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A rare primary bone dysplasia characterized by reduced bone mineral density (defined as a Z score below -2.0), vertebral compression fractures, and recurrent peripheral fractures caused by low-impact trauma, leading to bone pain and impaired mobility. Patients typically become symptomatic in childhood or adolescence. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	LRP5-related primary osteoporosis	None	4,600	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=498481	2021-01-23T17:30:59	{}
Idiopathic infantile hypercalcemia is a condition characterized by high levels of calcium in the blood (hypercalcemia). Two types of idiopathic infantile hypercalcemia have been identified and are distinguished by their genetic causes: infantile hypercalcemia 1 and infantile hypercalcemia 2. In infants with either type, hypercalcemia can cause vomiting, increased urine production (polyuria), dehydration, constipation, poor feeding, weight loss, and an inability to grow and gain weight as expected (failure to thrive). As they age, affected babies usually have delayed development of mental and movement abilities (psychomotor delay). Individuals with infantile hypercalcemia 1 or 2 may also have high levels of calcium in their urine (hypercalciuria) and deposits of calcium in their kidneys (nephrocalcinosis). With treatment, the outward symptoms of hypercalcemia, such as vomiting, dehydration, failure to thrive, and psychomotor delay, usually improve in childhood. However, affected children still tend to have higher-than-normal amounts of calcium in their blood and urine and calcium deposits in their kidneys. By adulthood, long-term hypercalcemia and hypercalciuria can lead to the formation of kidney stones (nephrolithiasis) and may damage the kidneys and impair their function. Affected adults may also develop calcium deposits in the joints or in the clear outer covering of the eye (the cornea), and some have low bone mineral density (osteoporosis). In rare cases, affected individuals do not have symptoms of hypercalcemia in infancy, and the condition begins in later childhood or adulthood. These individuals usually develop hypercalciuria, nephrocalcinosis, and nephrolithiasis, although the features may not cause any obvious health problems. Although most signs and symptoms are similar between the two known types of idiopathic infantile hypercalcemia, individuals with infantile hypercalcemia 2 have low levels of a mineral called phosphate in the blood (hypophosphatemia), while phosphate levels are typically normal in people with infantile hypercalcemia 1. ## Frequency Infantile hypercalcemia 1 and 2 are thought to be rare conditions, although their prevalence is unknown. ## Causes The two known types of idiopathic infantile hypercalcemia are caused by mutations in different genes. Infantile hypercalcemia 1 is caused by CYP24A1 gene mutations, and infantile hypercalcemia 2 is caused by SLC34A1 gene mutations. Both genes help maintain the proper balance of calcium or phosphate in the body, a process that can involve vitamin D. When turned on (active), this vitamin stimulates the absorption of both phosphate and calcium from the intestines into the bloodstream. Vitamin D can be acquired from foods in the diet or made in the body with help from sunlight exposure. The enzyme produced from the CYP24A1 gene helps control the amount of active vitamin D in the body. This enzyme, called 24-hydroxylase, helps break down active vitamin D when it is no longer needed, for example when the proper balance of calcium or phosphate in the body is reached. Mutations in the CYP24A1 gene reduce or eliminate the activity of the 24-hydroxylase enzyme, which impairs the breakdown of active vitamin D. The amount of phosphate in the body can also be maintained through reabsorption of the mineral in the kidneys so that it is not removed in urine. Reabsorption occurs by transport of the mineral through special channels formed from a protein called sodium-dependent phosphate transporter 2A (NaPi-IIa), which is produced from the SLC34A1 gene. Mutations in the SLC34A1 gene prevent the NaPi-IIa channels from transporting phosphate, reducing the amount of phosphate in the body. To increase phosphate levels, vitamin D is activated. Mutations in either the CYP24A1 or SLC34A1 gene result in too much active vitamin D in the body. This excess increases calcium absorption into the bloodstream, causing hypercalcemia. The abnormal balance of calcium leads to high levels of the mineral in urine and can result in deposition of calcium in the kidneys and the formation of kidney stones. It is thought that other factors, such as the amount of calcium in the diet, vitamin D supplementation, or prolonged sunlight exposure can influence the development and severity of signs and symptoms in affected individuals. Some people with idiopathic infantile hypercalcemia do not have mutations in the CYP24A1 or SLC34A1 gene. The cause of the condition in these cases is unknown. Other genes that have not been identified may be involved in development of the condition. ### Learn more about the genes associated with Idiopathic infantile hypercalcemia * CYP24A1 * SLC34A1 ## Inheritance Pattern Infantile hypercalcemia types 1 and 2 are thought to be inherited in an autosomal recessive pattern, which means both copies of the respective gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In some instances, individuals with one copy of the mutated gene have higher-than-normal levels of calcium in their blood or urine and may be more likely to develop kidney stones, but they do not typically have early, severe symptoms of infantile hypercalcemia 1 or 2. Nongenetic factors, such as the amount of calcium in the diet, vitamin D supplementation, or prolonged sunlight exposure, may influence whether signs and symptoms develop in individuals with one altered copy of the gene. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Idiopathic infantile hypercalcemia	c0268080	4,601	medlineplus	https://medlineplus.gov/genetics/condition/idiopathic-infantile-hypercalcemia/	2021-01-27T08:25:16	{"mesh": ["C562581"], "omim": ["143880", "616963"], "synonyms": []}
Schnyder crystalline corneal dystrophy Other namesCrystalline stromal dystrophy, Schnyder crystalline dystrophy sine crystals, Hereditary crystalline stromal dystrophy of Schnyder , Schnyder's crystalline corneal dystrophy Schnyder corneal dystrophy. Crystalline opacities are evident in the central cornea (Courtesy Dr. G.N. Foulks) SpecialtyOphthalmology Schnyder crystalline corneal dystrophy (SCD) is a rare form of corneal dystrophy. It is caused by heterozygous mutations in UBIAD1 gene.[1][2][3] Cells in the cornea accumulate cholesterol and phosopholipid deposits leading to the opacity, in severe cases requiring corneal transplants. Abnormal cholesterol metabolism has been noted in other cell types of affected patients (skin fibroblasts) suggesting that this may be a systemic disorder with clinical manifestations limited to the cornea. ## Notes[edit] 1. ^ Orr et al, PLoS One (2007) vol 2, e685 doi:10.1371/journal.pone.0000685 PMID 17668063 2. ^ Yellore et al, Molec Vision (2007) vol 13, 1777-1782 PMID 17960116 3. ^ Weiss et al, IOVS (2007) vol 48, 5007-5012 doi:10.1167/iovs.07-0845 PMID 17962451 ## External links[edit] Classification D * OMIM: 121800 * MeSH: C535475 C535475, C535475 External resources * eMedicine: article/1196212 * v * t * e Types of corneal dystrophy Epithelial and subepithelial * Epithelial basement membrane dystrophy * Gelatinous drop-like corneal dystrophy * Lisch epithelial corneal dystrophy * Meesmann corneal dystrophy * Subepithelial mucinous corneal dystrophy Bowman's membrane * Reis–Bucklers corneal dystrophy * Thiel-Behnke dystrophy Stroma * Congenital stromal corneal dystrophy * Fleck corneal dystrophy * Granular corneal dystrophy * Lattice corneal dystrophy * Macular corneal dystrophy * Posterior amorphous corneal dystrophy * Schnyder crystalline corneal dystrophy Descemet's membrane and endothelial * Congenital hereditary endothelial dystrophy * Fuchs' dystrophy * Posterior polymorphous corneal dystrophy * X-linked endothelial corneal dystrophy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Schnyder crystalline corneal dystrophy	c0271287	4,602	wikipedia	https://en.wikipedia.org/wiki/Schnyder_crystalline_corneal_dystrophy	2021-01-18T18:28:37	{"gard": ["9277"], "mesh": ["C535475"], "umls": ["C0271287"], "orphanet": ["98967"], "wikidata": ["Q4162393"]}
Damage to the tracheobronchial tree Tracheobronchial injury Reconstruction of the trachea and bronchi with x-ray computed tomography showing disruption of the right main bronchus with abnormal lucency (arrow)[1] SpecialtyEmergency medicine Tracheobronchial injury is damage to the tracheobronchial tree (the airway structure involving the trachea and bronchi).[2] It can result from blunt or penetrating trauma to the neck or chest,[3] inhalation of harmful fumes or smoke, or aspiration of liquids or objects.[4] Though rare, TBI is a serious condition; it may cause obstruction of the airway with resulting life-threatening respiratory insufficiency.[2] Other injuries accompany TBI in about half of cases.[5] Of those people with TBI who die, most do so before receiving emergency care, either from airway obstruction, exsanguination, or from injuries to other vital organs. Of those who do reach a hospital, the mortality rate may be as high as 30%.[6] TBI is frequently difficult to diagnose and treat.[7] Early diagnosis is important to prevent complications, which include stenosis (narrowing) of the airway, respiratory tract infection, and damage to the lung tissue. Diagnosis involves procedures such as bronchoscopy, radiography, and x-ray computed tomography to visualize the tracheobronchial tree. Signs and symptoms vary based on the location and severity of the injury; they commonly include dyspnea (difficulty breathing), dysphonia (a condition where the voice can be hoarse, weak, or excessively breathy), coughing, and abnormal breath sounds. In the emergency setting, tracheal intubation can be used to ensure that the airway remains open. In severe cases, surgery may be necessary to repair a TBI.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Mechanism * 3.1 Anatomy * 4 Diagnosis * 4.1 Classification * 5 Prevention * 6 Treatment * 7 Prognosis and complications * 8 Epidemiology * 9 History * 10 Notes * 11 References * 12 External links ## Signs and symptoms[edit] Pneumothoraces of both lungs (large arrows), pneumomediastinum (small arrow) and subcutaneous emphysema in a patient with complete disruption of the right bronchus. Air leak was continual despite suction.[1] Signs and symptoms vary depending on what part of the tracheobronchial tree is injured and how severely it is damaged.[6] There are no direct signs of TBI, but certain signs suggest the injury and raise a clinician's suspicion that it has occurred.[8] Many of the signs and symptoms are also present in injuries with similar injury mechanisms such as pneumothorax.[9] Dyspnea and respiratory distress are found in 76–100% of people with TBI, and coughing up blood has been found in up to 25%.[10] However, isolated TBI does not usually cause profuse bleeding; if such bleeding is observed it is likely to be due to another injury such as a ruptured large blood vessel.[2] The patient may exhibit dysphonia or have diminished breath sounds, and rapid breathing is common.[3] Coughing may be present,[11] and stridor, an abnormal, high-pitched breath sound indicating obstruction of the upper airway can also occur.[12] Damage to the airways can cause subcutaneous emphysema (air trapped in the subcutaneous tissue of the skin) in the abdomen, chest, neck, and head.[2] Subcutaneous emphysema, present in up to 85% of people with TBI,[10] is particularly indicative of the injury when it is only in the neck.[13] Air is trapped in the chest cavity outside the lungs (pneumothorax) in about 70% of TBI.[4][10] Especially strong evidence that TBI has occurred is failure of a pneumothorax to resolve even when a chest tube is placed to rid the chest cavity of the air; it shows that air is continually leaking into the chest cavity from the site of the tear.[11] Air can also be trapped in the mediastinum, the center of the chest cavity (pneumomediastinum).[4] If air escapes from a penetrating injury to the neck, a definite diagnosis of TBI can be made.[10] Hamman's sign, a sound of crackling that occurs in time with the heartbeat, may also accompany TBI.[14] ## Causes[edit] Injuries to the tracheobronchial tree within the chest may occur due to penetrating forces such as gunshot wounds, but are more often the result of blunt trauma.[6] TBI due blunt forces usually results from high-energy impacts such as falls from height and motor vehicle accidents; the injury is rare in low-impact mechanisms.[2] Injuries of the trachea cause about 1% of traffic-related deaths.[4] Other potential causes are falls from high places and injuries in which the chest is crushed.[15] Explosions are another cause.[16] Gunshot wounds are the commonest form of penetrating trauma that cause TBI.[15] Less commonly, knife wounds and shrapnel from motor vehicle accidents can also penetrate the airways.[6] Most injuries to the trachea occur in the neck,[3] because the airways within the chest are deep and therefore well protected; however, up to a quarter of TBI resulting from penetrating trauma occurs within the chest.[10] Injury to the cervical trachea usually affects the anterior (front) part of the trachea.[17] Certain medical procedures can also injure the airways; these include tracheal intubation, bronchoscopy, and tracheotomy.[4] The back of the trachea may be damaged during tracheotomy.[18] TBI resulting from tracheal intubation (insertion of a tube into the trachea) is rare, and the mechanism by which it occurs is unclear.[19] However, one likely mechanism involves an endotracheal tube catching in a fold of membrane and tearing it as it is advanced downward through the airway.[20] When an endotracheal tube tears the trachea, it typically does so at the posterior (back) membranous wall.[17] Unlike TBI that results from blunt trauma, most iatrogenic injuries to the airway involve longitudinal tears to the back of the trachea or tears on the side that pull the membranous part of the trachea away from the cartilage.[20] Excessive pressure from the cuff of an endotracheal tube can reduce blood supply to the tissues of the trachea, leading to ischemia and potentially causing it to become ulcerated, infected, and, later, narrowed.[4] The mucosal lining of the trachea may also be injured by inhalation of hot gases or harmful fumes such as chlorine gas.[17] This can lead to edema (swelling), necrosis (death of the tissue), scar formation, and ultimately stenosis.[17] However, TBI due to inhalation, foreign body aspiration, and medical procedures is uncommon.[17] ## Mechanism[edit] The structures in the tracheobronchial tree are well protected, so it normally takes a large amount of force to injure them.[6] In blunt trauma, TBI is usually the result of violent compression of the chest.[5][10] Rapid hyperextension of the neck, usually resulting from vehicle crashes, can also injure the trachea, and trauma to the neck can crush the trachea against the vertebrae.[10] A crush injury of the larynx or cervical trachea can occur in head-on collisions when the neck is hyperextended and strikes the steering wheel or dashboard; this has been called a "dashboard injury".[10] The larynx and cervical trachea may also be injured in front-on collisions by the seat belt.[10] Although the mechanism is not well understood, TBI due to blunt trauma is widely thought to be caused by any combination of three possible mechanisms: an increase in pressure within the airways, shearing, and pulling apart.[11] The first type of injury, sometimes called an "explosive rupture", may occur when the chest is violently compressed, for example when a driver strikes the steering wheel in a vehicle accident[4] or when the chest is crushed.[21] The pressure in the airways, especially the larger airways (the trachea and bronchi), quickly rises as a result of the compression,[22] because the glottis reflexively closes off the airways.[2] When this pressure exceeds the elasticity of the tissues, they burst; thus the membranous part of the trachea is more commonly affected by this mechanism of injury than cartilaginous portions.[22] The second mechanism may occur when the chest is suddenly decelerated, as occurs in vehicle accidents, producing a shearing force.[22] The lungs are mobile in the chest cavity but their movement is more restricted near the hilum.[22] Areas near the cricoid cartilage and carina are fixed to the thyroid cartilage and the pericardium respectively; thus if the airways move, they can tear at these points of fixation.[2] The third mechanism occurs when the chest is compressed from front to back, causing it to widen from side to side.[10] The lungs adhere to the chest wall because of the negative pressure between them and the pleural membranes lining the inside of the chest cavity; thus when the chest widens, they are pulled apart.[10] This creates tension at the carina; the airway tears if this tensile force exceeds its elasticity.[10] This mechanism may be the cause of injury when the chest is crushed.[22] Most TBI are probably due to a combination of these three mechanisms.[6] When airways are damaged, air can escape from them and be trapped in the surrounding tissues in the neck (subcutaneous emphysema) and mediastinum (pneumomediastinum); if it builds up to high enough pressures there, it can compress the airways.[2] Massive air leaks from a ruptured airway can also compromise the circulation by preventing blood from returning to the heart from the head and lower body; this causes a potentially deadly reduction in the amount of blood the heart is able to pump out.[7] Blood and other fluids can build up in the airways, and the injury can interfere with the patency of the airway and interfere with its continuity.[2] However, even if the trachea is completely transected, the tissues surrounding it may hold it together enough for adequate air exchange to occur, at least at first.[4] ### Anatomy[edit] Diagram of the larynx, trachea and bronchi. The trachea and bronchi form the tracheobronchial tree. The trachea is situated between the lower end of the larynx and the center of the chest, where it splits into the two bronchi at a ridge called the carina. The trachea is stabilized and kept open by rings made of cartilage that surround the front and sides of the structure; these rings are not closed and do not surround the back, which is made of membrane.[21] The bronchi split into smaller branches and then to bronchioles that supply air to the alveoli, the tiny air-filled sacs in the lungs responsible for absorbing oxygen. An arbitrary division can be made between the intrathoracic and cervical trachea at the thoracic inlet, an opening at the top of the thoracic cavity.[17] Anatomical structures that surround and protect the tracheobronchial tree include the lungs, the esophagus, large blood vessels, the rib cage, the thoracic spine, and the sternum.[17] Children have softer tracheas and a more elastic tracheobronchial trees than adults; this elasticity, which helps protect the structures from injury when they are compressed, may contribute to the lower incidence of TBI in children.[21] ## Diagnosis[edit] A patient with traumatic complete disruption of the right bronchus. Computed tomography scan following emergency chest tube drainage. Axial 1.25 mm thick sections with a lung window. (a) Persistent bilateral pneumothorax, pneumomediastinum and extensive subcutaneous emphysema. (b) Multiple lucencies around the right bronchial tree (curved arrow) precluding the correct recognition of the bronchial rupture. (c) The Macklin effect around the right lower pulmonary vein (white arrow). (d) Coronal view demonstrating multiple areas of alveolar consolidation in the right upper and lower lobes: intraparenchymal lucencies resulting from lung lacerations are visible on the right side (thick arrows). Rapid diagnosis and treatment are important in the care of TBI;[6] if the injury is not diagnosed shortly after the injury, the risk of complications is higher.[11] Bronchoscopy is the most effective method to diagnose, locate, and determine the severity of TBI,[6][10] and it is usually the only method that allows a definitive diagnosis.[23] Diagnosis with a flexible bronchoscope, which allows the injury to be visualized directly, is the fastest and most reliable technique.[8] In people with TBI, bronchoscopy may reveal that the airway is torn, or that the airways are blocked by blood, or that a bronchus has collapsed, obscuring more distal (lower) bronchi from view.[3] Chest x-ray is the initial imaging technique used to diagnose TBI.[17] The film may not have any signs in an otherwise asymptomatic patient.[15] Indications of TBI seen on radiographs include deformity in the trachea or a defect in the tracheal wall.[17] Radiography may also show cervical emphysema, air in the tissues of the neck.[2] X-rays may also show accompanying injuries and signs such as fractures and subcutaneous emphysema.[2] If subcutaneous emphysema occurs and the hyoid bone appears in an X-ray to be sitting unusually high in the throat, it may be an indication that the trachea has been severed.[4] TBI is also suspected if an endotracheal tube appears in an X-ray to be out of place, or if its cuff appears to be more full than normal or to protrude through a tear in the airway.[17] If a bronchus is torn all the way around, the lung may collapse outward toward the chest wall (rather than inward, as it usually does in pneumothorax) because it loses the attachment to the bronchus which normally holds it toward the center.[6] In a person lying face-up, the lung collapses toward the diaphragm and the back.[23] This sign, described in 1969, is called fallen lung sign and is pathognomonic of TBI (that is, it is diagnostic for TBI because it does not occur in other conditions); however it occurs only rarely.[6] In as many as one in five cases, people with blunt trauma and TBI have no signs of the injury on chest X-ray.[23] CT scanning detects over 90% of TBI resulting from blunt trauma,[3] but neither X-ray nor CT are a replacement for bronchoscopy.[6] At least 30% of TBI are not discovered at first;[4] this number may be as high as 50%.[24] In about 10% of cases, TBI has no specific signs either clinically or on chest radiography, and its detection may be further complicated by concurrent injuries, since TBI tends to occur after high-energy accidents.[2] Weeks or months may go by before the injury is diagnosed, even though the injury is better known than it was in the past.[22] ### Classification[edit] Lesions can be transverse, occurring between the rings of the trachea, longitudinal or spiral. They may occur along the membranous part of the trachea, the main bronchi, or both.[2] In 8% of ruptures, lesions are complex, occurring in more than one location, with more than one type of lesion, or on both of the main bronchi and the trachea.[2] Transverse tears are more common than longitudinal or complex ones.[17] The laceration may completely transect the airway or it may go only partway around. Partial tears that do not go all the way around the circumference of the airway do not allow a lacerated airway to become completely detached; tears that encircle the whole airway can allow separation to occur.[23] Lacerations may also be classified as complete or incomplete.[4] In an incomplete lesion, a layer of tissue surrounding the bronchus remains intact and can keep the air in the airway, preventing it from leaking into the areas surrounding the airways.[14] Incomplete lacerations may require closer scrutiny to detect[24] and may not be diagnosed right away.[14] Bronchial injuries are divided into those that are accompanied by a disruption of the pleura and those that are not; in the former, air can leak from the hole in the airway and a pneumothorax can form.[15] The latter type is associated with more minor signs; pneumothorax is small if it occurs at all, and although function is lost in the part of the lung supplied by the injured bronchus, unaffected parts of the lungs may be able to compensate.[15] Most TBI that results from blunt trauma occurs within the chest.[10] The most common tracheal injury is a tear near the carina or in the membranous wall of the trachea.[15] In blunt chest trauma, TBI occurs within 2.5 cm of the carina 40–80% of the time.[2] The injury is more common in the right main bronchus than the left, possibly because the former is near vertebrae, which may injure it.[2] Also, the aorta and other tissues in the mid chest that surround the left main bronchus may protect it.[22] Another possibility is that people with left main bronchus injuries are more likely to also have other deadly injuries and therefore die before reaching hospital, making them less likely to be included in studies that determine rates of injuries.[6] ## Prevention[edit] Vehicle occupants who wear seat belts have a lower incidence of TBI after a motor vehicle accident.[25] However, if the strap is situated across the front of the neck (instead of the chest), this increases the risk of tracheal injury.[10] Design of medical instruments can be modified to prevent iatrogenic TBI, and medical practitioners can use techniques that reduce the risk of injury with procedures such as tracheotomy.[18] ## Treatment[edit] An endotracheal tube may be used to bypass a disruption in the airway Treatment of TBI varies based on the location and severity of injury and whether the patient is stable or having trouble breathing,[2] but ensuring that the airway is patent so that the patient can breathe is always of paramount importance.[10] Ensuring an open airway and adequate ventilation may be difficult in people with TBI.[3] Intubation, one method to secure the airway, may be used to bypass a disruption in the airway in order to send air to the lungs.[3] If necessary, a tube can be placed into the uninjured bronchus, and a single lung can be ventilated.[3] If there is a penetrating injury to the neck through which air is escaping, the trachea may be intubated through the wound.[10] Multiple unsuccessful attempts at conventional (direct) laryngoscopy may threaten the airway, so alternative techniques to visualize the airway, such as fiberoptic or video laryngoscopy, may be employed to facilitate tracheal intubation.[10] If the upper trachea is injured, an incision can be made in the trachea (tracheotomy) or the cricothyroid membrane (cricothyrotomy, or cricothyroidotomy) in order to ensure an open airway.[6] However, cricothyrotomy may not be useful if the trachea is lacerated below the site of the artificial airway.[10] Tracheotomy is used sparingly because it can cause complications such as infections and narrowing of the trachea and larynx.[26] When it is impossible to establish a sufficient airway, or when complicated surgery must be performed, cardiopulmonary bypass may be used—blood is pumped out of the body, oxygenated by a machine, and pumped back in.[26] If a pneumothorax occurs, a chest tube may be inserted into the pleural cavity to remove the air.[12] A left main bronchus laceration, resulting in pneumothorax. Air is evacuated from the chest cavity with a chest tube. People with TBI are provided with supplemental oxygen and may need mechanical ventilation.[13] Employment of certain measures such as Positive end-expiratory pressure (PEEP) and ventilation at higher-than-normal pressures may be helpful in maintaining adequate oxygenation.[3] However, such measures can also increase leakage of air through a tear, and can stress the sutures in a tear that has been surgically repaired; therefore the lowest possible airway pressures that still maintain oxygenation are typically used.[3] Mechanical ventilation can also cause pulmonary barotrauma when high pressure is required to ventilate the lungs.[3] Techniques such as pulmonary toilet (removal of secretions), fluid management, and treatment of pneumonia are employed to improve pulmonary compliance (the elasticity of the lungs).[26] While TBI may be managed without surgery, surgical repair of the tear is considered standard in the treatment of most TBI.[3][27] It is required if a tear interferes with ventilation; if mediastinitis (inflammation of the tissues in the mid-chest) occurs; or if subcutaneous or mediastinal emphysema progresses rapidly;[3] or if air leak or large pneumothorax is persistent despite chest tube placement.[12] Other indications for surgery are a tear more than one third the circumference of the airway, tears with loss of tissue, and a need for positive pressure ventilation.[26] Damaged tissue around a rupture (e.g. torn or scarred tissue) may be removed in order to obtain clean edges that can be surgically repaired.[22] Debridement of damaged tissue can shorten the trachea by as much as 50%.[28] Repair of extensive tears can include sewing a flap of tissue taken from the membranes surrounding the heart or lungs (the pericardium and pleura, respectively) over the sutures to protect them.[2] When lung tissue is destroyed as a result of TBI complications, pneumonectomy or lobectomy (removal of a lung or of one lobe, respectively) may be required.[29] Pneumonectomy is avoided whenever possible due to the high rate of death associated with the procedure.[3] Surgery to repair a tear in the tracheobronchial tree can be successful even when it is performed months after the trauma, as can occur if the diagnosis of TBI is delayed.[3] When airway stenosis results after delayed diagnosis, surgery is similar to that performed after early diagnosis: the stenotic section is removed and the cut airway is repaired.[28] ## Prognosis and complications[edit] Bronchial stenosis (arrow) two weeks after surgery for a tracheobronchial laceration[1] Most people with TBI who die do so within minutes of the injury, due to complications such as pneumothorax and insufficient airway and to other injuries that occurred at the same time.[5] Most late deaths that occur in TBI are attributed to sepsis or multiple organ dysfunction syndrome (MODS).[2] If the condition is not recognized and treated early, serious complications are more likely to occur; for example,[29] pneumonia and bronchiectasis may occur as late complications.[3] Years can pass before the condition is recognized.[9][29] Some TBI are so small that they do not have significant clinical manifestations; they may never be noticed or diagnosed and may heal without intervention.[29] If granulation tissue grows over the injured site, it can cause stenosis of the airway, after a week to a month.[4] The granulation tissue must be surgically excised.[26] Delayed diagnosis of a bronchial rupture increases risk of infection and lengthens hospital stay.[28] People with a narrowed airway may suffer dyspnea, coughing, wheezing, respiratory tract infection, and difficulty with clearing secretions.[10] If the bronchiole is completely obstructed, atelectasis occurs: the alveoli of the lung collapse.[4] Lung tissue distal to a completely obstructed bronchiole often does not become infected. Because it is filled with mucus, this tissue remains functional.[22] When the secretions are removed, the affected portion of the lung is commonly able to function almost normally.[29] However, infection is common in lungs distal to a partially obstructed bronchiole.[22] Infected lung tissue distal to a stricture can be damaged, and wheezing and coughing may develop due to the narrowing.[15] In addition to pneumonia, the stenosis may cause bronchiectasis, in which bronchi are dilated, to develop.[22] Even after an airway with a stricture is restored to normal, the resulting loss of lung function may be permanent.[22] Complications may also occur with treatment; for example, a granuloma can form at the suture site.[2] Also, the sutured wound can tear again, as occurs when there is excessive pressure in the airways from ventilation.[2] However, for people who do receive surgery soon after the injury to repair the lesion, outcome is usually good; the long-term outcome is good for over 90% of people who have TBI surgically repaired early in treatment.[10] Even when surgery is performed years after the injury, the outlook is good, with low rates of death and disability and good chances of preserving lung function.[29] ## Epidemiology[edit] Rupture of the trachea or bronchus is the most common type of blunt injury to the airway.[22] It is difficult to determine the incidence of TBI: in as many as 30–80% of cases, death occurs before the person reaches a hospital, and these people may not be included in studies.[3] On the other hand, some TBI are so small that they do not cause significant symptoms and are therefore never noticed.[29] In addition, the injury sometimes is not associated with symptoms until complications develop later, further hindering estimation of the true incidence.[6] However, autopsy studies have revealed TBI in 2.5–3.2% of people who died after trauma.[3] Of all neck and chest traumas, including people that died immediately, TBI is estimated to occur in 0.5–2%.[29] An estimated 0.5% of polytrauma patients treated in trauma centers have TBI.[10] The incidence is estimated at 2% in blunt chest and neck trauma and 1–2% in penetrating chest trauma.[10] Laryngotracheal injuries occur in 8% of patients with penetrating injury to the neck, and TBI occurs in 2.8% of blunt chest trauma deaths.[6] In people with blunt trauma who do reach a hospital alive, reports have found incidences of 2.1% and 5.3%.[2] Another study of blunt chest trauma revealed an incidence of only 0.3%, but a mortality rate of 67% (possibly due in part to associated injuries).[6] The incidence of iatrogenic TBI (that caused by medical procedures) is rising, and the risk may be higher for women and the elderly.[30] TBI results about once every 20,000 times someone is intubated through the mouth, but when intubation is performed emergently, the incidence may be as high as 15%.[30] The mortality rate for people who reach a hospital alive was estimated at 30% in 1966;[2] more recent estimates place this number at 9%.[22] The number of people reaching a hospital alive has increased, perhaps due to improved prehospital care or specialized treatment centers.[10] Of those who reach the hospital alive but then die, most do so within the first two hours of arrival.[9] The sooner a TBI is diagnosed, the higher the mortality rate; this is likely due to other accompanying injuries that prove fatal.[22] Accompanying injuries often play a key role in the outcome.[10] Injuries that may accompany TBI include pulmonary contusion and laceration; and fractures of the sternum, ribs and clavicles.[2] Spinal cord injury, facial trauma, traumatic aortic rupture, injuries to the abdomen, lung, and head are present in 40–100%.[17] The most common accompanying injury is esophageal perforation or rupture (known as Boerhaave syndrome), which occurs in as many as 43% of the penetrating injuries to the neck that cause tracheal injury.[6] ## History[edit] Throughout most of history, the mortality rate of TBI was thought to be 100%.[5] However, in 1871 a healed TBI was noted in a duck that had been killed by a hunter, thus demonstrating that the injury could be survived, at least in the general sense.[6] This report, made by Winslow, was the first record in the medical literature of a bronchus injury.[22] In 1873, Seuvre made one of the earliest reports of TBI in the medical literature: a 74-year-old woman whose chest was crushed by a wagon wheel was found on autopsy to have an avulsion of the right bronchus.[22] Long-term survival of the injury was unknown in humans until a report was made of a person who survived in 1927.[5][6] In 1931, a report made by Nissen described successful removal of a lung in a 12-year-old girl who had had narrowing of the bronchus due to the injury.[22] Repair of TBI was probably first attempted in 1945, when the first documented case of a successful suturing of a lacerated bronchus was made.[6] Prior to 1950, the mortality rate was 36%; it had fallen to 9% by 2001;[3][22] this improvement was likely due to improvements in treatments and surgical techniques, including those for injuries commonly associated with TBI.[3] ## Notes[edit] 1. ^ a b c Le Guen M, Beigelman C, Bouhemad B, Wenjïe Y, Marmion F, Rouby JJ (2007). "Chest computed tomography with multiplanar reformatted images for diagnosing traumatic bronchial rupture: A case report". Critical Care. 11 (5): R94. doi:10.1186/cc6109. PMC 2556736. PMID 17767714. 2. ^ a b c d e f g h i j k l m n o p q r s t u v w x Chu CP, Chen PP (2002). "Tracheobronchial injury secondary to blunt chest trauma: Diagnosis and management". Anaesthesia and Intensive Care. 30 (2): 145–52. PMID 12002920. 3. ^ a b c d e f g h i j k l m n o p q r s t u Johnson SB (2008). "Tracheobronchial injury". Seminars in Thoracic and Cardiovascular Surgery. 20 (1): 52–57. doi:10.1053/j.semtcvs.2007.09.001. PMID 18420127. 4. ^ a b c d e f g h i j k l m Stark P (1995). "Imaging of tracheobronchial injuries". Journal of Thoracic Imaging. 10 (3): 206–19. doi:10.1097/00005382-199522000-00006. PMID 7674433. 5. ^ a b c d e Barmada H, Gibbons JR (1994). "Tracheobronchial injury in blunt and penetrating chest trauma" (PDF). Chest. 106 (1): 74–8. doi:10.1378/chest.106.1.74. PMID 8020323. 6. ^ a b c d e f g h i j k l m n o p q r s t Riley et al. (2004). pp. 544–7. 7. ^ a b Tovar JA (2008). "The lung and pediatric trauma". Seminars in Pediatric Surgery. 17 (1): 53–9. doi:10.1053/j.sempedsurg.2007.10.008. PMID 18158142. 8. ^ a b Rico FR, Cheng JD, Gestring ML, Piotrowski ES (2007). "Mechanical ventilation strategies in massive chest trauma". Critical Care Clinics. 23 (2): 299–315, xi. doi:10.1016/j.ccc.2006.12.007. PMID 17368173. 9. ^ a b c Nakayama DK, Rowe MI (1988). "Intrathoracic tracheobronchial injuries in childhood". International Anesthesiology Clinics. 26 (1): 42–9. doi:10.1097/00004311-198802610-00009. PMID 3283046. 10. ^ a b c d e f g h i j k l m n o p q r s t u v w x y Karmy-Jones R, Wood DE (2007). "Traumatic injury to the trachea and bronchus". Thoracic Surgery Clinics. 17 (1): 35–46. doi:10.1016/j.thorsurg.2007.03.005. PMID 17650695. 11. ^ a b c d Hwang JC, Hanowell LH, Grande CM (1996). "Peri-operative concerns in thoracic trauma". Baillière's Clinical Anaesthesiology. 10 (1): 123–153. doi:10.1016/S0950-3501(96)80009-2. 12. ^ a b c Wilderman MJ, Kaiser LR (2005). "Thoracic malignancy and pathophysiology". In Atluri P, Karakousis GC, Porrett PM, Kaiser LR (eds.). The Surgical Review: An Integrated Basic and Clinical Science Study Guide. Hagerstown, MD: Lippincott Williams & Wilkins. p. 376. ISBN 0-7817-5641-3. 13. ^ a b Paidas CN. (September 15, 2006) Thoracic Trauma. ped/3001 at eMedicine Retrieved on June 13, 2007. 14. ^ a b c Wong EH, Knight S (2006). "Tracheobronchial injuries from blunt trauma". ANZ Journal of Surgery. 76 (5): 414–5. doi:10.1111/j.1445-2197.2006.03738.x. PMID 16768706. 15. ^ a b c d e f g Smith M, Ball V (1998). "Thoracic trauma". Cardiovascular/respiratory physiotherapy. St. Louis: Mosby. p. 217. ISBN 0-7234-2595-7. Retrieved 2008-06-12. 16. ^ Gabor S, Renner H, Pinter H, et al. (2001). "Indications for surgery in tracheobronchial ruptures". European Journal of Cardio-Thoracic Surgery. 20 (2): 399–404. doi:10.1016/S1010-7940(01)00798-9. PMID 11463564. 17. ^ a b c d e f g h i j k l Euathrongchit J, Thoongsuwan N, Stern EJ (2006). "Nonvascular mediastinal trauma". Radiologic Clinics of North America. 44 (2): 251–58, viii. doi:10.1016/j.rcl.2005.10.001. PMID 16500207. 18. ^ a b Trottier SJ, Hazard PB, Sakabu SA, et al. (1999). "Posterior tracheal wall perforation during percutaneous dilational tracheostomy: An investigation into its mechanism and prevention". Chest. 115 (5): 1383–9. doi:10.1378/chest.115.5.1383. PMID 10334157. 19. ^ Miñambres E, González-Castro A, Burón J, Suberviola B, Ballesteros MA, Ortiz-Melón F (2007). "Management of postintubation tracheobronchial rupture: Our experience and a review of the literature". European Journal of Emergency Medicine. 14 (3): 177–79. doi:10.1097/MEJ.0b013e3280bef8f0. PMID 17473617. 20. ^ a b Conti M, Pougeoise M, Wurtz A, et al. (2006). "Management of postintubation tracheobronchial ruptures". Chest. 130 (2): 412–18. doi:10.1378/chest.130.2.412. PMID 16899839. 21. ^ a b c Granholm T, Farmer DL (2001). "The surgical airway". Respiratory Care Clinics of North America. 7 (1): 13–23. doi:10.1016/S1078-5337(05)70020-4. PMID 11584802. 22. ^ a b c d e f g h i j k l m n o p q r s Kiser AC, O'Brien SM, Detterbeck FC (2001). "Blunt tracheobronchial injuries: treatment and outcomes". Annals of Thoracic Surgery. 71 (6): 2059–65. doi:10.1016/S0003-4975(00)02453-X. PMID 11426809. 23. ^ a b c d Wintermark M, Schnyder P, Wicky S (2001). "Blunt traumatic rupture of a mainstem bronchus: Spiral CT demonstration of the "fallen lung" sign". European Radiology. 11 (3): 409–11. doi:10.1007/s003300000581. PMID 11288843. 24. ^ a b Scaglione M, Romano S, Pinto A, Sparano A, Scialpi M, Rotondo A (2006). "Acute tracheobronchial injuries: Impact of imaging on diagnosis and management implications". European Journal of Radiology. 59 (3): 336–43. doi:10.1016/j.ejrad.2006.04.026. PMID 16782296. 25. ^ Atkins BZ, Abbate S, Fisher SR, Vaslef SN (2004). "Current management of laryngotracheal trauma: Case report and literature review". Journal of Trauma. 56 (1): 185–90. doi:10.1097/01.TA.0000082650.62207.92. PMID 14749588. 26. ^ a b c d e Riley et al. (2004). pp. 548–9. 27. ^ Mussi, A.; Ambrogi, M. C.; Ribechini, A.; et al. (2001). "Acute major airway injuries: clinical features and management". European Journal of Cardio-Thoracic Surgery. 20 (1): 46–51. doi:10.1016/S1010-7940(01)00702-3. PMID 11423273. 28. ^ a b c Riley et al. (2004). pp. 550–51. 29. ^ a b c d e f g h Glazer ES, Meyerson SL (2008). "Delayed presentation and treatment of tracheobronchial injuries due to blunt trauma". Journal of Surgical Education. 65 (4): 302–8. doi:10.1016/j.jsurg.2008.06.006. PMID 18707665. 30. ^ a b Gómez-Caro Andrés A, Moradiellos Díez FJ, Ausín Herrero P, et al. (2005). "Successful conservative management in iatrogenic tracheobronchial injury". Annals of Thoracic Surgery. 79 (6): 1872–8. doi:10.1016/j.athoracsur.2004.10.006. PMID 15919275. ## References[edit] * Riley RD, Miller PR, Meredith JW (2004). "Injury to the esophagus, trachea, and bronchus". In Moore EJ, Feliciano DV, Mattox KL (eds.). Trauma. New York: McGraw-Hill, Medical Pub. Division. pp. 544–52. ISBN 0-07-137069-2. Retrieved 2008-06-15. ## External links[edit] Classification D * ICD-10: S27.4, S27.5 * ICD-9-CM: 862.21 External resources * eMedicine: radio/706 * v * t * e Chest injury, excluding fractures Cardiac and circulatory system injuries * vascular: Traumatic aortic rupture * Thoracic aorta injury * heart: Myocardial contusion/Commotio cordis * Cardiac tamponade * Hemopericardium * Myocardial rupture Lung and lower respiratory tract injuries * Pneumothorax * Hemothorax * Hemopneumothorax * Pulmonary contusion * Pulmonary laceration * Tracheobronchial injury * Diaphragmatic rupture [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Tracheobronchial injury	None	4,603	wikipedia	https://en.wikipedia.org/wiki/Tracheobronchial_injury	2021-01-18T18:54:40	{"icd-9": ["862.21"], "icd-10": ["S27.5", "S27.4"], "wikidata": ["Q7831313"]}
