the newborn is accompanied by a strong immune response and is correlated with the need for prolonged mechanical ventilation.[5] Infection with U. urealyticum in pregnancy and birth can be complicated by chorioamnionitis, stillbirth, premature birth,[1] and, in the perinatal period, pneumonia, bronchopulmonary dysplasia[6] and meningitis.[7] U. urealyticum has been found to be present in amniotic fluid in women who have had a premature birth with intact fetal membranes.[8] U. urealyticum has been noted as one of the infectious causes of sterile pyuria.[9] It increases the morbidity as a cause of neonatal infections.[5] It is associated with premature birth, preterm rupture of membranes, preterm labor, cesarean section, placental inflammation, congenital pneumonia, bacteremia, meningitis, fetal lung injury and death of infant.[4] Ureaplasma urealyticum is associated with miscarriage.[10] In addition, this pathogen may latently infect the chorionic villi tissues of pregnant women, thereby impacting pregnancy outcome.[11] ## Diagnosis[edit] This section is empty. You can help by adding to it. (March 2019) ## Treatment[edit] Doxycycline is the drug of choice, but azithromycin is also used as a five-day course rather than a single dose that would be used to treat Chlamydia infection;[12] streptomycin is an alternative, but is less popular because it must be injected. Penicillins are ineffective — U. urealyticum does not have a cell wall,[13] which is the drug's main target.[14][15] ## References[edit] 1. ^ a b Ljubin-Sternak, Suncanica; Mestrovic, Tomislav (2014). "Review: Chlamydia trachonmatis and Genital Mycoplasmias: Pathogens with an Impact on Human Reproductive Health". Journal of Pathogens. 2014 (183167): 183167. doi:10.1155/2014/183167. PMC 4295611. PMID 25614838. 2. ^ "Mycoplasma and Ureaplasma: Are they Sexually Transmitted Infections?". Treated.com. Retrieved 2019-04-23. 3. ^ C. Huang; H.L. Zhu; K.R. Xu; S.Y. Wang; L.Q. Fan; W.B. Zhu (September 2015). "Mycoplasma and ureaplasma infection and male infertility: a systematic review and meta-analysis". Andrology. 3 (5): 809–816. doi:10.1111/andr.12078. PMID 26311339. S2CID 39834287. 4. ^ a b Medscape (2017-11-17). "Ureaplasma Infection: Background, Pathophysiology, Epidemiology". Cite journal requires `\|journal=` (help) 5. ^ a b Pryhuber, Gloria S. (2015). "Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity". Clinics in Perinatology. 42 (4): 697–718. doi:10.1016/j.clp.2015.08.002. ISSN 0095-5108. PMC 4660246. PMID 26593074; Access provided by the University of Pittsburgh 6. ^ Kafetzis DA, Skevaki CL, Skouteri V, et al. (October 2004). "Maternal genital colonization with Ureaplasma urealyticum promotes preterm delivery: association of the respiratory colonization of premature infants with chronic lung disease and increased mortality". Clin. Infect. Dis. 39 (8): 1113–22. doi:10.1086/424505. PMID 15486833. 7. ^ Queena, John T. .; Spong, Catherine Y; Lockwood, Charles J., editors (2012). Queenan's management of high-risk pregnancy : an evidence-based approach (6th ed.). Chichester, West Sussex: Wiley-Blackwell. ISBN 9780470655764. 8. ^ Payne, Matthew S.; Bayatibojakhi, Sara (2014). "Exploring Preterm Birth as a Polymicrobial Disease: An Overview of the Uterine Microbiome". Frontiers in Immunology. 5: 595. doi:10.3389/fimmu.2014.00595. ISSN 1664-3224. PMC 4245917. PMID 25505898. 9. ^ Dieter RS (2000). "Sterile pyuria: a differential diagnosis". Compr Ther. 26 (3): 150–2. doi:10.1007/s12019-000-0001-1. PMID 10984817. S2CID 11629600. 10. ^ Cunningham, F, Leveno KJ, Bloom SL, Spong CY, Dashe JS, Hoffman BL, Casey BM, Sheffield JS (2013). "Abortion". Williams Obstetrics. McGraw-Hill. p. 5. 11. ^ Contini C, Rotondo JC, Magagnoli F, Maritati M, Seraceni S, Graziano A, Poggi A, Capucci R, Vesce F, Tognon M, Martini F (2018). "Investigation on silent bacterial infections in specimens from pregnant women affected by spontaneous miscarriage". J Cell Physiol. 234 (1): 100–9107. doi:10.1002/jcp.26952. PMID 30078192. 12. ^ "Ureaplasma Urealyticum and Parvum Test Online". thesticlinic.com. 13. ^ Vancutsem E, Soetens O, Breugelmans M, Foulon W, Naessens A (2011). "Modified Real-Time PCR for Detecting, Differentiating, and Quantifying Ureaplasma urealyticum and Ureaplasma parvum". J Mol Diagn. 13 (2): 206–12. doi:10.1016/j.jmoldx.2010.10.007. PMC 3128564. PMID 21354056.CS1 maint: multiple names: authors list (link) 14. ^ "Drugs — Pencillin". elmhurst.edu. 15. ^ Pignanelli S, Pulcrano G, Iula VD, Zaccherini P, Testa A, Catania MR (2013). "In vitro antimicrobial profile of Ureaplasma urealyticum from genital tract of childbearing-aged women in Northern and Southern Italy". APMIS. 122 (6): 552–5. doi:10.1111/apm.12184. PMID 24106832. S2CID 5120886. ## External links[edit] Classification D External resources * eMedicine: med/2340 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Ureaplasma urealyticum infection	None	2,289	wikipedia	https://en.wikipedia.org/wiki/Ureaplasma_urealyticum_infection	2021-01-18T18:58:36	{"wikidata": ["Q25091439"]}
A rare, neurodegenerative disease characterized by progressive dementia and ataxia, widespread cerebral amyloid angiopathy and parenchymal amyloid deposition. Two subtypes have been identified, ABri amyloidosis and ADan amyloidosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	ITM2B amyloidosis	c1861735	2,290	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=439254	2021-01-23T18:59:42	{"mesh": ["C538209"], "omim": ["117300", "176500"], "icd-10": ["E85.4+", "I68.0*"], "synonyms": ["Familial cerebral amyloid angiopathy", "ITM2B-related amyloidosis", "ITM2B-related cerebral amyloid angiopathy"]}
A number sign (#) is used with this entry because of evidence that colobomatous macrophthalmia with microcornea (MACOM) is a contiguous gene deletion syndrome resulting from an approximately 22-kb heterozygous deletion on chromosome 2p22.2, involving the CRIM1 (606189) and FEZ2 (604826) genes. Clinical Features Bateman and Maumenee (1984) described a family with colobomatous macrophthalmia with microcornea. The affected members, otherwise normal, were 1 woman and her monozygotic twin sister with 2 sons. The twins had bilateral microcornea, coloboma starting from the iris and extending to the optic nerve, axial enlargement, posterior staphyloma, and high myopia. The sons of the proposita's sister presented an incomplete and unilateral pattern of these defects, suggesting variability in the expression of the syndrome. Pallotta et al. (1998) described a second family in which the syndrome was transmitted through 4 generations with no male-to-male transmission. Toker et al. (2003) described a Turkish family with 13 affected individuals in 3 generations. All affected members of the family had bilateral involvement with typical inferonasal iris coloboma, chorioretinal coloboma, microcornea, and varying degrees of axial enlargement associated with myopia. Additional findings included flatter corneal curvatures and shallower anterior chambers. Iridocorneal angle abnormalities associated with elevation of intraocular pressure were detected in 3 patients. The pedigree confirmed the autosomal dominant pattern of inheritance with male-to-male transmission in 2 instances and with complete penetrance. Mapping Elcioglu et al. (2007) performed genotyping and linkage analysis in the 3-generation Turkish family with colobomatous macrophthalmia and microcornea reported by Toker et al. (2003) and obtained a maximum lod score of 3.61 (theta = 0) at marker D2S1788. Recombination events positioned the locus, which they called MACOM, on chromosome 2p23-p16 in a 22-Mb interval between D2S2263 and D2S1352; mutation analysis of 3 candidate genes, SIX2 (604994), SIX3 (603714), and CYP1B1 (601771), did not reveal any causative mutations. Cytogenetics By whole-exome sequencing and CNV analysis in the 3-generation Turkish family with MACOM mapping to chromosome 2p23-p16, originally reported by Toker et al. (2003), Beleggia et al. (2015) identified an approximately 22-kb heterozygous deletion on chromosome 2 that segregated fully with disease. The deletion encompassed exons 14 through 17 of the CRIM1 gene (606189) as well as most of the 3-prime UTR of the FEZ2 gene (604826). Analysis of polymorphisms in CRIM1 and FEZ2 showed significant reduction of the mutant allele of CRIM1, consistent with early degradation, whereas there was no significant reduction in the amount of the FEZ2 mutant allele. In mice homozygous for loss of Crim1 in the head surface ectoderm and ocular mesenchyme, the authors observed morphologic changes overlapping the developmental eye anomalies present in patients with MACOM syndrome, including microcornea, a shallow anterior chamber, and a narrower eye without diminished axial diameter. Beleggia et al. (2015) concluded that CRIM1 is the causative gene for MACOM syndrome. No causative mutation or deletion/duplication involving CRIM1 was identified in the index patient from the family with MACOM described by Bateman and Maumenee (1984), suggesting further genetic heterogeneity of MACOM syndrome. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus \- Strabismus \- Myopia \- Reduced visual acuity \- Microcornea \- Moderate flattening of corneal curvature \- Macrophthalmia \- Pupillary dislocation \- Coloboma of iris, choroid, and retina \- Diffuse atrophy of retinal pigment epithelium \- Macular atrophy \- Strands of uveal tissue covering trabecular meshwork (in some patients) \- Elevated intraocular pressure (in some patients) MISCELLANEOUS \- Severity of reduced vision ranges from 20/50 to light perception only \- Coloboma involves optic nerve in most patients MOLECULAR BASIS Contiguous gene syndrome caused by deletion of 22kb on 2p22.2 including the CRIM1 ( 606189 ) and FEZ2 ( 604826 ) genes ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	MACROPHTHALMIA, COLOBOMATOUS, WITH MICROCORNEA	c1865286	2,291	omim	https://www.omim.org/entry/602499	2019-09-22T16:13:39	{"mesh": ["C566533"], "omim": ["602499"], "orphanet": ["468672"], "synonyms": ["MACOM syndrome"]}
## Summary ### Clinical characteristics. Variegate porphyria (VP) is both a cutaneous porphyria (with chronic blistering skin lesions) and an acute porphyria (with severe episodic neurovisceral symptoms). The most common manifestation of VP is adult-onset cutaneous blistering lesions (subepidermal vesicles, bullae, and erosions that crust over and heal slowly) of sun-exposed skin, especially the hands and face. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. Cutaneous manifestations may improve in winter and be less prevalent in northern regions and in dark-skinned individuals. Acute neurovisceral symptoms can occur any time after puberty, but less often in the elderly. Acute manifestations are highly variable, but may be similar from episode to episode in a person with recurrent attacks; not all manifestations are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common manifestations are abdominal pain; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a primarily motor neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis. Psychiatric disturbances and autonomic neuropathy can also be observed. Acute attacks may be severe and are potentially fatal. ### Diagnosis/testing. The biochemical diagnosis of VP is established in an individual with elevated urine porphobilinogen (PBG) or porphyrins and a fluorescence peak at ~626 nm on plasma fluorescence scanning; fecal porphyrins are also elevated, with a predominance of coproporphyrin III and protoporphyrin. The molecular diagnosis of VP is established by identification of a heterozygous pathogenic variant in PPOX on molecular genetic testing. ### Management. Treatment of manifestations: The first step in treating either acute neurovisceral attacks or cutaneous manifestations is to identify and remove exacerbating factors (see Agents/circumstances to avoid). Most acute neurovisceral attacks require hospital admission; the presence of seizures, motor neuropathy, and hyponatremia suggest severe disease that ideally should be managed in an ICU. Narcotic analgesics are usually required for pain. Ondansetron or a related drug can be used for nausea and vomiting; phenothiazines can be effective for nausea, agitation, and hallucinations. Although mild attacks (without seizures, weakness, or hyponatremia and not requiring narcotics) can sometimes be treated in an outpatient setting with glucose loading, most attacks require treatment with intravenous hemin and in-patient observation for additional supportive management. Cutaneous manifestations are best managed by wearing protective clothing and avoiding exposure to sunlight. Symptoms may decrease when exacerbating factors are removed. No treatment is known to be effective in lowering porphyrin levels and reducing cutaneous symptoms. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Prevention of primary manifestations: Acute neurovisceral attacks are less likely to occur if exacerbating factors are corrected or avoided. Recurrent premenstrual acute attacks can be prevented with gonadotropin-releasing hormone analogs; weekly or biweekly hemin infusions to prevent frequent noncyclical attacks may be effective, but experience is lacking. Prevention of the skin manifestations requires protection from sunlight. Surveillance: Liver imaging at six-month intervals beginning at age 50 years in those who have experienced persistent elevations in porphobilinogen or porphyrins may detect early hepatocellular carcinoma. Agents/circumstances to avoid: Exacerbating factors that should be avoided include drugs such as: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated. Concomitant illnesses should be treated effectively using drugs that are considered safe whenever possible. Updated lists of safe and unsafe drugs are maintained at the websites of the American Porphyria Foundation and the European Porphyria Network. Evaluation of relatives at risk: At-risk family members can be offered molecular genetic testing for the family-specific PPOX pathogenic variant to identify those who are heterozygous (for the purpose of counseling regarding appropriate use of drugs and avoidance of known exacerbating factors). While biochemical testing, especially plasma fluorescence scanning and fecal porphyrin analysis, is also useful, it is less sensitive than molecular genetic testing. Pregnancy management: Exacerbations during pregnancy have been treated successfully with heme arginate or heme hydroxide (hematin); while neither preparation has been studied extensively during pregnancy, experience over many years suggests that treatment during pregnancy is unlikely to produce adverse fetal effects. ### Genetic counseling. VP is inherited in an autosomal dominant manner with reduced penetrance. De novo pathogenic variants are rare. Each child of an individual with VP has a 50% chance of inheriting the pathogenic variant; while offspring who inherit the variant may or may not develop manifestations, most do not. Prenatal testing for pregnancies at increased risk for VP is possible if the pathogenic variant in an affected family member has been identified. Of note, the presence of a PPOX pathogenic variant does not predict whether – or at what age – an individual will become symptomatic. ## Diagnosis ### Suggestive Findings Variegate porphyria (VP) should be suspected in individuals with the following clinical findings and initial laboratory findings. Clinical findings * Cutaneous manifestations include chronic blistering photosensitivity, most commonly on the backs of the hands. Chronic features include blisters, milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. The skin lesions are identical to those of porphyria cutanea tarda (PCT) and other blistering cutaneous porphyrias [Meissner et al 2003] (see Differential Diagnosis). * Neurovisceral symptoms most commonly include the following: * Abdominal pain. The pain is typically severe, steady rather than cramping, and diffuse rather than localized. Because the pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. Acute hepatic porphyrias should be suspected whenever abdominal pain remains unexplained after an initial workup for common causes. * Constipation * Pain in the back, chest, and extremities * Anxiety * Seizures * Muscle weakness due to a primarily motor neuropathy that usually begins in the proximal upper extremities and may progress to quadriparesis and respiratory paralysis. This is accompanied by pain and sometimes sensory loss. Hyperreflexia may be seen initially, followed by hyporeflexia as motor neuropathy progresses. * Hyponatremia, which increases the risk for seizures. It may be a manifestation of hypothalamic involvement and the syndrome of inappropriate antidiuretic hormone secretion [Anderson et al 2005]. Initial biochemical laboratory findings. As VP may present with blistering cutaneous lesions on sun-exposed skin, neurovisceral symptoms or both, initial first-line testing aims to detect all porphyrias that can cause either skin or neurovisceral manifestations (see Differential Diagnosis). * Blistering cutaneous porphyrias (including VP). When VP or any other blistering cutaneous porphyria is suspected, the recommended initial test is measurement of plasma or urine porphyrins. If elevated, further testing is needed to determine the type of porphyria or whether the porphyrin elevation – particularly in urine – represents nonspecific porphyrinuria rather than porphyria. * Acute porphyrias (including VP). Measurement of urinary porphobilinogen (PBG)* and total porphyrins. Urine δ-aminolevulinic acid (ALA) is often measured at the same time as PBG but this is not necessary for initial screening. Note: (1) If an acute porphyria is confirmed by substantial elevation of urinary PBG, treatment can be started, if appropriate, for symptoms of an acute attack (see Management, Treatment of Manifestations) while further biochemical testing is being performed to determine the type of acute porphyria (see Differential Diagnosis). (2) If PBG is normal, total porphyrins and ALA should be measured in the same urine sample, because total porphyrins often remain elevated longer than PBG. In ALA dehydratase-deficiency porphyria (ADP), the rarest type of porphyria, ALA and total porphyrins (but not PBG) are markedly elevated [Anderson et al 2005]. Substantial elevation in erythrocyte porphyrins is not consistent with VP, and points to an erythropoietic porphyria as a cause of blistering skin manifestations and elevation of urine and plasma porphyrins. Alternatively, substantial erythrocyte protoporphyrin in an individual with VP may suggest a concurrent condition that elevates zinc protoporphyrin, such as iron deficiency, lead poisoning, or another erythrocyte disorder. ### Establishing the Diagnosis #### Biochemical Diagnosis When initial biochemical laboratory findings support an acute porphyria (i.e., elevated urine PBG or porphyrins) or a blistering cutaneous porphyria (i.e., elevated plasma or urine porphyrins), further diagnostic biochemical testing (Table 1) is required to differentiate VP from other acute and cutaneous porphyrias and from conditions (e.g., liver disease) that cause nonspecific porphyrinuria: * Plasma fluorescence scanning can establish or exclude VP when urine PBG is elevated since a fluorescence peak at ~626 nm is not found in any other type of porphyria. * Fecal porphyrin analysis can differentiate VP, acute intermittent porphyria (AIP), and hereditary coproporphyria (HCP), the only diseases that substantially elevate urine PBG. * Fecal porphyrin analysis and plasma fluorescence scanning can also reliably distinguish VP from porphyria cutanea tarda (PCT) and other porphyrias that cause blistering skin lesions (see Differential Diagnosis). ### Table 1. Biochemical Characteristics of Variegate Porphyria (VP) View in own window Deficient EnzymeUrine PBG and PorphyrinsPlasma Fluorescence ScanningFecal Porphyrins ActiveAsxActiveAsxActiveAsx PPOX 1, 2↑ PBG, ALA & total porphyrins 3, 4, 5↑ or NI PBG, ALA & total porphyrins 6↑; see footnote 8↑; see footnote 8See footnote 7See footnote 8 Active = symptomatic PPOX heterozygotes; ALA = δ-aminolevulinic acid; Asx = asymptomatic PPOX heterozygotes; NI = not increased; PBG = porphobilinogen; PPOX = protoporphyrinogen oxidase 1\. This enzyme oxidizes protoporphyrinogen to protoporphyrin and its deficiency leads to accumulation of protoporphyrinogen in the liver, which subsequently is autoxidized to protoporphyrin. 2\. The enzyme assay is not needed for diagnostic purposes and is not widely available. 3\. PBG elevation should be detected by a quantitative method such as that described by Mauzerall & Granick [1956] which also measures ALA or mass spectrometry. Results of qualitative methods such as the Watson-Schwartz and Hoesch tests, which are considered obsolete, should be confirmed on the same sample by a quantitative method. ALA is less elevated than PBG. Note: ALA is elevated in ALAD porphyria (ADP), in which PBG is normal or only slightly increased. 4\. Active VP is suggested by a quantitative PBG that is substantially elevated. 5\. For screening, it is also useful to measure total porphyrins in the same urine sample, since levels of PBG can be less elevated in VP and HCP than in AIP and decrease to normal more rapidly. Note: Unlike a substantial increase in PBG, a substantial increase in urinary porphyrins does not indicate porphyria, as urinary porphyrins are increased in many other medical conditions, especially when the hepatobiliary system or bone marrow is affected. 6\. PBG and total porphyrins may not be elevated in persons whose symptoms have resolved. If an acute porphyria is suspected to have caused past symptoms, full biochemical testing to include urinary ALA, PBG, and porphyrins, fecal porphyrins, and plasma porphyrins may be indicated. 7\. Fecal porphyrins are markedly elevated in HCP and VP, whereas in AIP there is little or no elevation. The pattern of fecal porphyrins differentiates HCP and VP, with marked predominance of coproporphyrin III in HCP, and roughly equal elevations of coproporphyrin III and protoporphyrin in VP. 8\. A fluorescence scan of diluted plasma at neutral pH provides a fluorescence peak at wavelength ~626 nm in VP that is highly sensitive and specific for this porphyria [Poh-Fitzpatrick 1980]. This is the most sensitive biochemical method for establishing VP in the absence of symptoms. Fecal porphyrin analysis is somewhat less sensitive than plasma fluorescence scanning. #### Molecular Diagnosis Identification of the causative pathogenic variant is now considered standard of care in VP and other acute porphyrias to confirm the diagnosis and inform genetic counseling (see Genetic Counseling) (see Option 1 and Option 2). Option 1. It is generally preferred to establish the biochemical diagnosis of VP first, followed by confirmatory single-gene (PPOX) testing. However, a multigene panel (HMBS, CPOX, PPOX) can be used to establish the diagnosis when biochemical testing (e.g., substantial PBG elevation) indicates a diagnosis of AIP, HCP, or VP or when the individual to be tested has become asymptomatic and biochemical abnormalities are absent or nonspecific. * Single-gene testing of PPOX is generally recommended after a diagnosis of VP is established biochemically. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Standard practice is to perform sequence analysis first. If no PPOX pathogenic variant is found in an individual with biochemically proven VP, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: When VP is established biochemically in members of the Afrikaner population of South Africa, it is reasonable to consider targeted analysis for the founder variant, p.Arg59Trp, observed in about 95% of persons with variegate porphyria in that population [Dean 1971, Meissner et al 1996]. See Table 4. Notable PPOX Pathogenic Variants. * An acute porphyria multigene panel that includes PPOX and other genes of interest (particularly HMBS and CPOX; see Differential Diagnosis) is most likely to identify the genetic cause of symptoms and PBG elevation 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. ALAD, the gene encoding the enzyme ALA dehydratase (which is deficient in ALA dehydratase-deficiency porphyria) may also be included in the panel, but is only relevant when ALA and porphyrins (but not PBG) are elevated. Note: (1) The diagnostic sensitivity of the testing used for each gene may vary by laboratory and is likely to change over time. (2) 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. Option 2. Genomic testing is not recommended for initial diagnosis of acute porphyrias. However, when genomic testing obtained as part of a search for the cause of unexplained symptoms identifies HMBS, CPOX, or PPOX pathogenic variants or variants of uncertain significance, biochemical testing that documents elevations in PBG and porphyrins confirms porphyria as the cause of the symptoms – and confirms the diagnosis of VP. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 2. Molecular Genetic Testing Used in Variegate Porphyria View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method PPOXSequence analysis 396%-100% 4 Gene-targeted deletion/duplication analysis 5Unknown 6 Targeted analysis for pathogenic variantsp.Arg59Trp 7 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\. Whatley et al [2009] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Multiexon deletions of PPOX have been reported [Barbaro et al 2013]; however, no data on detection rate of gene-targeted deletion/duplication analysis are available. 7\. VP is especially common in South Africa, where the founder variant p.Arg59Trp [Dean 1971] accounts for about 95% of cases [Meissner et al 1996]. ## Clinical Characteristics ### Clinical Description Variegate porphyria (VP) is classified as both a cutaneous and an acute porphyria. It can present with chronic blistering cutaneous manifestations and/or acute attacks of neurovisceral manifestations that may become chronic. Cutaneous manifestations. Chronic blistering photosensitivity, typically on the backs of the hands, is the most common manifestation of VP. The lesions result from sun exposure that activates porphyrins and makes the skin fragile and prone to blister formation. Lesions are located on sun-exposed areas, especially the dorsal aspects of the hands and less frequently the face, neck, ears, and lower extremities. Because sun-induced damage is not acute, the role of sunlight is often not recognized. Cutaneous manifestations may improve in winter and be less prevalent in northern regions and in dark-skinned individuals. These and other manifestations of VP appear typically in adulthood and rarely before puberty. The subepidermal vesicles, bullae, and erosions crust over and heal slowly. When blisters rupture they may become infected and painful. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. The skin manifestations are identical to those seen in porphyria cutanea tarda (PCT) and hereditary coproporphyria (HCP), and less severe than those seen in congenital erythropoietic porphyria (CEP) and hepatoerythropoietic porphyria (HEP). They contrast with the acute non-blistering photocutaneous manifestations of erythropoietic protoporphyria (EPP) (see Table 3). Of note, the great majority of individuals who are heterozygous for a PPOX pathogenic variant are asymptomatic and are unlikely to be recognized unless they are screened for VP based on a family history of VP (see Genetic Counseling). In South Africa the frequency of acute attacks has decreased in recent decades. This may be due to less common use of harmful drugs such as barbiturates and sulfonamide antibiotics in clinical practice and perhaps better case recognition and better dissemination of information on how to avoid future attacks. VP now more commonly presents in South Africa with cutaneous rather than acute manifestations [Meissner et al 2003, Anderson et al 2005, Hift & Meissner 2005]. Neurovisceral symptoms can occur at any age after puberty as acute attacks, but may become chronic. Symptoms are more common in women than men, and occur less often in the elderly. The frequency and severity of attacks vary considerably and are determined, in part, by exacerbating factors such as certain drugs, hormones, and nutritional deficits [Anderson et al 2005]. The proportion of persons heterozygous for a PPOX pathogenic variant who experience acute attacks decreased from about 30%-40% in the 1980s to 5%-10% in 2005 [Hift & Meissner 2005]. The neurovisceral symptoms are identical to those in the other acute porphyrias (see Differential Diagnosis). Acute manifestations vary. The most common symptoms are abdominal pain; nausea and vomiting; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a predominantly motor peripheral neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis [Kauppinen & Mustajoki 1992, Meissner et al 2003, Anderson et al 2005, Hift & Meissner 2005]. Psychiatric disturbances and autonomic neuropathy can also be observed. Not all symptoms are present in a single episode and symptoms can vary from episode to episode; however, recurrent attacks are often similar. Acute attacks may be severe and are potentially fatal, but on average are less frequent and less severe than those observed in acute intermittent porphyria (AIP) [Hift & Meissner 2005]. Motor neuropathy usually manifests initially as proximal upper-extremity muscle weakness and can be difficult to detect. Hyperreflexia may be seen initially, followed by hyporeflexia as the motor neuropathy progresses. The motor neuropathy may be accompanied by sensory loss. Note: Motor neuropathy due to acute porphyrias is accompanied by little or no elevation of cerebrospinal fluid protein, which helps to differentiate it from the Landry Guillain-Barré syndrome [Anderson et al 2005]. Because abdominal pain is neuropathic rather than inflammatory, abdominal findings are minimal compared to the severity of the pain. Ileus and bladder distension may be present. An acute attack can be fatal in the presence of severe manifestations including neuropathy, seizures, and respiratory compromise. If managed properly, the outcome of an acute attack is generally good. Even severe motor neuropathy is reversible with recovery over a variable period of months and sometimes over several years. Factors that predispose to acute attacks that are often identified include exposure to a harmful drug, alcohol, reduced dietary intake, or stress from an infection or other illness. Most harmful drugs are known to be inducers of hepatic δ-aminolevulinic acid synthase (ALAS) and hepatic cytochrome P450 enzymes (see Agents/Circumstances to Avoid). Pregnancy is usually well tolerated but can precipitate acute attacks in some women. Physical findings such as tachycardia, hypertension, restlessness, and agitation result from autonomic neuropathy and increased circulating catecholamines. Chronic pain may be a manifestation of VP and other acute porphyrias. Depression may be more difficult to link to the disease. Chronic pain and depression may become important management issues. Chronic liver abnormalities, particularly mild elevation of serum transaminases, are common. Risks for development of hepatocellular carcinoma and chronic renal disease are increased in VP (as well as in AIP and HCP). Hepatocellular carcinoma may develop, especially after age 50 years in persons with persistent elevations in porphobilinogen and porphyrins. Note: The speculation that King George III (and perhaps others in the British royal family) had VP has been discounted [Peters 2011]. ### Genotype-Phenotype Correlations PPOX pathogenic variants are generally severe and result in little or no enzyme activity; the residual approximately half-normal enzyme activity is a product of the normal allele. Therefore, different pathogenic variants are not associated with differences in disease severity [Whatley et al 1999, Whatley et al 2009]. Double heterozygosity for pathogenic variants in two different genes in the heme biosynthetic pathway. A patient with cutaneous manifestations initially diagnosed as HCP was found to be a double heterozygote for pathogenic variants in PPOX and CPOX after other family members were found to have clinical and biochemical features of VP [van Tuyll van Serooskerken et al 2011]. The phenotypes of such rare double heterozygotes are not necessarily more severe than the phenotype associated with heterozygosity for a pathogenic variant in one gene alone, suggesting that individuals who are doubly heterozygous for pathogenic variants in genes causing two different types of acute porphyria may be more common than has been assumed. Note: Typically double heterozygosity is suspected because of unusual biochemical patterns, and thus is unlikely to be recognized without comprehensive biochemical testing [van Tuyll van Serooskerken et al 2011], which then identifies a need for additional molecular genetic testing. ### Penetrance PPOX pathogenic variants that result in VP produce little or no functional enzyme; the approximately 50% of normal residual enzyme activity results primarily from the normal allele. Penetrance is low, but may be increased by factors that increase the demand for hepatic heme synthesis. Penetrance is likely influenced by modifying genes that remain to be identified. ### Nomenclature Variegate porphyria (VP) and hereditary coproporphyria (HCP) were sometimes referred to as mixed porphyria, which is now an obsolete term. VP has also been referred to as South African acute porphyria or protocoproporphyria. In the past, familial porphyria cutanea tarda (PCT) may not have been clearly differentiated from VP in some instances. ### Prevalence It is estimated that in the South African population three individuals per 1,000 are heterozygous for the PPOX pathogenic variant p.Arg59Trp [Meissner et al 1996, Meissner et al 2003]. The prevalence of VP with present or past symptoms in Europe is about half that for acute intermittent porphyria (AIP), and has been estimated at 3.2:1,000,000 [Elder et al 2013]. ## Differential Diagnosis The genetic porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in characteristic patterns of accumulation of pathway intermediates (Figure 1). #### Figure 1. Excretion profile of the hepatic porphyrias Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Pathogenic variants that decrease the function of a particular (more...) In Table 3 the porphyrias are grouped by their principal clinical manifestations (neurovisceral or cutaneous) and the tissue origin of the excess production of pathway intermediates: liver (i.e., hepatic); or bone marrow (i.e., erythropoietic). Porphyrias with neurologic manifestations are considered acute because the symptoms usually occur as discrete, severe episodes, which may be induced by endogenous hormones, drugs and dietary changes; they are difficult to diagnose due to their rarity and the nonspecific nature of symptoms, even when severe. The four acute porphyrias (often referred to as acute hepatic porphyrias) are: ALA dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Only a few individuals with ADP have been reported in the world literature, and whether this porphyria is hepatic, erythropoietic, or both is uncertain. Porphyrias with cutaneous manifestations include those causing chronic blistering skin lesions (i.e., VP as well as porphyria cutanea tarda [PCT], HCP, congenital erythropoietic porphyria [CEP], and hepatoerythropoietic porphyria [HEP]) or acute non-blistering photosensitivity (i.e., EPP and XLP). ### Table 3. Classification of the Hereditary Porphyrias View in own window Type of PorphyriaGene(s)MOIFindings Neurovisceral 1Photocutaneous HepaticADPALADAR+0 AIPHMBSAD+0 HCPCPOXAD++ PCT type II 2URODAD0+ HEP 3AR0+ VPPPOXAD++ ErythropoieticCEP 4UROSAR0+ GATA1XL EPPFECHAR0\+ 5 XLPALAS2XL0\+ 5 0 = no symptoms; + = mild to severe symptoms; AD = autosomal dominant; ADP = ALA dehydratase-deficiency porphyria; AIP = acute intermittent porphyria; AR = autosomal recessive; CEP = congenital erythropoietic porphyria; EPP = erythropoietic protoporphyria; HCP = hereditary coproporphyria; HEP = hepatoerythropoietic porphyria; MOI = mode of inheritance; PCT = porphyria cutanea tarda; VP = variegate porphyria; XL = X-linked; XLP = X-linked protoporphyria 1\. Porphyrias with neurovisceral manifestations have been considered "acute" because symptoms usually occur acutely as discrete, severe episodes; however, some affected individuals develop chronic manifestations. 2\. PCT is primarily an acquired, iron-related disorder with multiple susceptibility factors. Approximately 20% of individuals with PCT have a heterozygous pathogenic variant in UROD, the gene encoding uroporphyrinogen decarboxylase, which is referred to as PCT type II (familial). In PCT type I (sporadic, ~80% of individuals with PCT) UROD is normal. Type III (rare) is also familial due to inherited factors other than UROD variants. Types I-III are clinically indistinguishable and respond to the same treatments. 3\. HEP is the homozygous form of PCT type II (familial). 4\. CEP is most commonly associated with biallelic UROS pathogenic variants and inherited in an autosomal recessive manner; on rare occasion, CEP is caused by mutation of GATA1 and inherited in an X-linked manner. 5\. Photocutaneous manifestations of EPP and XLP are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP). Acute neurologic porphyrias. The acute neurovisceral symptoms of VP are identical to those of the other acute porphyrias. VP can be differentiated from AIP and HCP by plasma fluorescence scanning and fecal porphyrin analysis (Table 1) or by molecular genetic testing (Table 2). In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias (AIP, VP, HCP, and ADP), the entity most likely to be considered is acute ascending polyneuropathy, the Landry Guillain-Barré syndrome. * Abdominal pain, constipation, and tachycardia usually accompany the acute neurologic illness in the acute porphyrias but not in Landry Guillain-Barré syndrome. * CSF protein is usually normal in the acute porphyrias, but usually elevated in Landry Guillain-Barré syndrome. * Most importantly, urinary PBG is markedly elevated in the acute porphyrias especially when symptoms are present, but normal in Landry Guillain-Barré syndrome. Chronic blistering photocutaneous porphyrias. VP can be readily differentiated from the following conditions by biochemical testing and ultimately confirmed by molecular genetic testing. * The blistering skin lesions of porphyria cutanea tarda (PCT), the most common human porphyria, are identical to those of VP. Because PCT is much more common than VP, patients with VP are often misdiagnosed as having PCT. Because treatment for PCT is not effective in VP, it is important to differentiate these disorders before initiating treatment. * HCP is associated with such skin manifestations much less commonly than VP. * Blistering skin manifestations occur in AIP only when concurrent end-stage renal disease impairs porphyrin excretion, and thus increases plasma porphyrin levels. * Cutaneous manifestations of CEP and HEP are also chronic and blistering but usually more severe than those of VP because circulating porphyrin levels are usually much higher (often by an order of magnitude) than in PCT and VP. Although the diagnosis in individuals with mild CEP and HEP is readily mistaken for VP, HCP, and PCT during clinical evaluation, these erythropoietic porphyrias are differentiated particularly by finding high levels of erythrocyte porphyrins. * Pseudoporphyria is a little-understood condition with cutaneous findings similar to PCT and VP but without significant porphyrin elevations. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and to plan the management of an individual diagnosed with variegate porphyria (VP), the following clinical and laboratory evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Degree of elevations on plasma and urine porphyrins and urine porphobilinogen (PBG), if not determined at the time of diagnosis * Clinical evaluation of any current acute neurovisceral manifestations to determine the need for hospital admission and treatment with hemin. * Nervous system. Assessment of the extent of neurologic involvement causing paresis, pain or sensory changes * Psychiatric evaluation if depression or other psychiatric features are present * Liver. Liver function tests to indicate chronic liver involvement and liver imaging in patients older than age 50 years * Kidneys. Kidney function tests to assess for presence and progression of kidney damage * Skin. Assessment of blistering cutaneous lesions to assess their relationship to VP * Contributions of medications (see Agents/Circumstances to Avoid), diet, and concurrent conditions to severity of VP * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations #### Neurovisceral Symptoms Most acute neurovisceral attacks require hospital admission; patients with mild attacks (not requiring narcotic analgesics and without hyponatremia, seizures, or muscle weakness) are sometimes treated as outpatients. A rapid, thorough, and multidisciplinary evaluation is optimized by in-patient management. As with other acute porphyrias, evaluation should include identification of exacerbating drugs and other precipitating factors. Harmful medications include barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Harmful medications should be discontinued [Balwani et al 2017]. Seizures, motor neuropathy, and hyponatremia suggest severe disease and should be managed in the ICU with adequate supportive treatment. Evidence of reversible cerebral vasospasm may be found by MRI [Webb et al 2016]. Narcotic analgesics are usually required for pain and ondansetron or a related drug for nausea and vomiting. A phenothiazine is also effective for nausea and for psychiatric symptoms (e.g., agitation, hallucinations) [Anderson et al 2005, Harper & Wahlin 2007]. Mild attacks (not requiring narcotics and without hyponatremia, seizures, or motor neuropathy) can be treated with glucose loading, but most attacks should be treated with intravenous hemin [Anderson et al 2005, Balwani et al 2017]. Note: "Hemin" refers to the oxidized form of iron protoporphyrin IX, but is also the generic term for heme preparations used as intravenous therapies for acute porphyrias, such as lyophilized hematin (heme hydroxide) and heme arginate. When these hemin preparations are infused intravenously, the heme is bound to circulating albumin as heme albumin. The latter is taken up by hepatocytes and decreases the synthesis of hepatic ALAS1, the rate-controlling enzyme for heme synthesis in the liver. Patients with acute attack should be carefully monitored for muscle weakness and respiratory impairment that may require ventilatory support. Hyponatremia should be corrected slowly and seizures treated with medications that do not exacerbate porphyria. Liver transplantation, which has been effective in persons with acute intermittent porphyria with severe repeated acute attacks that respond poorly to medical therapy, is also a consideration in VP [Dowman et al 2012]. Progression of renal disease may be prevented to some degree by controlling hypertension. #### Cutaneous Manifestations Porphyrin levels may decrease and photosensitivity improve if exacerbating factors can be identified and removed; otherwise, there is no effective treatment that lowers porphyrin levels. Treatment with hemin may lower porphyrins in the short term only. Patients should wear protective clothing and avoid exposure to sunlight. Analgesics may be needed for painful lesions and antibiotics for superimposed infection. Topical steroids are of little or no benefit. Specific measures effective in the treatment of porphyria cutanea tarda (i.e., phlebotomy and low-dose hydroxychloroquine or chloroquine) are not effective in the management of VP. ### Prevention of Primary Manifestations Acute attack * Attacks are less likely to occur in the future if exacerbating factors are corrected or avoided (see Agents/Circumstances to Avoid). * Recurrent premenstrual attacks of acute porphyrias, including VP, can be prevented with gonadotropin-releasing hormone analogs [Anderson et al 1990, Schulenburg-Brand et al 2017]. * Weekly or biweekly hemin infusions may prevent frequent noncyclical attacks; however, published experience is lacking [Marsden et al 2015]. * Givosiran, a small interfering RNA (siRNA) therapeutic, was recently approved by the FDA for treatment of acute porphyrias, including VP. In particular, monthly subcutaneous injections of givosiran can be effective for prevention of frequently recurring attacks [Sardh et al 2019]. Photocutaneous manifestations. Prevention of the skin manifestations of VP requires protection from sunlight. Avoidance of exacerbating factors may also be beneficial. ### Surveillance Hepatocellular carcinoma may develop especially after age 50 years in patients with acute porphyrias and persistent elevations in porphobilinogen or porphyrins; liver imaging at six-month intervals beginning at age 50 years may detect early lesions [Andant et al 2000, Schneider-Yin et al 2010]. ### Agents/Circumstances to Avoid Precipitating factors that should be avoided include: barbiturates, sulfonamide antibiotics, griseofulvin, rifampin, most anticonvulsants including phenytoin and carbamazepine, alcohol, ergot alkaloids, metoclopramide, and progestins. Updated lists are maintained at the websites of the American Porphyria Foundation and the European Porphyria Network. Although birth control pills should generally be avoided, low-dose hormonal preparations may be tolerated. Fasting and very low calorie diets should be avoided. Bariatric surgery should be avoided in patients who have had frequent exacerbations of VP and other acute porphyrias. Patients who wish to lose weight should do so gradually with moderate, long-term reductions in calorie intake under guidance of a dietician. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of a proband. This will identify individuals heterozygous for the familial PPOX pathogenic variant who may benefit from counseling regarding appropriate use of drugs and avoidance of known precipitating factors. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Pregnancy is usually well tolerated in women with variegate porphyria (VP); however, some women with VP may experience exacerbations during pregnancy. Badminton & Deybach [2006] published an anecdotal report of successful treatment of several pregnant women experiencing attacks of VP or other acute porphyrias during pregnancy with hemin (in the form of heme arginate) without adverse fetal effect. They emphasize that interruption of pregnancy is almost never indicated for management of acute porphyria. Experience with heme hydroxide (hematin) is also limited but suggests no adverse effects during pregnancy [Isenschmid et al 1992]. As noted (see Treatment of Manifestations, Neurovisceral Symptoms), hemin is delivered to tissues as heme albumin when administered as either heme arginate or heme hydroxide, and these preparations are expected to have similar safety profiles. A fetus heterozygous for a PPOX pathogenic variant has a good prognosis, because current postnatal management involves counseling the family regarding appropriate use of drugs and avoidance of known precipitating factors. 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 access to 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Variegate Porphyria	c0162532	2,292	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK121283/	2021-01-18T20:50:51	{"mesh": ["D046350"], "synonyms": ["Porphyria Variegata"]}
A number sign (#) is used with this entry because this form of nonspecific X-linked mental retardation is caused by mutation in the FTSJ1 gene (300499). Clinical Features Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. Hamel et al. (1999) described a 4-generation family segregating X-linked mental retardation. Affected members had nonprogressive mental retardation noted during childhood, and several demonstrated aggressive behavior. The mental retardation in tested members of the family was moderate to severe; none of the patients was able to read, write, or solve simple arithmetic problems. Froyen et al. (2007) reported 3 Caucasian brothers with nonsyndromic X-linked mental retardation. Two had moderate and 1 had severe intellectual handicap. The oldest patient had autistic behavior that lessened after age 5 years, as well as delayed speech and motor development. The 2 younger brothers also had seizures; 1 had flat nasal bridge and shortened distal phalanges. High-resolution array CGH identified a 50-kb microdeletion at Xp11.23 