Rasmussen's encephalitis Other namesChronic focal encephalitis Brain CT scan of a girl with Rasmussen's encephalitis. SpecialtyNeurology Rasmussen's encephalitis is a rare inflammatory neurological disease, characterized by frequent and severe seizures, loss of motor skills and speech, hemiparesis (weakness on one side of the body), encephalitis (inflammation of the brain), and dementia. The illness affects a single cerebral hemisphere and generally occurs in children under the age of 15. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 History * 6 Society * 7 References * 8 External links ## Signs and symptoms[edit] The condition mostly affects children, with an average age of 6 years. However, one in ten people with the condition develops it in adulthood.[citation needed] There are two main stages, sometimes preceded by a 'prodromal stage' of a few months. In the acute stage, lasting four to eight months, the inflammation is active and the symptoms become progressively worse. These include weakness of one side of the body (hemiparesis), loss of vision for one side of the visual field (hemianopia), and cognitive difficulties (affecting learning, memory or language, for example). Epileptic seizures are also a major part of the illness, although these are often partial. Focal motor seizures or epilepsia partialis continua are particularly common, and may be very difficult to control with drugs.[citation needed] In the chronic or residual stage, the inflammation is no longer active, but the sufferer is left with some or all of the symptoms because of the damage that the inflammation has caused. In the long term, most patients are left with some epilepsy, paralysis and cognitive problems, but the severity varies considerably.[1] ## Pathophysiology[edit] In Rasmussen's encephalitis, there is chronic inflammation of the brain, with infiltration of T lymphocytes into the brain tissue. In most cases, this affects only one cerebral hemisphere, either the left or the right. This inflammation causes permanent damage to the cells of the brain, leading to atrophy of the hemisphere; the epilepsy that this causes may itself contribute to the brain damage. The epilepsy might derive from a disturbed GABA release,[2] the main inhibitory neurotransmitter of the mammalian brain. The cause of the inflammation is not known: infection by a virus has been suggested, but the evidence for this is inconclusive.[1] In the 1990s it was suggested that auto-antibodies against the glutamate receptor GluR3 were important in causing the disease,[3] but this is no longer thought to be the case.[4] However, more recent studies report the presence of autoantibodies against the NMDA-type glutamate receptor subunit GluRepsilon2 (anti-NR2A antibodies) in a subset of patients with Rasmussen's encephalitis.[5] There has also been some evidence that patients suffering from RE express auto-antibodies against alpha 7 subunit of the nicotinic acetylcholine receptor.[6] By sequencing T cell receptors from various compartments it could be shown that RE patients present with peripheral CD8+ T-cell expansion which in some cases have been proven for years after disease onset.[7] Rasmussen's encephalitis has been recorded with a neurovisceral porphyria, and acute intermittent porphyria.[8] ## Diagnosis[edit] Brain biopsy in Rasmussen's encephalitis showing lymphocytic infiltrates staining for CD8 on immunohistochemistry Brain MRI of an 8-year-old female with Rasmussen's encephalitis. Left: December 2008, the patient was presented with headache and epilepsia partialis continua. There are lesions with local brain swelling in the right parietal and occipital lobes and right cerebellar hemisphere. Right: April 2009, the same patient, now she is comatose with epilepsia partialis continua. There is progression of the encephalitis - the left cerebral hemisphere has been involved with severe brain swelling and shift of the midline structures. The diagnosis may be made on the clinical features alone, along with tests to rule out other possible causes. An EEG will usually show the electrical features of epilepsy and slowing of brain activity in the affected hemisphere, and MRI brain scans will show gradual shrinkage of the affected hemisphere with signs of inflammation or scarring.[9] Brain biopsy can provide very strong confirmation of the diagnosis, but this is not always necessary.[9][10] ## Treatment[edit] During the acute stage, treatment is aimed at reducing the inflammation. As in other inflammatory diseases, steroids may be used first of all, either as a short course of high-dose treatment, or in a lower dose for long-term treatment. Intravenous immunoglobulin is also effective both in the short term and in the long term, particularly in adults where it has been proposed as first-line treatment.[11] Other similar treatments include plasmapheresis and tacrolimus, though there is less evidence for these. None of these treatments can prevent permanent disability from developing.[9][12] During the residual stage of the illness when there is no longer active inflammation, treatment is aimed at improving the remaining symptoms. Standard anti-epileptic drugs are usually ineffective in controlling seizures, and it may be necessary to surgically remove or disconnect the affected cerebral hemisphere, in an operation called hemispherectomy or via a corpus callosotomy. This usually results in further weakness, hemianopsia and cognitive problems, but the other side of the brain may be able to take over some of the function, particularly in young children. The operation may not be advisable if the left hemisphere is affected, since this hemisphere contains most of the parts of the brain that control language. However, hemispherectomy is often very effective in reducing seizures.[1][9] ## History[edit] It is named for the neurosurgeon Theodore Rasmussen [de] (1910–2002), who succeeded Wilder Penfield as head of the Montreal Neurological Institute, and served as Neurosurgeon-in-Chief at the Royal Victoria Hospital.[13][14] ## Society[edit] The Hemispherectomy Foundation was formed in 2008 to assist families with children who have Rasmussen's encephalitis and other conditions that require hemispherectomy.[15] The RE Children's Project was founded in 2010 to increase awareness of Rasmussen's encephalitis. Its primary purpose is to support scientific research directed toward finding a cure for this disease.[citation needed] ## References[edit] 1. ^ a b c Bien, CG; et al. (2005). "Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement". Brain. 128 (Pt 3): 454–471. doi:10.1093/brain/awh415. PMID 15689357. 2. ^ Rassner, Michael P.; van Velthoven-Wurster, Vera; Ramantani, Georgia; Feuerstein, Thomas J. (March 2013). "Altered transporter-mediated neocortical GABA release in Rasmussen encephalitis". Epilepsia. 54 (3): e41–e44. doi:10.1111/epi.12093. PMID 23360283. 3. ^ Rogers SW, Andrews PI, Gahring LC, et al. (1994). "Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis". Science. 265 (5172): 648–51. doi:10.1126/science.8036512. PMID 8036512. 4. ^ Watson R, Jiang Y, Bermudez I, et al. (2004). "Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis". Neurology. 63 (1): 43–50. doi:10.1212/01.WNL.0000132651.66689.0F. PMID 15249609. 5. ^ Takahashi Y, Mori H, Mishina M, et al. (2005). "Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRepsilon2 in patients with Rasmussen's encephalitis (RE) and chronic progressive epilepsia partialis continua". Epilepsia. 46 (Suppl 5): 152–158. doi:10.1111/j.1528-1167.2005.01024.x. PMID 15987271. 6. ^ Watson, R; Jepson, JE; Bermudez, I; Alexander, S; Hart, Y; McKnight, K; Roubertie, A; Fecto, F; Valmier, J; Sattelle, DB; Beeson, D; Vincent, A; Lang, B (Dec 13, 2005). "Alpha7-acetylcholine receptor antibodies in two patients with Rasmussen encephalitis". Neurology. 65 (11): 1802–4. doi:10.1212/01.wnl.0000191566.86977.04. PMID 16344526. 7. ^ Schneider-Hohendorf T, Mohan H, Bien CG, Breuer J, Becker A, Görlich D, Kuhlmann T, Widman G, Herich S, Elpers C, Melzer N, Dornmair K, Kurlemann G, Wiendl H, Schwab N (2016). "CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing". Nat Commun. 7: 11153. doi:10.1038/ncomms11153. PMC 4822013. PMID 27040081. 8. ^ Tziperman B, Garty BZ, Schoenfeld N, Hoffer V, Watemberg N, Lev D, Ganor Y, Levite M, Lerman-Sagie T (2007). "Acute intermittent porphyria, Rasmussen encephalitis, or both?". J. Child Neurol. 22 (1): 99–105. doi:10.1177/0883073807299962. PMID 17608316. 9. ^ a b c d Varadkar S, Bien CG, Kruse CA, Jensen FE, Bauer J, Pardo CA, Vincent A, Mathern GW, Cross JH (2014). "Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances". Lancet Neurol. 13 (2): 195–205. doi:10.1016/S1474-4422(13)70260-6. PMC 4005780. PMID 24457189. 10. ^ Owens GC, Chang JW, Huynh MN, Chirwa T, Vinters HV, Mathern GW (2016). "Evidence for Resident Memory T Cells in Rasmussen Encephalitis". Front Immunol. 7: 64. doi:10.3389/fimmu.2016.00064. PMC 4763066. PMID 26941743. 11. ^ Hart, YM; Cortez, Andermann; Hwang, Fish (1994). "Medical treatment of Rasmussen syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients". Neurology. 44 (6): 1030–1036. doi:10.1212/WNL.44.6.1030. PMID 8208394. 8208394. 12. ^ Takahashi Y, Yamazaki E, Mine J, Kubota Y, Imai K, Mogami Y, Baba K, Matsuda K, Oguni H, Sugai K, Ohtsuka Y, Fujiwara T, Inoue Y (2013). "Immunomodulatory therapy versus surgery for Rasmussen syndrome in early childhood". Brain Dev. 35 (8): 778–85. doi:10.1016/j.braindev.2013.01.010. PMID 23433490. 13. ^ Rasmussen's encephalitis at Who Named It? 14. ^ Rasmussen T, Olszewski J, Lloyd-Smith D (1958). "Focal seizures due to chronic localized encephalitis". Neurology. 8 (6): 435–45. doi:10.1212/WNL.8.6.435. PMID 13566382. 15. ^ "The Community News". Archived from the original on March 29, 2009. Retrieved 2009-02-25. ## External links[edit] Classification D * ICD-10: G04.8 * ICD-9-CM: 323.81 * MeSH: C535291 * DiseasesDB: 33757 * Rasmussen at NINDS (Note: parts of this entry were copied from this Public Domain source.) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Rasmussen's encephalitis	c2930868	4,604	wikipedia	https://en.wikipedia.org/wiki/Rasmussen%27s_encephalitis	2021-01-18T18:57:53	{"mesh": ["C535291"], "umls": ["C2930868"], "icd-9": ["323.81"], "icd-10": ["G04.8"], "orphanet": ["1929"], "wikidata": ["Q1637701"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Neonatal hypocalcemia" – news · newspapers · books · scholar · JSTOR (July 2014) (Learn how and when to remove this template message) 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. (July 2014) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Neonatal hypocalcemia SpecialtyNeonatology Neonatal hypocalcemia is an abnormal clinical and laboratory hypocalcemia condition that is frequently observed in infants. It is commonly presented within the first 72 hours of a newborn's life.[1] Healthy term infants go through a physiological nadir of serum calcium levels at 7.5 - 8.5 mg/dL by day 2 of life. Hypocalcemia is a low blood calcium level. A total serum calcium of less than 8 mg/dL (2mmol/L) or ionized calcium less than 1.2 mmol/L in term neonates is defined as hypocalcemia. In preterm infants, it is defined as less than 7mg/dL (1.75 mmol/L) total serum calcium or less than 4mg/dL (1 mmol/L) ionized calcium. Both early onset hypocalcemia (presents within 72h of birth) and late onset hypocalcemia (presents in 3-7 days after birth) require calcium supplementation treatment. Infants with intrauterine growth retardation, perinatal asphyxia, preterm, and diabetic mothers are most likely to develop neonatal hypocalcemia.[1] It is not understood why premature infants have hypocalcemia, but a proposed idea is that a large increase of calcitonin may lead to hypocalcemia. Another hypothesis includes impaired secretion of PTH or Parathyroid hormone.[2] ## Cause[edit] Risk factors of early neonatal hypocalcemia * Prematurity * Perinatal asphyxia * Diabetes mellitus in the mother * Maternal hyperparathyroidism * Intrauterine growth retardation (IUGR) * Iatrogenic ## Risk factors[edit] Risk factors of late neonatal hypocalcemia * Exogenous phosphate load * Use of gentamicin * Gender and ethnic: late neonatal hypocalcemia occurred more often in male infants and Hispanic infants * Others * Magnesium deficiency * Transient hypoparathyroidism of newborn * Hypoparathyroidism due to other causes (DiGeorge Syndrome) ## References[edit] 1. ^ a b Vuralli, Dogus (2019-06-19). "Clinical Approach to Hypocalcemia in Newborn Period and Infancy: Who Should Be Treated?". International Journal of Pediatrics. 2019: 1–7. doi:10.1155/2019/4318075. ISSN 1687-9740. 2. ^ Schafer, Anne L.; Shoback, Dolores (2013-07-19), "Hypocalcemia: Definition, Etiology, Pathogenesis, Diagnosis, and Management", Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Ames, USA: John Wiley & Sons, Inc., pp. 572–578, ISBN 978-1-118-45392-6, retrieved 2020-12-07 * Jain, A., Agarwal, R., Sankar, M. J., Deorari, A., & Paul, V. K. (2010). Hypocalcemia in the newborn. Indian Journal of Pediatrics, 77, 1123-1128. * Oden, J., Bourgeois, M. (2000). Neonatal endocrinology. Indian Journal of Pediatrics, 77, 21 Classification D External resources * eMedicine: article/921844 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Neonatal hypocalcemia	c0158984	4,605	wikipedia	https://en.wikipedia.org/wiki/Neonatal_hypocalcemia	2021-01-18T19:07:30	{"umls": ["C0158984", "C0342634"], "icd-9": ["775.4"], "icd-10": ["P71"], "wikidata": ["Q18391768"]}
A number sign (#) is used with this entry because LEOPARD syndrome-2 (LPRD2) is caused by heterozygous mutation in the RAF1 gene (164760) on chromosome 3p25. For a phenotypic description and a discussion of genetic heterogeneity of LEOPARD syndrome, see 151100. Clinical Features Pandit et al. (2007) reported 2 women with LEOPARD syndrome-2. Both patients had short stature, hypertrophic cardiomyopathy, lentigines and cafe au lait spots, craniofacial anomlies including dolichocephaly, downslanting palpebral fissures, hypertelorism, thick lips, low-set ears with thickened helix, and prominent chin, short webbed nedk, cubitus valgus, and delayed puberty. One patient had mitral valve anomaly and the other had pulmonary valve stenosis. Molecular Genetics Pandit et al. (2007) analyzed the RAF1 gene in 6 individuals with LEOPARD syndrome who did not have mutations in the PTPN11 gene (176876), and identified 2 unrelated patients with heterozygous missense mutations (S257L, 164760.0001 and L613V, 164760.0004). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	LEOPARD SYNDROME 2	c0175704	4,606	omim	https://www.omim.org/entry/611554	2019-09-22T16:03:08	{"doid": ["0080549"], "mesh": ["D044542"], "omim": ["611554"], "orphanet": ["500"], "genereviews": ["NBK1383"]}
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: "Listeriosis in animals" – news · newspapers · books · scholar · JSTOR (December 2019) (Learn how and when to remove this template message) Encephalitic form in a female sheep Listeriosis is an infectious but not contagious disease caused by the bacterium Listeria monocytogenes, far more common in domestics animals (domestic mammals and poultry), especially ruminants, than in human beings. It can also occur in feral animals—among others, game animals—as well as in poultry and other birds. The causative bacterium lives in the soil and in poorly made silage, and is acquired by ingestion. It is not contagious; over the course of a 30-year observation period of sheep disease in Morocco, the disease only appeared in the late 2000s (decade) when feeding bag-ensiled corn became common.[1] In Iceland, the disease is called "silage sickness".[2] The disease is sporadic, but can occur as farm outbreaks in ruminants. Three main forms are usually recognized throughout the affected species: * encephalitis, the most common form in ruminants. Meningitis or meningoencephalitis are possibilities. * late abortion * gastrointestinal sepsis with liver damage, in monogastric species as well as in preruminant calves and lambs[3] Listeriosis in animals can sometimes be cured with antibiotics (tetracyclines and benzyl penicillin) when diagnosed early. Goats, for example, can be treated upon noticing facial paralysis,[4][citation needed] but is generally fatal. ## Contents * 1 Listeriosis in sheep * 2 Further reading * 3 References * 4 External links ## Listeriosis in sheep[edit] Lateral deviation of head and neck In sheep, the disease is also called the "circling disease".[5] The most obvious signs for the veterinarians are neurological, especially lateral deviation of the neck and head. ## Further reading[edit] * [6] * [7] ## References[edit] 1. ^ Lucien Mahin, Observations on diseases of sheep in Morocco, 1977-2007, unpublished data.[better source needed] 2. ^ Siegmund, Otto H. (1967). The Merck veterinary manual: a handbook of diagnosis and therapy for the veterinarian (3rd ed.). Merck. p. 419. 3. ^ Roger W. Blowey & A. David Weaver, Color Atlas of Diseases and Disorders of Cattle, Elsevier, Oxford, ISBN 0-7234-3205-8. 4. ^ "Listeriosis in sheep and goats". Michigan State University. Retrieved 2019-02-25. 5. ^ Rue Jensen & Brinton L. Swift, Diseases of sheep, Lea & Febiger, Philadelphia ISBN 0-8121-0836-1, p. 159. 6. ^ "Overview of Listeriosis - Generalized Conditions". Merck Veterinary Manual. 7. ^ "Listeria monocytogenes - Infectious Disease and Antimicrobial Agents". www.antimicrobe.org. ## External links[edit] * Listeriosis in Cattle * Description of the disease in the Merck Veterinary Manual [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Listeriosis in animals	None	4,607	wikipedia	https://en.wikipedia.org/wiki/Listeriosis_in_animals	2021-01-18T18:33:46	{"wikidata": ["Q4591781"]}
Periventricular heterotopia is a condition in which the nerve cells (neurons) do not migrate properly during early development of the fetal brain. People with this condition typically develop recurrent seizures (epilepsy) beginning in mid-adolescence. Intelligence is usually normal, but some people may have mild intellectual disability, including difficulty with reading or spelling. Less common features include microcephaly, developmental delay, recurrent infections, and blood vessel abnormalities. Some cases are caused by changes (mutations) in the FLNA gene and are inherited in an X-linked dominant manner. Other cases are caused by mutations in the ARFGEF2 gene and are inherited in an autosomal recessive manner. Rarely, periventricular heterotopia is associated with a duplication of genetic material on chromosome 5. Treatment is generally focused on managing recurrent seizures with medications. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Periventricular heterotopia	c1868720	4,608	gard	https://rarediseases.info.nih.gov/diseases/12724/periventricular-heterotopia	2021-01-18T17:58:22	{"mesh": ["D054091"], "orphanet": ["98892"], "synonyms": ["Periventricular nodular heterotopia", "PVNH"]}
A rare, genetic, syndromic intellectual disability disorder characterized by severe psychomotor development delay (without development of primary motor abilities and speech) and sever intellectual disability, associated with marfanoid habitus, joint laxity, bilateral hip luxation, hypotonia, scoliosis, and characteristic facial dysmorphism (i.e. high nasal bridge, sharp nose, short philtrum, large mouth, full lips and maxillary hypoplasia). There have been no further description in the literature since 1994. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Fryns-Smeets-Thiry syndrome	None	4,609	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2058	2021-01-23T18:00:34	{"gard": ["2409"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-113 (DFNB113) is caused by homozygous mutation in the CEACAM16 gene (614591) on chromosome 19q13. Description DFNB113 is characterized by postlingual progressive hearing impairment (Booth et al., 2018). Clinical Features Booth et al. (2018) studied 7 affected individuals from 2 unrelated consanguineous Iranian families, L-890076 and L-8800015, with progressive, mild to moderate sensorineural hearing loss. All patients had postlingual hearing loss that started in the second decade of life. Clinical evaluation showed that affected individuals had normal vestibular reflexes, vision, skin, cognitive function, and speech development. Molecular Genetics Using OtoSCOPE V.7 to screen the probands in 2 unrelated consanguineous Iranian families with postlingual progressive sensorineural hearing loss, Booth et al. (2018) identified homozygosity for 2 different splicing mutations in the CEACAM16 gene (614591.0003 and 614591.0004) that segregated with disease in the respective families. The authors stated that the deafness phenotype in the 2 families was identical to that reported in patients with heterozygous mutations in CEACAM16 (DFNA4B; 614614), with onset of postlingual progressive hearing loss initially affecting high frequencies in the late first or early second decade of life. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Sensorineural hearing loss, prelingual progressive MISCELLANEOUS \- Onset in second decade of life MOLECULAR BASIS \- Caused by mutation in the carcinoembryonic antigen-related cell adhesion molecule-16 gene (CEACAM16, 614591.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	DEAFNESS, AUTOSOMAL RECESSIVE 113	None	4,610	omim	https://www.omim.org/entry/618410	2019-09-22T15:42:06	{"omim": ["618410"], "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"]}
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: "Serpiginous choroiditis" – news · newspapers · books · scholar · JSTOR (January 2013) (Learn how and when to remove this template message) Serpiginous choroiditis Other namesGeographic helicoid peripapillary choroidopathy Serpiginous choroiditis, also known as geographic or helicoid choroidopathy, is an uncommon chronic progressive inflammatory disease affecting adult men and women equally in the second to seventh decades of life.[1] ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Presentation[edit] In this condition the posterior uveitis shows a geographic pattern. The inflammation begins in the juxtapapillary choroid and intermittently spreads centrifugally. The overlying retinal pigment epithelium and the outer retina are involved in the inflammatory process. A closely related condition is multifocal serpiginoid choroiditis. This is caused by tuberculosis.[2] The distinction between these two conditions is important as the latter responds to anti tuberculosis treatment while the former does not. ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## References[edit] 1. ^ American academy of Ophthalmology (2012). Basic&Clinical Science Course: Intraocular inflammation and uveitis (2011-2012 last major rev. 2010-2012. ed.). American Academy of Ophthalmology. ISBN 978-1615251162.[page needed] 2. ^ Bansal, Reema; Sharma, Kusum; Gupta, Amod; Sharma, Aman; Singh, Mini P; Gupta, Vishali; Mulkutkar, Samyak; Dogra, Mohit; Dogra, Mangat R; Kamal, Shivali; Sharma, Surya Parkash; Fiorella, Paul D (2015). "Detection of Mycobacterium tuberculosis Genome in Vitreous Fluid of Eyes with Multifocal Serpiginoid Choroiditis". Ophthalmology. 122 (4): 840–50. doi:10.1016/j.ophtha.2014.11.021. PMID 25578256. ## External links[edit] Classification D * ICD-10: H30.8 External resources * Orphanet: 35686 This article about an ophthalmic disease is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Serpiginous choroiditis	c0729842	4,611	wikipedia	https://en.wikipedia.org/wiki/Serpiginous_choroiditis	2021-01-18T18:31:27	{"gard": ["31"], "umls": ["C0729842"], "orphanet": ["35686"], "wikidata": ["Q7455142"]}
McKusick–Kaufman syndrome McKusick–Kaufman syndrome is inherited in an autosomal recessive manner McKusick–Kaufman syndrome is a genetic condition associated with MKKS. The condition is named for Dr. Robert L. Kaufman and Victor McKusick.[1] It is sometimes known by the abbreviation MKS.[2] In infancy it can be difficult to distinguish between MKS and the related Bardet–Biedl syndrome, as the more severe symptoms of the latter condition rarely materialise before adulthood.[3] McKusick-Kaufman syndrome affects 1 in 10,000 people in the Old Order Amish population. Research has not identified cases outside of this population.[4] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Presentation[edit] Clinically, McKusick–Kaufman syndrome is characterized by a combination of three features: postaxial polydactyly, heart defects, and genital abnormalities: * Vaginal atresia with hydrometrocolpos * Double vagina and/or uterus. * Hypospadias, chordee (a downward-curving penis), and undescended testes (cryptorchidism). * ureter stenosis or ureteric atresia ## Genetics[edit] MKS is inherited in an autosomal recessive dominance pattern.[5] Both parents of the affected must be heterozygous carriers of the pathogenic variant. Heterozygous carriers for MKS show no symptoms of the disorder, nor can they develop the disorder. Each child of these carriers has a 1/4 chance of being affected by MKS, a 1/2 chance of being carriers themselves, and a 1/4 chance of being unaffected and a non carrier. ## Diagnosis[edit] Clinical findings support the diagnosis of MKS, including identification of biallelic pathogenetic variants. Diagnosis additionally requires ruling out Bardot-Biedl Syndrome.[6] ## Treatment[edit] Treatments are available for accompanying symptoms of MKS, including addressing polydactyly and congenital heart defects.[7] ## See also[edit] * Bardet–Biedl syndrome * Dominance (genetics) ## References[edit] 1. ^ McKusick-Kaufman syndrome at Who Named It? 2. ^ Abbreviation cited at Genetics Home Reference. 3. ^ Reference, Genetics Home. "McKusick-Kaufman syndrome". Genetics Home Reference. Retrieved 2018-11-07. 4. ^ Reference, Genetics Home. "McKusick-Kaufman syndrome". Genetics Home Reference. Retrieved 2018-11-07. 5. ^ Slavotinek AM, "McKusick-Kaufam Syndrome", GeneReviews, 1993-2015 6. ^ Slavotinek, Anne M. (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "McKusick-Kaufman Syndrome", GeneReviews®, University of Washington, Seattle, PMID 20301675, retrieved 2018-11-07 7. ^ Slavotinek, Anne M. (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "McKusick-Kaufman Syndrome", GeneReviews®, University of Washington, Seattle, PMID 20301675, retrieved 2018-11-07 ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 236700 * MeSH: C538159 C538159, C538159 * DiseasesDB: 33261 External resources * GeneReviews: McKusick-Kaufman Syndrome * Orphanet: :2473 * GeneReview/NIH/UW entry on McKusick–Kaufman Syndrome * v * t * e Diseases of cilia Structural * receptor: Polycystic kidney disease * cargo: Asphyxiating thoracic dysplasia * basal body: Bardet–Biedl syndrome * mitotic spindle: Meckel syndrome * centrosome: Joubert syndrome Signaling * Nephronophthisis Other/ungrouped * Alström syndrome * Primary ciliary dyskinesia * Senior–Løken syndrome * Orofaciodigital syndrome 1 * McKusick–Kaufman syndrome * Autosomal recessive polycystic kidney See also: ciliary proteins This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	McKusick–Kaufman syndrome	c0948368	4,612	wikipedia	https://en.wikipedia.org/wiki/McKusick%E2%80%93Kaufman_syndrome	2021-01-18T18:30:13	{"gard": ["3427"], "mesh": ["C538159"], "umls": ["C0948368"], "orphanet": ["2473"], "wikidata": ["Q3508674"]}
Folliculitis decalvans SpecialtyDermatology Folliculitis decalvans is an inflammation of the hair follicle that leads to bogginess or induration of involved parts of the scalp along with pustules, erosions, crusts, ulcers, and scale.[1]:649[2]:760–1 It begins at a central point and spreads outward, leaving scarring, sores, and, due to the inflammation, hair loss in its wake.[3] No permanent cure has been found for this condition, but there is promise in a regimen of dual therapy with rifampin 300 mg twice daily and clindamycin 300 mg twice daily. This new treatment can be used to control the condition, and tests have indicated that after 3 to 5 months long uninterrupted courses of treatment, many patients have seen limited to no recurrence.[4] ## Contents * 1 Causes * 2 Diagnosis * 3 Management * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Causes[edit] This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (January 2019) (Learn how and when to remove this template message) There is no certainty about the cause of this disorder, but the bacterial species Staphylococcus aureus has a central role and can be detected in the lesions of most patients. It is unclear if another primarily sterile process with secondary colonization by Staphylococcus aureus is present, or if Staphylococcus aureus starts the process by causing a strong immune reaction. Another possibility is that Staphylococcus aureus produces toxins that act as superantigens which directly activate the T-cells over the variable domain of T-cell receptors. Nonetheless Staphylococcus aureus can by found in almost all patients affected by this disorder, while it is detected in only 20–30% of non-affected people. As Staphylococcus aureus is not always found in people that suffer from folliculitis decalvans, other factors must be present. Through examinations in families it was found that there is a family connection to the occurrences, which leads to the conclusion that there is a genetic predisposition for it; for example, patients with folliculitis decalvans could have a hereditary different opening of the hair follicle that could facilitate the lodging of the bacteria. Immunologically, another possibility is that especially strong intercellular fixation protein ICAM-1 contributes to inflammation with its strong effect of attracting white blood cells such as granulocytes and lymphocytes. ## Diagnosis[edit] This section is empty. You can help by adding to it. (April 2017) ## Management[edit] This section is empty. You can help by adding to it. (April 2017) ## Epidemiology[edit] This disorder was first described by Charles-Eugène Quinquaud in 1888. He isolated bacteria from the hair follicles of affected patients and introduced them in rats, mice and rabbits, with no result. In 1905 it was then differentiated from other scarring alopecias and the name Folliculitis decalvans, that remains current, was introduced. About 11% of the occurrences of scarring alopecias are of this type. Men are more commonly affected than women and its appearance is usually between the late teens and middle adult years. According to studies in the United States, African Americans are more frequently affected than White Americans. ## See also[edit] * Cicatricial alopecia ## References[edit] 1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Otberg N, Kang H, Alzolibani AA, Shapiro J (2008). "Folliculitis decalvans". Dermatologic Therapy. 21 (4): 238–44. doi:10.1111/j.1529-8019.2008.00204.x. ISSN 1396-0296. PMID 18715292. 4. ^ Powell JJ, Dawber RP, Gatter K (February 1999). "Folliculitis decalvans including tufted folliculitis: clinical, histological and therapeutic findings". The British Journal of Dermatology. 140 (2): 328–33. doi:10.1046/j.1365-2133.1999.02675.x. PMID 10233232. ## External links[edit] Classification D * ICD-10: L66.2 (ILDS L66.200) * ICD-9-CM: 704.09 * DiseasesDB: 33787 * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Folliculitis decalvans	c2608043	4,613	wikipedia	https://en.wikipedia.org/wiki/Folliculitis_decalvans	2021-01-18T18:47:59	{"gard": ["373"], "icd-9": ["704.09"], "icd-10": ["L66.2"], "orphanet": ["346"], "synonyms": [], "wikidata": ["Q1435530"]}
A number sign (#) is used with this entry because of evidence that Waldner blood group expression is caused by a point mutation in the SLC4A1 gene (109270). Lewis and Kaita (1981) found a 'new' red cell antigen in Hutterites of the surname Waldner. Zelinski et al. (1995) stated that the WD blood group antigen had been identified in Khoisans in South Africa and in a family in Holland. By genetic linkage analysis, they showed that WD is loosely linked to the reference marker D17S41 at 17q12-q24 and closely linked to the SLC4A1 locus at 17q12-q21. Bruce et al. (1995) demonstrated that the Wd(a) results from a substitution of methionine for valine-557 in erythrocyte band-3 (109270.0011). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	BLOOD GROUP--WALDNER TYPE	c1862191	4,614	omim	https://www.omim.org/entry/112010	2019-09-22T16:44:11	{"omim": ["112010"], "synonyms": ["Alternative titles", "WALDNER BLOOD GROUP ANTIGEN"]}
Endomyocardial fibroelastosis is a cause of unexplained childhood cardiac insufficiency. It results from diffuse thickening of the endocardium leading to dilated myocardiopathy in the majority of cases and restrictive myocardiopathy in rare cases. It may occur as a primary disorder or may be secondary to another cardiac malformation, notably aortic stenosis or atresia. ## Epidemiology The incidence at birth is estimated at 1 in 5 000. ## Clinical description In the majority of cases, endomyocardial fibroelastosis is diagnosed at between 3 and 6 months of age. The cardiac insufficiency may be acute with a severe prognosis or chronic. ## Etiology The underlying cause of the sporadic cases is unknown: it may be associated with an antenatal viral infection, subendocardial ischemia or metabolic anomalies. ## Genetic counseling The primary form is mainly sporadic but 10% of cases are familial with all possible modes of transmission (autosomal dominant, autosomal recessive, X-linked). ## Management and treatment Treatment is the same as that used for cardiac insufficiency. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Endocardial fibroelastosis	c0014117	4,615	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2022	2021-01-23T18:51:00	{"gard": ["2121", "6336"], "mesh": ["D004695"], "omim": ["226000"], "umls": ["C0014117"], "icd-10": ["I42.4"], "synonyms": ["Endomyocardial fibroelastosis"]}
## Summary ### Clinical characteristics. Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include chronic obstructive pulmonary disease, diabetes mellitus as a result of insulin resistance, and cancer of a wide variety of types and anatomic sites. ### Diagnosis/testing. The diagnosis of BSyn is established in a proband with characteristic clinical features and/or biallelic pathogenic variants in BLM identified on molecular genetic testing. Identification of increased frequency of sister-chromatid exchanges on specialized cytogenetic studies and exclusion of RMI1, RMI2, and TOP3A-related disorders may be helpful in establishing the diagnosis in those with characteristic clinical features who do not have biallelic pathogenic variants in BLM. ### Management. Treatment of manifestations: Skin protection, including coverage of exposed skin and use of broad-spectrum sunscreen with SPF of at least 30 to reduce the sun-sensitive rash. Increased-calorie-density formulas and foods may promote weight gain. Although growth hormone treatment may improve linear growth, many clinicians caution against its use because of reports of early onset of cancer in some treated children. Developmental services and therapies as needed. Hyperglycemia from insulin resistance is treated as in type 2 diabetes. In persons with BSyn who have cancer, reduced chemotherapy dosage and duration to reduce risks of severe complications; caution should be exercised with use of ionizing radiation or alkylating agents, particularly busulfan, cyclophosphamide, or melphalan. Individuals with recurrent infections and defects in humoral immunity may be treated with gamma globulin infusions to decrease frequency and severity of infections. Surveillance: Abdominal ultrasound examination every three months until age eight years for Wilms tumor. Screening and family education regarding signs/symptoms of leukemia and lymphoma at every health visit. Whole-body MRI every one to two years beginning at age 12-13 years for risk of lymphoma. Annual colonoscopy beginning at age 10-12 years. Fecal immunochemical testing every six months beginning at age 10-12 years. Annual breast MRI in women beginning at age 18 years. Annual fasting blood glucose and hemoglobin A1C beginning at age ten years. Annual serum TSH with reflex to T4 beginning at age ten years. Annual lipid profile beginning at age ten years. Agents/circumstances to avoid: Sun exposure may provoke an erythematous rash, especially on the face. Exposure to ionizing radiation should be minimized. ### Genetic counseling. BSyn is inherited in an autosomal recessive manner. Identification of both pathogenic BLM variants in the proband is required for carrier (heterozygote) testing in at-risk families. BLM is included in expanded carrier screening panels, and most pathogenic variants can be identified through sequencing. Preimplantation and prenatal diagnosis are possible if the BLM pathogenic variants have been identified in the at-risk couple. ## Diagnosis ### Suggestive Findings Bloom syndrome (BSyn) should be suspected in an individual with any of the following clinical or cytogenetic findings. Clinical findings * Prenatal-onset growth deficiency that usually includes linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood * Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution * Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population Cytogenetic findings * Increased numbers of sister-chromatid exchanges * Increased quadriradial configurations (Qrs) in cultured blood lymphocytes (a mean of 1%-2% Qrs are observed in cultured blood lymphocytes from a person with BSyn vs none in controls) * Chromatid gaps, breaks, and rearrangements ### Establishing the Diagnosis The diagnosis of BSyn is established in a proband by identification of biallelic pathogenic variants in BLM on molecular genetic testing (see Table 1). Note: An increased frequency of sister-chromatid exchanges (SCEs) on specialized cytogenetic studies may be helpful in circumstances where BLM variant analysis is inconclusive. SCE analysis alone is not sufficient to confirm a diagnosis of BSyn because increased SCEs are also observed in persons with biallelic pathogenic variants in RMI1, RMI2, and TOP3A [Hudson et al 2016, Martin et al 2018]. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, 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 BSyn is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with growth deficiency are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Bloom syndrome molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of BLM 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 only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes BLM 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 many other inherited disorders characterized by growth deficiency, 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. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Bloom Syndrome View in own window Gene 1Test Method% of Pathogenic Variants 2 Detectable by This Method Ashkenazi Jewish AncestryNon-Jewish Ancestry BLMTargeted analysis for c.2207_2212delinsTAGTTC93% 36% 4 Sequence analysis 5~99% 387% 4 Gene-targeted deletion/duplication analysis 61% 44% 4 Unknown 7NA 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. German et al [2007] 4\. Bloom Syndrome Registry 5\. 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. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. In nine individuals with BSyn, pathogenic variants in BLM were not detected, suggesting the possibility of locus heterogeneity [German et al 2007]. Sister-chromatid exchanges (SCEs). Individuals with BSyn have a mean of 40-100 SCEs per metaphase (normal SCEs: <10 per metaphase). Increased frequency of SCEs is demonstrable in BSyn cultured cells (including lymphocytes, fibroblasts, and amniocytes) allowed to proliferate in a medium containing 5'bromo-2'-deoxyuridine (BrdU). Increased SCEs are not unique to BSyn. Three additional autosomal recessive disorders (RMI1-, RMI2-, and TOP3A-related disorders) are associated with increased SCEs and similar clinical findings to individuals with BSyn. SCE analysis may be a useful adjunct for diagnosis of BSyn, in the circumstance where only one BLM pathogenic variant is identified, and molecular genetic testing finds no pathogenic variants in RMI1, RMI2, or TOP3A. The presence of increased SCEs alone, however, is not sufficient to confirm the diagnosis of BSyn. ## Clinical Characteristics ### Clinical Description The range of clinical features in persons with Bloom syndrome (BSyn) has been tracked through the Bloom Syndrome Registry. The clinical and genetic histories have been obtained from registered persons diagnosed between 1954 and 2018 and their clinical courses have been followed [German & Passarge 1989, German 1993, German & Ellis 2002]. The main clinical features of BSyn are the following: * Size and appearance. The most consistent clinical feature of BSyn seen throughout all stages of life is growth deficiency affecting height, weight, and head circumference. Body proportions are normal. Subcutaneous adipose tissue is sparse throughout childhood and adolescence, but adults may develop central obesity. Providing increased calories in childhood and adolescence does not usually result in substantial changes in growth parameters, particularly linear growth. Plasma growth hormone concentration is normal. The affected fetus is smaller than normal for gestational age. The mean birth weight of affected males is 1,760 g (range 900-3,189 g) and of affected females, 1,754 g (range 700-2,892 g). The average adult height of men is 149 cm (range 128-164 cm) and of women, 138 cm (range 115-160 cm). The facial appearance of people with BSyn is variable and may be indistinguishable from unaffected persons of similar age and size. More commonly, the face appears narrow, with underdeveloped malar and mandibular prominences and retrognathia or micrognathia. A paucity of subcutaneous fat may cause the nose and/or ears to appear prominent. * Feeding problems. Most parents report that feeding is an issue for their newborns, infants, and young children. The child with BSyn characteristically feeds slowly, has a decreased appetite, and eats a limited variety of foods. In a minority of infants with BSyn, nursing and eating are normal. Because of their slow growth and weight gain, many children are prescribed formula with increased caloric density and later are prescribed nutritional supplements that provide extra calories. Many infants have had gastrostomy tubes placed. Despite these maneuvers, weight gain continues to be modest, and children are rarely in the normal range for growth. Gastroesophageal reflux is common and may contribute to the feeding issues. * Skin lesions. The skin at birth and during early infancy appears normal; however, typically following sun exposure during the first or second year of life, a red, sun-sensitive rash appears on the nose and cheeks and sometimes also on the dorsa of the hands and forearms. This rash varies in severity and extent among affected individuals; in some, it is minimal. It is usually characterized by telangiectasia but in others is described as poikiloderma. In severely affected individuals, the lesion can be bright red and can extend onto adjacent areas. Additional dermatologic manifestations include cheilitis, blistering and fissuring of the lips, eyebrow and eyelash hair loss, alopecia areata, and vesicular and bullous lesions with excessive or intense sun exposure. Café au lait macules and areas of hypopigmented skin are more numerous and larger than in those without BSyn. * Immunodeficiency. In children and adults who have had laboratory evaluation of their immune system, the concentration of one or more of the plasma immunoglobulins is usually abnormally low. IgM and IgA levels are most commonly affected. Although the numbers of T and B cells are usually normal, variable abnormalities of the adaptive immune system suggest a possible role in the frequent infections reported in affected individuals. * Infections. Parents of children with BSyn report that their affected children have more childhood infections than their sibs and peers; none, however, has had an opportunistic infection, and few persons with BSyn have had bacterial sepsis, meningitis, or pneumonia. * Fertility. Most men with BSyn appropriately examined have had azoospermia or severe oligospermia. There is, however, one confirmed case of paternity [Ben Salah et al 2014]. Women with BSyn, although often fertile, may enter menopause prematurely. Eleven women with BSyn followed in the Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size. * Intelligence. There are no systematic studies of academic achievement or cognitive performance in persons with BSyn. The great majority appear to perform within the normal range of intellectual development. Some have required academic support for attention-related issues and task orientation, but it is not clear that the prevalence of these problems is different from that seen in the general population. Many others have excelled in school, with some earning graduate degrees. * Other clinical features. Major anatomic defects are not increased in frequency. In the 281 persons in the Registry as of 2018, only single examples of the following have occurred: tracheoesophageal fistula, cardiac malformation, absent thumbs, and absence of a toe and malformation of a thumb. Medical complications of BSyn, all serious, in order of increasing frequency are the following: * Chronic obstructive pulmonary disease. Chronic bronchitis and bronchiectasis are common, and pulmonary failure has been the cause of death in six persons. * Myelodysplasia has been diagnosed in 23 persons in the Registry at a median age of 22.1 years (range 3-47), and it has progressed to acute myelogenous leukemia in at least seven. In all but three, the myelodysplasia was preceded by some form of cancer for which chemotherapy and/or radiotherapy had been administered. * Diabetes mellitus. Abnormalities in insulin release and glucose tolerance have been detected in the eight healthy children (ages 9 months to 13 years) and the three healthy young adults with BSyn (ages 22, 28, and 28 years) appropriately studied [Diaz et al 2006]. Because of insulin resistance, the diabetes mellitus of BSyn resembles type 2 diabetes but has a much earlier age of onset than in the general population. Paradoxically, diabetes in persons with BSyn commonly occurs in the setting of low body mass index (BMI), rather than high BMI. Diabetes has been diagnosed in 47 of 281 persons in the Registry (16.7%) at a mean age of 26.6 years (range 4-45 years). Although most individuals do not have severe complications, 16 have required insulin, and retinopathy has developed in two. Lipid profile abnormalities were also identified by Diaz et al [2006] in five of the ten subjects tested. * Cancer is the most frequent medical complication in BSyn and the most common cause of death. Although the wide distribution of cell types and anatomic sites of cancer resemble that in the general population, it occurs more frequently and at much earlier ages in BSyn. Development of multiple cancers in a single individual is also much more common. Table 2 summarizes the cancers diagnosed in individuals followed in the Registry. ### Table 2. The 226 Malignant Neoplasms Diagnosed in 145 Persons in the Bloom Syndrome Registry (1954-2018) View in own window Malignancy Type / TissueSubtypeFrequencyAge at Diagnosis (years) MedianMeanRange LeukemiaAcute myeloid1721196-32 Acute lymphoblastic1114174-40 Other/biphenotypic/undefined1218192-40 Lymphoma\--3720214-49 OropharyngealTongue9373730-48 Pharynx63234.831-45 Tonsil4403825-46 Other5NANANA Upper GIEsophageal5393725-48 Gastric5312924-33 Other4NANANA Colorectal\--28373516-49 GenitourinaryCervical5222119-23 Other9NANANA Breast\--24333321-52 SkinBasal cell13292818-38 Squamous cell (uncategorized)5353535-36 Other/undefined4NANANA Wilms tumor\--8331-8 Lung\--4373632-40 All other\--12NANANA GI = gastrointestinal Adapted from Cunniff et al [2018] ### Genotype-Phenotype Correlations Homozygotes and compound heterozygotes. A similar phenotype is produced by either homozygosity or compound heterozygosity for any of the more than 60 pathogenic variants in BLM identified to date. ### Prevalence Few individuals with BSyn have been reported in the medical literature since its description half a century ago [Bloom 1954], and fewer than 300 are known to the Bloom Syndrome Registry. Although rare in all populations, BSyn is relatively less rare among Ashkenazi Jews. Sixty-seven of the 281 persons in the Registry are of Ashkenazi Jewish ancestry. The predominant BLM pathogenic variant identified in Ashkenazi Jews is c.2207_2212delinsTAGATTC, a 6-bp deletion/7-bp insertion in exon 10 of BLM, often (for brevity) designated blmAsh; the second most common pathogenic variant is c.2407dupT. The approximate carrier frequency of the blmAsh allele: * One in 100 Ashkenazi Jews dwelling both in New York City [Li et al 1998] and in Israel [Peleg et al 2002] * One in 37 Ashkenazi Jews dwelling in Israel, all four of whose grandparents were from Poland [Shahrabani-Gargir et al 1998] ## Differential Diagnosis ### Table 3. Other Genetic Etiologies of Interest in the Differential Diagnosis of Bloom Syndrome (BSyn) View in own window Gene(s) / Genetic MechanismDisorderMOIClinical Features of Differential Diagnosis Disorder Overlapping w/BSynDistinguishing from BSyn RMI1 1RECQ-mediated genome instability 1 (OMIM 610404)AR * ↑ SCE * Small size * Multiple café au lait macules in persons w/TOP3A & RMI2 pathogenic variants * Cancer not observed, but reported persons are all relatively young: cancer predisposition may be identified in future. * No abnormal skin findings in persons w/RMI1 pathogenic variants * No malar rash in persons w/TOP3A pathogenic variants RMI2 1RECQ-mediated genome instability 2 (OMIM 612426)AR TOP3A 1Microcephaly, growth restriction, & increased sister-chromatid exchange 2 (OMIM 618097)AR Chromosome 11p15 hypomethylation or matUPD7Silver-Russell syndromeSee footnote 2Growth deficiency * Not associated w/↑ SCE * Ophthalmalogic abnormalities ATMAtaxia-telangiectasiaAR * Small stature * Evidence of excessive genomic instability * Telangiectasis * Sinopulmonary infection * Immunodeficiency * Progressive cerebellar ataxia from early childhood * ↑ alpha-fetoprotein levels BRCA2 BRIP1 FANCA FANCB FANCC FANCD2 FANCE FANCF FANCG FANCI 3Fanconi anemiaAR (AD XL) * Small stature * Evidence of excessive genomic instability * ↑ cancer susceptibility * Cutaneous abnormalities (café au lait macules, hyper- or hypopigmentation) * ↓ fertility * Endocrinopothy * Skeletal malformations * Bone marrow failure MRE11Ataxia-telangiectasia-like disorder (OMIM 604391)AR * Small stature * Evidence of excessive genomic instability * Progressive cerebellar degeneration * No telangiectasias or immunodeficiency NBNNijmegen breakage syndromeAR * Small stature * Evidence of excessive genomic instability * Immunodeficiency * Café au lait macules * Predisposition to lymphoid malignancy * Decline in intellectual performance * No telangiectasias WRNWerner syndromeAR * Small stature * Evidence of excessive genomic instability * ↑ incidence of diabetes * Premature artherosclerosis * Prematurely aged appearance AD = autosomal dominant; AR = autosomal recessive; matUPD7 = maternal uniparental disomy for chromosome 7; MOI = mode of inheritance; SCE = sister-chromatid exchange; XL = X-linked 1\. RMI1, RMI2, and TOP3A encode proteins that make up the BTRR complex. The BLM protein forms the BTRR complex with topoisomerase III alpha (TopIIIa) and RecQ-mediated genome instability proteins 1 and 2 (RMI1 and RMI2, respectively). Together, these proteins process double Holliday junctions that arise as a result of homologous-recombination-mediated repair of double-stranded DNA breaks during DNA synthesis. 2\. Silver-Russell syndrome has multiple etiologies including: epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, maternal UPD7, and (infrequently) autosomal dominant or autosomal recessive inheritance. 3\. Listed genes represent the most common genetic causes of Fanconi anemia. For other genes associated with this phenotype (20 genes have been identified), see Fanconi anemia. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Bloom syndrome (BSyn), in addition to the routine medical history, family history, and physical examination, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Bloom Syndrome (BSyn) View in own window System/ConcernEvaluationComment GastrointestinalConsultation w/gastroenterologist &/or feeding specialistEvaluation for gastroesophageal reflux & problem feeding behaviors Colonoscopy & fecal immunochemical testingIn probands age ≥10 yrs DermatologicCareful history & skin examination for sun-sensitive skin rash & for moles or nevi suspicious for basal cell or squamous cell carcinoma Immune * Immunodeficiency screening incl immunoglobulin level, antibody responses to vaccines, & number of B & T lymphocytes * Referral to immunologist as needed If patient has experienced severe &/or recurrent infections EndocrineFasting blood glucose & hemoglobin A1C concentrationIn probands age ≥10 yrs to evaluate for evidence of diabetes mellitus Thyroid function testing: TSH w/reflex to T4At any age Lipid profileBeginning at age 10 yrs RenalAbdominal ultrasound examination for Wilms tumorIn probands age ≤8 yrs LymphoreticularWhole-body MRI scan for lymphomaIn probands age ≥12 yrs BreastBreast MRI scanIn female probands age ≥18 yrs DevelopmentalDevelopmental assessmentIf indicated based on developmental history OtherConsultation w/clinical geneticist &/or genetic counselor ### Treatment of Manifestations Health supervision recommendations that address diagnosis, treatment, and surveillance for complications in persons with BSyn have been published [Cunniff et al 2018]. Skin. Reduce excessive exposure to sunlight by seeking shade, particularly between 10 am and 4 pm. Cover exposed skin with clothing, including a broad-brimmed hat and UV-blocking sunglasses. Apply a broad-spectrum sunscreen with SPF of 30 twice daily, or every two to three hours if outdoors. Psychosocial. Family and teachers are encouraged to relate to persons with BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Growth. Growth hormone administration to children with BSyn has not consistently increased growth rate in most persons, but some have experienced improved linear growth. Use of growth hormone has been approached cautiously in this population because of concerns regarding an increased risk of developing tumors as a result of their treatment. If growth hormone is prescribed, the growth response and serum IGF-1 and IGFBP-3 levels should be closely monitored, and unless there is an increase in growth velocity while under treatment, it should be discontinued. Nutrition. Until additional information is available regarding treatment of problematic feeding behaviors and gastrointestinal symptoms, standard treatment for these concerns is recommended. This may include consultation with a gastroenterologist or feeding specialist, use of high-calorie diets, institution of reflux precautions, and use of anti-reflux medications. Studies of small cohorts of individuals with BSyn have shown that supplemental feeding may result in increased fat deposition but not in improved linear growth. Because abnormalities have been identified in the lipid profile of persons with BSyn, caution should be exercised in the use of high-fat and/or high-cholesterol diets. Cognitive. Infants, toddlers, and preschool-age children with BSyn should have close developmental monitoring and referral for early intervention services. If developmental delays are present, physical, occupational, and speech therapy can help. School performance should be assessed regularly and parents made aware of available educational support. Diabetes mellitus. Treatment of diabetes mellitus in BSyn is the same as in other persons. Hypothyroidism. Thyroid hormone replacement therapy is recommended according to standard protocols. Dyslipidemia. Dietary treatment according to standard protocols is recommended. Cancer. The hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation ordinarily necessitates modification of standard cancer treatment regimens, which usually includes a reduction of both dosage and duration. Individuals with BSyn have usually tolerated doses at or below 50% of the standard chemotherapy dosage, with no clear evidence that this has resulted in poorer outcomes. However, full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors. Absence of information as to the ideal dosages makes such treatment particularly challenging to the physician; nevertheless, the fact that the cancers themselves often appear unusually responsive to the treatment justifies the special effort. Bone marrow transplantation (BMT). Hematopoietic stem cell transplantation (HSCT) has been performed in three persons in the Bloom Syndrome Registry. One person had more than five years of disease-free survival before succumbing to another cancer, and the other two persons died in the immediate post-transplant period. If HSCT is being contemplated, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens. Additionally, the required ablative therapy prior to BMT often may require modification of standard protocols because of the hypersensitivity of persons with BSyn to DNA-damaging agents. Immune. Defects in humoral immunity can be managed with weekly subcutaneous or monthly intravenous infusions of gamma globulin. Cough assist devices, vibration vests, and daily nasal lavage can be used for mucociliary clearance for bronchiectasis. If an individual with BSyn experiences recurrent, severe, or opportunistic infection, immunodeficiency screening (including immunoglobulin level, antibody responses to vaccines, and quantitative B- and T-lymphocyte measurements) is recommended. Fertility * Men with BSyn can undergo semen analysis to reveal azoospermia, oligospermia, or asthenospermia. Those who wish to conceive should consider consulting a fertility specialist. It is unclear if assisted reproductive technology (ART) may be helpful in persons with oligospermia or other abnormalities. * Women with BSyn should be aware of signs of early menopause. Oocyte cryopreservation can be considered. Additionally, ART may be beneficial if natural conception is not possible; the authors are not aware of any prior use of ART in this population. ### Surveillance Health supervision recommendations for surveillance in persons with BSyn have been published [Cunniff et al 2018]. It should be recognized, however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case-control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment. ### Table 5. Recommended Surveillance for Individuals with Bloom Syndrome (BSyn) View in own window ManifestationEvaluationFrequency Wilms tumor * Abdominal ultrasound * Screen for signs/symptoms incl hematuria & a painless abdominal mass Every 3 mos from time of diagnosis to age 8 yrs LeukemiaScreening & family education on signs/symptoms incl pallor, abnormal bleeding, petechiae, fatigue, unintentional weight lossEvery health visit LymphomaScreening & family education on signs/symptoms incl enlarged lymph nodes, unexplained fevers, drenching night sweats, fatigue, unintentional weight lossEvery health visit Whole-body MRIEvery 1-2 yrs from age 12-13 yrs Colorectal cancerColonoscopyAnnually from age 10-12 yrs Fecal immunochemical testingEvery 6 mos from age 10-12 yrs Breast cancerBreast MRI in femalesAnnually from age 18 yrs Skin cancerSkin examination w/dermatologist for any suspicious skin lesionsOn recognition of suspicious lesions & annually thereafter Diabetes mellitus * Fasting blood glucose & hemoglobin A1C * Screening & family education on signs/symptoms of polyuria, polydipsia, weight loss Annually from age 10 yrs Hypothyroidism * Serum TSH w/reflex to T4 * Screening & family education on signs/symptoms incl fatigue, constipation, cold sensitivity, weight gain Annually from age 10 yrs DyslipidemiaLipid profileAnnually from age 10 yrs ### Agents/Circumstances to Avoid Sun exposure to the face and other exposed areas, particularly in infancy and early childhood, should be avoided. Exposure to ionizing radiation should be minimized. ### Evaluation of Relatives at Risk It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from avoidance of sun exposure to the face and early surveillance for cancer (see Surveillance). * Molecular genetic testing can be used to evaluate sibs if the BLM pathogenic variants in the family are known. * An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing. See Genetic Counseling for issues related to the testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Eleven women with BSyn followed in the Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size. See MotherToBaby for more information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Bloom Syndrome	c0005859	4,616	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1398/	2021-01-18T21:39:07	{"mesh": ["D001816"], "synonyms": []}
Usher syndrome is a genetic disorder characterized by sensorineural hearing loss or deafness and progressive vision loss due to retinitis pigmentosa. Sensorineural hearing means it is caused by abnormalities of the inner ear. Retinitis pigmentosa is an eye disease that affects the layer of light-sensitive tissue at the back of the eye (the retina). Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. Night vision loss begins first, followed by blind spots that develop in the side (peripheral) vision, that can enlarge and merge to produce tunnel vision (loss of all peripheral vision). In some cases, vision is further impaired by clouding of the lens of the eye (cataracts). Three major types of Usher syndrome have been described - types I, II, and III. The different types are distinguished by their severity and the age when signs and symptoms appear. All three types are inherited in an autosomal recessive manner. Treatment for the hearing loss may include hearing aids or surgery for a cochlear implant. Vitamin A palmitate is useful for treating the vision loss in people with Usher syndrome type II. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Usher syndrome	c0271097	4,617	gard	https://rarediseases.info.nih.gov/diseases/7843/usher-syndrome	2021-01-18T17:57:13	{"mesh": ["D052245"], "umls": ["C0271097"], "orphanet": ["886"], "synonyms": ["Deafness-retinitis pigmentosa syndrome", "Dystrophia retinae pigmentosa-dysostosis syndrome", "Graefe-Usher syndrome", "Hallgren syndrome", "Usher's syndrome"]}
For the genus of fungi, see Piloderma. Pyoderma Pyodermia of parasitic origin SpecialtyDermatology Pyoderma means any skin disease that is pyogenic (has pus). These include superficial bacterial infections such as impetigo, impetigo contagiosa, ecthyma, folliculitis, Bockhart's impetigo, furuncle, carbuncle, tropical ulcer, etc.[1][2] Autoimmune conditions include pyoderma gangrenosum. Pyoderma affects more than 111 million children worldwide, making it one of the three most common skin disorders in children along with scabies and tinea.[1] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ a b Andrews RM, McCarthy J, Carapetis JR, Currie BJ (December 2009). "Skin disorders, including pyoderma, scabies, and tinea infections". Pediatr. Clin. North Am. 56 (6): 1421–40. doi:10.1016/j.pcl.2009.09.002. PMID 19962029. 2. ^ Page 348 in: Fisher, Bruce; Harvey, Richard P.; Champe, Pamela C. (2007). Lippincott's Illustrated Reviews: Microbiology (Lippincott's Illustrated Reviews Series). Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-8215-5. ## External links[edit] Classification D * ICD-10: L08.0 * ICD-9-CM: 686.0 * MeSH: D011711 * v * t * e Bacterial skin disease Gram +ve Firmicutes * Staphylococcus * Staphylococcal scalded skin syndrome * Impetigo * Toxic shock syndrome * Streptococcus * Impetigo * Cutaneous group B streptococcal infection * Streptococcal intertrigo * Cutaneous Streptococcus iniae infection * Erysipelas / Chronic recurrent erysipelas * Scarlet fever * Corynebacterium * Erythrasma * Listeriosis * Clostridium * Gas gangrene * Dermatitis gangrenosa * Mycoplasma * Erysipeloid of Rosenbach Actinobacteria * Mycobacterium-related: Aquarium granuloma * Borderline lepromatous leprosy * Borderline leprosy * Borderline tuberculoid leprosy * Buruli ulcer * Erythema induratum * Histoid leprosy * Lepromatous leprosy * Leprosy * Lichen scrofulosorum * Lupus vulgaris * Miliary tuberculosis * Mycobacterium avium-intracellulare complex infection * Mycobacterium haemophilum infection * Mycobacterium kansasii infection * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Rapid growing mycobacterium infection * Scrofuloderma * Tuberculosis cutis orificialis * Tuberculosis verrucosa cutis * Tuberculous cellulitis * Tuberculous gumma * Tuberculoid leprosy * Cutaneous actinomycosis * Nocardiosis * Cutaneous diphtheria infection * Arcanobacterium haemolyticum infection * Group JK corynebacterium sepsis Gram -ve Proteobacteria * α: Endemic typhus * Epidemic typhus * Scrub typhus * North Asian tick typhus * Queensland tick typhus * Flying squirrel typhus * Trench fever * Bacillary angiomatosis * African tick bite fever * American tick bite fever * Rickettsia aeschlimannii infection * Rickettsialpox * Rocky Mountain spotted fever * Human granulocytotropic anaplasmosis * Human monocytotropic ehrlichiosis * Flea-borne spotted fever * Japanese spotted fever * Mediterranean spotted fever * Flinders Island spotted fever * Verruga peruana * Brill–Zinsser disease * Brucellosis * Cat-scratch disease * Oroya fever * Ehrlichiosis ewingii infection * β: Gonococcemia/Gonorrhea/Primary gonococcal dermatitis * Melioidosis * Cutaneous Pasteurella hemolytica infection * Meningococcemia * Glanders * Chromobacteriosis infection * γ: Pasteurellosis * Tularemia * Vibrio vulnificus * Rhinoscleroma * Haemophilus influenzae cellulitis * Pseudomonal pyoderma / Pseudomonas hot-foot syndrome / Hot tub folliculitis / Ecthyma gangrenosum / Green nail syndrome * Q fever * Salmonellosis * Shigellosis * Plague * Granuloma inguinale * Chancroid * Aeromonas infection * ε: Helicobacter cellulitis Other * Syphilid * Syphilis * Chancre * Yaws * Pinta * Bejel * Chlamydia infection * Leptospirosis * Rat-bite fever * Lyme disease * Lymphogranuloma venereum Unspecified pathogen * Abscess * Periapical abscess * Boil/furuncle * Hospital furunculosis * Carbuncle * Cellulitis * Paronychia / Pyogenic paronychia * Perianal cellulitis * Acute lymphadenitis * Pilonidal cyst * Pyoderma * Folliculitis * Superficial pustular folliculitis * Sycosis vulgaris * Pimple * Ecthyma * Pitted keratolysis * Trichomycosis axillaris * Necrotizing fascitis * Gangrene * Chronic undermining burrowing ulcers * Fournier gangrene * Elephantiasis nostras * Blistering distal dactylitis * Botryomycosis * Malakoplakia * Gram-negative folliculitis * Gram-negative toe web infection * Pyomyositis * Blastomycosis-like pyoderma * Bullous impetigo * Chronic lymphangitis * Recurrent toxin-mediated perineal erythema * Tick-borne lymphadenopathy * Tropical ulcer This infection-related 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Pyoderma	c0034212	4,618	wikipedia	https://en.wikipedia.org/wiki/Pyoderma	2021-01-18T18:35:21	{"mesh": ["D011711"], "umls": ["C0034212"], "wikidata": ["Q2119633"]}
Annual ryegrass toxicity (ARGT) is the poisoning of livestock from toxin contained in bacterially infected annual ryegrass (Lolium rigidum). The toxin is produced by the bacterium Rathayibacter toxicus (formerly Clavibacter toxicus), which is carried into the ryegrass by the nematode Anguina funesta.[1] ## Contents * 1 History * 2 Symptoms * 3 Prevention * 4 References ## History[edit] ARGT was first recorded in vicinity of Black Springs, South Australia, in the 1950s and then near Gnowangerup, Western Australia, in the 1960s. The disease has spread rapidly and approximately 40,000 to 60,000 square kilometres of farmland in Western Australia, and similar areas in South Australia are now infested by the ARGT-causing organisms. Most ARGT-related livestock losses occur during October to January, but losses have been recorded as late as April. ## Symptoms[edit] ARGT is a neurological condition and affects the brain. Sheep may at first appear perfectly normal, but if driven for a hundred metres or so, the slight stress will cause mildly affected animals to lag behind the rest of the flock and exhibit a high-stepping gait. More seriously affected animals may lose co-ordination and stumble, but will usually recover and join the rest of the flock if left quietly alone. The most-severely affected sheep will fall repeatedly and may be unable to get up. These sheep are likely to die, with death sometimes occurring within a few hours of the first symptoms appearing.[2] ## Prevention[edit] Herbicide applications aimed to reduce ryegrass population have been successful in reducing the risk of ARGT but have undesirable effects such as rapid reduction in pasture productivity and increase in ryegrass herbicide resistance. A recently released biological control agent, the twist fungus, has been demonstrated to be effective in reducing the risk ARGT without the need of controlling ryegrass. The first use of the twist fungus inoculum was in 1997. ## References[edit] 1. ^ Simpson, Wayne (1 August 2013). "Annual ryegrass staggers". Merck. Retrieved 9 December 2015. 2. ^ "Annual ryegrass toxicity". SheepConnect. Retrieved 9 December 2015. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Annual ryegrass toxicity	None	4,619	wikipedia	https://en.wikipedia.org/wiki/Annual_ryegrass_toxicity	2021-01-18T18:58:14	{"wikidata": ["Q4769699"]}
This article's lead section may be too short to adequately summarize its key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (January 2016) Corneal neovascularization Blood vessels in the cornea SpecialtyOphthalmology Corneal neovascularization (CNV) is the in-growth of new blood vessels from the pericorneal plexus into avascular corneal tissue as a result of oxygen deprivation.[1] Maintaining avascularity of the corneal stroma is an important aspect of corneal pathophysiology as it is required for corneal transparency and optimal vision. A decrease in corneal transparency causes visual acuity deterioration. Corneal tissue is avascular in nature and the presence of vascularization, which can be deep or superficial, is always pathologically related.[2] Corneal neovascularization is a sight-threatening condition that can be caused by inflammation related to infection, chemical injury, autoimmune conditions, post-corneal transplantation, and traumatic conditions among other ocular pathologies. Common causes of CNV within the cornea include trachoma, corneal ulcers, phylctenular keratoconjunctivitis, rosacea keratitis, interstitial keratitis, sclerosing keratitis, chemical burns, and wearing contact lenses for over-extended periods of time.[3] Superficial presentations of CNV are usually associated with contact lens wear, while deep presentations may be caused by chronic inflammatory and anterior segment ocular diseases.[4] Corneal neovascularization is becoming increasingly common worldwide with an estimated incidence rate of 1.4 million cases per year, according to a 1998 study by the Massachusetts Eye and Ear Infirmary. The same study found that the tissue from twenty percent of corneas examined during corneal transplantations had some degree of neovascularization, negatively impacting the prognosis for individuals undergoing keratoplasty procedures.[1] ## Contents * 1 Presentation * 1.1 Complications * 2 Causes * 3 Pathogenesis * 4 Treatment * 5 Research * 6 References * 7 External links ## Presentation[edit] Diagram of the Human Eye Cross-section of a normal cornea ### Complications[edit] In advanced stages, corneal neovascularization can threaten eyesight, which is why routine (annual) eye exams are recommended for contact lens patients.[4] ## Causes[edit] CNV causes may be congenital in nature, such as with Aniridia, or acquired. Frequently, inflammatory, infectious, degenerative, traumatic or iatrogenic (e.g. contact lenses) conditions can be responsible for acquired CNV.[1] Some major acquired inflammatory conditions include graft rejection following keratoplasty, graft or host diseases of the new tissue, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, and Steven's Johnson syndrome.[3] Infections responsible for CNV range from bacterial (chlamydia, syphilis, pseduomonas), viral (herpes simplex & herpes zoster viruses), fungal (candida, asperigillus, fusarium), to parasitic (onchocerca volvolus) infection.[1] Degenerative diseases such as pterygiums and terrien's marginal degeneration may also be responsible.[1] Traumatic causes of CNV include ulceration, alkali burns, and stem cell deficiency.[1] One of the most common causes of corneal neovascularization is iatrogenic pathology from extended contact lens wear. This is especially likely with lenses made with older hydrogel materials such as HEMA (2-hydroxyethyl methacrylate) for both daily and extended wear. Such older hydrogel materials have a relatively low oxygen transmissibility so the cornea becomes starved of oxygen; this leads to the ingress of blood capillaries into the clear cornea, in an attempt to provide more oxygen to the affected area. Older estimates cite 128,000 to 470,000 cases of lens-induced CNV each year, but this may be decreasing due to the increasing popularity of daily disposable lenses.[5] The risk for CNV is elevated in certain instances for patients following penetrating keratoplasty without active inflammation or epithelial defects. For example, the condition is more likely to occur in those with active blepharitis, those who receive sutured knots in their host stromas, and those with a large recipient area.[1] ## Pathogenesis[edit] The in-growth of new blood vessels is mediated by the upregulation of angiogenic cytokines. The enzyme metalloproteinase degrades the cornea's basement membrane and extracellular matrix, while proteolytic enzymes allow vascular epithelial cells to enter the stromal layer of the cornea. When ocular inflammation occurs, corneal epithelial and endothelial cells, macrophages and certain inflammatory cells produce angiogenic growth factors, namely vascular endothelial growth factor (VEGF) and fibroblast growth factors. VEGF paves the way for new blood vessel formation by upregulating matrix metalloproteinases production by endothelial cells in the limbal vascular plexus.[4] ## Treatment[edit] Treatments for corneal neovascularization are predominately off-lab with a multitude of complications as a result. The desired results from medical therapy may not always occur, ergo an invasive procedure may be needed to prevent further decrease in corneal avascularity. For contact lenses related hypoxia, ceasing the use of contact lenses is the first step until corneal neovascularization is addressed by a physician. Modern rigid gas permeable and silicon hydrogel contact lenses have a much higher level of oxygen transmissibility, making them effective alternatives to help prevent corneal neovascularization. Topical administration of steroids and non-steroid anti-inflammatory drugs are first-line treatment for individuals with CNV. The administration of steroids can increase the risk of infection, glaucoma, cataracts, herpes simplex recurrence. The anti-inflammatory drugs, however, increase the risk of corneal ulceration and melting. Since VEGF plays an important role in vasculogenesis and pathologic neovascularization associated with eye diseases, a potential treatment for CNV is to inhibit VEGF activity by competing the binding of VEGF with specific neutralizing anti-VEGF antibody. VEGF inhibitors include pegatanib sodium, ranibizumab, and off-label bevacizumab are currently used for treatment of various retinal disease.[6] Anti-VEGF antibodies such as the application of ranibizumab or bevacizumab have has been shown to reduce corneal neovascularization. Both ranibizumab and bevacizumab uses the same mechanism and inhibits all iso-forms of VEGF.[6] The significant reduction in invasion of in-growth blood vessels in terms of neovascular area and vessel caliber suggests that treatment with ranibizumab induces thinning of the blood vessels, however, there's no significant change of the blood vessel's length.[6] Using anti-VEGF antibodies to treat CNV has some limitations such as it is not a cure and may require repeated treatments to maintain positive effects over time. Topical and/or subconjunctival administration of bevaicizumab or ranibizumab have demonstrated short-term safety and efficacy,[4] however long term effects have not been documented. Anti-VEGF therapy is currently an experimental treatment. If the cornea is inflamed via corneal neovascularization, the suppression of enzymes can block CNV by compromising with corneal structural integrity. Corneal neovascularization can be suppressed with a combination of orally administration of doxycycline and with topical corticosteroid. Surgical Options Invasive solutions for corneal neovascularization are reserved when the medical therapies do not provide the desired results. Invading blood tissues and ablating tissues in the cornea can be obstructed by the use of laser treatments such as Argon and Nd:YAG lasers.[7] Irradiation and/or damages to adjacent tissues caused by the procedure can result in corneal hemorrhage and corneal thinning. Obstruction of the blood vessels can be unsuccessful due to the depth, size, and, high blood flow rate of the vessels. In conjunction, thermal damage from the lasers can trigger inflammatory response which can exaggerate the neovascularization. An effective treatment is photodynamic therapy, however, this treatment has limited clinical acceptance due to high costs and many potential complications involved that are also related to laser ablation. Complications can include irradiation from previously injected photosensitive dye inducing apoptosis and necrosis of the endothelium and basement membrane. Diathermy and cautery is a treatment where an electrolysis needle is inserted into the feeder vessels in the limbus. The vessels are obstructed by a coagulating current through the use of unipolar diathermy unit or by thermal cautery.[7] ## Research[edit] Reduction of neovascularization has been achieved in rats by the topical instillation of commercially available triamcinolone and doxycycline.[8] Some evidence exists to suggest that the Angiotensin II receptor blocker drug telmisartan will prevent corneal neovascularization.[2] Recent treatment developments include topical application of bevacizumab, an anti-VEGF.[9] ## References[edit] 1. ^ a b c d e f g Abdelfattah N. S., Amgad M., Zayed A. A., Salem H., Elkhanany A. E., Hussein H., El-Baky N. A. (2015). "Clinical correlates of common corneal neovascular diseases: a literature review". International Journal of Ophthalmology. 8 (1): 182.CS1 maint: multiple names: authors list (link) 2. ^ a b Usui, T.; Sugisaki, K.; Iriyama, A.; Yokoo, S.; Yamagami, S.; Nagai, N.; Ishida, S.; Amano, S. (2008). "Inhibition of Corneal Neovascularization by Blocking the Angiotensin II Type 1 Receptor". Investigative Ophthalmology & Visual Science. 49 (10): 4370–4376. doi:10.1167/iovs.07-0964. PMID 18829859. 3. ^ a b Nema, HV; Nema, Nitin (2008). Textbook of Ophthalmology, 5th Edition. New Delhi: Jaypee Brothers Medical Publishers (p) LTD. p. 174. ISBN 978-81-8448-307-9. 4. ^ a b c d Chiang, Homer; Hemmati, Houman (2013). "Treatment of Corneal Neovascularization". Ophthalmic Pearls: 35–36 – via Eyenet Magazine. 5. ^ Lee P., Wang C. C., Adamis A. P. (1998). "Ocular neovascularization: an epidemiologic review". Survey of Ophthalmology. 43 (3): 245–269. doi:10.1016/s0039-6257(98)00035-6.CS1 maint: multiple names: authors list (link) 6. ^ a b c Voiculescu, Voinea, Alexandrescu (2015). "Corneal Neovascularization and Biological Therapy". Journal of Medicine and Life. 8: 444–448.CS1 maint: multiple names: authors list (link) 7. ^ a b Chiang, Homer; Hemmati, Houman (2013). "Treatment of Corneal Neovascularization". Ophthalmic Pearls: 35–36. 8. ^ Riazi-Esfahani, M; Peyman, GA; Aydin, E; Kazi, AA; Kivilcim, M; Sanders, DR (August 2006). "Prevention of corneal neovascularization: evaluation of various commercially available compounds in an experimental rat model". Cornea. 25 (7): 801–5. doi:10.1097/01.ico.0000220768.11778.60. PMID 17068457. 9. ^ Cheng, Sheng-Fu; Dastjerdi, Mohammad H.; Ferrari, Giulio; Okanobo, Andre; Bower, Kraig S.; Ryan, Denise S.; Amparo, Francisco; Stevenson, William; Hamrah, Pedram; Nallasamy, Nambi; Dana, Reza (December 2012). "Short-Term Topical Bevacizumab in the Treatment of Stable Corneal Neovascularization". American Journal of Ophthalmology. 154 (6): 940–948.e1. doi:10.1016/j.ajo.2012.06.007. PMC 3498533. PMID 22967868. ## External links[edit] Classification D * ICD-10: H16.4 * MeSH: D016510 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Corneal neovascularization	c0085109	4,620	wikipedia	https://en.wikipedia.org/wiki/Corneal_neovascularization	2021-01-18T19:08:08	{"mesh": ["D016510"], "umls": ["C0085109"], "wikidata": ["Q1266519"]}
Leptin receptor deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. The extreme hunger leads to chronic excessive eating (hyperphagia) and obesity. Beginning in early childhood, affected individuals develop abnormal eating behaviors such as fighting with other children over food, hoarding food, and eating in secret. People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Affected individuals experience delayed puberty or do not go through puberty, and they may be unable to conceive children (infertile). ## Frequency Leptin receptor deficiency is a rare cause of obesity. Its prevalence is unknown. ## Causes Leptin receptor deficiency is caused by mutations in the LEPR gene. This gene provides instructions for making a protein called the leptin receptor, which is involved in the regulation of body weight. The leptin receptor protein is found on the surface of cells in many organs and tissues of the body including a part of the brain called the hypothalamus. The hypothalamus controls hunger and thirst as well as other functions such as sleep, moods, and body temperature. It also regulates the release of many hormones that have functions throughout the body. The leptin receptor is turned on (activated) by a hormone called leptin that attaches (binds) to the receptor, fitting into it like a key into a lock. Normally, the body's fat cells release leptin in proportion to their size. As fat cells become larger, they produce more leptin. This rise in leptin indicates that fat stores are increasing. In the hypothalamus, the binding of leptin to its receptor triggers a series of chemical signals that affect hunger and help produce a feeling of fullness (satiety). LEPR gene mutations that cause leptin receptor deficiency prevent the receptor from responding to leptin, leading to the excessive hunger and weight gain associated with this disorder. Because hypogonadotropic hypogonadism occurs in leptin receptor deficiency, researchers suggest that leptin receptor signaling is also involved in regulating the body's response to hormones that control sexual development, and that this response is affected by LEPR gene mutations. However, the mechanism of this effect is unknown. ### Learn more about the gene associated with Leptin receptor deficiency * LEPR ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Leptin receptor deficiency	c3554225	4,621	medlineplus	https://medlineplus.gov/genetics/condition/leptin-receptor-deficiency/	2021-01-27T08:25:21	{"omim": ["614963"], "synonyms": []}