involving the FTSJ1 and SLC38A5 (300649) genes. Detailed mapping studies suggested that the deletion breakpoints involved the repeat region of the SSX1 gene (312820). The unaffected mother also carried the deletion, but showed complete inactivation of the aberrant X chromosome. Froyen et al. (2007) concluded that the cognitive impairment in this family was most likely due to absence of the FTSJ1 gene. Mapping Willems et al. (1993) described linkage studies in a family classified as MRX9 in the nomenclature proposed by Mulley et al. (1992) and reviewed by Neri et al. (1992). The studies suggested localization in the pericentromeric region, namely, Xp21-q13. Winnepenninckx et al. (2002) restudied the Belgian family reported by Willems et al. (1993) and refined the mapping of the MRX9 gene to Xp11.4-p11.22. Hamel et al. (1999) performed linkage analysis in family MRX44 and obtained a maximum lod score of 2.90 (theta = 0.0) with marker DXS1204. Haplotype construction defined the region to Xp11.3-p11.21, spanning an approximately 10-cM interval flanked by markers DXS1003 and ALAS2. Molecular Genetics The MRX44 family of Hamel et al. (1999) was shown by Freude et al. (2004) to carry a mutation in the FTSJ1 gene (300499.0001), resulting in deletion of exon 9. In the Belgian MRX9 family reported by Willems et al. (1993), Ramser et al. (2004) established a gene catalog for the candidate region defined by Winnepenninckx et al. (2002). Comprehensive mutation analysis by direct sequencing identified an alteration in the conserved acceptor splice site of intron 3 of the FTSJ1 gene (300499.0004). INHERITANCE \- X-linked recessive HEAD & NECK Ears \- Large ears Eyes \- Wide palpebral fissures \- Periorbital fullness Mouth \- Full lower lip NEUROLOGIC Central Nervous System \- Mental retardation, moderate to severe \- Psychomotor delay Behavioral Psychiatric Manifestations \- Aggressive outbursts (in some patients) MOLECULAR BASIS \- Caused by mutation in the FTSJ homolog 1 gene (FTSJ1, 300449.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	MENTAL RETARDATION, X-LINKED 9	c2931498	2,293	omim	https://www.omim.org/entry/309549	2019-09-22T16:17:48	{"doid": ["0050776"], "mesh": ["C567906"], "omim": ["309549"], "orphanet": ["777"], "synonyms": ["Alternative titles", "MENTAL RETARDATION, X-LINKED 44"]}
A number sign (#) is used with this entry because of evidence that this phenotype results from mutation in the RAD50 gene (604040). Clinical Features Barbi et al. (1991) reported a microcephalic, growth-retarded newborn girl without major anomalies who had chromosome instability in lymphocytes and fibroblasts. Frequent involvement of bands 7p13, 7q34, 14q11, and 14q32 suggested the diagnosis of ataxia-telangiectasia (AT; 208900). She had radioresistant DNA synthesis in fibroblasts and radiation hypersensitivity of short-term lymphocyte cultures. Follow-up at 4 years of age showed largely normal development and no signs of telangiectasia, ataxia, or immunodeficiency. Serum AFP levels were elevated at age 5 months, but declined to normal by age 2 years. Fibroblasts showed radioresistant DNA synthesis typical of AT or the Nijmegen breakage syndrome (251260). Waltes et al. (2009) reported further phenotyping of this female, who was 23 years of age at that time. She had mild to moderate retardation of psychomotor development, mild spasticity, and very modestly impaired sensomotor coordination manifesting as a slight and nonprogressive ataxia. Physical exam showed a bird-like face and height, weight, and head circumference well below the third percentile. Puberty and secondary sexual characteristics appeared normal. She had areas of hyper- and hypopigmentation diffusely and had severe hyperopia. She had no history of infections, had normal immunoglobulin subclasses, and no evidence of malignancy. By the age of 23 years, she was living in her own apartment in an assisted living facility. Molecular Genetics In a patient with a Nijmegen breakage syndrome-like disorder (NBSLD), Waltes et al. (2009) identified compound heterozygosity mutations in the RAD50 gene, a maternally inherited nonsense mutation (604040.0001) and a paternally inherited point mutation that resulted in extension of the protein by 66 amino acids (604040.0002). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	NIJMEGEN BREAKAGE SYNDROME-LIKE DISORDER	c2751318	2,294	omim	https://www.omim.org/entry/613078	2019-09-22T15:59:43	{"mesh": ["C567767"], "omim": ["613078"], "orphanet": ["240760"], "synonyms": ["Alternative titles", "NBS-LIKE DISORDER", "RAD50 DEFICIENCY", "MICROCEPHALY AND SPONTANEOUS CHROMOSOME INSTABILITY WITHOUT IMMUNODEFICIENCY"]}
A rare congenital limb malformation characterized by duplication of the fifth digit in a hand or foot, the sixth digit being rudimentary, poorly developed, and non-functional, frequently consisting of additional soft tissue on a pedicle. The anomaly can be unilateral or bilateral. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Postaxial polydactyly type B	c1868120	2,295	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93335	2021-01-23T17:02:15	{"mesh": ["C562429"], "omim": ["174200"], "umls": ["C1868120"], "icd-10": ["Q69.0"]}
Hypertrichosis cubiti is a rare hair anomaly characterized by symmetrical, congenital or early-onset, bilateral hypertrychosis localized on the externsor surfaces of the upper extremities (especially the elbows). Short stature, or other abnormalities, such as developmental delay, facial anomalies and intellectual disability, may or may not 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 [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Hypertrichosis cubiti	c1841696	2,296	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2220	2021-01-23T18:35:06	{"gard": ["143"], "mesh": ["C535618"], "omim": ["139600"], "umls": ["C1841696"], "icd-10": ["Q84.2"], "synonyms": ["Hairy elbows syndrome", "MacDermot-Patton-Williams syndrome"]}
## Clinical Features Irons et al. (1996) reported 2 brothers with lymphedema of the lower limbs, hydrocele, atrial septal defects (ASD), epicanthus, and wide nasal bridge. Their stillborn sister, who was born after a pregnancy complicated by preeclampsia, had severe hydrops fetalis, omphalocele, ASD, and polysplenia. The family history was unremarkable. Irons et al. (1996) considered this complex to be a previously unknown syndrome with autosomal recessive inheritance. Van Steensel et al. (2007) described a 3-year-old Dutch girl with features similar to those in the patients reported by Irons et al. (1996). She was born prematurely at 35 weeks with a dizygotic twin sister. The parents were nonconsanguineous and 3 sibs were healthy. During pregnancy, fetal hydrops was detected from weeks 16 to 20. At birth, she was noted to have bilateral swelling of the lower legs consistent with lymphedema. She also had atrial flutter, a large perimembranous ventricular septal defect with significant left/right shunting, a secundum type atrial septal defect type II, and an overriding aorta with vascular ring. At age 2 months, the ventricular septal defect was closed, the vascular ring corrected, and an aortopexia was performed. Progressive bilateral lower leg lymphedema was noted at 3 years of age. Physical examination at that time revealed nonpitting edema of the toes, feet, and lower legs. Her face showed epicanthal folds, flat nasal bridge with telecanthus, and a high forehead. Lymphoscintigraphy revealed complete absence of lymph drainage in both lower legs. Karyotype was normal 46,XX, and a 22q11 deletion was excluded by FISH. Analysis of several genes known to be involved in syndromes with lymphedema detected no pathogenic mutations. Levine and Echiverri (2009) reported a 22-year-old African American man with mild mental retardation, mild dysmorphic features, history of a congenital atrial septal defect, massive lymphedema of the lower limbs, and hydrocele. Dysmorphic features included prominent forehead, bitemporal narrowing, epicanthal folds, hypertelorism, and flat and wide nasal bridge. Levine and Echiverri (2009) noted that the patient resembled the brothers reported by Irons et al. (1996), although their patient did not have deep-set nails or a horizontal chin cleft, and had more severe cognitive impairment. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Round face \- Prominent forehead \- Horizontal chin cleft \- High forehead Eyes \- Epicanthal folds \- Upslanting palpebral fissures \- Telecanthus Nose \- Flat nasal bridge \- Broad nasal tip Mouth \- Thin upper lip CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect \- Atrial flutter Vascular \- Patent ductus arteriosus \- Overriding aorta \- Vascular ring ABDOMEN External Features \- Omphalocele GENITOURINARY External Genitalia (Male) \- Hydrocele SKIN, NAILS, & HAIR Nails \- Short, deep-set toenails MUSCLE, SOFT TISSUES \- Lymphedema (lower limbs) NEUROLOGIC Central Nervous System \- Speech delay PRENATAL MANIFESTATIONS \- Severe hydrops fetalis Amniotic Fluid \- Oligohydramnios ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	LYMPHEDEMA, CARDIAC SEPTAL DEFECTS, AND CHARACTERISTIC FACIES	c2677167	2,297	omim	https://www.omim.org/entry/601927	2019-09-22T16:14:09	{"mesh": ["C567398"], "omim": ["601927"], "orphanet": ["86915"], "synonyms": ["Alternative titles", "IRONS-BIANCHI SYNDROME", "LYMPHEDEMA, ATRIAL SEPTAL DEFECT, AND CHARACTERISTIC FACIES"]}
For other uses, see Dripping (disambiguation). 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: "Dripping" – news · newspapers · books · scholar · JSTOR (August 2009) (Learn how and when to remove this template message) A type of dripping from Yorkshire, United Kingdom, where it is known as "mucky fat" Dripping, also known usually as beef dripping or, more rarely, as pork dripping, is an animal fat produced from the fatty or otherwise unusable parts of cow or pig carcasses. It is similar to lard, tallow and schmaltz. ## Contents * 1 History * 2 Pastry * 3 See also * 4 References ## History[edit] It is used for cooking, especially in British cuisine, significantly so in the Midlands and Northern England, though towards the end of the 20th century dripping fell out of favour due to it being regarded as less healthy than vegetable oils such as olive or sunflower. Traditionally fish and chips were fried in beef dripping, and while this practice does continue in some places,[1] most shops now use vegetable oils.[citation needed] Preparation is traditionally described as collection of the residue from meat roasts but modern production is from such residue added to boiling water with a generous amount of salt (about 2g per litre). The stock pot should be chilled and the solid lump of dripping (the cake) which settles when chilled should be scraped clean and re-chilled for future use. The residue can be reprocessed for more dripping and strained through a cheesecloth lined sieve as an ingredient for a fine beef stock. Dripping can be clarified by adding a sliced raw potato and cooking until potato turns brown. The cake will be the colour and texture of ghee. Pork or beef dripping can be served cold, spread on bread and sprinkled with salt and pepper (bread and dripping). If the flavourful brown sediment and stock from the roast has settled to the bottom of the dripping and coloured it brown, then in parts of Yorkshire it is known colloquially as a "mucky fat" sandwich. ## Pastry[edit] Dripping can be used to make pastry, for pasties and other foods.[2] ## See also[edit] Look up dripping in Wiktionary, the free dictionary. * Food portal * Dripping cake ## References[edit] 1. ^ "Upton Chippy". Upton Chippy. 2. ^ Cornish Pasties Recipe \| Leite's Culinaria * v * t * e Edible fats and oils Fats Pork fats * Fatback * Lardo * Salo * Salt pork * Szalonna * Lard * Lardon * Pork belly * Bacon * Pancetta * Tocino * Speck Beef/mutton fats * Dripping * Suet * Tallow * Tail fat Dairy fats * Butter * Clarified butter * Ghee * Niter kibbeh * Smen Poultry fats * Chicken fat * Duck fat * Schmaltz Other animal fats * Blubber * Muktuk * Whale oil Vegetable fats * Borneo tallow * Cocoa butter * Mango butter * Margarine * Shea butter * Vegetable shortening Oils Fish oils * Cod liver oil * Shark liver oil Vegetable oils Major oils * Coconut oil * Corn oil * Cottonseed oil * Olive oil * Palm oil * palm kernel oil * Peanut oil * Rapeseed oil * Canola oil and Colza oil (toxic oil syndrome) * Safflower oil * Soybean oil * Sunflower oil Nut oils * Almond oil * Argan oil * Cashew oil * Hazelnut oil * Macadamia oil * Marula oil * Mongongo nut oil * Pecan oil * Pine nut oil * Pistachio oil * Walnut oil Fruit and seed oils * Ambadi seed oil * Avocado oil * Castor oil * Grape seed oil * Hemp oil * Linseed oil (flaxseed oil) * Mustard oil * Olive oil * Perilla oil * Poppyseed oil * Pumpkin seed oil * Rice bran oil * Sesame oil * Tea seed oil * Watermelon seed oil See also List of vegetable oils Cooking oil Essential oil [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Dripping	None	2,298	wikipedia	https://en.wikipedia.org/wiki/Dripping	2021-01-18T18:47:27	{"wikidata": ["Q17105036"]}
intestinopsthy SpecialtyGastroenterology Enteropathy refers to any pathology of the intestine.[1] Although enteritis specifically refers to an inflammation of the intestine, and is thus a more specific term than "enteropathy", the two phrases are sometimes used interchangeably. ## Contents * 1 Types * 2 References * 3 External links ## Types[edit] Specific types of enteropathy include: * Enteropathy-associated T-cell lymphoma * Environmental enteropathy An incompletely defined syndrome of inflammation related to the quality of the environment. Signs and symptoms include reduced absorptive capacity and reduced intestinal barrier function of the small intestine. It is widespread among children and adults in low- and middle-income countries.[2] * Eosinophilic enteropathy A condition in which eosinophils (a type of white blood cell) accumulate in the gastrointestinal tract and in the blood. Eosinophil build up in the gastrointestinal tract can result in polyp formation, tissue break down, inflammation, and ulcers.[3] * Gluten-sensitive enteropathy (which can progress to coeliac disease) * Coeliac disease A malabsorption syndrome precipitated by the ingestion of foods containing gluten in a predisposed individual. It is characterized by inflammation of the small intestine, loss of microvilli structure, deficient nutrient absorption, and malnutrition.[4] * Human immunodeficiency virus (HIV) HIV Enteropathy Characterized by chronic diarrhea more than one month in duration with no obvious infectious cause in an HIV-positive individual. Thought to be due to direct or indirect effects of HIV on the enteric mucosa.[5] * Immunodysregulation polyendocrinopathy and enteropathy, X-linked (see FOXP3) * Protein-losing enteropathy[6] * Radiation enteropathy[7] * Tropical enteropathy If the condition also involves the stomach, it is known as "gastroenteropathy". In pigs, porcine proliferative enteropathy is a diarrheal disease.[8] ## References[edit] 1. ^ "enteropathy" at Dorland's Medical Dictionary 2. ^ Crane, Rosie J.; Jones, Kelsey D. J.; Berkley, James A. (2015-03-01). "Environmental enteric dysfunction: An overview". Food and Nutrition Bulletin. 36 (1 0): S76–S87. doi:10.1177/15648265150361S113. ISSN 0379-5721. PMC 4472379. PMID 25902619. 3. ^ "Eosinophilic enteropathy \| Disease \| Overview \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2016-07-09. 4. ^ "Celiac Disease - MeSH - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-07-09. 5. ^ "HIV Enteropathy - MeSH - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-07-09. 6. ^ "eMedicine - Protein-Losing Enteropathy : Article by Naeem Aslam". 7. ^ "MedlinePlus Medical Encyclopedia: Radiation enteritis". 8. ^ "Porcine Proliferative Enteritis". Merck Veterinary Manual. ## External links[edit] Classification D * ICD-9-CM: 569.9 * MeSH: D007410 * 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 This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein	Enteropathy	c0021831	2,299	wikipedia	https://en.wikipedia.org/wiki/Enteropathy	2021-01-18T19:06:53	{"mesh": ["D007410"], "umls": ["C0021831"], "orphanet": ["117569"], "wikidata": ["Q3055380"]}

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