Optic neuritis is inflammation of the optic nerve, the nerve that carries the visual signal from the eye to the brain. The condition may cause sudden, reduced vision in the affected eye(s). While the cause of optic neuritis is unknown, it has been associated with autoimmune diseases, infections, multiple sclerosis, drug toxicity and deficiency of vitamin B-12. Vision often returns to normal within 2-3 weeks without treatment. In some cases, corticosteroids are given to speed recovery. If known, the underlying cause should be treated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Optic neuritis	c0029134	4,622	gard	https://rarediseases.info.nih.gov/diseases/7320/optic-neuritis	2021-01-18T17:58:35	{"mesh": ["D009902"], "umls": ["C0029134"], "synonyms": []}
Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis is a type 2 collagen-related bone disorder characterized by precocious, generalized osteoarthritis (with onset as early as childhood) and mild, dysplastic spinal changes (flattening of vertebrae, irregular endplates and wedge-shaped deformities) resulting in a mildly short trunk. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis	c0432214	4,623	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93279	2021-01-23T17:23:32	{"mesh": ["C565740"], "omim": ["604864"], "icd-10": ["Q77.7"]}
Onychomatricoma SpecialtyDermatology Onychomatricoma is a cutaneous condition characterized by a distinctive tumor of the nail matrix.[1] This nail disease can mimic many nail problems and should be examined and biopsied by a dermatologist.[2] In particular, a main concern is the malignant and destructive potential that may exist.[3] ## See also[edit] * Nail anatomy * List of cutaneous conditions * Nail disease ## References[edit] 1. ^ Freedberg, Irwin M.; Eisen, Arthur Z.; Wolff, Klaus; Austen, K. Frank; Goldsmith, Lowell A.; Katz, Stephen I., eds. (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). McGraw-Hill. p. 667. ISBN 978-0-07-138076-8. 2. ^ Onychomatricoma at eMedicine 3. ^ Rashid, Rashid M.; Swan, James (2006). "Onychomatricoma: Benign sporadic nail lesion or much more?". Dermatology Online Journal. 12 (6): 4. PMID 17083884. This condition of the skin appendages article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Onychomatricoma	None	4,624	wikipedia	https://en.wikipedia.org/wiki/Onychomatricoma	2021-01-18T19:08:48	{"orphanet": ["300512"], "synonyms": [], "wikidata": ["Q7095153"]}
Darier disease (DD) is a keratinization disorder characterized by the development of keratotic papules in seborrheic areas and specific nail anomalies. ## Epidemiology The prevalence is estimated at around 1/50,000. ## Clinical description Onset of the disease usually occurs around puberty. Patients present with greasy and colored (yellow-brown or brown) keratotic papules, which may be isolated or grouped forming plaques. The skin lesions often become infected and malodorous, and are responsible for major discomfort. They may be exacerbated by exposure to sunlight or artificial UVB radiation, heat, sweating, friction, and infections. The sites of predilection are the seborrheic areas of the trunk and face: upper chest, back, sides of the neck, forehead, ears, and scalp. The flexures are also frequently involved (the groins, axillae, and anogenital region). Hands and feet may also show discrete papules on the dorsal surfaces. Careful examination of the palms and soles frequently reveals small pits or punctuated keratoses that are highly suggestive, if not specific, of DD. They show the specific combination of red and white longitudinal stripes and present subungual hyperkeratosis. The hard palate, oral mucosa, esophagus, vulva and rectum may be the site of whitish small papules, often densely grouped (leukoplakia). Nail abnormalities are almost constant and highly suggestive. The nails are fragile and have a V-shaped defect. Patients have an increased susceptibility to herpes simplex and pyogenic infections. Severity of the disease is highly variable, even within the same family. ## Etiology DD is caused by mutations in the ATP2A2 gene (12q23-q24.1) encoding a Ca2+ pump of the endoplasmic reticulum. ## Diagnostic methods The diagnosis is based on histological examination of skin lesion biopsies revealing hyperkeratosis, focal dyskeratosis and suprabasal acantholysis. ## Differential diagnosis Differential diagnoses include Hailey-Hailey disease, pemphigus and warty dyskeratoma (see these terms), as well as transient acantholytic dermatosis. ## Genetic counseling Transmission is autosomal dominant. Genetic counseling should be offered, although prenatal diagnosis is not appropriate in the majority of cases. ## Management and treatment Management is symptomatic. Patients should avoid sun and heat. Emollients containing urea or lactic acid are of benefit for more limited lesions. Topical application of tretinoin or isotretinoin is effective against hyperkeratosis, but the risk of irritation limits their use. Topical steroids may reduce irritation, but they are not effective when used alone. Retinoids such as tazarotene are better tolerated. In case of severe disease, acitretin (an oral retinoid) is the most effective treatment, but possible side-effects must be monitored. Depression and neuropsychological manifestations have been reported and specific psychological support may be necessary. ## Prognosis DD runs a chronic and relapsing course. It may cause considerable social handicap. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Darier disease	c0022595	4,625	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=218	2021-01-23T19:03:27	{"gard": ["6243"], "mesh": ["D007644"], "omim": ["124200"], "umls": ["C0022595"], "icd-10": ["Q82.8"], "synonyms": ["Darier-White disease", "Keratosis follicularis"]}
A number sign (#) is used with this entry because of evidence that dystrophic epidermolysis bullosa (DEB) pruriginosa is caused by mutations in the COL7A1 gene (120120). See also autosomal dominant DEB (131750) and autosomal recessive DEB (226600), allelic disorders with overlapping phenotypes. Description Dystrophic epidermolysis bullosa is an inherited skin fragility disorder associated with anchoring fibril abnormalities and sublamina densa blistering. EB pruriginosa is a rare distinct clinical subtype of dystrophic EB in which skin fragility, blistering, and scar formation are associated with intense pruritus, nodular prurigo-like lichenified lesions, nail dystrophy, and variable presence of albopapuloid lesions (McGrath et al., 1994; Cambiaghi et al., 1997). The onset of these clinical features may be evident in early childhood, but in some cases is delayed until the second or third decade of life. Autosomal dominant, autosomal recessive, and sporadic inheritance patterns have all been described in this disorder. Clinical Features Drera et al. (2006) reported 7 unrelated Italian patients with EB pruriginosa. Three patients had a family history of the disorder consistent with autosomal dominant inheritance. Six patients reported onset of symptoms at birth or early childhood. Most had relatively mild skin involvement with blistering lesions located primarily at trauma sites. Four patients reported gradual amelioration during childhood or adolescence. Other disease features included nail dystrophy, skin atrophy and milia formation, and a single patient had albopapuloid lesions. All patients reported worsening of the skin phenotype after the onset of itching. Physical exam showed excoriated and lichenified papules, nodules, and plaques associated with scarring on the shins, foot dorsum, elbows, wrists, and back. Pruritus occurred at puberty in 4 patients and in adulthood in 3. Pruritus was severe, generalized, and unresponsive to conventional therapies. Two patients had increased serum IgE. Skin biopsies showed deposition of variable amounts of collagen VII at the dermal-epidermal junction. Ee et al. (2007) reported a Chinese-Singaporean family with autosomal dominant EB pruriginosa. The proband was a 53-year-old woman with a blistering skin eruption over the back, nape of the neck, both shins, and elbows. She had a history of intermittent blistering since age 25 years. The blisters were provoked by scratching and were pruritic; mucous membranes were not affected. Physical examination showed linear erosions and hypertrophic scars on the affected areas with some milia formation. Skin biopsy showed blister formation below the lamina densa and decreased numbers of anchoring fibrils in nonblistered skin. At least 5 of her sibs were similarly affected. Pathogenesis The possibility of additional immune-mediated factors in the pathogenesis of this characteristic form of epidermolysis bullosa has been suggested and was supported by the report of Yamasaki et al. (1997) describing clinical improvement with cyclosporin A. In the patients studied by Mellerio et al. (1999), there was no evidence for other causes of itching, such as thyroid dysfunction or low ferritin levels. They pointed out, however, that because the pathophysiology of itch is poorly understood, other potential modifying factors may be elucidated. Molecular Genetics In affected members of a Taiwanese pedigree with autosomal dominant EB pruriginosa, Lee et al. (1997) identified a heterozygous mutation in the COL7A1 gene (120120.0017). Mellerio et al. (1999) identified the same mutation in a British family with dominant epidermolysis bullosa pruriginosa. Mellerio et al. (1999) identified mutations in the COL7A1 gene (see, e.g., 120120.0020) in 5 unrelated patients with EB pruriginosa. One patient was compound heterozygous for 2 mutations (120120.0018; 120120.0019). Drera et al. (2006) identified 9 mutations in the COL7A1 gene among 7 unrelated Italian patients with EB pruriginosa (see, e.g., 120120.0032; 120120.0033). Six of the mutations had previously been reported in EB patients without pruriginosa (see, e.g., 120120.0009; 120120.0010). Drera et al. (2006) stated that 16 distinct mutations in the COL7A1 gene had been reported in patients with EB pruriginosa. Ee et al. (2007) identified a heterozygous mutation in the COL7A1 gene (G2251E; 120120.0014) in affected members of a Chinese-Singaporean family with dominant inheritance of EB pruriginosa. INHERITANCE \- Autosomal dominant \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Epidermolysis bullosa, dystrophic \- Blistering, recurrent \- Skin fragility \- Erosions \- Pruritis, intense \- Prurigo \- Nodular lesions \- Lichenified lesions \- Hypertrophic scarring \- Milia \- Albopapuloid lesions may occur Electron Microscopy \- Sublamina densa level of tissue separation beneath basal membrane \- Decreased number of anchoring fibrils at dermal-epidermal junction \- Hypotrophic anchoring fibrils \- Decreased staining for collagen VII Nails \- Dystrophic nails \- Nail atrophy MISCELLANEOUS \- Variable age at onset from childhood to adulthood \- Blisters are precipitated by minor skin trauma \- Blistering and erosions tend to occur on extensor surfaces or over bony prominences \- Blistering frequency may decrease with age \- Intrafamilial variability \- See also dominant DEB ( 131750 ), an allelic disorder with a similar phenotype MOLECULAR BASIS \- Caused by mutation in the collagen type VII, alpha-1 gene (COL7A1, 120120.0009 ). ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	EPIDERMOLYSIS BULLOSA PRURIGINOSA	c1275114	4,626	omim	https://www.omim.org/entry/604129	2019-09-22T16:12:28	{"mesh": ["C563192"], "omim": ["604129"], "orphanet": ["89843"], "synonyms": ["Alternative titles", "DYSTROPHIC EPIDERMOLYSIS BULLOSA PRURIGINOSA", "DEB, PRURIGINOSA"], "genereviews": ["NBK1304"]}
The possibility of an X-linked form was raised by Partington (1985) on the basis of the following observations: 2 brothers, aged 7 and 4, had prenatal growth retardation, triangular facies and cafe-au-lait (CAL) spots. Both had asthma. The mother was 160 cm tall and had CAL spots. Her 4 brothers were tall with no spots. Of her 5 sisters, 3 were over 168 cm tall and had no spots; 2 were 156 cm tall and had CAL spots. Partington (1985) suggested that this may represent X-linked inheritance with severe expression in males and mild expression in females. In the full report with illustrations (Partington, 1986), the pigmentary anomaly was presented as quite different from cafe-au-lait spots. The changes were progressive, starting at age 1 year in the younger child. Both pigmented and achromatic areas developed on the trunk and limbs sparing the face. Growth \- Prenatal growth retardation Inheritance \- X-linked, severe in males and mild in females Facies \- Triangular facies Skin \- Cafe-au-lait spots \- Achromatic skin areas of trunk and limbs ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	RUSSELL-SILVER SYNDROME, X-LINKED	c0175693	4,627	omim	https://www.omim.org/entry/312780	2019-09-22T16:17:18	{"mesh": ["D056730"], "omim": ["312780"], "orphanet": ["813"], "synonyms": ["Alternative titles", "RUSSELL-SILVER-LIKE SYNDROME WITH SKIN PIGMENTATION", "PARTINGTON SYNDROME"]}
A number sign (#) is used with this entry because of evidence that long QT syndrome-10 (LQT10) and familial atrial fibrillation-17 (ATFB17) are caused by heterozygous mutation in the SCN4B gene (608256) on chromosome 11q23. For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500). For a discussion of genetic heterogeneity of familial atrial fibrillation, see ATFB1 (608583). Clinical Features ### Long QT Syndrome 10 Medeiros-Domingo et al. (2007) reported a 5-year-old Mexican mestizo girl who at 21 months of age was found to have asymptomatic bradycardia with rates less than 60 bpm. An ECG revealed profound QT prolongation with a QTc of 712 ms and intermittent 2:1 AV block; during 1:1 conduction, macroscopic T-wave alternans was observed. The patient's medical history included fetal bradycardia noted at 24 weeks of gestation and a small ventricular septal defect that spontaneously closed by 6 months of age. She remained asymptomatic after placement of an epicardial pacemaker. She had 2 paternal great aunts who had sudden cardiac death, 1 at age 35 years after delivery of twins and 1 at age 8 years during exercise. Medeiros-Domingo et al. (2007) noted that the ECG features in the proband, with a long isoelectric ST segment, late-onset T wave, and 2:1 AV block, were similar to those seen in SCN5A (600163)-mediated LQT3 (603830). ### Familial Atrial Fibrillation 17 Li et al. (2013) studied 2 Han Chinese families with atrial fibrillation (AF). One family consisted of a 62-year-old mother with permanent AF, who had 2 sons with paroxysmal AF. Diagnosis occurred in the fourth decade for all 3 patients. The mother had recurrent syncopal episodes from age 26, mostly preceded by emotional or physical stress. On ECG, she had a markedly prolonged QT interval (QTc, 542 msec); echocardiogram showed a structurally normal heart. Her 2 sons with AF also met the criteria for LQT, with a QTc of 445 msec and 444 msec, respectively. The second family consisted of a 46-year-old woman with persistent AF, who had onset of AF at 38 years of age. Her 69-year-old father had permanent AF, which began at 41 years of age, and her 22-year-old son had paroxysmal AF, which began at age 21 years. Corrected QT intervals in members of the second family were within the normal range. Molecular Genetics ### Long QT Syndrome 10 In affected members of a 4-generation Mexican mestizo pedigree with long QT syndrome, Medeiros-Domingo et al. (2007) analyzed the 9 known LQTS-associated genes (see LQT1; 192500) but found no mutations. Analysis of the 4 genes encoding sodium channel beta subunits, SCN1B (600235), SCN2B (601327), SCN3B (608214), and SCN4B (608256), revealed heterozygosity for a missense mutation in SCN4B (608256.0001) that segregated with the phenotype in the pedigree with incomplete penetrance. The mutation was not found in 800 control alleles, 400 of which were ethnically matched. ### Familial Atrial Fibrillation 17 Li et al. (2013) sequenced the SCN4B gene in 170 Han Chinese probands with familial atrial fibrillation and identified 2 probands who were heterozygous for missense mutations, V162G (608256.0002) and I166L (608256.0003), respectively. The mutations, which segregated with disease in each of the families, were not found in 200 ethnically matched controls. In the family with the V162G mutation, all 3 individuals with atrial fibrillation also had corrected QT intervals that met the criteria for long QT syndrome. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Prolongation of corrected QT interval (in some patients) \- Long isoelectric ST segment (in some patients) \- Late-onset T wave (in some patients) \- Atrioventricular node block, 2:1, intermittent (in some patients) \- Atrial fibrillation (in some patients) MISCELLANEOUS \- Risk of sudden death with exertion MOLECULAR BASIS \- Caused by mutation in the type IV voltage-gated sodium channel beta subunit gene (SCN4B, 608256.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	LONG QT SYNDROME 10	c1141890	4,628	omim	https://www.omim.org/entry/611819	2019-09-22T16:02:48	{"doid": ["0110651"], "omim": ["611819"], "orphanet": ["768", "334", "101016"], "genereviews": ["NBK1129"]}
Unusually small penis For the legal term, see Small penis rule. Micropenis A flaccid micropenis SpecialtyUrology DurationPermanent (Lifetime) Frequencyaround 0.6% of men. Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) erect penile length of at least 2.5 standard deviations smaller than the mean human penis size,[1] or smaller than about 7 cm (2 3⁄4 in) for an adult when compared with an average erection of 12.5 cm (5 in).[2] The condition is usually recognized shortly after birth. The term is most often used medically when the rest of the penis, scrotum, and perineum are without ambiguity, such as hypospadias. Micropenis occurs in about 0.6% of males.[2] ## Contents * 1 Causes * 2 Treatment * 2.1 Hormone treatment * 2.2 Surgery * 3 See also * 4 References * 5 External links ## Causes Measuring an erect micropenis Of the abnormal conditions associated with micropenis, most are conditions of reduced prenatal androgen production or effect, such as abnormal testicular development (testicular dysgenesis), Klinefelter syndrome, Leydig cell hypoplasia, specific defects of testosterone or dihydrotestosterone synthesis (17,20-lyase deficiency, 5α-reductase deficiency), androgen insensitivity syndromes, inadequate pituitary stimulation (gonadotropin deficiency), and other forms of congenital hypogonadism. Micropenis can also occur as part of many genetic malformation syndromes that do not involve the sex chromosomes. It is sometimes a sign of congenital growth-hormone deficiency or congenital hypopituitarism. Several homeobox genes affect penis and digit size without detectable hormone abnormalities. In addition, in utero exposure to some estrogen based fertility drugs like diethylstilbestrol (DES) has been linked to genital abnormalities or a smaller than normal penis.[3] After evaluation to detect any of the conditions described above, micropenis can often be treated in infancy with injections of various hormones, such as human chorionic gonadotropin and testosterone. Most eight- to fourteen-year-old boys referred for micropenis do not have the micropenis condition. Such concerns are usually explained by one of the following: * a penis concealed in suprapubic fat (extra fat around the mons pubis) * a large body and frame for which a prepubertal penis simply appears too small * delayed puberty with every reason to expect future growth ## Treatment ### Hormone treatment Growth of the penis both before birth and during childhood and puberty is strongly influenced by testosterone and, to a lesser degree, the growth hormone. However, later endogenous hormones mainly have value in the treatment of micropenis caused by hormone deficiencies, such as hypopituitarism or hypogonadism. Regardless of the cause of micropenis, if it is recognized in infancy, a brief course of testosterone is often prescribed[4] (usually no more than 3 months). This usually induces a small amount of growth, confirming the likelihood of further growth at puberty, but rarely achieves normal size. No additional testosterone is given during childhood, to avoid unwanted virilization and bone maturation. (There is also some evidence that premature administration of testosterone can lead to reduced penis size in the adult.)[5] Testosterone treatment is resumed in adolescence only for boys with hypogonadism. Penile growth is completed at the end of puberty, similar to the completion of height growth, and provision of extra testosterone to post-pubertal adults produces little or no further growth. ### Surgery Because hormone treatment rarely achieves average size, several surgical techniques similar to phalloplasty for penis enlargement have been devised and performed; but they are not generally considered successful enough to be widely adopted and are rarely performed in childhood. In extreme cases of micropenis, there is barely any shaft, and the glans appears to sit almost on the pubic skin. From the 1960s until the late 1970s, it was common for sex reassignment and surgery to be recommended. This was especially likely if evidence suggested that response to additional testosterone and pubertal testosterone would be poor. With parental acceptance, the boy would be reassigned and renamed as a girl, and surgery performed to remove the testes and construct an artificial vagina. This was based on the now-questioned idea that gender identity was shaped entirely from socialization, and that a man with a small penis can find no acceptable place in society. Johns Hopkins Hospital, the center most known for this approach, performed twelve such reassignments from 1960 to 1980, most notably[citation needed] that of David Reimer (whose penis was destroyed by a circumcision accident), overseen by John Money. By the mid-1990s, reassignment was less often offered, and all three premises had been challenged. Former subjects of such surgery, vocal about their dissatisfaction with the adult outcome, played a large part in discouraging this practice. Sexual reassignment is rarely performed today for severe micropenis (although the question of raising the boy as a girl is sometimes still discussed.)[6] (See "History of intersex surgery" for a fuller discussion.) ## See also * Intersex * Penis size * Buried penis * Webbed penis ## References 1. ^ Lee PA, Mazur T, Danish R, et al. (1980). "Micropenis. I. Criteria, etiologies and classification". The Johns Hopkins Medical Journal. 146 (4): 156–63. PMID 7366061. 2. ^ a b ScienceDaily.com (2004). "Surgeons Pinch More Than An Inch From The Arm To Rebuild A Micropenis," 6 Dec. 2004, URL accessed 2 April 2012. 3. ^ Center for Disease Control. "DES Update: Consumers". 4. ^ Ishii T, Sasaki G, Hasegawa T, Sato S, Matsuo N, Ogata T (2004). "Testosterone enanthate therapy is effective and independent of SRD5A2 and AR gene polymorphisms in boys with micropenis". J. Urol. 172 (1): 319–24. doi:10.1097/01.ju.0000129005.84831.1e. PMID 15201804. 5. ^ McMahon DR, Kramer SA, Husmann DA (1995). "Micropenis: does early treatment with testosterone do more harm than good?". J. Urol. 154 (2 Pt 2): 825–9. doi:10.1016/S0022-5347(01)67175-1. PMID 7609189. 6. ^ Calikoglu AS; Calikoglu, A (1999). "Should boys with micropenis be reared as girls?". J. Pediatr. 134 (5): 537–8. doi:10.1016/S0022-3476(99)70236-2. PMID 10228285. ## External links Classification D * ICD-9-CM: 752.64 * OMIM: 607306 * DiseasesDB: 14839 External resources * eMedicine: ped/1448 * Media related to Micropenis at Wikimedia Commons * Into the Hands of Babes, by Melissa Hendricks, Johns Hopkins Magazine * Effect of penile size on nocturnal erections: evaluation with NPTR testing with men having micropenis from the International Journal of Impotence Research * v * t * e Male congenital anomalies of the genitalia, including Intersex and DSD Internal Testicle * Cryptorchidism * Polyorchidism * Monorchism * Anorchia * Sertoli cell-only syndrome * True hermaphroditism * Mixed gonadal dysgenesis * Swyer syndrome Vas deferens * Congenital absence of the vas deferens Other * Persistent Müllerian duct syndrome External Penis * Hypospadias * Epispadias * Chordee * Micropenis * Penile agenesis * Diphallia * Penoscrotal transposition Other * Pseudohermaphroditism [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Micropenis	c0266435	4,629	wikipedia	https://en.wikipedia.org/wiki/Micropenis	2021-01-18T18:34:55	{"umls": ["C0266435", "C1387005"], "icd-9": ["752.64"], "orphanet": ["95707"], "wikidata": ["Q1471642"]}
Kienbock disease is a rare bone disorder of unknown etiology characterized clinically by osteonecrosis of the carpal lunate, eventually leading to collapse of the lunate bone impacting wrist function. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Kienbock disease	c0022682	4,630	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97332	2021-01-23T18:29:30	{"gard": ["9690"], "mesh": ["D010020"], "umls": ["C0022682"], "icd-10": ["M92.2", "M93.2"], "synonyms": ["Aseptic necrosis of the lunate bone", "Lunatomalacia", "Osteochondrosis of the lunate bone", "Progressive avascular necrosis of the lunate bone"]}
Pesme et al. (1950) and Reichel et al. (1992) described sporadic cases of bilateral ectopia lentis associated with craniosynostosis. Cruysberg et al. (1999) observed the combination in twin sisters. Molecular studies yielded a probability of monozygosity of more than 0.98. Surgical correction of the craniosynostosis was performed in one sister at the age of 14 months and in the other at the age of 23 months. Quercia and Teebi (2002) reported female first cousins once removed who were both born with unilateral coronal synostosis. One cousin also had peripheral pulmonic branch stenosis at birth and was later found to have ectopia lentis and severe myopia. The other cousin had an atrial septal defect, mitral valve prolapse, and only mild myopia. Their intelligence was normal. Quercia and Teebi (2002) suggested that inheritance is probably autosomal dominant with variable expression and incomplete penetrance. They concluded that the syndrome includes congenital heart defects. Guven et al. (2005) observed a 6-year-old Turkish individual with craniosynostosis and ectopia lentis whose parents were second cousins. Synostosis of the right parietal and temporoparietal sutures resulted in craniofacial asymmetry. Ectopia lentis was 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	CRANIOSYNOSTOSIS WITH ECTOPIA LENTIS	c1863678	4,631	omim	https://www.omim.org/entry/603595	2019-09-22T16:12:49	{"mesh": ["C566357"], "omim": ["603595"]}
Gastroparesis, or delayed gastric emptying, is a disorder where the food does not move or moves very slowly from the stomach to the small intestine. In gastroparesis, the muscles of the stomach do not work well and digestion takes an abnormally long time. Symptoms of gastroparesis include bloating, nausea, vomiting, weight loss due to poor absorption of nutrients, early fullness while eating meals, heartburn, and abdominal pain. Complications can occur including dehydration, electrolyte abnormalities, blood sugar abnormalities, malnutrition, vitamin deficiencies, stomach ulcers, gastroesophageal reflux, esophagitis, small bowel bacterial overgrowth, and metabolic bone disease. In rare cases, food that is poorly digested can collect in the stomach and form a bezoar, a mass of undigested material that can cause a blockage in the gastrointestinal tract. Gastroparesis is more common in people with diabetes and those who have had recent stomach or intestinal surgery. Other causes include infections, hormonal disorders like hypothyroidism, connective tissue disorders like scleroderma, autoimmune conditions, neuromuscular diseases, psychological conditions, and eating disorders. In some cases, the cause is not known (idiopathic). Diagnosis is made on the basis of a radiographic gastric emptying test. Treatment may include dietary modifications such as adjusting the timing and size of meals, consuming more liquid-based meals, or avoiding foods that are more difficult to digest (such as fatty foods, or foods with too much fiber). Other treatments may include endoscopic procedures to break the bezoar apart and remove it, feeding tubes, surgery, placement of an electrical stimulator, and medication such as metoclopramide, domperidone, erythromycin and cisapride. With proper management many people with gastroparesis can live a relatively normal life. However, others may not tolerate treatment and may experience significant complications, a decreased quality of life, and reduced survival. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Gastroparesis	c0152020	4,632	gard	https://rarediseases.info.nih.gov/diseases/12278/gastroparesis	2021-01-18T18:00:22	{"mesh": ["D018589"], "synonyms": ["Delayed gastric emptying"]}
A number sign (#) is used with this entry because of evidence that elliptocytosis-1 (EL1) is caused by heterozygous or homozygous mutation in the gene encoding erythrocyte membrane protein 4.1 (EPB41; 130500) on chromosome 1p35. Description Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Usually inherited as an autosomal dominant trait, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton (summary by McGuire et al., 1988). ### Genetic Heterogeneity of Elliptocytosis Elliptocytosis-2 (130600) is caused by mutation in the SPTA1 gene (182860). Elliptocytosis-3 (617948) is caused by mutation in the SPTB gene (182870). Elliptocytosis-4 (166900), also known as Southeast Asian ovalocytosis, is caused by mutation in the SLC4A1 gene (109270). Also see pyropoikilocytosis (266140). See Delaunay (2007) for a discussion of the molecular basis of hereditary red cell membrane disorders. Clinical Features Because of the existence of at least 2 forms of elliptocytosis, one linked to Rh and one unlinked (Morton, 1956), phenotypic differences correlating with the differences in linkage relationships were sought. Geerdink et al. (1967) found more hemolysis in the 'unlinked' type than in the 'linked' type. Lux and Wolfe (1980) delineated 6 clinical varieties of hereditary elliptocytosis (HE). Peters et al. (1966), studying isolated red cell membranes, demonstrated an abnormality in erythrocyte sodium transport. The extensive study of elliptocytosis in Iceland reported by Jensson et al. (1967) showed how widely the manifestations may vary. All cases were plausibly considered to have the same gene. Additional evidence of heterogeneity in elliptocytosis may be provided by the effects of combination with beta-thalassemia. Aksoy and Erdem (1968) concluded that the combination sometimes results in mutual enhancement, whereas in other instances it does not. Nielsen and Strunk (1968) described a Dutch family in which, among the 7 offspring of related parents, both with elliptocytosis, 2 died in infancy of severe anemia; a third had erythrocytes that showed more marked morphologic changes than in heterozygotes and had severe anemia which was compensated by splenectomy. All 3 were presumably homozygotes. Three other sibs were heterozygotes and one was stillborn. The elliptocytosis was of the Rh-linked variety. Lipton (1955) had reported an instance of presumed homozygosity; both parents had elliptocytosis without hemolysis and were second cousins. The child had hemolytic anemia. Splenectomy was beneficial. Early demonstrations of abnormalities of band 4.1 were provided by Alloisio et al. (1981) and Tchernia et al. (1981). Tchernia et al. (1981) studied a family in which 3 of 5 sisters had severe hemolytic anemia, marked red cell fragmentation, and elliptocytic poikilocytosis. They were presumed to be homozygotes because both parents and a clinically unaffected (or minimally affected) sister had conventional elliptocytosis and were probably heterozygous. The parents were consanguineous. All 7 members of the nuclear family were Rh-identical (Rh-negative), making linkage study impossible. Band 4.1 in the red cell membrane proteins was markedly reduced in the 3 patients and reduced to an intermediate level in the 3 putative heterozygotes. Thus, band 4.1 is probably central to normal membrane stability and normal cell shape. The critical role of protein 4.1 in red cell membrane stability was demonstrated by the restoration of normal membrane stability with purified protein 4.1 (Takakuwa et al., 1986). Alloisio et al. (1982) described a heritable variant of protein 4.1 that consists of shortening by about 75 amino acids, affecting both subcomponents a and b and involving one or more phosphorylation sites. The proposita was normal and was identified because of complete lack of protein 4.1 in her son with elliptocytosis. The father had elliptocytosis and reduced band 4.1. The son was presumably a compound heterozygote. Homozygotes with elliptocytosis and total absence of band 4.1 were described also by Feo et al. (1980). Morle et al. (1985) gave further information on the family reported by Alloisio et al. (1982) and referred to the variant as protein 4.1 Presles. Alloisio et al. (1985) suggested that the heterozygous state of this form of hereditary elliptocytosis, called the 4.1(-) trait, results in a characteristic clinical picture. In the course of an elliptocytosis screening of 10 families from southeastern France and North Africa, Alloisio et al. (1985) found 4 in which a clinically silent, dominantly transmitted form of hereditary elliptocytosis was associated in every case with a decrease of band 4.1. In the other families, band 4.1 was normal, clinical signs were sometimes present, and in 3 the mode of inheritance was uncertain. Whereas heterozygous 4.1 deficiency accounts for one-fourth to one-third of hereditary elliptocytosis in Caucasians, homozygosity is rare. Dalla Venezia et al. (1992) suggested that the rarity of homozygous 4.1 deficiency is related to the severe effects on other cell types in addition to red cells. Dhermy et al. (1986) reported studies of 38 cases of hereditary elliptocytosis. Fifteen patients showed a deficiency in protein 4.1. The other 24 patients showed a spectrin self-association defect (type I HE). A shortened spectrin beta chain was found in 1 family with a spectrin self-association defect. All patients with the protein 4.1 deficiency were Caucasian; most of the type I HE cases were of black extraction. Lambert and Zail (1987) described partial deficiency of protein 4.1 as the cause of autosomal dominant hereditary elliptocytosis. They studied a total of 14 families, of which 1 was black, residing in South Africa. Morle et al. (1987) described 2 sibs with severe congenital hemolytic anemia and red cells displaying a variety of abnormal shapes. Protein 4.1 was reduced by 30%. The parents, who were consanguineous, were devoid of any biochemical abnormality; however, their red cells were not normal. Whether the primary defect resided in protein 4.1 was not clear. Mapping On the basis of a family segregating for elliptocytosis and PGD (172200) as well as the common polymorphisms Rh, PGM1 and alpha-fucosidase, Cook et al. (1977) concluded that the map of 1p is, in the male, 1pter--PGD--18%--El--2%--Rh--2%--alpha-FUC--25%--PGM1--centromere. In the female, the above intervals were estimated to be 22, 4, 2, and 37%, respectively. As knowledge of the molecular genetics of the red cell membrane proteins advanced, light was thrown on the early demonstration of linkage of Rh with one form of elliptocytosis and nonlinkage with other forms. The protein 4.1 gene was mapped to chromosome 1pter-p32 (Conboy et al. (1985, 1986)) by hybridization to chromosomes sorted onto nitrocellulose filters using a fluorescence-activated cell sorter. Studies of translocations also localized the gene to chromosome 1pter-p32, the region of the Rh gene (Kan, 1986). Thus, it seemed certain that the protein 4.1 gene is mutant in Rh-linked elliptocytosis. Parra et al. (1998) stated that the EPB41 gene is located on chromosome 1p33-p32. Molecular Genetics By Southern blot analysis of genomic DNA from affected members of an Algerian family with elliptocysis, Conboy et al. (1986) showed that the mutant protein 4.1 gene had a DNA rearrangement upstream from the initiation codon for translation (130500.0001). The mRNA from the mutant gene was aberrantly spliced. McGuire and Agre (1987) demonstrated Rh linkage in 2 Caucasian families with a defect in protein 4.1. In 1 family the 4.1 band showed a reduction to about 65% of normal; in the other, a high molecular weight 4.1 was present. (A third proband had unstable 4.1.) McGuire et al. (1988) found that variants of erythrocyte protein 4.1 were inherited in linkage with elliptocytosis and with Rh type in 3 white families. Partial deletion of protein 4.1 was found in 1 family with elliptocytosis (Kan, 1986). Lambert et al. (1988) found an elliptocytosis family in which an apparent rearrangement of the coding region of the protein 4.1 gene led to restriction fragment length polymorphism when DNA was tested using a fragment of the cDNA that encompassed the coding region of the gene. History In a family in which both elliptocytosis and hereditary hemorrhagic telangiectasia were segregating, Roberts (1945) pointed out that even small bodies of data are useful for excluding close linkage. The elliptocytosis/Rh linkage was one of the first autosomal linkages to be demonstrated (Morton, 1956). INHERITANCE \- Autosomal dominant \- Autosomal recessive ABDOMEN Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Pallor \- Jaundice HEMATOLOGY \- Elliptocytosis \- Anemia \- Aplastic crisis (in some patients) MISCELLANEOUS \- Affected individuals may have heterozygous or homozygous mutations \- Patients with heterozygous mutations may be clinically asymptomatic MOLECULAR BASIS \- Caused by mutation in the erythrocyte membrane protein band 4.1 gene (EPB41, 130500.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	ELLIPTOCYTOSIS 1	c0013902	4,633	omim	https://www.omim.org/entry/611804	2019-09-22T16:02:50	{"doid": ["2373"], "mesh": ["D004612"], "omim": ["611804"], "orphanet": ["288"], "synonyms": ["Alternative titles", "ELLIPTOCYTOSIS, RHESUS-LINKED TYPE", "PROTEIN 4.1 OF ERYTHROCYTE MEMBRANE, DEFECT OF", "4.1-MINUS TRAIT", "4.1- TRAIT"]}
A number sign (#) is used with this entry because this tumor predisposition syndrome (TPDS) can be caused by heterozygous germline mutation in the BAP1 gene (603089) on chromosome 3p21. Description This tumor predisposition syndrome is inherited in an autosomal dominant pattern. Individuals carrying heterozygous BAP1 mutations are at high-risk for the development of a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma (155720), cutaneous melanoma (155600), malignant mesothelioma on exposure to asbestos (156240), and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma (summary by Wiesner et al., 2011, Testa et al., 2011, Abdel-Rahman et al., 2011, and Popova et al., 2013). Clinical Features Wiesner et al. (2011) reported 2 unrelated families with autosomal dominant inheritance of a skin tumor predisposition syndrome. In the second decade of life, affected individuals progressively developed multiple skin-colored to reddish-brown, dome-shaped to pedunculated, well-circumscribed papules with an average size of 5 mm all over the body. The number of tumors per individual varied markedly, ranging from 5 to over 50. Histopathologic examination showed dermal tumors composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and prominent nucleoli. The melanocytes often contained large, vesicular nuclei that varied substantially in size and shape. The lesions were distinct from common acquired nevi. Some of the neoplasms showed atypical features such as high cellularity or nuclear pleomorphism, and were classified as 'neoplasms of uncertain malignant potential;' these individuals were managed as if they had melanoma. Both families were identified because of the occurrence of multiple epithelioid melanocytic tumors, but, in each family, 1 affected individual had uveal melanoma, at ages 72 and 44, respectively, and 3 members of family 2 developed cutaneous melanoma. None of the affected individuals had intellectual disabilities or dysmorphic features, or lung or breast cancer. Testa et al. (2011) reported 2 unrelated families with multiple cases of malignant mesothelioma apparently transmitted in an autosomal dominant pattern. Affected members of both families had only household exposure to asbestos, but not occupational exposure. In 1 family, there were 5 affected individuals spanning 3 generations. There was also 1 case each of ovarian cancer, breast cancer, and renal cell carcinoma in other members of this family. The second family had 7 cases of mesothelioma. In addition, there was 1 case each of squamous cell carcinoma, basal cell carcinoma, and pancreatic cancer in other family members. One of the mesothelioma patients also had a uveal melanoma, and 1 additional family members reportedly had a uveal melanoma, but no DNA was available from the latter patient. Abdel-Rahman et al. (2011) reported a family in which multiple members spanning 5 generations had different types of cancer. The proband was ascertained due to the onset of uveal melanoma at age 52 years, and she also had lung adenocarcinoma. She was found to carry a heterozygous truncating mutation in the BAP1 gene (Q267X; 603089.0007). Three additional living family members with cancer also carried the mutation: 1 had cutaneous melanoma, 1 had meningioma, and 1 had uveal melanoma and neuroendocrine carcinoma. There were 2 deceased obligate carriers, who had a history of abdominal adenocarcinoma, likely ovarian, and mesothelioma, respectively. One additional mutation carrier was cancer-free at age 55 years. Tumor tissue from lung adenocarcinoma, meningioma, and uveal melanoma of 3 patients all showed somatic loss of heterozygosity for the BAP1 gene, and all had decreased BAP1 nuclear expression by immunohistochemical studies. The findings were consistent with biallelic inactivation of the BAP1 gene. Abdel-Rahman et al. (2011) concluded that this family had a hereditary cancer predisposition syndrome that increased the risk of several different types of tumors. The proband in this family was the only 1 of 53 unrelated patients with uveal melanoma and evidence of a familial cancer syndrome screened for BAP1 mutations who was found to carry a mutation, suggesting that is it a rare cause of hereditary uveal melanoma. Molecular Genetics Using array-based comparative genomic hybridization, Wiesner et al. (2011) found loss of chromosome 3p in 50% of skin tumors from 3 affected individuals in a family with melanocytic tumors, suggesting that this was a second hit resulting in the elimination of the remaining wildtype allele of a mutated tumor suppressor gene in this chromosomal region. Haplotype analysis showed segregation of the maternal allele in affected family members of 2 generations, and sequence analysis of this region identified a heterozygous germline mutation in the BAP1 gene (603089.0001) that segregated with the phenotype. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and a uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. Immunohistochemical studies showed loss of BAP1 nuclear expression in the melanocytic neoplasms. Molecular analysis of a second family with a similar phenotype identified a different heterozygous germline mutation in the BAP1 gene (603089.0002). Somatic inactivation of the remaining allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in the 1 uveal melanoma, and in a cutaneous melanoma from 1 patient. A metastatic melanoma from another family member did not show LOH for BAP1, but no additional tissue was available to investigate alternative mechanisms of BAP1 inactivation. In contrast, microscopic examination of common acquired flat nevi from these patients showed small uniform melanocytes and strong nuclear expression of BAP1. In addition, 37 (88%) of 42 tumors in both families showed a somatic V600E mutation in the BRAF gene (164757.0001). Notably, the families had a low number of melanomas compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. Using array-comparative genomic hybridization, Testa et al. (2011) found loss of BAP1 at 3p21 in 2 malignant mesothelioma tumors from 2 unrelated families. Subsequent linkage analysis of these families identified an inherited susceptibility locus on chromosome 3p21, and sequence analysis identified a heterozygous mutation in the BAP1 gene (603089.0003 and 603089.0004, respectively) in each family that segregated with the phenotype. Tumor tissue showed loss of BAP1 nuclear expression by immunohistochemistry. The findings were consistent with somatic loss of the second BAP1 allele in tumor tissue. Further analysis of 26 germline DNA samples from patients with sporadic mesothelioma found that 2 carried heterozygous BAP1 deletions (603089.0005 and 603089.0006, respectively). Each of these patients also had a history of uveal melanoma. In affected members of a large family with a tumor predisposition syndrome characterized mainly be renal cell carcinoma (RCC), Popova et al. (2013) identified a heterozygous germline mutation in the BAP1 gene (603089.0008). The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. Subsequently, sequence analysis identified heterozygous truncating mutations in the BAP1 gene (see, e.g., 603089.0009-603089.0010) in 11 (18%) of 60 unrelated families with either uveal melanoma, cutaneous melanoma, or mesothelioma. A total of 33 individuals were diagnosed with these 3 cancers in diverse associations; 14 individuals had other cancers, including renal, lung, breast, prostatic, thyroid, and bladder carcinomas. Nine RCCs were reported in 6 of the 11 families with BAP1 mutations, indicating that RCC should be added to the tumor spectrum of this syndrome. However, no BAP1 mutations were detected in a separate series of 32 French families with only RCC, suggesting that germline BAP1 mutations rarely explain families affected only with RCC. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Uveal melanoma RESPIRATORY Lung \- Mesothelioma, malignant, after asbestos exposure \- Lung adenocarcinoma SKIN, NAILS, & HAIR Skin \- Melanocytic skin tumors/papules, skin-colored to reddish-brown, dome-shaped or pedunculated, well circumscribed with an average size of 5 mm (in 2 families) \- Cutaneous melanoma Skin Histology \- Dermal tumors composed of epithelioid melanocytes \- Abundant cytoplasm \- Prominent nucleoli \- Melanocytes contain large vesicular nuclei with varying shapes \- Some show atypical features, such as nuclear pleomorphism NEUROLOGIC Central Nervous System \- Meningioma NEOPLASIA \- Mesothelioma, malignant, after asbestos exposure \- Uveal melanoma \- Cutaneous melanoma \- Meningioma \- Renal cell carcinoma, usually clear cell type MISCELLANEOUS \- Tumor predisposition syndrome MOLECULAR BASIS \- Caused by mutation in the BRCA1-associated protein 1 (BAP1, 603089.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	TUMOR PREDISPOSITION SYNDROME	c3280492	4,634	omim	https://www.omim.org/entry/614327	2019-09-22T15:55:41	{"omim": ["614327"], "orphanet": ["289539"], "synonyms": ["Tumor susceptibility linked to germline BAP1 mutations"], "genereviews": ["NBK390611"]}
Hemochromatosis type 4 (also called ferroportin disease) is a disease in which too much iron builds up in the body. This is also called iron overload. Accumulation of iron in the organs is toxic and can cause organ damage. While many organs can be affected, iron overload is especially likely to affect the liver, heart, and pancreas. Hemochromatosis type 4 can be further divided into two subtypes: * Hemochromatosis type 4A * Hemochromatosis type 4B People with hemochromatosis type 4A might not have any symptoms of the disease. Other individuals may develop liver disease as they get older. Hemochromatosis type 4B can be associated with fatigue, weakness, and joint pain. Other symptoms may include abdominal pain, loss of sex drive, liver disease, diabetes, heart problems, difficulty breathing, and skin discoloration. Symptoms of hemochromatosis type 4B can begin anytime from childhood to adulthood. Hemochromatosis type 4 is most common in people of southern European ancestry. Hemochromatosis type 4 is caused by genetic changes (mutations or pathogenic variants) to the SLC40A1 gene. The disease is inherited in an autosomal dominant manner. A diagnosis of hemochromatosis type 4 is suspected when a doctor observes signs and symptoms of the disease. A doctor may decide to order laboratory tests including a liver biopsy, MRI, or blood test. The diagnosis can be confirmed with genetic testing. Treatment of hemochromatosis type 4B usually involves reducing iron levels by removing blood (phlebotomy) or iron chelation. These treatments can prevent additional organ damage but typically do not reverse existing damage. People with hemochromatosis type 4A may not be recommended to have phlebotomy because it can increase the risk for complications such as anemia. To learn more about other types of hemochromatosis click on the disease names below: * Hemochromatosis type 1 * Hemochromatosis type 2 * Hemochromatosis type 3 * Hemochromatosis type 5 * Neonatal hemochromatosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Hemochromatosis type 4	c1853733	4,635	gard	https://rarediseases.info.nih.gov/diseases/10094/hemochromatosis-type-4	2021-01-18T18:00:07	{"mesh": ["C537249"], "omim": ["606069"], "umls": ["C1853733"], "orphanet": ["139491"], "synonyms": ["HFE4", "Hemochromatosis, autosomal dominant", "Hemochromatosis due to defect in ferroportin", "Autosomal dominant hereditary hemochromatosis", "Ferroportin disease"]}
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome. Clinical Features Vincent et al. (1994) analyzed a de novo 8q12.2-q21.2 deletion with the identification of a proposed 'new' contiguous gene syndrome consisting of the branchiootorenal (BOR) syndrome (113650), Duane syndrome (126800), hydrocephalus (600256), and aplasia of the trapezius muscle. This was the first reported localization of the genes responsible for Duane syndrome and for a dominant form of hydrocephalus. Linkage analysis of affected families consistently mapped the BOR gene to the region involved in the deletion. Using new algorithms, Vincent et al. (1994) constructed a YAC contig and used it to localize the breakpoint of another chromosomal rearrangement associated with the branchiootic syndrome to a 500-kb interval within the deletion. Eyes \- Duane syndrome Neuro \- Hydrocephalus Inheritance \- Autosomal dominant contiguous gene syndrome Lab \- Deletion of 8q12.2-q21.2 Muscle \- Trapezius muscle aplasia Ears \- Branchiootorenal (BOR) syndrome ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	CHROMOSOME 8q12.1-q21.2 DELETION SYNDROME	c1838346	4,636	omim	https://www.omim.org/entry/600257	2019-09-22T16:16:28	{"mesh": ["C536574"], "omim": ["600257"], "synonyms": ["Alternative titles", "BOR-DUANE HYDROCEPHALUS CONTIGUOUS GENE SYNDROME"]}
Jung and Smith (1980) described mother and daughter with asymmetric short stature associated with craniofacial, ocular, and skeletal anomalies. The mother was 132 cm tall; the daughter was 82 cm tall at 3.5 years of age (-4 SD). Both showed mild frontal bossing, small almost beaked nose, mandibular hypoplasia with dental crowding, esotropia, and hyperopia. The right leg was shorter than the left with pelvic tilt and lumbar scoliosis. Fusion and atypicality of cervical vertebrae, carpal bones and ribs were shown in the mother by radiographs. Intelligence was normal. This was the mother's only pregnancy; there was no increased incidence of abortion to suggest X-linked dominance with lethality in the hemizygous male. The disorder could be confused with Russell-Silver syndrome (180860) or Hallermann-Streiff syndrome (234100). Asymmetric short stature and facial anomalies including small nose occur also with chondrodysplasia punctata (118650). Radiology \- Fused atypical cervical vertebrae, carpal bones and ribs Head \- Mild frontal bossing \- Small almost beaked nose \- Mandibular hypoplasia Growth \- Asymmetric short stature Neuro \- Normal intelligence Teeth \- Dental crowding Spine \- Pelvic tilt \- Lumbar scoliosis Limbs \- Asymmetric leg shortening Inheritance \- ? Autosomal dominant Eyes \- Esotropia \- Hyperopia ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	ASYMMETRIC SHORT STATURE SYNDROME	c1862458	4,637	omim	https://www.omim.org/entry/108450	2019-09-22T16:44:43	{"mesh": ["C566248"], "omim": ["108450"]}
Anencephaly is a condition that prevents the normal development of the brain and the bones of the skull. This condition results when a structure called the neural tube fails to close during the first few weeks of embryonic development. The neural tube is a layer of cells that ultimately develops into the brain and spinal cord. Because anencephaly is caused by abnormalities of the neural tube, it is classified as a neural tube defect. Because the neural tube fails to close properly, the developing brain and spinal cord are exposed to the amniotic fluid that surrounds the fetus in the womb. This exposure causes the nervous system tissue to break down (degenerate). As a result, people with anencephaly are missing large parts of the brain called the cerebrum and cerebellum. These brain regions are necessary for thinking, hearing, vision, emotion, and coordinating movement. The bones of the skull are also missing or incompletely formed. Because these nervous system abnormalities are so severe, almost all babies with anencephaly die before birth or within a few hours or days after birth. ## Frequency Anencephaly is one of the most common types of neural tube defect, affecting about 1 in 1,000 pregnancies. However, most of these pregnancies end in miscarriage, so the prevalence of this condition in newborns is much lower. An estimated 1 in 10,000 infants in the United States is born with anencephaly. ## Causes Anencephaly is a complex condition that is likely caused by the interaction of multiple genetic and environmental factors. Some of these factors have been identified, but many remain unknown. Changes in dozens of genes in individuals with anencephaly and in their mothers may influence the risk of developing this type of neural tube defect. The best-studied of these genes is MTHFR, which provides instructions for making a protein that is involved in processing the vitamin folate (also called vitamin B9). While a shortage (deficiency) of this vitamin is an established risk factor for neural tube defects, there are many factors that can contribute to folate deficiency. Changes in other genes related to folate processing and genes involved in the development of the neural tube have also been studied as potential risk factors for anencephaly. However, no genes appear to play a major role in causing the condition. Researchers have also examined environmental factors that could contribute to the risk of anencephaly. Folate deficiency plays a significant role. Studies have shown that women who take supplements containing folic acid (the synthetic form of folate) before they get pregnant and very early in their pregnancy are significantly less likely to have a baby with a neural tube defect, including anencephaly. Other possible maternal risk factors for anencephaly include diabetes mellitus, obesity, exposure to high heat (such as a fever or use of a hot tub or sauna) in early pregnancy, and the use of certain anti-seizure medications during pregnancy. However, it is unclear how these factors may influence the risk of anencephaly. ### Learn more about the gene associated with Anencephaly * MTHFR ## Inheritance Pattern Most cases of anencephaly are sporadic, which means they occur in people with no history of the disorder in their family. A small percentage of cases have been reported to run in families; however, the condition does not have a clear pattern of inheritance. For parents who have had a child with anencephaly, the risk of having another affected child is increased compared with the risk in the general population. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Anencephaly	c0002902	4,638	medlineplus	https://medlineplus.gov/genetics/condition/anencephaly/	2021-01-27T08:24:36	{"gard": ["5808"], "mesh": ["D000757"], "omim": ["206500", "601634", "182940"], "synonyms": []}
von Zumbusch (acute) generalized pustular psoriasis (acute GPP) is the most severe form of generalized pustular psoriasis, and can be associated with life-threatening complications.[1] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 History * 5 References * 6 External links ## Signs and symptoms[edit] Patients with acute GPP experience the eruption of multiple isolated sterile pustules generalized over the body, recurrent fevers, fatigue, and laboratory abnormalities (elevated ESR, elevated CRP, combined with leukocytosis).[2] ## Diagnosis[edit] Kogoj's spongiform pustules can be observed via histopathology to confirm acute GPP.[2] ## Treatment[edit] Acute GPP typically requires inpatient management including both topical and systemic therapy, and supportive measures.[3] Systemic glucocorticoid withdrawal is a common causative agent.[4] Withdrawal or administration of certain drugs in the patient's previous medication regimen may be required. Oral retinoids are the most effective treatment, and are considered first line.[2] Cyclosporine or infliximab may be required for particularly acute cases.[5][6] ## History[edit] The disorder has been named after Leo Ritter von Zombusch, who first described two cases of a brother and a sister in 1910.[7] The patients experienced patterns of redness and pustule formation over several years, often associated with use of topical medications.[2] Unfortunately one of the two siblings died from complications of the disease. ## References[edit] 1. ^ Varman, Katherine M.; Namias, Nicholas; Schulman, Carl I.; Pizano, Louis R. (2014-06-01). "Acute generalized pustular psoriasis, von Zumbusch type, treated in the burn unit. A review of clinical features and new therapeutics". Burns. 40 (4): e35–e39. doi:10.1016/j.burns.2014.01.003. ISSN 0305-4179. PMID 24491419. 2. ^ a b c d Griffiths, C; Barker, Jonathan; Bleiker, Tanya; Chalmers, Robert; Creamer, Daniel (2016). Rook's textbook of dermatology. John Wiley & Sons Inc. ISBN 9781118441190. OCLC 949329582. 3. ^ Varman, Katherine M.; Namias, Nicholas; Schulman, Carl I.; Pizano, Louis R. (2014-06-01). "Acute generalized pustular psoriasis, von Zumbusch type, treated in the burn unit. A review of clinical features and new therapeutics". Burns: Journal of the International Society for Burn Injuries. 40 (4): e35–39. doi:10.1016/j.burns.2014.01.003. ISSN 1879-1409. PMID 24491419. 4. ^ Choon, Siew Eng; Lai, Nai Ming; Mohammad, Norshaleyna A.; Nanu, Nalini M.; Tey, Kwee Eng; Chew, Shang Fern (2014-06-01). "Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia". International Journal of Dermatology. 53 (6): 676–684. doi:10.1111/ijd.12070. ISSN 1365-4632. PMID 23967807. S2CID 44470715. 5. ^ Robinson, Amanda; Van Voorhees, Abby S.; Hsu, Sylvia; Korman, Neil J.; Lebwohl, Mark G.; Bebo, Bruce F.; Kalb, Robert E. (2012-08-01). "Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation". Journal of the American Academy of Dermatology. 67 (2): 279–288. doi:10.1016/j.jaad.2011.01.032. ISSN 1097-6787. PMID 22609220. 6. ^ Viguier, Manuelle; Aubin, François; Delaporte, Emmanuel; Pagès, Cécile; Paul, Carle; Beylot-Barry, Marie; Goujon, Catherine; Rybojad, Michel; Bachelez, Hervé (2012-12-01). "Efficacy and safety of tumor necrosis factor inhibitors in acute generalized pustular psoriasis". Archives of Dermatology. 148 (12): 1423–1425. doi:10.1001/2013.jamadermatol.80. ISSN 1538-3652. PMID 23247492. 7. ^ Zumbusch, Leo Ritter von (1909-02-01). "Psoriasis und pustulöses Exanthem". Archiv für Dermatologie und Syphilis (in German). 99 (1–2): 335–346. doi:10.1007/BF01910970. ISSN 0365-6020. S2CID 11086906. ## External links[edit] Classification D * ICD-10: L40.1 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	(von Zumbusch) acute generalized pustular psoriasis	c0343056	4,639	wikipedia	https://en.wikipedia.org/wiki/(von_Zumbusch)_acute_generalized_pustular_psoriasis	2021-01-18T18:46:16	{"umls": ["C0343056", "C2888177"], "wikidata": ["Q30602307"]}
A rare neurologic disorder characterized by spontaneous periodic hypothermia and hyperhidrosis in the absence of hypothalamic lesions. ## Epidemiology Spontaneous periodic hypothermia (SPH) prevalence is unknown but to date more than 50 cases of spontaneous periodic hypothermia have been described in the world literature. ## Clinical description SPH can occur at any age (ranging from 6 months to 62 years). The clinical manifestations of the disease comprise recurrent episodes of hypothermia (core temperature <35°C) with profuse sweating, nausea and vomiting, that occur in the absence of any detectable infectious or endocrine cause. Periodicity of hypothermic episodes may range from hours to years and the episodes themselves may last from hours to weeks. The sensation is usually experienced as a ''funny feeling'' in the head and is described as powerful, consuming and combined with a sense of weakness, incoordination and gait unsteadiness. Additional features include drowsiness, deep sleep, hypothermic syncope, mild bradycardia, and pale and cool skin. There are usually no associated complaints of diarrhea, confusion, wheezing, rash, seizure activity, shivering or shakiness. Polyuria and polydipsia during the attacks have been described in only one case. Recurrent hypothermia attacks were reported in two siblings. ## Etiology The exact pathophysiological mechanism for this syndrome is still not understood. Postulated mechanisms include hypothalamic dysfunction, neurochemical abnormalities, inflammatory processes, and epileptic activity. ## Diagnostic methods Diagnosis includes physical and systemic examinations which show a pale, cold skin and normal blood count and electrolyte levels. Imaging studies may in some cases reveal confluent lesions in the corpus callosum and a circumscribed lesion in the right posterior thalamus. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels in cerebrospinal fluid may be below the normal ranges. ## Differential diagnosis Differential diagnosis of SPH severe hypothyroidism, hypoglycemia or attacks of diabetic ketoacidosis. ## Management and treatment There is no cure for SPH. Management is mainly supportive and includes re-warming with a warm blanket. Carbamazepine, clonidine, cyproheptadine, glycopyrrolate, bromocriptine, chlorpromazine, beta1 blockers or sympathectomy are used with varying responses. ## Prognosis SPH is a benign disease and may cease spontaneously. Some patients have been reported to have hyperthermia attacks during the course of the disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Spontaneous periodic hypothermia	c2931542	4,640	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=29822	2021-01-23T18:41:01	{"gard": ["4815"], "mesh": ["C537594"], "umls": ["C2931542"], "icd-10": ["G90.8"], "synonyms": ["Episodic spontaneous hypothermia", "Shapiro syndrome"]}
Myopathic gait SpecialtyNeurology Causesweakness of the proximal muscles of the pelvic girdle Myopathic gait (or waddling gait) is a form of gait abnormality. The "waddling" is due to the weakness of the proximal muscles of the pelvic girdle.[1] The patient uses circumduction to compensate for gluteal weakness.[2] Conditions associated with a myopathic gait include pregnancy, congenital hip dysplasia, muscular dystrophies and spinal muscular atrophy. ## References[edit] 1. ^ "Gait > Abnormal". 2. ^ Saint, Sanjay; Wiese, Jeff; Bent, Stephen (2006). Clinical clerkships: the answer book. Hagerstown, MD: Lippincott Williams & Wilkins. p. 219. ISBN 0-7817-3754-0. ## See also[edit] * Myopathy * v * t * e Symptoms and signs relating to movement and gait Gait * Gait abnormality * CNS * Scissor gait * Cerebellar ataxia * Festinating gait * Marche à petit pas * Propulsive gait * Stomping gait * Spastic gait * Magnetic gait * Truncal ataxia * Muscular * Myopathic gait * Trendelenburg gait * Pigeon gait * Steppage gait * Antalgic gait Coordination * Ataxia * Cerebellar ataxia * Dysmetria * Dysdiadochokinesia * Pronator drift * Dyssynergia * Sensory ataxia * Asterixis Abnormal movement * Athetosis * Tremor * Fasciculation * Fibrillation Posturing * Abnormal posturing * Opisthotonus * Spasm * Trismus * Cramp * Tetany * Myokymia * Joint locking Paralysis * Flaccid paralysis * Spastic paraplegia * Spastic diplegia * Spastic paraplegia * Syndromes * Monoplegia * Diplegia / Paraplegia * Hemiplegia * Triplegia * Tetraplegia / Quadruplegia * General causes * Upper motor neuron lesion * Lower motor neuron lesion Weakness * Hemiparesis Other * Rachitic rosary * Hyperreflexia * Clasp-knife response This medical sign article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Myopathic gait	c0547001	4,641	wikipedia	https://en.wikipedia.org/wiki/Myopathic_gait	2021-01-18T18:35:21	{"wikidata": ["Q6947994"]}
Autosomal recessive spastic paraplegia type 15 is a complex form of hereditary spastic paraplegia characterized by a childhood to adulthood onset of slowly progressive lower limb spasticity (resulting in gait disturbance, extensor plantar responses and decreased vibration sense) associated with mild intellectual disability, mild cerebellar ataxia, peripheral neuropathy (with distal upper limb amyotrophy) and retinal degeneration. Thin corpus callosum is a common imaging finding. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Autosomal recessive spastic paraplegia type 15	c1849128	4,642	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100996	2021-01-23T18:29:28	{"gard": ["9581"], "mesh": ["C536642"], "omim": ["270700"], "umls": ["C1849128"], "icd-10": ["G11.4"], "synonyms": ["Hereditary spastic paraparesis type 15", "Kjellin syndrome", "SPG15", "Spastic paraplegia-retinal degeneration syndrome"]}
Pneumoscrotum SpecialtyUrology Pneumoscrotum is a rare medical condition in which gas accumulates in the scrotum. It has a variety of possible causes.[1][2][3][4] ## See also[edit] * Pneumothorax * Pneumatocele * Scrotal inflation ## References[edit] 1. ^ Firman, R; Heiselman, D; Lloyd, T; Mardesich, P (1993). "Pneumoscrotum". Annals of Emergency Medicine. 22 (8): 1353–6. doi:10.1016/s0196-0644(05)80122-2. PMID 8333643. 2. ^ Watson, H. S.; Klugo, R. C.; Coffield, K. S. (1992). "Pneumoscrotum: Report of two cases and review of mechanisms of its development". Urology. 40 (6): 517–21. doi:10.1016/0090-4295(92)90406-m. PMID 1466104. 3. ^ Yang, B; Jiang, S. X.; Fan, Z. L. (2007). "Pneumoscrotum induced by spontaneous colon perforation: A case report and review of the literature". Zhonghua Nan Ke Xue = National Journal of Andrology. 13 (8): 744–5. PMID 17918718. 4. ^ Lostoridis, E; Gkagkalidis, K; Varsamis, N; Salveridis, N; Karageorgiou, G; Kampantais, S; Tourountzi, P; Pouggouras, K (2013). "Pneumoscrotum as complication of blunt thoracic trauma: A case report". Case Reports in Surgery. 2013: 392869. doi:10.1155/2013/392869. PMC 3557629. PMID 23401836. This article about a disease of the genitourinary system is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Pneumoscrotum	None	4,643	wikipedia	https://en.wikipedia.org/wiki/Pneumoscrotum	2021-01-18T18:55:56	{"wikidata": ["Q17153307"]}
Salivary gland–like carcinoma of the lung SpecialtyOncology Salivary gland–like carcinomas of the lung generally refers a class of rare cancers that arise from the uncontrolled cell division (mitosis) of mutated cancer stem cells in lung tissue. They take their name partly from the appearance of their abnormal cells, whose structure and features closely resemble those of cancers that form in the major salivary glands (parotid glands, submandibular glands and sublingual glands) of the head and neck.[1] Carcinoma is a term for malignant neoplasms derived from cells of epithelial lineage, and/or that exhibit cytological or tissue architectural features characteristically found in epithelial cells.[2][1] ## Contents * 1 Types * 2 Diagnosis * 2.1 Classification * 3 Treatment * 4 References * 5 External links ## Types[edit] This class of primary lung cancers contains several histological variants, including mucoepidermoid carcinoma of the lung, adenoid cystic carcinoma of the lung, epithelial-myoepithelial carcinoma of the lung, and other (even more rare) variants. .[1] ## Diagnosis[edit] ### Classification[edit] Lung cancer is a large and exceptionally heterogeneous family of malignancies.[3] Over 50 different histological variants are explicitly recognized within the 2004 revision of the World Health Organization (WHO) typing system ("WHO-2004"), currently the most widely used lung cancer classification scheme.[1] Many of these entities are rare, recently described, and poorly understood.[4] However, since different forms of malignant tumors generally exhibit diverse genetic, biological, and clinical properties — including response to treatment — accurate classification of lung cancer cases are critical to assuring that patients with lung cancer receive optimum management.[5][6] Under WHO-2004, lung carcinomas are divided into 8 major taxa:[1] * Squamous cell carcinoma * Small cell carcinoma * Adenocarcinoma * Large cell carcinoma * Adenosquamous carcinoma * Sarcomatoid carcinoma * Carcinoid tumor * Salivary gland-like carcinoma ## Treatment[edit] This section is empty. You can help by adding to it. (March 2018) ## References[edit] 1. ^ a b c d e Travis, William D; Brambilla, Elisabeth; Muller-Hermelink, H Konrad; et al., eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 92-832-2418-3. Retrieved 27 March 2010. 2. ^ Travis WD, Travis LB, Devesa SS (January 1995). "Lung cancer". Cancer. 75 (1 Suppl): 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996. 3. ^ Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R (June 1985). "Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases". Hum. Pathol. 16 (6): 569–79. doi:10.1016/S0046-8177(85)80106-4. PMID 2987102. 4. ^ Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y (December 2001). "The new World Health Organization classification of lung tumours". Eur. Respir. J. 18 (6): 1059–68. doi:10.1183/09031936.01.00275301. PMID 11829087. S2CID 3108488. 5. ^ Rossi G, Marchioni A, Sartori1 G, Longo L, Piccinini S, Cavazza A (2007). "Histotype in non-small cell lung cancer therapy and staging: The emerging role of an old and underrated factor". Curr Resp Med Rev. 3: 69–77. doi:10.2174/157339807779941820. S2CID 52904357.CS1 maint: multiple names: authors list (link) 6. ^ Vincent MD (August 2009). "Optimizing the management of advanced non-small-cell lung cancer: a personal view". Curr Oncol. 16 (4): 9–21. doi:10.3747/co.v16i4.465. PMC 2722061. PMID 19672420. ## External links[edit] * Lung Cancer Home Page. The National Cancer Institute site containing further reading and resources about lung cancer. * [1]. World Health Organization Histological Classification of Lung and Pleural Tumours. 4th Edition (2004). * v * t * e Cancer involving the respiratory tract Upper RT Nasal cavity Esthesioneuroblastoma Nasopharynx Nasopharyngeal carcinoma Nasopharyngeal angiofibroma Larynx Laryngeal cancer Laryngeal papillomatosis Lower RT Trachea * Tracheal tumor Lung Non-small-cell lung carcinoma * Squamous-cell carcinoma * Adenocarcinoma (Mucinous cystadenocarcinoma) * Large-cell lung carcinoma * Rhabdoid carcinoma * Sarcomatoid carcinoma * Carcinoid * Salivary gland–like carcinoma * Adenosquamous carcinoma * Papillary adenocarcinoma * Giant-cell carcinoma Small-cell carcinoma * Combined small-cell carcinoma Non-carcinoma * Sarcoma * Lymphoma * Immature teratoma * Melanoma By location * Pancoast tumor * Solitary pulmonary nodule * Central lung * Peripheral lung * Bronchial leiomyoma Pleura * Mesothelioma * Malignant solitary fibrous tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Salivary gland–like carcinoma of the lung	c3873334	4,644	wikipedia	https://en.wikipedia.org/wiki/Salivary_gland%E2%80%93like_carcinoma_of_the_lung	2021-01-18T18:32:34	{"umls": ["C3873334"], "wikidata": ["Q7404869"]}
Collagen disease SpecialtyRheumatology Collagen disease is a term previously used to describe systemic autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. The term "collagen disease" was coined by Dr. Alvin F. Coburn in 1932, on his quest to discover streptococcal infection as the cause for rheumatic fever.[1] ## See also[edit] * Collagenopathy, types II and XI * Connective tissue disease ## References[edit] 1. ^ Coburn, Alvin (1974). Commitment Total. United States of America: Walker and Company. pp. 54, xi. ISBN 0-8027-0449-2. ## External links[edit] * Collagen disease entry in the public domain NCI Dictionary of Cancer Terms Classification D * MeSH: D003095 This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms". * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous proteins Authority control * NDL: 00566160 This article about a disease of musculoskeletal and connective tissue is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Collagen disease	c0009326	4,645	wikipedia	https://en.wikipedia.org/wiki/Collagen_disease	2021-01-18T19:00:23	{"mesh": ["D003095"], "umls": ["C0009326"], "wikidata": ["Q1446169"]}
Trophoblastic neoplasm Micrograph of intermediate trophoblast and a hydatidiform mole (bottom of image). H&E stain. SpecialtyOncology Gestational trophoblastic neoplasia (GTN) is group of rare diseases related to pregnancy and included in gestational trophoblastic disease (GTD) in which abnormal trophoblast cells grow in the uterus.[1] GTN can be classified into benign and malignant lesions. Benign lesions include placental site nodule and hydatidiform moles while malignant lesions have[2] four subtypes including invasive mole, gestational choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT).[3] The choriocarcinoma has 2 significant subtypes including gestational and non-gestational and they are differentiated by their different biological feature and prognosis.[4] Signs and symptoms of GTN will appear vary from person to person and depending upon the type of the disease. They may include uterine bleeding not related to menstruation, pain or pressure in pelvis, large uterus and high blood pressure during pregnancy. The cause of this disease is unknown but the identification of the tumor based on total beta-human chorionic gonadotropin (β-hCG) in the serum. Management of GTN requires pathology review, treatment options and monitoring of hCG. Therefore, it can be treated with curettage, hysterectomy and single agent or multi agent chemotherapy.[5] Although this group of diseases are highly susceptible to chemotherapy, prognosis depends on the type of GTN and whether the tumor has spread to other areas of the body.[6] ## Contents * 1 Cause and Risk factors * 2 Signs and Symptoms * 3 Diagnosis * 3.1 Tumor staging * 4 Pathophysiology * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 Research * 9 References * 10 External links ## Cause and Risk factors[edit] The exact cause of gestational trophoblastic neoplasia (GTN) is unknown. GTN often arises after molar pregnancies but can also occur after any gestation including miscarriages and term pregnancies.[7] Although risk factors may impact on the development of the tumor, most do not directly cause of disease. According to the some studies, the risk of complete molar pregnancy is highest in women over age 35 and younger than 20. The risk is even higher for women over age 45.[8][9] ## Signs and Symptoms[edit] The symptoms of GTN will vary from person to person. People with the same disease may not have all the symptoms listed. * Most common presenting symptom is vaginal bleeding, which is associated with mild elevation of serum β hCG (< 2,500 IU/l).[10] Vaginal bleeding may also occur after delivery that continues for longer than normal. * A uterus that is larger than expected during pregnancy * Pain or pressure in the pelvis. * Severe nausea and vomiting during pregnancy. * High blood pressure with headache and swelling of feet and hands early in the pregnancy. * Fatigue, shortness of breath, dizziness, and a fast or irregular heartbeat caused by anemia. * If metastases are present, signs and symptoms associated with the metastatic disease and more severe symptoms may be present.[11] ## Diagnosis[edit] Initial screening tests for GTN include: * Internal pelvic exam: to check for lumps or anything unusual changes. * Ultrasound exam of the pelvis: Also called a sonogram, an ultrasound creates a picture of the internal organ. In a transvaginal ultrasound, an ultrasound wand is inserted into the vagina and directed at the uterus to take the pictures.[12] * Blood chemistry studies: It can be done to check the levels of certain hormones and other substances that may be impacted by the presence of GTN.[13] * Serum tumor marker test: For GTN, the blood is checked for the level of β-hCG, a hormone that is made by the body during pregnancy. β-hCG in the blood of a woman who is not pregnant may be a sign of GTN and also helpful tests to monitor a woman’s recovery during and after treatment. Placental side trophoblastic tumor (PSTT) is differentiated by low β-hCG levels because it is a neoplastic proliferation of intermediate trophoblastic cells.[14] * Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, bacteria, and the level of β-hCG.[15] * Spinal tap: Cerebrospinal fluid is tested for high amounts of the hormone β-hCG if the GTN has spread to the brain or spinal cord. * Computed tomography (CT): A CT scan can be used to measure the tumor's size. * Chest x-ray: It may be done if the tumor has spread outside of the uterus. ### Tumor staging[edit] FIGO (International Federation of Gynecology and Obstetrics) 2000 Anatomical staging is commonly used to evaluate stage of GTN. Stage I - Disease confined to the uterus Stage II - GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament) Stage III - GTN extends to the lungs, with or without known genital tract involvement Stage IV - All other metastatic sites [16] ## Pathophysiology[edit] High magnification micrograph of choriocarcinoma. H&E stain. All types of gestational trophoblastic neoplasia originate from the placenta. A placenta develops in the uterus during pregnancy and becomes first site of nutrient and gas exchange between mother and fetus. It has two components such as fetal component and mother component. A fetal component is composed of cytotrophoblast and syncytiotrophoblast.[17] The exact pathogenesis of choriocarcinoma has not been fully understood, but studies have shown cytotrophoblast cells function as stem cells and transform into malignant form. The neoplastic cytotrophoblast further differentiates into either intermediate trophoblasts or syncytiotrophoblast. ## Treatment[edit] Several treatment methods are available for GTN that include surgery, chemotherapy or combination of these. Surgery treatment is most common initial method for some types of the disease but it depends on the stage of the tumor. Common surgical options include dilation and curettage, and hysterectomy. ## Prognosis[edit] FIGO modified Prognostic Scoring System. The system evaluates the patients to those with GTN as low-risk and high-risk based on several risk factors such as age, pregnancy or interval of pregnancies, size or metastases of tumor and prior chemotherapy. Each risk factors are rated at levels 0-4 scores. The numbers are then added up, and the overall score determines a woman's risk level. * Women with a score of 6 or less are at low risk and tend to have a good prognosis regardless of how far the cancer has spread which usually respond well to chemotherapy. * Women with a score of 7 or more are at high risk, and their tumors tend to respond less well to chemotherapy, even if they haven't spread much. They may require more intensive chemotherapy.[18] Therefore, some studies have shown that the condition is harder to cure if the cancer has spread to the liver or brain or β-hCG level is higher than 40,000 mIU/mL when treatment begins, cancer returns after having chemotherapy or symptoms/ pregnancy occurred for more than 4 months before treatment.[19] ## Epidemiology[edit] According to studies, GTN is found more frequently in Asia compared to North America or Europe.[20] As of 2020, the reported incidence of choriocarcinoma ranges from 1 in 40 000 pregnancies in North America and Europe, to 9.2 and 3.3 per 40 000 pregnancies in Southeast Asia and Japan, respectively. Epidemiological studies have reported that hydatidiform mole appears to be caused by abnormal gametogenesis and fertilization more frequent at the extremes of reproductive age of younger than 15 and older than 45 years of age and pregnancies at these ages are a risk factor for hydatidiform mole. The risk increases after age 35 and there is a 5–10 times increased risk after 45 years.[21] ## Research[edit] Recently, in order to provide more comprehension tools of GTN pathogenesis, epigenetic modifications and molecular biology techniques could be applied for proper diagnosis, management, and treatment of such neoplasia. The progression of anti-angiogenesis therapy and molecular targeted cancer therapies would be capable of improving the therapeutic perspective among patients with drug resistance.[22] Although chemotherapy and hysterectomy are currently used in a clinical setting, the use of diverse treatments including anti-body and gene therapy also being attempted to cure GTN. In addition, gene delivery tools using genetically engineered neural stem cells are presently being examined for the treatment of GTN and previous studies have indicated a significant inhibitory effect on tumor growth.[23] ## References[edit] 1. ^ "Gestational Trophoblastic Disease Treatment (PDQ®)–Patient Version - National Cancer Institute". www.cancer.gov. 2020-05-11. Retrieved 2020-12-16. 2. ^ Scott, Eirwen M.; Smith, Ashlee L.; Desouki, Mohamed Mokhtar; Olawaiye, Alexander B. (2012-12-02). "Epithelioid Trophoblastic Tumor: A Case Report and Review of the Literature". Case Reports in Obstetrics and Gynecology. Retrieved 2020-12-16. 3. ^ "Gestational trophoblastic tumor \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2020-12-16. 4. ^ Bishop, Bradie N.; Edemekong, Peter F. (2020), "Choriocarcinoma", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30571055, retrieved 2020-12-16 5. ^ Bishop, Bradie N.; Edemekong, Peter F. (2020), "Choriocarcinoma", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30571055, retrieved 2020-12-16 6. ^ "Gestational Trophoblastic Disease Treatment (PDQ®)–Patient Version - National Cancer Institute". www.cancer.gov. 2020-05-11. Retrieved 2020-12-16. 7. ^ May, Taymaa; Goldstein, Donald P.; Berkowitz, Ross S. (2011-05-11). "Current Chemotherapeutic Management of Patients with Gestational Trophoblastic Neoplasia". Chemotherapy Research and Practice. Retrieved 2020-12-16. 8. ^ "References: Gestational Trophoblastic Disease". www.cancer.org. Retrieved 2020-12-16. 9. ^ "Gestational Trophoblastic Disease - Risk Factors". Cancer.Net. 2012-06-25. Retrieved 2020-12-16. 10. ^ "Epithelioid trophoblastic tumor", Definitions, Qeios, 2020-02-10, retrieved 2020-12-16 11. ^ "Gestational Trophoblastic Neoplasia Clinical Presentation: History, Physical, Causes". emedicine.medscape.com. Retrieved 2020-12-16. 12. ^ "Gestational Trophoblastic Disease - Diagnosis". Cancer.Net. 2012-06-25. Retrieved 2020-12-16. 13. ^ "Gestational Trophoblastic Disease". www.hopkinsmedicine.org. Retrieved 2020-12-16. 14. ^ Kim, Seung Jo (December 2003). "Placental site trophoblastic tumour". Best Practice & Research. Clinical Obstetrics & Gynaecology. 17 (6): 969–984. doi:10.1016/s1521-6934(03)00095-6. ISSN 1521-6934. PMID 14614893. 15. ^ "Gestational Trophoblastic Disease Treatment (PDQ®)–Patient Version - National Cancer Institute". www.cancer.gov. 2020-05-11. Retrieved 2020-11-02. 16. ^ "Table 1 \| Current Chemotherapeutic Management of Patients with Gestational Trophoblastic Neoplasia". www.hindawi.com. Retrieved 2020-12-16. 17. ^ AlJulaih, Ghadeer H.; Muzio, Maria Rosaria (2020), "Gestational Trophoblastic Neoplasia", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965896, retrieved 2020-12-16 18. ^ "Gestational Trophoblastic Disease Stages". www.cancer.org. Retrieved 2020-12-17. 19. ^ "Choriocarcinoma: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2020-12-17. 20. ^ AlJulaih, Ghadeer H.; Muzio, Maria Rosaria (2020), "Gestational Trophoblastic Neoplasia", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965896, retrieved 2020-11-12 21. ^ Ngan, Hextan Y.S.; Seckl, Michael J.; Berkowitz, Ross S.; Xiang, Yang; Golfier, François; Sekharan, Paradan K.; Lurain, John R.; Massuger, Leon (October 2018). "Update on the diagnosis and management of gestational trophoblastic disease". International Journal of Gynecology & Obstetrics. 143: 79–85. doi:10.1002/ijgo.12615. 22. ^ Sharami, Seyedeh Reyhaneh Yousefi; Saffarieh, Elham (2020-03-26). "A review on management of gestational trophoblastic neoplasia". Journal of Family Medicine and Primary Care. 9 (3): 1287–1295. doi:10.4103/jfmpc.jfmpc_876_19. ISSN 2249-4863. PMC 7266251. PMID 32509606. 23. ^ Kim, Gyu-Sik; Hwang, Kyung-A; Choi, Kyung-Chul (March 2019). "A promising therapeutic strategy for metastatic gestational trophoblastic disease: Engineered anticancer gene-expressing stem cells to selectively target choriocarcinoma". Oncology Letters. 17 (3): 2576–2582. doi:10.3892/ol.2019.9911. ISSN 1792-1074. PMC 6396211. PMID 30867726. ## External links[edit] Classification D * MeSH: D014328 * SNOMED CT: 115234004 * 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 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Trophoblastic neoplasm	c0041182	4,646	wikipedia	https://en.wikipedia.org/wiki/Trophoblastic_neoplasm	2021-01-18T18:42:13	{"mesh": ["D014328"], "umls": ["C0041182"], "orphanet": ["59305"], "wikidata": ["Q7845637"]}
For a clinical description of atopic dermatitis and an overview of linkage studies, see 603165. Mapping Esparza-Gordillo et al. (2009) conducted a genomewide association study in 939 individuals with atopic dermatitis and 975 controls as well as 270 complete nuclear families with 2 affected sibs. Single-nucleotide polymorphisms (SNPs) consistently associated with atopic dermatitis in both discovery sets were then investigated in 2 additional independent replication sets totaling 2,637 cases and 3,957 controls. Highly significant association was found with allele A of rs7927894 on chromosome 11q13.5, located 38 kb downstream of C11ORF30 (608574) (combined P = 7.6 x 10(-10)). Approximately 13% of individuals of European origin are homozygous for rs7927894(A), and their risk of developing atopic dermatitis is 1.47 times that of noncarriers. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	DERMATITIS, ATOPIC, 7	c2751599	4,647	omim	https://www.omim.org/entry/613064	2019-09-22T15:59:52	{"mesh": ["C567796"], "omim": ["613064"]}
A number sign (#) is used with this entry because of evidence that immunodeficiency-64 (IMD64) is caused by homozygous or compound heterozygous mutation in the RASGRP1 gene (603962) on chromosome 15q14. Description Immunodeficiency-64 (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity (summary by Salzer et al., 2016, Mao et al., 2018, and Winter et al., 2018). Clinical Features Salzer et al. (2016) reported a 15-year-old boy, born of consanguineous parents, with a primary immunodeficiency associated with lymphoma. He presented in the first years of life with recurrent bacterial and viral respiratory infections resulting in bronchiectasis, as well as failure to thrive. During adenotomy, an EBV-associated lymphoma was discovered, and he underwent chemotherapy and hematopoietic stem cell transplantation. Immunologic workup showed normal numbers of total lymphocytes, but a progressive decrease in CD4+ T cells, inverted CD4+/CD8+ T-cell ratio, increased delta/gamma T cells, a progressive decrease in B-cell counts, and decreased NK cells. Immunophenotyping of patient T cells showed an exhausted phenotype, as indicated by expansion of effector memory T cells. There was also a decrease in memory B cells and an increase of transitional B cells compared to controls. Immunoglobulin levels were normal, but there was an insufficient antibody response to vaccination. In addition, NK cells showed impaired cytotoxicity associated with defective formation of the immunologic synapse. The patient had no signs of autoimmunity. Family history revealed 3 older sibs who died in the first years of life, possibly as a result of immunodeficiency; material from these patients was not available. Platt et al. (2017) reported a girl, born of consanguineous Iraqi parents, with IMD64. She presented in early childhood with recurrent respiratory, dermal, and gastrointestinal infections. She also had warts consistent with epidermodysplasia verruciformis. At age 10 years, she presented with splenomegaly and lymphadenopathy; biopsy showed EBV-positive lymphoproliferative disease and a B-cell lymphoma. Immunologic workup showed CD4+ T-cell lymphopenia, increased CD8+ T cells, decreased numbers of naive T cells, low B cells, and transient hypogammaglobulinemia. She had poor T-cell proliferation responses and impaired NK cell cytolytic activity. Despite treatment, she died of complications of lymphoma. Mao et al. (2018) reported 2 sibs, born of unrelated parents, with a complex immunologic disorder. Both presented in early childhood with features of autoimmunity, including immune thrombocytopenia, autoimmune hemolytic anemia, chronic lymphadenopathy and hepatosplenomegaly, and autoantibodies. The patients also had recurrent infections with various bacterial, fungal, and viral pathogens. One developed hemophagocytic lymphohistiocytosis and the other developed a leiomyoma of the adrenal gland and liver. Laboratory studies showed autoantibodies, hypergammaglobulinemia, and increased numbers of delta/gamma T cells. B cells and regulatory T cells were normal. Winter et al. (2018) reported 2 sibs, born of consanguineous parents, with onset of EBV-positive lymphoma at 5 to 6 years of age. They also had recurrent infections, including disseminated tuberculosis. One of the patients also developed an adrenal EBV smooth muscle tumor and died at age 11 following relapse of lymphoma. Immunologic workup years after chemotherapy showed decreased numbers of B cells, T cells, NK cells, and MAIT cells (mucosal associated invariant T cells), absence of iNKT cells, and impaired T-cell proliferative responses. Immunoglobulin levels were normal or slightly elevated. Inheritance The transmission pattern of IMD64 in the family reported by Salzer et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In a 12-year-old boy, born of consanguineous parents, with IMD64, Salzer et al. (2016) identified a homozygous nonsense mutation in the RASGRP1 gene (R246X; 603962.0001) that segregated with the disorder in the family. Analysis of patient cells showed absence of the full-length protein, consistent with a loss of function. Patient T and B cells showed impaired proliferation, activation, and motility, as well as reduced ERK phosphorylation, which could be rescued by expression of wildtype RASGRP1. Patient lymphocytes and cells with shRNA-knockdown of the RASGRP1 gene showed signaling and phosphorylation defects downstream of RASGRP1; these abnormalities could be rescued by expression of wildtype RASGRP1. Patient CD8+ T cells showed slower actin turnover and impaired migration compared to controls, which was associated with impaired activation of RhoA following stimulation with CXCL12 (600835); treatment of the cells with lenalidomide resulted in increased RhoA activity and reversed the migration and activation defects. Patient NK cells showed defective lytic granule motility and impaired formation of the immunologic synapse. The findings suggested that RASGRP1 deficiency results in a partial T-cell defect and also affects NK cell cytotoxicity by impairing both actin polymerization and the convergence of lytic granules to the microtubule organizing center (MTOC) in T cells. These defects may be explained by an abrogated interaction with cytoplasmic dynein. In a girl, born of consanguineous Iraqi parents, with IMD64, Platt et al. (2017) identified a homozygous nonsense mutation in the RASGRP1 gene (W257X; 603962.0002). The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Her unaffected brother was heterozygous for the mutation, indicating segregation within the family. The patient died at 11 years of age; her cells were not available for study. In 2 sibs with IMD64, Mao et al. (2018) identified compound heterozygous mutations in the RASGRP1 gene (T214I, 603962.0003 and K322X, 603962.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed normal RASGRP1 protein expression, but impaired function. Patient T cells showed impaired proliferation, activation, and ERK phosphorylation upon stimulation, whereas the B-cell ERK response was normal. Patient cells showed impaired apoptosis, which correlated with the lymphoproliferative phenotype. In 2 sibs, born of consanguineous parents, with IMD64, Winter et al. (2018) identified a homozygous frameshift mutation in the RASGRP1 gene (603962.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed no detectable RASGRP1 expression, as well as impaired ERK phosphorylation after stimulation, which could be restored by expression of wildtype RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27 (186711)-dependent proliferation toward CD70 (602840)-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1 (123860), an important enzyme involved in DNA synthesis. The results showed that RASGRP1 deficiency leads to susceptibility to EBV infection, and demonstrated the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes. Animal Model Priatel et al. (2007) found that Rasgrp1 -/- mice remained both T-cell lymphopenic and free of overt disease until at least 1 year of age, but their proliferating Cd4 T cells expressed a marker of T-cell exhaustion, Pdcd1 (600244), as well as Pdcd ligand-1 (PDCD1LG1; 605402), but not Pdcd1lg2 (605723). Challenge with Listeria monocytogenes or lymphocytic choriomeningitis virus resulted in delayed pathogen clearance and an impaired T-cell response. Priatel et al. (2007) attributed the T-cell immunodeficiency to loss of Rasgrp1 protein in thymocytes and/or T cells rather than defects in innate immunity. Priatel et al. (2007) concluded that RASGRP1 has a role in determining a normal immune status and is an essential regulator of adaptive T-cell immunity in experimental infection. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	IMMUNODEFICIENCY 64	None	4,648	omim	https://www.omim.org/entry/618534	2019-09-22T15:41:31	{"omim": ["618534"]}
Omenn syndrome Omenn syndrome has an autosomal recessive pattern of inheritance. SpecialtyHematology Omenn syndrome is an autosomal recessive severe combined immunodeficiency.[1] It is associated with hypomorphic missense mutations in immunologically relevant genes of T-cells (and B-cells) such as recombination activating genes (RAG1 and RAG2), Interleukin-7 receptor-α (IL7Rα), DCLRE1C-Artemis, RMRP-CHH, DNA-Ligase IV, common gamma chain, WHN-FOXN1, ZAP-70 and complete DiGeorge syndrome. It is fatal without treatment. ## Contents * 1 Symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Symptoms[edit] A 5-month-old female infant with Omenn syndrome; she has red, scaly skin all over her body. The symptoms are very similar to graft-versus-host disease (GVHD). This is because the patients have some T cells with limited levels of recombination with the mutant RAG genes. These T cells are abnormal and have a very specific affinity for self antigens found in the thymus and in the periphery. Therefore, these T cells are auto-reactive and cause the GVHD phenotype. A characteristic symptom is chronic inflammation of the skin, which appears as a red rash[2] (early onset erythroderma). Other symptoms include eosinophilia, failure to thrive, swollen lymph nodes, swollen spleen, diarrhea, enlarged liver, low immunoglobulin levels (except immunoglobulin E, which is elevated), low T cell levels, and no B cells.[3] ## Genetics[edit] Omenn syndrome is caused by a partial loss of RAG gene function and leads to symptoms similar to severe combined immunodeficiency syndrome, including opportunistic infections. The RAG genes are essential for gene recombination in the T-cell receptor and B-cell receptor, and loss of this ability means that the immune system has difficulty recognizing specific pathogens.[2] Omenn Syndrome is characterised by the loss of T-cell function, leading to engraftment of maternal lymphocytes in the foetus and the co-existence of clonally expanded autologous and transplacental-acquired maternal lymphocytes.[4] Omenn syndrome can occasionally be caused in other recombination genes, including IL-7Rα and RMRP.[3] ## Diagnosis[edit] In order to diagnose a patient specifically with Omenn Syndrome, an autosomal recessive form of SCID, a physician can order a genetic testing panel to look for 22q11 microdeletions or mutations of the RAG1/RAG2 genes.[5] ## Treatment[edit] The only treatment for Omenn syndrome is chemotherapy followed by a bone marrow transplantation.[3] Without treatment, it is rapidly fatal in infancy.[2] ## See also[edit] * Purine nucleoside phosphorylase deficiency * List of cutaneous conditions ## References[edit] 1. ^ Santagata S, Villa A, Sobacchi C, Cortes P, Vezzoni P (2000). "The genetic and biochemical basis of Omenn syndrome". Immunol Rev. 178: 64–74. doi:10.1034/j.1600-065X.2000.17818.x. PMID 11213808. 2. ^ a b c Parham, Peter (2009). The Immune System (3rd ed.). Taylor & Francis Group. p. 128. ISBN 9781136977107. 3. ^ a b c Geha, Raif; Notarangelo, Luigi (2012). Case Studies in Immunology: A Clinical Companion (6th ed.). Garland Science. ISBN 978-0-8153-4441-4. 4. ^ Lev A, Simon AJ, Ben-Ari J, Takagi D, Stauber T, Trakhtenbrot L, Rosenthal E, Rechavi G, Amariglio N, Somech R (2014). "Co-existence of clonal expanded autologous and transplacental-acquired maternal T cells in recombination activating gene-deficient severe combined immunodeficiency". Clin Exp Immunol. 176 (3): 380–6. doi:10.1111/cei.12273. PMC 4008982. PMID 24666246. 5. ^ U.S. Department of Health and Human Services, National Institutes of Health, Genetic and Rare Diseases Information Center (last updated 2016). Omenn Syndrome. Retrieved from: https://rarediseases.info.nih.gov/diseases/8198/omenn-syndrome ## External links[edit] Classification D * ICD-10: D81.2 (ILDS D81.210) * OMIM: 603554 * DiseasesDB: 32676 External resources * eMedicine: ped/1640 * Orphanet: 39041 * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Omenn syndrome	c1801959	4,649	wikipedia	https://en.wikipedia.org/wiki/Omenn_syndrome	2021-01-18T19:06:40	{"gard": ["8198"], "umls": ["C1801959"], "orphanet": ["39041"], "wikidata": ["Q2214419"]}
Heerfordt syndrome Other namesUveoparotid fever,[1] Heerfordt–Mylius syndrome, Heerfordt–Waldenström syndrome, and Waldenström's uveoparotitis[2] SpecialtyAngiology Heerfordt syndrome is a rare manifestation of sarcoidosis. The symptoms include inflammation of the eye (uveitis), swelling of the parotid gland, chronic fever, and in some cases, palsy of the facial nerves.[1] ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 Prevalence * 5 History * 6 See also * 7 Notes * 8 References * 9 External links ## Causes[edit] The exact cause of Heerfordt syndrome has not yet been definitively determined. Of those patients who have been diagnosed with Heerfordt syndrome, 15% have a close relative who also has the syndrome. One possible explanation is that the syndrome results from a combination of an environmental agent and a hereditary predisposition. Mycobacterium and Propionibacteria species have both been suggested as the environmental agent, though the evidence for this is inconclusive.[1] ## Diagnosis[edit] In patients that have already been diagnosed with sarcoidosis, Heerfordt syndrome can be inferred from the major symptoms of the syndrome, which include parotitis, fever, facial nerve palsy and anterior uveitis. In cases of parotitis, ultrasound-guided biopsy is used to exclude the possibility of lymphoma.[3] There are many possible causes of facial nerve palsy, including Lyme disease, HIV, Melkersson–Rosenthal syndrome, schwannoma, and Bell's palsy. Heerfordt syndrome exhibits spontaneous remission. ## Treatment[edit] Treatments for sarcoidosis include corticosteroids and immunosuppressive drugs.[1] ## Prevalence[edit] In the United States, sarcoidosis has a prevalence of approximately 10 cases per 100,000 whites and 36 cases per 100,000 blacks.[4] Heerfordt syndrome is present in 4.1 to 5.6% of those with sarcoidosis.[5] ## History[edit] The condition was first described in 1909 by Danish ophthalmologist Christian Frederick Heerfordt, for whom the syndrome is now named.[6] It was originally attributed to mumps, but after further studies by Swedish doctor Jan G. Waldenström in 1937, it was classified as a distinct manifestation of sarcoidosis.[2][7] ## See also[edit] * Darier–Roussy disease * Sarcoidosis * List of cutaneous conditions ## Notes[edit] * Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. ## References[edit] 1. ^ a b c d Evanchan, Jason; Barreiro, Timothy J.; Gemmel, David (May 2010). "Uveitis, salivary gland swelling, and facial nerve palsy in a febrile woman". Journal of the American Academy of Physician Assistants. 23 (5): 46–50. doi:10.1097/01720610-201005000-00012. PMID 20480871. 2. ^ a b synd/3546 at Who Named It? 3. ^ Fischer, T.; et al. (January 2002). "Diagnosis of Heerfordt's syndrome by state-of-the-art ultrasound in combination with parotid biopsy: a case report". European Radiology. 12 (1): 134–7. doi:10.1007/s003300100879. PMID 11868089. S2CID 1088521. 4. ^ Iannuzzi, Michael C.; Rybicki, Benjamin A.; Teirstein, Alvin S. (22 November 2007). "Sarcoidosis". New England Journal of Medicine. 357 (21): 2153–65. doi:10.1056/NEJMra071714. PMID 18032765. 5. ^ Fukuhara K, Fukuhara A, et al. (August 2013). "Radiculopathy in patients with Heerfordt's syndrome: two case presentations and review of the literature". Brain and Nerve. 65 (8): 989–92. PMID 23917502. 6. ^ Heerfordt C. F. (1909). "Über eine "Febris uveo-parotidea subchronica" an der Glandula parotis und der Uvea des Auges lokalisiert und häufug mit Paresen cerebrospinaler Nerven kompliziert". Albrecht von Grafes Archiv für Ophthalmologie. 70 (2): 254–273. doi:10.1007/bf02008817. S2CID 10880812. 7. ^ Waldenström, J. G. (1937). "Some observations on uveoparotitis and allied conditions with special reference to the symptoms from the nervous system". Acta Medica Scandinavica. 91 (1–2): 53–68. doi:10.1111/j.0954-6820.1937.tb16029.x. ## External links[edit] Classification D * MeSH: D014608 * DiseasesDB: 33567 * v * t * e Sarcoidosis * Skin * Lupus pernio * Neurosarcoidosis * Löfgren syndrome * Heerfordt's syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Heerfordt syndrome	c0042171	4,650	wikipedia	https://en.wikipedia.org/wiki/Heerfordt_syndrome	2021-01-18T18:42:14	{"mesh": ["D014608"], "umls": ["C0042171"], "wikidata": ["Q1593605"]}
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Insulin resistance" – news · newspapers · books · scholar · JSTOR (October 2015) Insulin resistance SpecialtyEndocrinology Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that allows glucose to enter cells which also reduces blood glucose (blood sugar). Insulin is released by the pancreas in response to carbohydrates consumed in the diet. In states of insulin resistance, the same amount of insulin does not have the same effect on glucose transport and blood sugar levels. There are many causes of insulin resistance and the underlying process is still not completely understood. Risk factors for insulin resistance include obesity, sedentary lifestyle, family history of diabetes, various health conditions, and certain medications. Insulin resistance is considered a component of the metabolic syndrome. There are multiple ways to measure insulin resistance such as fasting insulin levels or glucose tolerance tests but these are not often used in clinical practice. Insulin resistance can be improved or reversed with lifestyle approaches such as exercise and dietary changes. ## Contents * 1 Cause * 1.1 Risk factors * 1.2 Lifestyle factors * 1.3 Medications * 1.4 Hormones * 1.5 Diseases * 1.6 Inflammation * 1.7 Genetics * 2 Pathophysiology * 2.1 Molecular mechanism * 3 Diagnosis * 3.1 Fasting insulin levels * 3.2 Glucose tolerance testing * 3.3 Hyperinsulinemic euglycemic clamp * 3.4 Modified insulin suppression test * 3.5 Alternatives * 4 Prevention and management * 5 History * 5.1 Adaptive explanations * 6 See also * 7 References * 8 Further reading * 9 External links ## Cause[edit] ### Risk factors[edit] There are a number of risk factors for insulin resistance, including being overweight or obese or having a sedentary lifestyle.[1] Various genetic factors can increase risk, such as a family history of diabetes, and there are some specific medical conditions associated with insulin resistance, such as polycystic ovary syndrome.[1] The National Institute of Diabetes and Digestive and Kidney Diseases state specific risks that may predispose an individual to insulin resistance also include: * being aged 45 or older * having African American, Alaska Native, American Indian, Asian American, Hispanic/Latino, Native Hawaiian, or Pacific Islander American ethnicity * having health conditions such as high blood pressure and abnormal cholesterol levels * having a history of gestational diabetes * having a history of heart disease or stroke.[1] In addition some medications and other health conditions can raise the risk.[1] ### Lifestyle factors[edit] Dietary factors likely contribute to insulin resistance, however, causative foods are difficult to determine given the limitations of nutrition research. Foods that have independently been linked to insulin resistance include those high in sugar with high glycemic indices, high in dietary fat and fructose, low in omega-3 and fiber, and which are hyper-palatable which increases risk of overeating.[2] Overconsumption of fat- and sugar-rich meals and beverages have been proposed as a fundamental factor behind the metabolic syndrome epidemic. Diet also has the potential to change the ratio of polyunsaturated to saturated phospholipids in cell membranes. The percentage of polyunsaturated fatty acids (PUFAs) is inversely correlated with insulin resistance.[3] It is hypothesized that increasing cell membrane fluidity by increasing PUFA concentration might result in an enhanced number of insulin receptors, an increased affinity of insulin to its receptors, and reduced insulin resistance.[4] Vitamin D deficiency has also been associated with insulin resistance.[5] Sedentary lifestyle increases the likelihood of development of insulin resistance.[6] In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.[7] Studies have consistently shown that there is a link between insulin resistance and circadian rhythm, with insulin sensitivity being higher in the morning and lower in the evening. A mismatch between the circadian rhythm and the meals schedule, such as in circadian rhythm disorders, may increase insulin resistance.[8][9][10] ### Medications[edit] Some medications are associated with insulin resistance including corticosteroids, protease inhibitors (type of HIV medication),[11] and atypical antipsychotics.[12] ### Hormones[edit] Many hormones can induce insulin resistance including cortisol,[13] growth hormone, and human placental lactogen.[14] Cortisol counteracts insulin and can lead to increased hepatic gluconeogenesis, reduced peripheral utilization of glucose, and increased insulin resistance.[15] It does this by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[16][17] Based on the significant improvement in insulin sensitivity in humans after bariatric surgery and rats with surgical removal of the duodenum,[18][19] it has been proposed that some substance is produced in the mucosa of that initial portion of the small intestine that signals body cells to become insulin resistant. If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity. No such substance has been found as yet, and the existence of such a substance remains speculative.[citation needed] Leptin, a hormone produced from the ob gene and adipocytes[20] Its physiological role is to regulate hunger by alerting the body when it is full.[21] Studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance.[22] ### Diseases[edit] Polycystic ovary syndrome[23] and non-alcoholic fatty liver disease (NAFLD) are associated with insulin resistance. Hepatitis C also makes people three to four times more likely to develop type 2 diabetes and insulin resistance.[24] ### Inflammation[edit] Acute or chronic inflammation, such as in infections, can cause insulin resistance. TNF-α is a cytokine that may promote insulin resistance by promoting lipolysis, disrupting insulin signaling, and reducing the expression of GLUT4.[25] ### Genetics[edit] Several genetic loci have been determined to be associated with insulin insensitivity. This includes variation in loci near the NAT2, GCKR, and IGFI genes associated with insulin resistance. Further research has shown that loci near the genes are linked to insulin resistance. However, these loci are estimated to only account for 25-44% of the genetic component of insulin resistance.[26] ## Pathophysiology[edit] In normal metabolism, the elevated blood glucose instructs beta (β) cells in the Islets of Langerhans, located in the pancreas, to release insulin into the blood. The insulin makes insulin-sensitive tissues in the body (primarily skeletal muscle cells, adipose tissue, and liver) absorb glucose which provides energy as well as lowers blood glucose.[27] The beta cells reduce insulin output as the blood glucose level falls, allowing blood glucose to settle at a constant of approximately 5 mmol/L (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. When the body produces insulin under conditions of insulin resistance, the cells are unable to absorb or use it as effectively and it stays in the bloodstream. Certain cell types such as fat and muscle cells require insulin to absorb glucose and when these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver normally helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. However, in insulin resistance, this normal reduction in the liver's glucose production may not occur, further contributing to elevated blood glucose.[28] Insulin resistance in fat cells results in reduced uptake of circulating lipids and increased hydrolysis of stored triglycerides. This leads to elevated free fatty acids in the blood plasma and can further worsen insulin resistance.[29][30][31] Since insulin is the primary hormonal signal for energy storage into fat cells, which tend to retain their sensitivity in the face of hepatic and skeletal muscle resistance, IR stimulates the formation of new fatty tissue and accelerates weight gain.[2] In states of insulin resistance, beta cells in the pancreas increase their production of insulin. This causes high blood insulin (hyperinsulinemia) to compensate for the high blood glucose. During this compensated phase on insulin resistance, insulin levels are higher, and blood glucose levels are still maintained. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) glucose concentrations increase. Eventually, type 2 diabetes occurs when glucose levels become higher as the resistance increases and compensatory insulin secretion fails.[32][33] The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to type 2 diabetes. Insulin resistance is strongly associated with intestinal-derived apoB-48 production rate in insulin-resistant subjects and type 2 diabetic patients. [34]Insulin resistance often is found in people with visceral adiposity, hypertension, hyperglycemia, and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels. With respect to visceral adiposity, a great deal of evidence suggests two strong links with insulin resistance. First, unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), and Interleukins-1 and −6, etc. In numerous experimental models, these proinflammatory cytokines disrupt normal insulin action in fat and muscle cells and may be a major factor in causing the whole-body insulin resistance observed in patients with visceral adiposity. Much of the attention on production of proinflammatory cytokines has focused on the IKK-beta/NF-kappa-B pathway, a protein network that enhances transcription of inflammatory markers and mediators that may cause insulin resistance. Second, visceral adiposity is related to an accumulation of fat in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD). The result of NAFLD is an excessive release of free fatty acids into the bloodstream (due to increased lipolysis), and an increase in hepatic glycogenolysis and hepatic glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increasing the likelihood of Type 2 diabetes mellitus.[citation needed] The excessive expansion of adipose tissue that tends to occur under sustained energy balance (as in overeating) has been postulated by Vidal-Puig to induce lipotoxic and inflammatory effects that may contribute to causing insulin resistance and its accompanying disease states.[35] Also, insulin resistance often is associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.[36] ### Molecular mechanism[edit] At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as PI3K/Akt/mTOR signaling pathway.[37] Recent studies suggested that the pathway may operate as a bistable switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon.[38][37][39] The pathway's sensitivity to insulin may be blunted by many factors such as free fatty acids,[40] causing insulin resistance. From a broader perspective, however, sensitivity tuning (including sensitivity reduction) is a common practice for an organism to adapt to the changing environment or metabolic conditions.[41] Pregnancy, for example, is a prominent change of metabolic conditions, under which the mother has to reduce her muscles' insulin sensitivity to spare more glucose for the brains (the mother's brain and the fetal brain). This can be achieved through raising the response threshold (i.e., postponing the onset of sensitivity) by secreting placental growth factor to interfere with the interaction between insulin receptor substrate (IRS) and PI3K, which is the essence of the so-called adjustable threshold hypothesis of insulin resistance.[38] Insulin resistance has been proposed to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.[42] ## Diagnosis[edit] ### Fasting insulin levels[edit] A fasting serum insulin level greater than 25 mU/L or 174 pmol/L indicates insulin resistance. The same levels apply three hours after the last meal.[43] ### Glucose tolerance testing[edit] During a glucose tolerance test (GTT), which may be used to diagnose diabetes mellitus, a fasting patient takes a 75 gram oral dose of glucose. Then blood glucose levels are measured over the following two hours. Interpretation is based on WHO guidelines. After two hours a glycemia less than 7.8 mmol/L (140 mg/dL) is considered normal, a glycemia of between 7.8 and 11.0 mmol/L (140 to 197 mg/dL) is considered as impaired glucose tolerance (IGT), and a glycemia of greater than or equal to 11.1 mmol/L (200 mg/dL) is considered diabetes mellitus. An oral glucose tolerance test (OGTT) may be normal or mildly abnormal in simple insulin resistance. Often, there are raised glucose levels in the early measurements, reflecting the loss of a postprandial peak (after the meal) in insulin production. Extension of the testing (for several more hours) may reveal a hypoglycemic "dip," that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.[citation needed] ### Hyperinsulinemic euglycemic clamp[edit] The gold standard for investigating and quantifying insulin resistance is the "hyperinsulinemic euglycemic clamp," so-called because it measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia.[44] It is a type of glucose clamp technique. The test is rarely performed in clinical care, but is used in medical research, for example, to assess the effects of different medications. The rate of glucose infusion commonly is referred to in diabetes literature as the GINF value.[45] The procedure takes about two hours. Through a peripheral vein, insulin is infused at 10–120 mU per m2 per minute. In order to compensate for the insulin infusion, glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol/L. The rate of glucose infusion is determined by checking the blood sugar levels every five to ten minutes.[45] The rate of glucose infusion during the last thirty minutes of the test determines insulin sensitivity. If high levels (7.5 mg/min or higher) are required, the patient is insulin-sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive, and suggest "impaired glucose tolerance," an early sign of insulin resistance.[45] This basic technique may be enhanced significantly by the use of glucose tracers. Glucose may be labeled with either stable or radioactive atoms. Commonly used tracers are 3-3H glucose (radioactive), 6,6 2H-glucose (stable) and 1-13C Glucose (stable). Prior to beginning the hyperinsulinemic period, a 3h tracer infusion enables one to determine the basal rate of glucose production. During the clamp, the plasma tracer concentrations enable the calculation of whole-body insulin-stimulated glucose metabolism, as well as the production of glucose by the body (i.e., endogenous glucose production).[45] ### Modified insulin suppression test[edit] Another measure of insulin resistance is the modified insulin suppression test developed by Gerald Reaven at Stanford University. The test correlates well with the euglycemic clamp, with less operator-dependent error. This test has been used to advance the large body of research relating to the metabolic syndrome.[45] Patients initially receive 25 μg of octreotide (Sandostatin) in 5 mL of normal saline over 3 to 5 minutes via intravenous infusion (IV) as an initial bolus, and then, are infused continuously with an intravenous infusion of somatostatin (0.27 μg/m2/min) to suppress endogenous insulin and glucose secretion. Next, insulin and 20% glucose are infused at rates of 32 and 267 mg/m2/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and thereafter, every 10 minutes for the last half-hour of the test. These last four values are averaged to determine the steady-state plasma glucose level (SSPG). Subjects with an SSPG greater than 150 mg/dL are considered to be insulin-resistant.[45] ### Alternatives[edit] Given the complicated nature of the "clamp" technique (and the potential dangers of hypoglycemia in some patients), alternatives have been sought to simplify the measurement of insulin resistance. The first was the Homeostatic Model Assessment (HOMA), and a more recent method is the Quantitative insulin sensitivity check index (QUICKI). Both employ fasting insulin and glucose levels to calculate insulin resistance, and both correlate reasonably with the results of clamping studies. ## Prevention and management[edit] Maintaining a healthy body weight and being physically active can help reduce the risk of developing insulin resistance.[1] The primary treatment for insulin resistance is exercise and weight loss.[46] Both metformin and thiazolidinediones improve insulin resistance. Metformin is approved for prediabetes and type 2 diabetes and has become one of the more commonly prescribed medications for insulin resistance.[47] The Diabetes Prevention Program (DPP) showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes.[48] However, the participants in the DPP trial regained about 40% of the weight that they had lost at the end of 2.8 years, resulting in a similar incidence of diabetes development in both the lifestyle intervention and the control arms of the trial.[49] In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.[50] Resistant starch from high-amylose corn, amylomaize, has been shown to reduce insulin resistance in healthy individuals, in individuals with insulin resistance, and in individuals with type 2 diabetes.[51] Some types of polyunsaturated fatty acids (omega-3) may moderate the progression of insulin resistance into type 2 diabetes,[52][53][54] however, omega-3 fatty acids appear to have limited ability to reverse insulin resistance, and they cease to be efficacious once type 2 diabetes is established.[55] ## History[edit] The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Professor Wilhelm Falta and published in Vienna in 1931,[56] and confirmed as contributory by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936,[57] however, type 2 diabetes does not occur unless there is concurrent failure of compensatory insulin secretion.[58] ### Adaptive explanations[edit] Some scholars go as far as to claim that neither insulin resistance, nor obesity really are metabolic disorders per se, but simply adaptive responses to sustained caloric surplus, intended to protect bodily organs from lipotoxicity (unsafe levels of lipids in the bloodstream and tissues): "Obesity should therefore not be regarded as a pathology or disease, but rather as the normal, physiologic response to sustained caloric surplus... As a consequence of the high level of lipid accumulation in insulin target tissues including skeletal muscle and liver, it has been suggested that exclusion of glucose from lipid-laden cells is a compensatory defense against further accumulation of lipogenic substrate."[59] Other prevailing thoughts that insulin resistance can be an evolutionary adaptation include the thrifty gene hypothesis. This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 diabetes, these phenotypes should be selected against.[60] Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population.[61] J.V. Neel postulates that originally in times of increased famine in ancient humans ancestors, that genes conferring a mechanism for increased glucose storage would be advantageous. In the modern environment today however this is not the case.[60] Evidence is contradictory to Neel in studies of the Pima Indians, which indicate that the people with higher insulin sensitives tended to weigh the most and conversely people with insulin resistance tended to weigh less on average in this demographic.[62] Modern hypotheses suggest that insulin metabolism is a socio-ecological adaptation with insulin being the means for differentiating energy allocation to various components of the body and insulin sensitivity an adaptation to manipulate where the energy is diverted to. The Behavioral Switch Hypothesis posits that insulin resistance results in two methods to alter reproductive strategies and behavioral methods. The two strategies are coined as “r to K” and “soldier to diplomat.” The r to K strategy involves diverting insulin via placenta to the fetus. This has demonstrated weight gain in the fetus, but not the mother indicating a method of increased parental investment (K strategy). In the “soldier to diplomat” the insensitivity of skeletal muscle to insulin could divert the glucose to the brain, which doesn't require insulin receptors. This has shown increased in cognitive development across various studies.[63] ## See also[edit] * Chronic Somogyi rebound * Hyperinsulinemia * Resistin * Chronic stress * Systemic inflammation * Circadian rhythm disruption * Advanced glycation end-products * Polycystic ovary syndrome ## References[edit] 1. ^ a b c d e "Insulin Resistance & Prediabetes". National Institute of Diabetes and Digestive and Kidney Diseases. May 2018. 2. ^ a b Isganaitis E, Lustig RH (December 2005). "Fast food, central nervous system insulin resistance, and obesity". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (12): 2451–62. doi:10.1161/01.ATV.0000186208.06964.91. PMID 16166564. 3. ^ Haugaard SB, Madsbad S, Høy CE, Vaag A (February 2006). "Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in skeletal muscle membrane phospholipids of obese subjects. Implications for insulin sensitivity". Clinical Endocrinology. 64 (2): 169–78. doi:10.1111/j.1365-2265.2006.02444.x. PMID 16430716. S2CID 22878943. 4. ^ Russo GL (March 2009). "Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention". Biochemical Pharmacology. 77 (6): 937–46. doi:10.1016/j.bcp.2008.10.020. PMID 19022225. 5. ^ Chiu KC, Chu A, Go VL, Saad MF (May 2004). "Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction". The American Journal of Clinical Nutrition. 79 (5): 820–5. doi:10.1093/ajcn/79.5.820. PMID 15113720. 6. ^ Ivy JL (November 1997). "Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus". Sports Medicine. Auckland, NZ. 24 (5): 321–36. doi:10.2165/00007256-199724050-00004. PMID 9368278. S2CID 29053249. 7. ^ Kyu, Hmwe H.; Bachman, Victoria F.; Alexander, Lily T.; Mumford, John Everett; Afshin, Ashkan; Estep, Kara; Veerman, J. Lennert; Delwiche, Kristen; Iannarone, Marissa L.; Moyer, Madeline L.; Cercy, Kelly (2016-08-09). "Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013". BMJ (Clinical Research Ed.). 354: i3857. doi:10.1136/bmj.i3857. ISSN 1756-1833. PMC 4979358. PMID 27510511. 8. ^ Stenvers DJ, Scheer FA, Schrauwen P, la Fleur SE, Kalsbeek A (February 2019). "Circadian clocks and insulin resistance" (PDF). Nature Reviews. Endocrinology. 15 (2): 75–89. doi:10.1038/s41574-018-0122-1. hdl:20.500.11755/fdb8d77a-70e3-4ab7-a041-20b2303b418b. PMID 30531917. S2CID 54449238. 9. ^ Reutrakul S, Van Cauter E (July 2018). "Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes". Metabolism. 84: 56–66. doi:10.1016/j.metabol.2018.02.010. PMID 29510179. 10. ^ Mesarwi O, Polak J, Jun J, Polotsky VY (September 2013). "Sleep disorders and the development of insulin resistance and obesity". Endocrinology and Metabolism Clinics of North America. 42 (3): 617–34. doi:10.1016/j.ecl.2013.05.001. PMC 3767932. PMID 24011890. Lay summary. 11. ^ Fantry, Lori E (2003-03-24). "Protease Inhibitor-Associated Diabetes Mellitus: A Potential Cause of Morbidity and Mortality". Journal of Acquired Immune Deficiency Syndromes. 32 (3): 243–4. doi:10.1097/00126334-200303010-00001. PMID 12626882{{inconsistent citations}}. 12. ^ Burghardt KJ, Seyoum B, Mallisho A, Burghardt PR, Kowluru RA, Yi Z (April 2018). "Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies". 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"Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes". PLOS ONE. 1 (1): e31. Bibcode:2006PLoSO...1...31N. doi:10.1371/journal.pone.0000031. PMC 1762367. PMID 17183659. 37. ^ a b Wang G (December 2010). "Singularity analysis of the AKT signaling pathway reveals connections between cancer and metabolic diseases". Physical Biology. 7 (4): 046015. Bibcode:2010PhBio...7d6015W. doi:10.1088/1478-3975/7/4/046015. PMID 21178243. 38. ^ a b Wang G (December 2014). "Raison d'être of insulin resistance: the adjustable threshold hypothesis". Journal of the Royal Society, Interface. 11 (101): 20140892. doi:10.1098/rsif.2014.0892. PMC 4223910. PMID 25320065. 39. ^ Wang G (October 2012). "Optimal homeostasis necessitates bistable control". Journal of the Royal Society, Interface. 9 (75): 2723–34. doi:10.1098/rsif.2012.0244. PMC 3427521. PMID 22535698. 40. ^ Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, et al. (June 2010). "Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis". Diabetes. 59 (6): 1349–57. doi:10.2337/db09-0745. PMC 2874695. PMID 20299466. 41. ^ Wang G, Zhang M (February 2016). "Tunable ultrasensitivity: functional decoupling and biological insights". Scientific Reports. 6: 20345. Bibcode:2016NatSR...620345W. doi:10.1038/srep20345. PMC 4742884. PMID 26847155. 42. ^ Hoehn KL, Salmon AB, Hohnen-Behrens C, Turner N, Hoy AJ, Maghzal GJ, et al. (October 2009). "Insulin resistance is a cellular antioxidant defense mechanism". Proceedings of the National Academy of Sciences of the United States of America. 106 (42): 17787–92. Bibcode:2009PNAS..10617787H. doi:10.1073/pnas.0902380106. PMC 2764908. PMID 19805130. 43. ^ Insulin at eMedicine 44. ^ DeFronzo RA, Tobin JD, Andres R (September 1979). "Glucose clamp technique: a method for quantifying insulin secretion and resistance". The American Journal of Physiology. 237 (3): E214-23. doi:10.1152/ajpendo.1979.237.3.e214. PMID 382871. S2CID 7192984. 45. ^ a b c d e f Muniyappa R, Lee S, Chen H, Quon MJ (January 2008). "Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage". American Journal of Physiology. Endocrinology and Metabolism. 294 (1): E15-26. doi:10.1152/ajpendo.00645.2007. PMID 17957034. S2CID 848540. 46. ^ Davidson LE, Hudson R, Kilpatrick K (Jan 2009). "Effects of Exercise Modality on Insulin Resistance and Functional Limitation in Older Adults". JAMA. doi:10.1001/archinternmed.2008.558. Retrieved 17 Sep 2020. Cite journal requires `\|journal=` (help) 47. ^ Giannarelli R, Aragona M, Coppelli A, Del Prato S (September 2003). "Reducing insulin resistance with metformin: the evidence today". Diabetes & Metabolism. 29 (4 Pt 2): 6S28–35. doi:10.1016/s1262-3636(03)72785-2. PMID 14502098. 48. ^ Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (February 2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". The New England Journal of Medicine. 346 (6): 393–403. doi:10.1056/NEJMoa012512. PMC 1370926. PMID 11832527. 49. ^ Kahn R (January 2012). "Reducing the impact of diabetes: is prevention feasible today, or should we aim for better treatment?". Health Affairs. 31 (1): 76–83. doi:10.1377/hlthaff.2011.1075. PMID 22232097. 50. ^ Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH (August 2016). "Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013". BMJ. 354: i3857. doi:10.1136/bmj.i3857. PMC 4979358. PMID 27510511. 51. ^ Keenan MJ, Zhou J, Hegsted M, Pelkman C, Durham HA, Coulon DB, Martin RJ (March 2015). "Role of resistant starch in improving gut health, adiposity, and insulin resistance". Advances in Nutrition. 6 (2): 198–205. doi:10.3945/an.114.007419. PMC 4352178. PMID 25770258. 52. ^ Lovejoy JC (October 2002). "The influence of dietary fat on insulin resistance". Current Diabetes Reports. 2 (5): 435–40. doi:10.1007/s11892-002-0098-y. PMID 12643169. S2CID 31329463. 53. ^ Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H (June 2004). "Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats". Experimental Biology and Medicine. 229 (6): 486–93. doi:10.1177/153537020422900606. PMID 15169967. S2CID 20966659. 54. ^ Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, et al. (June 1996). "Dietary fats and insulin action". Diabetologia. 39 (6): 621–31. doi:10.1007/BF00418533. PMID 8781757. S2CID 33171616. 55. ^ Delarue J, LeFoll C, Corporeau C, Lucas D (2004). "N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity?". Reproduction, Nutrition, Development. 44 (3): 289–99. doi:10.1051/rnd:2004033. PMID 15460168. 56. ^ Falta, W.; Boller, R. (1931). "Insulärer und Insulinresistenter Diabetes". Klinische Wochenschrift. 10 (10): 438–43. doi:10.1007/BF01736348. S2CID 32359074. 57. ^ Himsworth, H (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin insensitive types". The Lancet. 227 (5864): 127–30. doi:10.1016/S0140-6736(01)36134-2. 58. ^ Nolan CJ (October 2010). "Failure of islet β-cell compensation for insulin resistance causes type 2 diabetes: what causes non-alcoholic fatty liver disease and non-alcoholic steatohepatitis?". Journal of Gastroenterology and Hepatology. 25 (10): 1594–7. doi:10.1111/j.1440-1746.2010.06473.x. PMID 20880166. 59. ^ Unger RH, Scherer PE (June 2010). "Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity". Trends in Endocrinology and Metabolism. 21 (6): 345–52. doi:10.1016/j.tem.2010.01.009. PMC 2880185. PMID 20223680. 60. ^ a b Neel JV (December 1962). "Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?". American Journal of Human Genetics. 14 (4): 353–62. PMC 1932342. PMID 13937884. 61. ^ Ioannou GN, Bryson CL, Boyko EJ (2007-11-01). "Prevalence and trends of insulin resistance, impaired fasting glucose, and diabetes". Journal of Diabetes and Its Complications. 21 (6): 363–70. doi:10.1016/j.jdiacomp.2006.07.005. PMID 17967708. 62. ^ Swinburn BA, Nyomba BL, Saad MF, Zurlo F, Raz I, Knowler WC, et al. (July 1991). "Insulin resistance associated with lower rates of weight gain in Pima Indians". The Journal of Clinical Investigation. 88 (1): 168–73. doi:10.1172/JCI115274. PMC 296017. PMID 2056116. 63. ^ Watve MG, Yajnik CS (April 2007). "Evolutionary origins of insulin resistance: a behavioral switch hypothesis". BMC Evolutionary Biology. 7: 61. doi:10.1186/1471-2148-7-61. PMC 1868084. PMID 17437648. ## Further reading[edit] * Reaven GM (2005). "The insulin resistance syndrome: definition and dietary approaches to treatment". Annual Review of Nutrition (review). 25: 391–406. doi:10.1146/annurev.nutr.24.012003.132155. PMID 16011472. S2CID 24849146. * Rao G (March 2001). "Insulin resistance syndrome". American Family Physician (review). US. 63 (6): 1159–63, 1165–6. PMID 11277552. ## External links[edit] Classification D * MeSH: D007333 External resources * eMedicine: med/1173 * Insulin resistance at Curlie * "Insulin resistance". Diabetes. US: NIH. * v * t * e Diabetes Types * Type 1 * Type 2 * LADA * Gestational diabetes * Diabetes and pregnancy * Prediabetes * Impaired fasting glucose * Impaired glucose tolerance * Insulin resistance * KPD * MODY * Neonatal * Transient * Permanent * Type 3c (pancreatogenic) * Type 3 Blood tests * Blood sugar level * Glycosylated hemoglobin * Glucose tolerance test * Postprandial glucose test * Fructosamine * Glucose test * C-peptide * Noninvasive glucose monitor * Insulin tolerance test Management * Diabetic diet * Anti-diabetic drugs * Insulin therapy * intensive * conventional * pulsatile * Cure * Embryonic stem cells * Artificial pancreas * Other * Gastric bypass surgery Complications * Diabetic comas * Hypoglycemia * Ketoacidosis * Hyperosmolar hyperglycemic state * Diabetic foot * ulcer * Neuropathic arthropathy * Organs in diabetes * Blood vessels * Muscle * Kidney * Nerves * Retina * Heart * Diabetic skin disease * Diabetic dermopathy * Diabetic bulla * Diabetic cheiroarthropathy * Neuropathic ulcer * Hyperglycemia * Hypoglycemia Other * Glossary of diabetes * History of diabetes * Notable people with type 1 diabetes * v * t * e Disease of the pancreas and glucose metabolism Diabetes * Types * type 1 * type 2 * gestational * MODY 1 2 3 4 5 6 * Complications * See Template:Diabetes Abnormal blood glucose levels * Hyperglycaemia * Oxyhyperglycemia * Hypoglycaemia * Whipple's triad Insulin disorders * Insulin resistance * Hyperinsulinism * Rabson–Mendenhall syndrome Other pancreatic disorders * Insulinoma * Insulitis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Insulin resistance	c3714619	4,651	wikipedia	https://en.wikipedia.org/wiki/Insulin_resistance	2021-01-18T18:32:40	{"mesh": ["D007333"], "umls": ["C3714619"], "orphanet": ["181368"], "wikidata": ["Q1053470"]}
Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) is a neurological disorder that can also affect many other body systems. This condition primarily affects neurological development, causing intellectual disability, delayed development of speech and motor skills (such as sitting and walking), or autism spectrum disorder, which is a condition that affects communication and social interaction. Some affected individuals have additional neurological features, such as weak muscle tone (hypotonia), behavioral problems, and seizures. NEDBEH can affect development of many other parts of the body. Some affected individuals have abnormalities of brain structures, such as the tissue that connects the left and right halves of the brain (the corpus callosum), a tissue called white matter, the fluid-filled cavities (ventricles) near the center of the brain, or a structure at the back of the brain known as the cerebellar vermis. Eye abnormalities that can occur include a gap or hole in one of the structures of the eye (coloboma), underdevelopment (hypoplasia) or breakdown (atrophy) of the nerves that carry information from the eyes to the brain (optic nerves), or unusually small eyeballs (microphthalmia). These eye problems can cause vision impairment. Some affected individuals have heart defects, most commonly ventricular septal defect, which is a hole in the muscular wall (septum) that separates the right and left sides of the heart's lower chambers. Less commonly, other systems are affected in NEDBEH, including the kidneys and inner ear. Problems with the inner ear can lead to hearing impairment (sensorineural hearing loss). The signs and symptoms in some people with NEDBEH resemble those of another condition known as CHARGE syndrome; however, people with NEDBEH do not have changes in the gene associated with CHARGE syndrome. ## Frequency NEDBEH is a rare disorder with unknown prevalence. About twenty individuals with this condition have been described in the medical literature. ## Causes NEDBEH is caused by mutations in a gene called RERE. This gene provides instructions for making a protein that is critical for normal development before birth. It helps control the activity of a number of genes that are important for early development of the brain, eyes, inner ear, heart, and kidneys. Researchers suspect that RERE gene mutations reduce or eliminate the function of the RERE protein. A shortage of RERE protein function likely alters the activity of several genes involved in development before birth. These changes prevent the normal development of tissues in the brain, eyes, heart, and other organs. Researchers are working to identify which genes are affected and how changes in their activity lead to the signs and symptoms of NEDBEH. It is unknown why some people with NEDBEH have only neurological problems and others also have structural abnormalities. Researchers suspect that the severity of the condition may be related to the location and type of mutation in the RERE gene. Additional genetic factors that have not been identified, including variations in other genes, may also help determine which body systems are affected. ### Learn more about the gene associated with Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart * RERE ## 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. Most cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual’s parent or in early embryonic development. These cases occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart	c4310772	4,652	medlineplus	https://medlineplus.gov/genetics/condition/neurodevelopmental-disorder-with-or-without-anomalies-of-the-brain-eye-or-heart/	2021-01-27T08:25:07	{"omim": ["616975"], "synonyms": []}
Animation illustrating the normal activation of the electrical conduction system of the heart: starting from the sinoatrial node, an electrical impulse spreads across the atria, then passes through the atrioventricular node (AV node) and conducts on via the bundle branches towards the ventricles. In cardiology, a ventricular escape beat is a self-generated electrical discharge initiated by, and causing contraction of, the ventricles of the heart; normally the heart rhythm is begun in the atria of the heart and is subsequently transmitted to the ventricles. The ventricular escape beat follows a long pause in ventricular rhythm and acts to prevent cardiac arrest. It indicates a failure of the electrical conduction system of the heart to stimulate the ventricles (which would lead to the absence of heartbeats, unless ventricular escape beats occur). ## Contents * 1 Causes * 2 Diagnosis * 3 Management * 3.1 Cilostazol * 3.2 Ouabain * 4 References ## Causes[edit] Ventricular escape beats occur when the rate of electrical discharge reaching the ventricles (normally initiated by the heart's sinoatrial node (SA node), transmitted to the atrioventricular node (AV node), and then further transmitted to the ventricles) falls below the base rate determined by the rate of Phase 4 spontaneous depolarisation of ventricular pacemaker cells.[1] An escape beat usually occurs 2–3 seconds after an electrical impulse has failed to reach the ventricles.[2] This phenomenon can be caused by the sinoatrial node (SA node) failing to initiate a beat, by a failure of the conductivity from the SA node to the atrioventricular node (AV node), or by atrioventricular block (especially third degree AV block). Normally, the pacemaker cells of the sinoatrial node discharge at the highest frequency and are thus dominant over other cells with pacemaker activity. The AV node normally has the second fastest discharge rate. When the sinus rate falls below the discharge rate of the AV node, this becomes the dominant pacemaker, and the result is called a junctional escape beat. If the rate from both the SA and AV node fall below the discharge rate of ventricular pacemaker cells, a ventricular escape beat ensues. An escape beat is a form of cardiac arrhythmia, in this case known as an ectopic beat. It can be considered a form of ectopic pacemaker activity that is unveiled by lack of other pacemakers to stimulate the ventricles. Ventricular pacemaker cells discharge at a slower rate than the SA or AV node. While the SA node typically initiates a rate of 70 beats per minute (BPM), the atrioventricular node (AV node) is usually only capable of generating a rhythm at 40-60 BPM or less. Ventricular contraction rate is thus reduced by 15-40 beats per minute.[3] If there are only one or two ectopic beats, they are considered escape beats. If this causes a semi-normal rhythm to arise it is considered an idioventricular rhythm. The escape arrhythmia is a compensatory mechanism that indicates a serious underlying problem with the SA node or conduction system (commonly due to heart attack or medication side effect), and because of its low rate, it can cause a drop in blood pressure and syncope. ## Diagnosis[edit] An electrocardiogram can be used to identify a ventricular escape beat. The QRS portion of the electrocardiogram represents the ventricular depolarisation; in normal circumstances the QRS complex forms a sharp sudden peak. For a patient with a ventricular escape beat, the shape of the QRS complex is broader as the impulse can not travel quickly via the normal electrical conduction system.[4] The first 2.5 seconds show a normal cardiac cycle. This is followed by a period of delayed sinus activity which initiates a takeover response by the ventricular pacemaker cells resulting in a ventricular escape beat. Two escape beats are shown between 5-8 seconds. Ventricular escape beats differ from ventricular extrasystoles (or premature ventricular contractions), which are spontaneous electrical discharges of the ventricles. These are not preceded by a pause; on the contrary they are often followed by a compensatory pause. ## Management[edit] ### Cilostazol[edit] Third degree AV block can be treated with Cilostazol which acts to increase Ventricular escape rate [5] ### Ouabain[edit] Ouabain infusion decreases ventricular escape time and increases ventricular escape rhythm. However, a high dose of ouabain can lead to ventricular tachycardia.[2] ## References[edit] 1. ^ C. Andreasen, et al. (2006) Mosby Elsevier, Mosby's Dictionary of Medicine, Nursing & Health Professions 7th edition, p1951 2. ^ a b Banka VS, Scherlag BJ, Helfant RH (January 1975). "Contractile and electrophysiological responses to progressive digitalis toxicity". Cardiovasc. Res. 9 (1): 65–72. doi:10.1093/cvr/9.1.65. PMID 1122512. 3. ^ D.D. Costa, W.J. Brady, J. Edhouse (March 2002), BMJ Publishing Group Ltd., ABC of clinical electrocardiography, British Medical Journal: 324:535-538. 4. ^ Adams MG, Pelter MM (September 2003). "Ventricular escape rhythms". Am. J. Crit. Care. 12 (5): 477–8. PMID 14503433. 5. ^ Kodama-Takahashi K, Kurata A, Ohshima K, et al. (April 2003). "Effect of cilostazol on the ventricular escape rate and neurohumoral factors in patients with third-degree atrioventricular block". Chest. 123 (4): 1161–9. doi:10.1378/chest.123.4.1161. PMID 12684307. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Ventricular escape beat	c0232214	4,653	wikipedia	https://en.wikipedia.org/wiki/Ventricular_escape_beat	2021-01-18T18:55:29	{"umls": ["C0232214"], "wikidata": ["Q7920315"]}
Animal A royal white elephant, as depicted in a Thai painting A white elephant ( not as totally similar to albino elephant as most of westeners thought.) is a rare kind of elephant, but not a distinct species. In Hindu puranas, the god Indra has a white elephant. Although often depicted as snow white, their skin is normally a soft reddish-brown, turning a light pink when wet.[1] They have fair eyelashes and toenails. The traditional "white elephant" is commonly misunderstood as being albino, but the Thai term chang samkhan, actually translates as 'auspicious elephant', being "white" in terms of an aspect of purity.[2] White elephants are only nominally white. Of those currently kept by the Burmese rulers—General Than Shwe regards himself as the heir of the Burmese kings—one is grey and the other three are pinkish, but all are officially white. The king of Thailand also keeps a number of white elephants, eleven of which are still alive.[3] Former U.S. Vice President Spiro Agnew once presented a white elephant to King Norodom Sihanouk of Cambodia. "Rustam Dragging the Khaqan of China from His White Elephant", Persian miniature from Shahnama ## Contents * 1 Persia * 2 Hinduism * 3 Thailand * 4 Myanmar * 5 Africa * 6 Western cultural references * 7 See also * 8 References * 9 External links ## Persia[edit] There were white elephants in the army of the Sasanian king Khusrau II. According to al-Tabari, a white elephant killed the commander of the Arab Muslims Abu Ubayd al-Thaqafi in the Battle of the Bridge. ## Hinduism[edit] Indra (alias Sakra) and Sachi Riding the five-headed Divine Elephant Airavata, Folio from a Jain text, circa 1670-1680, Painting in LACMA museum, originally from Amber, Rajasthan The white elephant is considered to belong to the god Indra. The name of the elephant is Airavata and it is a flying elephant. Airavata is made the King of all elephants by Lord Indra. King Bimbisara had one such white elephant, which he had captured in a forest when the elephant was in his musth period. He named the bull elephant Sechanaka which means "watering" as the elephant used to water the plants by himself without any prior training. It is said the cost of this elephant was more the half of Magadha. He later gave it to his son Vihallakumara, which made his other son Ajatashatru jealous. Ajatashatru tried to steal it many times, which resulted in two of the most terrible wars called the Mahasilakantaka & Ratha-musala. (see Ajatashatru). ## Thailand[edit] "The white elephant flag", flag of Siam in 1855–1916 "According to Brahmanic belief, if a monarch possessed one or more 'white' elephants, it was a glorious and happy sign." King Trailok possessed the first. In the Thai language, they are called albino, not white, indicating "pale yellow eyes and white nails", with white hair. The "rough skin was either pink all over or had pink patches on the head, trunk, or forelegs." "They were not worshipped for themselves and were regarded as an appendage to the King's majesty."[4]:39 In Thailand, white elephants (ช้างเผือก, chang phueak) (also known as Pink Elephants) are considered sacred and are a symbol of royal power; all those discovered are presented to the king (although this presentation is usually a ceremonial one—the elephants are not actually taken into captivity). Historically, the status of kings has been evaluated by the number of white elephants in their possession. The late king Bhumibol Adulyadej owned as many as 21 white elephants — considered an unprecedented achievement, making him the monarch who owned the greatest number of Chang Phueak in Thai history.[5] The first elephant found in King Bhumibol's reign was regarded as the most important elephant in the whole realm; it received the royal title which bears his majesty's own name: Phra Savet Adulyadej Pahol Bhumibol Navanatta-parami (พระเศวตอดุลยเดชพาหล ภูมิพลนวนาถบารมี).[6] However, the King did not bestow royal titles to all of the white elephants in his possession. Today eleven of these elephants are still alive and only five have royal titles.[6] A white elephant in Thailand is not necessarily albino, although it must have pale skin. After being discovered, the elephants are assigned to one of four graded categories before being offered to the king, although the lower grades are sometimes refused. In the past, lower grade white elephants were given as gifts to the king's friends and allies. The animals needed a lot of care and, being sacred, could not be put to work, so were a great financial burden on the recipient - only the monarch and the very rich could afford them. According to one story, white elephants were sometimes given as a present to some enemy (often a lesser noble with whom the king was displeased). The unfortunate recipient, unable to make any profit from it, and obliged to take care of it, would suffer bankruptcy and ruin.[7] ## Myanmar[edit] A white elephant outside of Yangon in 2013 In Myanmar as well, white elephants have been revered symbols of power and good fortune. The announcement by the ruling military regime of the finding of white elephants in 2001[8] and 2002[9] was seen by opponents as being aimed at bolstering support for their regime. As of 2010[update], Myanmar has nine white elephants (as of February 2014).[when?] The last white elephant was found in Basein area, in the South-Western part of Myanmar on 27 February 2015. Three white elephants are currently held[10] in a pavilion on the outskirts of Yangon. The rest are kept at Uppatasanti Pagoda in Naypyidaw, the new Myanmar administrative capital. ## Africa[edit] An albino elephant from Kruger National Park, South Africa Wikinews has related news: * Pink elephant spotted in Botswana Albinos are much more rare among African elephants than in Asia. They are reddish-brown or pink, and may suffer blindness or skin problems from sun exposure.[11] ## Western cultural references[edit] Main article: White elephant In English, the term "white elephant" has come to mean a spectacular and prestigious thing that is more trouble than it is worth, or has outlived its usefulness to the person who has it. While the item may be useful to others, its current owner would usually be glad to be rid of it. ## See also[edit] * Abul-Abbas, a (possibly) white elephant given to Charlemagne by Harun al-Rashid * Airavata, a white elephant whom the god Indra rides * Hanno (elephant), the pet of Pope Leo X * Seeing pink elephants, a euphemistic term for visual hallucination arising from alcohol intoxication * White elephant gift exchange, a popular winter holiday party game in the U.S. ## References[edit] Wikimedia Commons has media related to White elephants. 1. ^ Men ride albino elephants, Reuters via The Atlantic, 1 March 2012. 2. ^ "Royal Elephant Stable". Thai Elephant Conservation Center. Retrieved 7 September 2014. 3. ^ "งดงามยิ่งนัก !! ชมประวัติช้างเผือกคู่พระบารมีพระบาทสมเด็จพระเจ้าอยู่หัวในพระบรมโกศ (รายละเอียด)". www.tnews.co.th. 4. ^ Chakrabongse, C., 1960, Lords of Life, London: Alvin Redman Limited 5. ^ "งดงามยิ่งนัก !! ชมประวัติช้างเผือกคู่พระบารมีพระบาทสมเด็จพระเจ้าอยู่หัวในพระบรมโกศ (รายละเอียด)". www.tnews.co.th. 6. ^ a b Ibid 7. ^ "Home : Oxford English Dictionary". Oed.com. Retrieved 2013-01-07. 8. ^ 'Lucky' white elephant for Burma, BBC, 9 November 2001. 9. ^ "Second White Elephant Found". Archived from the original on June 23, 2002. Retrieved 2007-03-11.CS1 maint: bot: original URL status unknown (link) 10. ^ "White Elephants Snubbed by Junta". Archived from the original on June 6, 2011. Retrieved 2010-06-07.CS1 maint: bot: original URL status unknown (link) 11. ^ Rebecca Morelle. Pink elephant is caught on camera, BBC News, 20 March 2009 ## External links[edit] * "Royal Elephant Stables". Thai Elephant Conservation Center. – Story and history of Royal White Elephants * The Royal White Elephants, 2002, Mahidol University [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	White elephant (animal)	None	4,654	wikipedia	https://en.wikipedia.org/wiki/White_elephant_(animal)	2021-01-18T18:31:23	{"wikidata": ["Q3629117"]}
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-45 (SCA45) is caused by heterozygous mutation in the FAT2 gene (604269) on chromosome 5q33. For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Nibbeling et al. (2017) reported a family (RF14) in which 6 patients spanning 2 generations had late-onset spinocerebellar ataxia after age 40. The proband was noted to have a relatively pure cerebellar syndrome with limb and gait ataxia, downbeat nystagmus, and dysarthria. No detailed clinical information was available for the remaining affected family members. An unrelated patient (case DNA056251) had onset of slowly progressive gait and limb ataxia and dysarthria at around 50 years of age. He did not have nystagmus. Brain MRI showed atrophy of the cerebellar vermis and hemosiderin deposits in the mesencephalon. Inheritance The transmission pattern of SCA45 in the family reported by Nibbeling et al. (2017) was consistent with autosomal dominant inheritance. Molecular Genetics In 5 affected members of a family (RF14) with SCA45, Nibbeling et al. (2017) identified a heterozygous missense mutation in the FAT2 gene (K3586N; 604269.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family was 1 of 20 unrelated families with autosomal dominant SCA who underwent whole-exome sequencing. A second heterozygous missense mutation (R3649E; 604269.0002) was subsequently identified in a patient (case DNA056251) with apparently sporadic SCA45. This patient was 1 of 96 individuals with SCA who were screened with a gene panel. In vitro studies modeling the variants to corresponding variants in mouse cDNA showed that the mutant proteins had significantly increased colocalization with markers in the Golgi apparatus compared to wildtype, and functional studies suggested that the mutations, particularly K3587N, may change cell aggregation and adhesion properties. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus (in some patients) NEUROLOGIC Central Nervous System \- Spinocerebellar ataxia \- Gait ataxia \- Limb ataxia \- Dysarthria \- Cerebellar atrophy MISCELLANEOUS \- Adult onset (after age 40 years) \- Slow progression \- One family and 1 unrelated patient have been reported (last curated November 2017) MOLECULAR BASIS \- Caused by mutation in the FAT atypical cadherin 2 gene (FAT2, 604269.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	SPINOCEREBELLAR ATAXIA 45	c4540400	4,655	omim	https://www.omim.org/entry/617769	2019-09-22T15:44:49	{"omim": ["617769"]}
## Summary ### Clinical characteristics. Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: * Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; * Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; * Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; * Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding. ### Diagnosis. The diagnosis of VWD typically requires characteristic results of assays of hemostasis factors specific for VWD and/or identification of a heterozygous, homozygous, or compound heterozygous pathogenic variant(s) in VWF by molecular genetic testing. In addition, the diagnosis requires (in most cases) a positive family history. In those with a risk factor for bleeding (VWF levels >30 and <50 IU/dL), family history may not be positive because of incomplete penetrance and variable expressivity. ### Management. Treatment of manifestations: Affected individuals benefit from care in a comprehensive bleeding disorders program. The two main treatments are desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and clotting factor concentrates (recombinant and plasma-derived) containing both VWF and FVIII (VWF/FVIII concentrate). Indirect hemostatic treatments that can reduce symptoms include fibrinolytic inhibitors; hormones for menorrhagia are also beneficial. Individuals with VWD should receive prompt treatment for severe bleeding episodes. Pregnant women with VWD are at increased risk for bleeding complications at or following childbirth. Prevention of primary manifestations: Prophylactic infusions of VWF/FVIII concentrates in individuals with type 3 VWD to prevent musculoskeletal bleeding and subsequent joint damage. Prevention of secondary complications: Cautious use of desmopressin (particularly in those age <2 years because of the potential difficulty in restricting fluids in this age group). Vaccination for hepatitis A and B. Surveillance: Follow up in centers experienced in the management of bleeding disorders. Periodic evaluation by a physiotherapist of those with type 3 VWD to monitor joint mobility. Agents/circumstances to avoid: Activities involving a high risk of trauma, particularly head injury; medications with effects on platelet function (ASA, clopidogrel, or NSAIDS). Circumcision in infant males should only be considered following consultation with a hematologist. Evaluation of relatives at risk: If the familial pathogenic variant(s) are known, molecular genetic testing for at-risk relatives to allow early diagnosis and treatment, if needed. Pregnancy management: As VWF levels increase throughout pregnancy, women with baseline VWF and FVIII levels greater than 30 IU/dL are likely to achieve normal levels by the time of delivery. However, those with a basal level lower than 20 IU/dL and those with baseline VWF:RCo or other VWF activity measurement/VWF:Ag ratio <0.6 are likely to require replacement therapy. Desmopressin has been successfully used to cover delivery in women with type 1 VWD and a proportion of pregnant women with type 2 VWD; delayed, secondary postpartum bleeding may be a problem. ### Genetic counseling. VWD types 2B and 2M are inherited in an autosomal dominant manner. VWD types 1 and 2A are typically inherited in an autosomal dominant manner but may also be inherited in an autosomal recessive manner. VWD types 2N and 3 are inherited in an autosomal recessive manner. * AD inheritance. Most affected individuals have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with AD VWD has a 50% chance of inheriting the pathogenic variant. * AR inheritance. At conception, each sib of an individual with AR VWD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for family members at risk for AR VWD is possible once the pathogenic variants have been identified in the family. Prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known. ## Diagnosis Several guidelines and testing algorithms have been published [Keeney et al 2008, Nichols et al 2008, Lassila et al 2011, Laffan et al 2014]. See Figures 1 and 2. #### Figure 1. Initial testing algorithm for von Willebrand disease From Nichols et al [2008]. Reprinted with permission of John Wiley and Sons. #### Figure 2. Algorithm for additional testing for von Willebrand disease subtype From Laffan et al [2014]. Reprinted with permission of John Wiley and Sons. Von Willebrand disease (VWD) is caused by deficient or defective plasma von Willebrand factor (VWF), a large multimeric glycoprotein that plays a pivotal role in primary hemostasis by mediating platelet hemostatic function and stabilizing blood coagulation factor VIII (FVIII). There are three types of VWD [Sadler et al 2006]: * Type 1. Partial quantitative deficiency of essentially normal VWF * Type 2. Qualitative deficiency of defective VWF; divided into four subtypes depending on VWF function perturbed: 2A, 2B, 2M, 2N * Type 3. Complete quantitative deficiency of (virtually absent) VWF ### Suggestive Findings Von Willebrand disease (VWD) should be suspected in individuals with excessive mucocutaneous bleeding including the following: * Bruising without recognized trauma * Prolonged, recurrent nosebleeds * Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions * Menorrhagia, particularly if occurring since menarche * Prolonged bleeding following surgery, trauma, or childbirth * Gastrointestinal bleeding The utility of standard clinical assessment tools to score occurrence of symptoms and their severity as part of VWD diagnosis is increasingly recognized [Tosetto et al 2006, Rodeghiero et al 2010, Elbatarny et al 2014, Mittal et al 2015]. These tools can: determine if there is more bleeding than in the general population; justify the diagnosis of a bleeding disorder; quantify the extent of symptoms; indicate situations requiring clinical intervention; and be used to indicate that a bleeding disorder is unlikely [Tosetto et al 2011]. Additionally, bleeding severity assessment correlates with the long-term probability of bleeding [Tosetto 2016]. ### Establishing the Diagnosis The diagnosis of VWD is established in a proband with excessive mucocutaneous bleeding and characteristic results of assays of hemostasis factors specific for VWD (see Clinical Laboratory Testing and Table 1) and/or identification of a heterozygous, homozygous, or compound heterozygous pathogenic variant(s) in VWF by molecular genetic testing (see Table 2). In addition, the diagnosis requires (in most cases) a positive family history. Note: In those with a risk factor for bleeding (VWF levels >30 and <50 IU/dL), family history may not be positive because of incomplete penetrance and variable expressivity. #### Clinical Laboratory Testing Screening tests * Complete blood count (CBC) may be normal, but could also show a microcytic anemia (if the individual is iron deficient) or a low platelet count (thrombocytopenia), specifically in type 2B VWD. * Activated partial thromboplastin time (aPTT) is often normal, but may be prolonged when the factor VIII (FVIII:C) level is reduced to below 30-40 IU/dL, as can be seen in severe type 1 VWD, type 2N VWD, or type 3 VWD. The normal range for FVIII:C clotting activity is approximately 50-150 IU/dL. * Prothrombin time is normal in VWD. * Other. Although some laboratories may also include a skin bleeding time and platelet function analysis (PFA closure time) in their evaluation of an individual with suspected VWD, these tests lack sensitivity in persons with mild bleeding disorders. Hemostasis factor assays. The following specific hemostasis factor assays (see Table 1) should be performed even if the screening tests are normal in an individual in whom VWD is suspected [Budde et al 2006]. Note: Normal ranges are determined by the individual laboratory and thus are indicative only. The International Society on Thrombosis and Haemostasis has recently published new guidance on assays that measure von Willebrand factor activity (VWF:Act) [Bodó et al 2015]. These tests include: * VWF:RCo. Ristocetin cofactor activity: all assays that use platelets and ristocetin. Ability of VWF to agglutinate platelets, initiated by the antibiotic ristocetin (normal range ~50-200 IU/dL) * VWF:GPIbR. All assays that are based on the ristocetin-induced binding of VWF to a recombinant WT GPIb fragment * VWF:GPIbM. All assays that are based on the spontaneous binding of VWF to a gain-of-function variant GPIb fragment * VWF:Ab. All assays that are based on the binding of a monoclonal antibody (mAb) to a VWF A1 domain epitope * VWF:Ag. Quantity of VWF protein (antigen) in the plasma, measured antigenically using enzyme-linked immunosorbant assay (ELISA) or by latex immunoassay (LIA) [Castaman et al 2010a] (normal range ~50-200 IU/dL). A reduced ratio (<0.6) of VWF:Act to VWF:Ag can indicate loss of high-molecular-weight (HMW) multimers. * Factor VIII:C level. Functional FVIII assay (i.e., activity of FVIII in the coagulation cascade) (normal range ~50-150 IU/dL) If abnormalities in the tests above are identified, specialized coagulation laboratories may also perform the following assays to determine the subtype of VWD: * VWF multimer analysis. SDS-agarose electrophoresis used to determine the complement of VWF oligomers in the plasma. Normal plasma contains VWF ranging from dimers to multimers comprising more than 40 dimers and molecular weight into gigadaltons. Multimers are classified as low (1-5-dimer), intermediate (6-10-dimer), and high (≥10-dimer) molecular weight. HMW multimers are decreased or missing in type 2A VWD and often in 2B VWD; intermediate MW may also be lost in type 2A VWD. Abnormalities in satellite ("triplet") band patterns can give clues as to pathogenesis and help to classify subtypes of type 2 VWD [Budde et al 2008]. * Ristocetin-induced platelet agglutination (RIPA). Ability of VWF to agglutinate platelets at two to three concentrations of ristocetin. Agglutination at a low concentration (~0.5-0.7 mg/mL) is abnormal and may indicate type 2B or platelet-type pseudo VWD (PT-VWD) caused by pathogenic variants in GP1BA (see Differential Diagnosis), in which enhanced VWF-platelet binding is present. * Binding of FVIII by VWF (VWF:FVIIIB). Ability of VWF to bind FVIII. Useful, but not widely used to identify type 2N VWD. * Collagen binding assay (VWF:CB). Ability of VWF to bind to collagen (a sub-endothelial matrix component). Used to help define functional VWF discordance (i.e., to help distinguish types 1 and 2 VWD) [Flood et al 2013]. Collagen I/III mixture is often used, but isolated deficient binding to collagen types IV and VI has recently been recognized [Flood et al 2012]. Normal range is approximately 50-200 IU/dL. A reduced ratio of VWF:CB/VWF:Ag can indicate loss of HMW multimers. * VWF:GP1BA. Functional tests are used to determine how well VWF binds to GpIbα. Previously, this was assessed using the VWF:RCo assay. Currently, this analysis is undertaken as part of the newer activity assays. ### Table 1. Classification of VWD Based on Specific VWF Tests View in own window VWD TypeVWF:Act 1VWF:Ag 1Act/AgFVIII:C IU/dL 1Multimer Pattern 2Other 1LowLowEquivalent~1.5x VWF:AgEssentially normal 2ALowLowVWF:Act < VWF:AgLow or normalAbnormal ↓ HMW↓ VWF:GP1BA binding 2BLowLowVWF:Act < VWF:AgLow or normalOften abnormal ↓ HMW↑ RIPA 3 (↓ platelet count) 2MLowLowVWF:Act << VWF:AgLow or normalNo loss of HMW↓ VWF:GP1BA binding ↓VWF:collagen binding 4 2NNormal/lowNormal/lowEquivalent<40Normal in most cases↓ VWF:FVIIIB 5 3AbsentAbsentNA<10Absent 1\. Relative to the reference range (approximate values); VWF:Act (50-200 IU/dL), VWF:Ag (50-200 IU/dL), FVIII:C (50-150 IU/dL). VWF activity (VWF:Act) includes VWF:RCo and the newer VWF activity assays in this instance. 2\. HMW multimers 3\. Increased agglutination at low concentrations of ristocetin 4\. Reduction in the ability of VWF to bind to collagen. Types I/III are bound by the A3 domain while types IV and VI are bound by the A1 domain. The latter types are not commonly analyzed. 5\. Ability of VWF to bind and protect FVIII is reduced. VWF and FVIII levels can look exactly like those in males with mild hemophilia A or in symptomatic hemophilia A carrier females. #### Molecular Genetic Testing Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing: * Single-gene testing. Sequence analysis of VWF is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. * A multigene panel that includes VWF and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Note: Analysis of exons 23 to 34 of VWF is complicated by the presence of a partial pseudogene, VWFP1. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 2. Molecular Genetic Testing Used in von Willebrand Disease (VWD) View in own window Gene 1VWD Type(s) 2Proportion of VWD Attributed to This TypeMethodProportion of Probands with a Pathogenic Variant 3 Detectable by Method VWF1~30%Sequence analysis 480% 5 Gene-targeted deletion/duplication analysis 66% 7 All type 2 forms~60%Sequence analysis 4~90% 7 Gene-targeted deletion/duplication analysis 60.2% 7 3<10% 8Sequence analysis 4~90% 7 Gene-targeted deletion/duplication analysis 63.7% 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. Recent changes in the von Willebrand factor (VFW) level used for diagnosis have significantly altered the proportion of patients classified with each disease type [Lassila et al 2011, Castaman et al 2013, Laffan et al 2014]. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Cumming et al [2006], Goodeve et al [2007], James et al [2007a], Yadegari et al [2012], Veyradier et al [2016] 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Veyradier et al [2016] 8\. In populations with frequent consanguineous partnerships, the rate of recessive forms of VWD may be elevated and type 3 VWD comprises a larger proportion of affected individuals. ## Clinical Characteristics ### Clinical Description Von Willebrand disease (VWD) is a congenital bleeding disorder; however, symptoms may only become apparent on hemostatic challenge and bleeding history may become more apparent with increasing age. Thus, it may take some time before a bleeding history becomes apparent. Recent guidelines on VWD have recommended taking von Willebrand factor (VWF) levels of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type [Lassila et al 2011, Castaman et al 2013, Laffan et al 2014]. Bleeding history also depends on disease severity; type 3 VWD is often apparent early in life, whereas mild type 1 VWD may not be diagnosed until midlife, despite a history of bleeding episodes. Individuals with VWD primarily manifest excessive mucocutaneous bleeding (e.g., bruising, epistaxis, menorrhagia) and do not tend to experience musculoskeletal bleeding unless the FVIII:C level is lower than 10 IU/dL, as can be seen in type 2N or type 3 VWD. Bleeding score. In general, there is an inverse relationship between the VWF level and the severity of bleeding [Tosetto et al 2006]. Bleeding scores (BS) have been documented in several cohort studies and give an indication of the range of bleeding severity associated with different VWD types: ### Table 3. Bleeding Scores (BS) Reported in VWD by Type View in own window Patient GroupStudy# of PatientsBS MedianBS Range Type 1Goodeve et al [2007]1509-1-24 Type 2ACastaman et al [2012]46116-16 Type 2BFederici et al [2009]4054-24 Type 2MCastaman et al [2012]6174-28 Type 3Solimando et al [2012]9156-26 Type 3Bowman et al [2013]42133-30 The higher the bleeding score, the greater the bleeding severity Note: While the studies reported have all used similar bleeding assessment tools, slight variations in the tools and their application may have contributed to differences in bleeding scores. Recently established cutoffs for an abnormal BS (≥4 for adult males, ≥6 for adult females, ≥3 for children) can be utilized to objectively assess the affected status of individuals tested using the ISTH-bleeding assessment tool (BAT) in a standard fashion [Elbatarny et al 2014]. BS in adults has also been shown to be a predictor of future bleeding [Federici et al 2014]. Type 1 VWD accounts for approximately 30% of all VWD in populations with infrequent consanguineous partnerships [Batlle et al 2016, Veyradier et al 2016]. It typically manifests as mild mucocutaneous bleeding; however, symptoms can be more severe when VWF levels are lower than 15 IU/dL. Epistaxis and bruising are common symptoms among children. Menorrhagia is the most common finding in women of reproductive age [Ragni et al 2016]. Type 2 VWD accounts for approximately 60% of all VWD. The relative frequency of the subtypes is 2A>2M>2N>2B in European populations [Batlle et al 2016, Veyradier et al 2016]. * Type 2A VWD. Individuals with type 2A VWD usually present with mild to moderate mucocutaneous bleeding [Veyradier et al 2016]. * Type 2B VWD. Individuals typically present with mild-moderate mucocutaneous bleeding. Thrombocytopenia may be present. A hallmark of type 2B VWD is a worsening of thrombocytopenia during stressful situations, such as severe infection or during surgery or pregnancy, or if treated with desmopressin [Federici et al 2009]. * Type 2M VWD. Individuals typically present with mild-moderate mucocutaneous bleeding symptoms, but bleeding episodes can be severe, particularly in the presence of very low or absent VWF:RCo [Castaman et al 2012, Larsen et al 2013]. * Type 2N VWD. Symptoms are essentially the same as those seen in mild hemophilia A and include excessive bleeding at the time of surgery or procedures as both disorders result from reduced FVIII:C [van Meegeren et al 2015]. Type 3 VWD accounts for up to 10% of VWD (except in areas where consanguineous partnerships are common, where a higher proportion may be found). It manifests with severe bleeding including both excessive mucocutaneous bleeding and musculoskeletal bleeding [Metjian et al 2009, Ahmad et al 2013, Kasatkar et al 2014]. Associated complications * Gastrointestinal angiodysplasia occurs most commonly in middle-aged/elderly individuals with types 2A and 3 VWD and affects the colon, small intestine, and stomach [Franchini & Mannucci 2014]. Lack of VWF in Weibel-Palade bodies promotes angiogenesis in endothelial cells [Starke et al 2011]. The disorder has also been reported in types 1 and 2B VWD [Hertzberg et al 1999, Siragusa et al 2008]. * Menorrhagia is experienced by a large proportion of women with VWD. * The development of alloantibodies against VWF is an uncommon but serious complication of VWD treatment. An estimated 5%-10% of individuals with type 3 VWD may experience this complication. Affected individuals present with reduced or absent response to infused VWF concentrates or, in rare cases, with anaphylactic reaction. Individuals who have had multiple transfusions are at highest risk for this complication. ### Genotype-Phenotype Correlations The three phenotypes reflect a partial (type 1 VWD) or complete (type 3 VWD) quantitative deficiency of VWF or qualitative deficits (type 2 VWD) of VWF. See Molecular Genetics, Pathogenic variants for details regarding the genotypes associated with each subtype of VWD. Individuals with large deletions of VWF are at highest risk for alloantibody development, although some with other null alleles have also been reported to develop this complication [James et al 2013]. ### Penetrance Type 1 VWD (AD) * VWF level. Pathogenic variants resulting in plasma VWF levels lower than 25 IU/dL are mostly fully penetrant. Those resulting in higher VWF levels are often incompletely penetrant. * ABO blood group appears to be an important contributor to penetrance and reduced VWF level in type 1 VWD [Goodeve et al 2007, James et al 2007a]. Blood group contributes approximately 25% of the variance in plasma VWF level; ABO glycosylation of VWF influences its rate of clearance [Jenkins & O'Donnell 2006]. Individuals with non-O blood groups have higher VWF levels than those with O blood group; those with group AB have the highest levels. Other AD types (2A, 2B, and 2M). Pathogenic variants are often fully penetrant. ### Nomenclature Changes in nomenclature: * von Willebrand's disease has been replaced by von Willebrand disease. * vWF has been replaced by VWF. * vWD has been replaced by VWD. * RiCof (ristocetin cofactor activity) has been replaced by VWF:RCo [Mazurier & Rodeghiero 2001]. * FVIII RAg (FVIII related antigen) has been replaced by VWF:Ag. * Platelet-type pseudo von Willebrand (PT-VWD), also called pseudo-VWD, is caused by pathogenic variants in GP1BA and, thus, is not a form of VWD (see Differential Diagnosis). * Acquired von Willebrand syndrome (AVWS), previously known as acquired VWD, is the preferred terminology for defects in VWF concentration, structure, or function that are neither inherited nor reflective of pathogenic variants in VWF, but arise as consequences of other medical conditions (see brief discussion of AVWS under Differential Diagnosis). See also Mazurier & Rodeghiero [2001] and Bodó et al [2015]. ### Prevalence VWD affects 0.1% to 1% of the population; 1:10,000 seek tertiary care referral. VWD type 3 affects 0.5:1,000,000-6:1,000,000 population, increasing with the rate of consanguinity. ## Differential Diagnosis Two disorders can be difficult to distinguish phenotypically from von Willebrand disease (VWD): * Mild hemophilia A, caused by pathogenic variants in F8, resembles type 2N VWD in that reduced levels of FVIII:C (~5-40 IU/dL) and normal-to-borderline low levels of VWF can be seen in both disorders. In families with reduced FVIII:C, an X-linked pattern of inheritance can help identify those with mild hemophilia A. The VWF:FVIIIB test, which determines the ability of VWF to bind FVIII, can be used to discriminate between the two disorders [Casonato et al 2007] and a commercial assay is now available [Veyradier et al 2011], although on a limited basis. Alternatively, molecular genetic testing can be used to distinguish the two disorders. Both molecular and phenotypic testing have some fallibilities in interpretation. * PT-VWD (pseudo VWD) (OMIM 177820), caused by pathogenic variants in GP1BA, may be difficult to distinguish from type 2B VWD; one study identified pathogenic variants in GP1BA in up to 15% of persons diagnosed with 2B VWD [Hamilton et al 2011]. The two disorders can be distinguished by mixing patient/control plasma and platelets to determine which component is defective [Othman et al 2016] or by molecular testing. PT-VWD has been shown to be less severe than type 2B VWD using a bleeding assessment tool [Kaur et al 2014]. The two disorders require different treatment. In PT-VWD, VWF concentrate is needed to correct the reduced VWF level, but platelet transfusion may also be required if there is significant thrombocytopenia. The half-life of replaced VWF is reduced as a result of binding to the abnormal GpIbα, necessitating more frequent administration of VWF concentrate than in VWD. Acquired von Willebrand syndrome (AVWS) is a mild-moderate bleeding disorder that can occur in a variety of conditions [Sucker et al 2009, Federici et al 2013, Mital 2016] but is not caused by pathogenic variants in VWF. It is most often seen in persons older than age 40 years with no prior bleeding history. AVWS has diverse pathology and a number of possible causes: * Lymphoproliferative or plasma cell proliferative disorders, paraproteinemias (monoclonal gammopathy of unknown significance [MGUS]), multiple myeloma, and Waldenstrom macroglobulinemia. Antibodies against VWF have been detected in some of these cases. * Autoimmune disorders including systemic lupus erythrematosus (SLE), scleroderma, and antiphospholipid antibody syndrome * Shear-induced VWF conformational changes leading to increased VWF proteolysis (e.g., aortic valve stenosis, ventricular septal defect) * Markedly increased blood platelet count (e.g., essential thrombocythemia or other myeloproliferative disorders) * Removal of VWF from circulation by aberrant binding to tumor cells (e.g., Wilm's tumor or certain lymphoproliferative disorders) * Decreased VWF synthesis (e.g., hypothyroidism) * Certain drugs (e.g., valproic acid, ciprofloxacin, griseofulvin, hydroxyethyl starch) ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with von Willebrand disease (VWD), the following evaluations are recommended: * A personal and family history of bleeding to help predict severity and tailor treatment. Use of a bleeding assessment tool can facilitate standardized assessment [Kaur et al 2016, Tosetto 2016, ISTH-BAT]. * A joint and muscle evaluation for those with type 3 VWD (Musculoskeletal bleeding is rare in types 1 and 2 VWD.) * Screening for hepatitis B and C as well as HIV if the diagnosis is type 3 VWD or if the individual received blood products or plasma-derived clotting factor concentrates before 1985 * Baseline serum concentration of ferritin to assess iron stores, as many individuals with VWD (particularly women with menorrhagia) are iron deficient * Gynecologic evaluation for women with menorrhagia [Rodeghiero 2008] * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations See Nichols et al [2008] (full text), Castaman et al [2013] (full text), and Laffan et al [2014] (full text) for treatment guidelines. Individuals with VWD benefit from referral to a comprehensive bleeding disorders program for education, treatment, and genetic counseling. #### Medical Treatments The two main treatments are desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and clotting factor concentrates (recombinant and plasma-derived) containing both VWF and FVIII (VWF/FVIII concentrate). Indirect hemostatic treatments are also beneficial. Individuals with VWD should receive prompt treatment for severe bleeding episodes. Desmopressin * Most individuals with type 1 VWD and some with type 2 VWD respond to intravenous or subcutaneous treatment with desmopressin [Castaman et al 2008, Federici 2008, Leissinger et al 2014], which promotes release of stored VWF and raises levels three- to fourfold. Intranasal preparations are also available. * Following VWD diagnosis, a desmopressin challenge is advisable to assess VWF response. * Desmopressin is the treatment of choice for acute bleeding episodes or to cover surgery. * It has been used successfully to cover delivery in women with type 1 VWD and also for a proportion of pregnant women with type 2 VWD (where a desmopressin trial has previously proved efficacious) [Castaman et al 2010b] (see Pregnancy Management). * Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years, for whom VWF/FVIII concentrate is required. * In persons who do not tolerate desmopressin or who have a poor VWF response, clotting factor concentrate is required. Note: Because desmopressin can cause hyponatremia (which can lead to seizures and coma), fluid intake should be restricted for 24 hours following its administration to minimize this risk. Intravenous infusion of VWF/FVIII clotting factor concentrates * In those who are non-responsive to desmopressin (i.e., VWF deficiency is not sufficiently corrected) and for those in whom desmopressin is contraindicated (see Treatment by VWD Type), bleeding episodes can be prevented or controlled with intravenous infusion of recombinant VWF or virally inactivated plasma-derived clotting factor concentrates containing both VWF and FVIII [Castaman & Linari 2016, Windyga et al 2016a, Windyga et al 2016b]. * Plasma-derived concentrates are prepared from pooled blood donations from many donors. Virus inactivation procedures eliminate potential pathogens. * Recombinant VWF Vonvendi® was licensed for use in adults (18+ years) by the US FDA in December 2015 [Franchini & Mannucci 2016]. Indirect treatments. In addition to treatments that directly increase VWF levels, individuals with VWD often benefit from indirect hemostatic treatments, including: * Fibrinolytic inhibitors (i.e., tranexamic acid for treatment or prevention of bleeding episodes); * Hormonal treatments (i.e., the combined oral contraceptive pill for the treatment of menorrhagia). Combined treatments for menorrhagia. Current treatments and a proposed future treatment trial are described by Ragni et al [2016]. 1,321 women with VWD were assessed between 2011 and 2014, and of these 816 (61.8%) had menorrhagia. * Treatments used most commonly were combined oral contraceptives, tranexamic acid, and desmopressin as first- and second-line therapies, whereas VWF concentrate was the most common third-line therapy used by 13 women (1.6%). * Review of information on 88 women from six published studies showed that a VWF dose of 33-100 IU kg-1 reduced menorrhagia on days one to six of the menstrual cycle in 101 women. #### Treatment by VWD Type Type 1 VWD. Treatments that directly increase VWF levels (e.g., desmopressin or VWF/FVIII clotting factor concentrates) are usually only needed for the treatment or prevention of severe bleeding, as with major trauma or surgery. Indirect treatment with fibrinolytic inhibitors or hormones is often effective. Type 2A VWD. Treatment with clotting factor concentrates is usually only required for the treatment or prevention of severe bleeding episodes such as during surgery. Responsiveness to desmopressin is variable and should be confirmed prior to therapeutic use. Indirect treatments can be beneficial. Type 2B VWD. Clotting factor concentrates are usually required to treat severe bleeding or at the time of surgery. Treatment with desmopressin should be undertaken cautiously as it can precipitate a worsening of any thrombocytopenia. Individuals with mild or atypical type 2B VWD (caused by p.Pro1266Leu, p.Pro1266Glu, and p.Arg1308Leu variants), however, do not appear to develop thrombocytopenia when exposed to desmopressin [Federici et al 2009]. Indirect treatments (i.e., fibrinolytic inhibitors) can be useful. Type 2M VWD. Because desmopressin response is generally poor, VWF/FVIII concentrate is the treatment of choice. Type 2N VWD. Desmopressin can be used for minor bleeding, but because the FVIII level will drop rapidly (as FVIII is not protected by VWF), concentrate containing VWF as well as FVIII is required to cover surgical procedures. Type 3 VWD. Treatment often requires the repeated infusion of VWF/FVIII clotting factor concentrates [Franchini & Mannucci 2016, Lavin & O'Donnell 2016, Lissitchkov et al 2017]. Desmopressin is not effective in type 3 VWD. Indirect treatments may also be beneficial. #### Pediatric Issues Special considerations for the care of infants and children with VWD include the following: * Infant males should be circumcised only after consultation with a pediatric hemostasis specialist. * Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group. * VWF levels are higher in the neonatal period [Klarmann et al 2010]; thus, phenotypic testing for milder forms of VWD should be delayed until later in childhood. ### Prevention of Primary Manifestations Individuals with type 3 VWD are often given prophylactic infusions of VWF/FVIII concentrates to prevent musculoskeletal bleeding and subsequent joint damage. ### Prevention of Secondary Complications Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group. Individuals with VWD should be vaccinated for hepatitis A and B [Nichols et al 2008, Castaman et al 2013]. Prevention of chronic joint disease is a concern for individuals with type 3 VWD. However, controversy exists regarding the specific schedule and dosing of prophylactic regimens. An international trial that investigated prophylactic treatment for symptoms including joint bleeding, nosebleeds, and menorrhagia concluded that rates of bleeding within individuals during prophylaxis were significantly lower than levels prior to prophylaxis [Berntorp et al 2010, Abshire et al 2013]. Additionally, rates of bleeding were also significantly reduced in a trial of the recombinant VWF product Vonvendi®, which was licensed for use in adults in 2015 [Franchini & Mannucci 2016]. ### Surveillance Individuals with milder forms of VWD can benefit from being followed by treatment centers with experience in the management of bleeding disorders. Individuals with type 3 VWD should be followed in experienced centers and should have periodic evaluations by a physiotherapist to monitor joint mobility. ### Agents/Circumstances to Avoid Activities with a high risk of trauma, particularly head injury, should be avoided. Medications that affect platelet function (ASA, clopidogrel, or NSAIDs) should be avoided as they can worsen bleeding symptoms. Infant males should be circumcised only after consultation with a pediatric hemostasis specialist. ### Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual to allow early diagnosis and treatment as needed [Goodeve 2016]. Evaluations can include: * Molecular genetic testing if the pathogenic variant(s) in the family are known; * VWD hemostasis factor assays if the pathogenic variant(s) in the family are not known. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management VWF levels increase throughout pregnancy with the peak occurring four hours after delivery [James et al 2015]. Nonetheless, pregnant women with VWD are at increased risk for bleeding complications and care should be provided in centers with experience in perinatal management of bleeding disorders [Pacheco et al 2010, Castaman 2013, Biguzzi et la 2015, Reynen & James 2016, Roth & Syed 2016]. Women with baseline VWF and FVIII levels higher than 30 IU/dL are likely to achieve normal levels by the time of delivery, whereas those with a basal level lower than 20 IU/dL and those with baseline VWF:Act/VWF:Ag ratio <0.6 are likely to require replacement therapy [Castaman et al 2010b, James et al 2015, Hawke et al 2016]. Although deliveries should occur based on obstetric indications, instrumentation should be minimized [Demers et al 2005]. Delayed, secondary postpartum bleeding may be a problem. VWF level rapidly returns to pre-pregnancy level following delivery [Castaman et al 2013]. ### 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	von Willebrand Disease	c0042974	4,656	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK7014/	2021-01-18T20:50:42	{"mesh": ["D014842"], "synonyms": ["von Willebrand Factor Deficiency"]}
## Description Mandibular prognathism is a dentofacial anomaly characterized by protrusion of the mandible, with lower incisors often overlapping the upper incisors. The protruding lower jaw is caused by a forward positioning of the mandible itself (summary by Stiles and Luke, 1953). Nomenclature The 'Habsburg Jaw' is an eponymous designation for patients with mandibular prognathism/hyperplasia since members of the ruling Habsburg (sometimes spelled 'Hapsburg') family, dominant in Europe between the 13th and 20th centuries, had seemingly large lower jaws. However, the facial abnormalities in this family may have been due to maxillary deficiency rather than mandibular prognathism (summary by Peacock et al., 2014; see HISTORY below). Clinical Features Thompson and Winter (1988) described affected individuals in 3 generations. They pointed out that in addition to mandibular prognathism, there is thickened lower lip, flat malar areas, and mildly everted lower eyelids. One child in the family had craniosynostosis. Chudley (1998) presented examples of the Habsburg jaw printed on postage stamps of Spain. Inheritance Mandibular prognathism was transmitted through many generations of the Hapsburg line as a dominant trait with incomplete penetrance (Rubbrecht, 1930; Strohmayer, 1937). Stiles and Luke (1953) described a family in which members of 4 generations had mandibular prognathism. The pedigree pattern was consistent with autosomal dominant inheritance with incomplete penetrance. Mandibular prognathism is a feature of the XXY, XXXY, and XXXXY syndromes and of interest is the progressive increase of this feature as the number of X chromosomes increases (Gorlin et al., 1965). Although the X chromosome has a role, the mendelian trait is not X-linked. Wolff et al. (1993) assembled an extraordinary pedigree covering 23 generations and comprising 13 European noble families with mandibular prognathism. Pedigree analysis using the Elston-Stewart algorithm yielded a maximum likelihood estimate of penetrance of 95.5%. Cruz et al. (2008) analyzed 55 Brazilian families with mandibular prognathism comprising 158 affected men and 214 affected women (male to female ratio of 1:1.35, p = 0.030). Inheritance was consistent with an autosomal dominant pattern in 89.1% of families. Thirty-two families had incomplete penetrance, and 17 showed complete penetrance. The incidence of mandibular prognathism was 14.3%, and heritability was estimated at 0.316. Cruz et al. (2008) concluded that there is a major gene that influences the expression of the trait with clear signs of mendelian inheritance. History The prominent appearance of the jaw in members of the ruling Habsburg family in Europe, which has been documented in numerous portraits, has been attributed to mandibular prognathism. However, in a visual assessment of at least 3 portraits of 7 Spanish Habsburg emperors performed by 4 individuals specializing in oral and maxillofacial surgery, dentistry, and plastic and oral surgery, Peacock et al. (2014) concluded that the primary deformity in this family is maxillary deficiency resulting in midface hypoplasia rather than absolute mandibular prognathism. Eleven dysmorphic features for maxillary deficiency and 7 for mandibular prognathism were chosen and scored for diagnosis. The results also suggested that the Habsburg nasal deformity, characterized by a dorsal hump and overhanging nasal tip, and everted lower lip may both be explained by maxillary deficiency. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Mandibular prognathism \- Flat malar areas Eyes \- Mildly everted lower eyelids Mouth \- Thick lower lip MISCELLANEOUS \- Incomplete penetrance ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	PROGNATHISM, MANDIBULAR	c0399526	4,657	omim	https://www.omim.org/entry/176700	2019-09-22T16:35:42	{"mesh": ["D008313"], "omim": ["176700"], "icd-9": ["524.23"], "icd-10": ["M26.213"], "orphanet": ["2964"], "synonyms": ["'HABSBURG JAW'", "Alternative titles", "'HAPSBURG JAW'"]}
A number sign (#) is used with this entry because Diamond-Blackfan anemia-1 (DBA1) is caused by heterozygous mutation in the gene encoding ribosomal protein S19 (RPS19; 603474) on chromosome 19q13. Description Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents in the first year of life. The main features are normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. Patients show growth retardation, and approximately 30 to 50% have craniofacial, upper limb, heart, and urinary system congenital malformations. The majority of patients have increased mean corpuscular volume, elevated erythrocyte adenosine deaminase activity, and persistence of hemoglobin F. However, some DBA patients do not exhibit these findings, and even in the same family, symptoms can vary between affected family members (summary by Landowski et al., 2013). ### Genetic Heterogeneity of Diamond-Blackfan Anemia A locus for DBA (DBA2; 606129) has been mapped to chromosome 8p23-p22. Other forms of DBA include DBA3 (610629), caused by mutation in the RPS24 gene (602412) on 10q22; DBA4 (612527), caused by mutation in the RPS17 gene (180472) on 15q; DBA5 (612528), caused by mutation in the RPL35A gene (180468) on 3q29; DBA6 (612561), caused by mutation in the RPL5 gene (603634) on 1p22.1; DBA7 (612562), caused by mutation in the RPL11 gene (604175) on 1p36; DBA8 (612563), caused by mutation in the RPS7 gene (603658) on 2p25; DBA9 (613308), caused by mutation in the RPS10 gene (603632) on 6p; DBA10 (613309), caused by mutation in the RPS26 (603701) gene on 12q; DBA11 (614900), caused by mutation in the RPL26 gene (603704) on 17p13; DBA12 (615550), caused by mutation in the RPL15 gene (604174) on 3p24; DBA13 (615909), caused by mutation in the RPS29 gene (603633) on 14q; DBA14 (300946), caused by mutation in the TSR2 gene (300945) on Xp11; DBA15 (606164), caused by mutation in the RPS28 gene (603685) on 19p13; DBA16 (617408), caused by mutation in the RPL27 gene (607526) on 17q21; DBA17 (617409), caused by mutation in the RPS27 gene (603702) on 1q21; DBA18 (618310), caused by mutation in the RPL18 gene (604179) on 19q; DBA19 (618312), caused by mutation in the RPL35 gene (618315) on 9q33; and DBA20 (618313), caused by mutation in the RPS15A gene (603674) on 16p. Boria et al. (2010) reviewed the molecular basis of Diamond-Blackfan anemia, emphasizing that it is a disorder of defective ribosome synthesis. Gazda et al. (2012) completed a large-scale screen of 79 ribosomal protein genes in families with Diamond-Blackfan anemia and stated that of the 10 known DBA-associated genes, RPS19 accounts for approximately 25% of patients; RPS24, 2%; RPS17, 1%; RPL35A, 3.5%; RPL5, 6.6%; RPL11, 4.8%; RPS7, 1%; RPS10, 6.4%; RPS26, 2.6%; and RPL26, 1%. Gazda et al. (2012) stated that in total these mutations account for approximately 54% of all DBA patients. In a study of 98 Japanese patients with DBA, Wang et al. (2015) detected probable causative mutations or large deletions in ribosomal protein genes in 56 (55%) of the patients, involving the RPS19 gene in 16 patients, RPL5 in 12, RPS17 in 7, RPL35A in 7, RPL11 in 5, and RPS26 in 4; RPS7, RPS10, RPL27, and RPS27 were each mutated in 1 patient. Clinical Features Diamond et al. (1961) observed triphalangeal thumbs in 1 of 30 patients with congenital erythroid hypoplastic anemia. Alter (1978) pointed out that triphalangeal thumbs occurred in 6 of 133 cases of congenital hypoplastic anemia. In all, 45 of the 133 cases (34%) had associated hand anomalies of some kind. Cathie (1950) described a similar facial appearance in 4 unrelated affected children with erythrogenesis imperfecta, including snub noses, thick upper lips, and widely separated eyes. A propensity for the development of leukemia has been reported (Krishnan et al., 1978; Wasser et al., 1978). Ball et al. (1996) analyzed retrospective data from 80 cases of DBA (33 male, 47 female) born in the U.K. in a 20-year period (1975-1994), representing an annual incidence of 5 per million live births. Ten children from 7 families had an apparently familial disorder. Thirteen percent were anemic at birth, and 72.5% had presented by the age of 3 months. Sixty-seven percent had macrocytosis at presentation, 72% responded initially to steroids, and at the time of study, 61% were transfusion-dependent, 45% were steroid-dependent, and 39% required regular transfusions. Unequivocal physical anomalies, predominantly craniofacial, were present in 37%, and were more likely in boys (52%) than girls (25%). Eighteen percent had thumb anomalies. Height was below the 3rd centile for age in 28%; 31% had neither short stature nor physical anomalies. In 4 children without physical abnormalities, red cell indices were normal and steroid-independent remission was achieved, suggesting transient erythroblastopenia of childhood (227050) rather than DBA. The birth month distribution of children with sporadic DBA and craniofacial dysmorphism suggested a possible seasonality, consistent with a viral etiology. In the familial cases, affected males had unequivocal anomalies, whereas females had only short stature or equivocal anomalies. In 3 families, 2 generations were affected; in 1 family, 3 generations were affected. Willig et al. (1999) reported 42 probands with DBA caused by mutation in the RPS19 gene. The mean age at presentation was 2 months, and approximately 40% had associated physical anomalies, including triphalangeal thumb, duplication of thumb, short stature, ventricular septal defects, kidney hypoplasia, low hairline, and congenital glaucoma. ### Clinical Variability Anur et al. (2009) reported a patient with nonclassical Diamond-Blackfan anemia. She presented at age 17 years with progressive pancytopenia and bone marrow hypoplasia diagnosed after nausea and vomiting following outpatient surgery for correction of a flexion contracture of the finger. She became transfusion-dependent and the disorder was steroid-resistant. Erythrocyte adenosine deaminase was increased, consistent with the diagnosis. She underwent bone marrow transplantation, but died of complications. Molecular studies were not performed on this patient. Anur et al. (2009) emphasized the unusual and late clinical presentation of DBA in this patient, who had rapidly progressive aplastic anemia and did not show typical physical stigmata of the disorder. Inheritance Willig et al. (1999) stated that although the majority of DBA cases are sporadic, approximately 10 to 25% are familial, with most showing autosomal dominant inheritance. Gazda et al. (2012) stated that approximately 40 to 50% of DBA cases are familial and show autosomal and commonly dominant inheritance. Familial cases of congenital erythroid hypoplastic anemia were reported by Burgert et al. (1954) and by Diamond et al. (1961). Wallman (1956) described a father and daughter with erythroid hypoplasia, but the ages of onset (34 and 6 years, respectively) were beyond the usual limits of the Diamond-Blackfan syndrome. Forare (1963) observed affected brother and sister with the same father but different mothers. Although he referred to them as 'step-sibs,' they are actually half-sibs. Mott et al. (1969) reported a similar situation of 3 affected children from 2 mothers and the same father. Falter and Robinson (1972) described affected mother and daughter. Only the mother had aminoaciduria, suggesting that it was unrelated to the hematologic disorder. Lawton et al. (1974) described father and son with documented erythroid anemia from infancy. The father's anemia remitted at age 6 years, but he continued to have macrocytosis, reticulocytosis, and raised fetal hemoglobin. Hamilton et al. (1974) described affected mother and daughter. Other families with possible autosomal dominant transmission were reported by Hunter and Hakami (1972), Wang et al. (1978), and Gray (1982). Sensenbrenner (1972) described affected brother and sister. Pallor was first noted in the male at age 4 months and heart failure from anemia occurred at 10 months. Prednisone effectively controlled the anemia, but the brother developed aseptic necrosis of the left hip. Both patients had height below the 3rd percentile; at age 16, the brother was 147 cm tall, and at age 11, the sister was 127 cm tall. Both patients showed appropriate sexual maturation. Viskochil et al. (1990) reported a kindred with 7 affected members in 4 sibships spanning 3 generations, with several instances of male-to-male transmission. Hurst et al. (1991) described a mother and son with congenital erythroid hypoplastic anemia; the son had a right radial club hand with absent thumb and conjoined radius and ulna on the right with small, useless thumb on the left. Gojic et al. (1994) reported a family in which 4 males in 3 successive generations had congenital hypoplastic anemia. None of these individuals had malformations; specifically, the thumbs and radii were normal. Two brothers were of short stature: 162 and 156 cm. Of 6 pedigrees presented by Gustavsson et al. (1997), 2 families suggested autosomal recessive inheritance, and 4 families showed dominant inheritance with variable expressivity. In 1 family, the disease was evident in 3 generations with 2 instances of male-to-male transmission. In 2 families, the mother showed a mild anemia. In a fourth family, no phenotype was detected in the parents but the segregation of haplotypes indicated dominant inheritance from the mother. Among 38 multiplex families with DBA collected from multiple geographic areas, Gazda et al. (2001) found a pedigree pattern consistent with autosomal dominant inheritance in all but 3. The 3 exceptions were small pedigrees consisting of 2 affected children and unaffected parents. Diagnosis Using custom enrichment technology combined with high-throughput sequencing of 80 ribosomal protein genes, Gerrard et al. (2013) identified and validated inactivating mutations in samples from 15 (88%) of 17 patients with Diamond-Blackfan anemia. Mutations in 8 different genes were identified; the most commonly affected gene in this cohort was RPL5 (603634), found in 5 patients, including an affected mother and daughter. The results indicated that this methodology is efficient for diagnosing the disorder. ### Prenatal Diagnosis McLennan et al. (1996) made the prenatal diagnosis of congenital hypoplastic anemia causing hydrops fetalis in a child born to a 26-year-old woman with steroid-dependent Blackfan-Diamond syndrome. The diagnosis of BDS had been made in the mother at the age of 2 years following investigation of short stature and failure to thrive. From the age of 4 years, she had been treated with steroids, titrated to maintain a hemoglobin level between 7 and 8.5 g/dl. There was no relevant family history. Her first pregnancy ended in a spontaneous abortion at 8 weeks. In the second pregnancy, failure to visualize cardiac structures adequately at 22 weeks led to referral to a tertiary center. Cardiomegaly and a small pericardial effusion with structurally normal heart were demonstrated. By 33 weeks, the mother developed severe ascites and enlargement of the heart, which occupied nearly the entire chest. Cordocentesis at that time confirmed severe fetal anemia, and transfusion of packed red cells was undertaken. The infant was delivered by cesarean section at 34 weeks. No physical anomalies were found except for proximal and superior displacement of the first metatarsophalangeal joint of an otherwise normal left great toe. Mild cardiac failure had resolved by day 14. Bone marrow at 3 months of age showed a cellular marrow with normal megakaryocytes and myeloid differentiation but virtual absence of red cell precursors. Prednisolone was introduced at that stage without any significant response over the next 2 months. At 14 months of age, the baby was being managed with intermittent transfusions and continued steroid administration. Clinical Management Pfeiffer and Ambs (1983) reported a patient in whom, as in other reported patients, treatment with prednisone was effective. In 2 out of 6 patients, Dunbar et al. (1991) observed sustained remission following treatment with interleukin-3 (IL3; 147740). Willig et al. (1999) assembled a registry of 229 DBA patients, including 151 from France, 70 from Germany, and 8 from other countries. Of 222 available for long-term follow-up analysis, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was significantly and independently associated with older age at presentation, family history of DBA, and normal platelet count at the time of diagnosis. Severe evolution of the disease, transfusion dependence or death, was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a family history of the disease experienced a better outcome. The authors found that reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients was useful. Bone marrow transplantation was successful in 11 of 13 cases. They suggested that HLA typing of probands and sibs should be performed early if patients are transfusion-dependent, and cord blood should be preserved. In families with dominant inheritance, no parental imprinting effect or anticipation phenomenon could be demonstrated. Pathogenesis Nathan et al. (1978) suggested that Diamond-Blackfan anemia may be a 'congenital abnormality of erythropoietin (EPO; 133170) responsiveness that causes a functional, if not absolute, deficiency of erythroid precursors.' Halperin and Freedman (1989) noted that erythroid stem cells in DBA are partly or completely refractory to EPO. However, they noted that patients have normal EPO structure and no anti-EPO antibodies, suggesting that there may be an abnormality in EPO receptor expression, EPO binding, or EPO signal transduction. Glader et al. (1983) found increased adenosine deaminase (ADA; 608958) activity in red cells of patients with DBS. Whitehouse et al. (1984) found heterogeneity in DBS with respect to erythrocyte ADA activity and concluded that increased ADA activity was not limited to erythroid cells. Two sibs in 1 family showed increased red cell ADA activity over 4 months of multiple blood sampling. Both patients had the ADA 2-1 electrophoretic pattern and both allelozymes showed hyperactivity, indicating that there was not a mutation at the ADA locus. Abkowitz et al. (1991) cultured marrow and blood mononuclear cells from 10 Diamond-Blackfan patients with various hematopoietic growth factors in the presence or absence of stem cell factor (SCF; mast cell growth factor; Steel factor; SF; 184745). Because of erythroid bursts observed in cultures containing SCF, the authors speculated that the SCF axis may be involved in the pathogenesis of Diamond-Blackfan anemia, and suggested that a therapeutic trial of SCF in patients would be worthwhile. Similar results were obtained by Bagnara et al. (1991) and by Carow et al. (1991). Sieff et al. (1992) investigated whether DBA was due to hyporesponsiveness to or hypoproduction of Steel factor. By studying long-term bone marrow cultures, they found that the DBA patients studied responded to SCF and produced SCF mRNA normally, indicating that SCF itself was not involved in DBA pathophysiology. Olivieri et al. (1991) found no gross abnormalities in the structure of either stem cell factor or its tyrosine kinase receptor (KIT; 164920) in 10 DBA patients. Spritz and Freedman (1993) found no mutations in either the SCF or KIT genes in patients with DBA. Dianzani et al. (1996) stated that there was neither molecular nor clinical evidence for the involvement of stem cell factor or interleukin-3 (IL3; 147740) in the pathogenesis of DBA. Dianzani et al. (1996) also found no abnormality of the coding sequence of the EPOR gene (133171) in 23 DBA patients using SSCP. A Southern blot hybridization with an EPOR probe was negative in 7 patients. Furthermore, linkage studies showed that the disorder did not segregate with the EPOR gene in 2 informative DBA families. Using gene expression profiling, Gazda et al. (2006) found that erythroid precursors of 3 patients with RPS19-association DBA in remission showed downregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in transcription and translation compared to cells from 6 control individuals. DBA cells also showed upregulation of several proapoptotic genes, including TNFRSF10B (603612) and TNFRSF6 (134637). In addition, DBA cells showed downregulation of MYB (189990) and changes in expression of other cancer-related genes. Some of these changes were validated by RT-PCR studies. Gazda et al. (2006) concluded that DBA results from impaired ribosome biogenesis and decreased protein translation. Using small interfering RNA (siRNA), Flygare et al. (2007) showed that reduced expression of RPS19 in a human erythroleukemia cell line led to a defect in maturation of the 40S ribosomal subunits, affected erythroid differentiation, and increased apoptosis. Cells expressing siRNA targeting RPS19 failed to efficiently cleave 21S pre-rRNAs at the E site within internal transcribed sequence-1, which would normally lead to formation of the mature 3-prime end of the 18S rRNA. CD34 (142230)-negative and CD34-positive bone marrow cells from DBA patients with mutations in RPS19 showed an increased ratio of 21S to 18SE pre-rRNA compared with healthy controls, and the defect was more pronounced in CD34-negative patient cells. The findings indicated that RPS19 is required for efficient maturation of 40S ribosomal subunits. The results showed that cells from patients with DFA have a defect in pre-rRNA processing, and Flygare et al. (2007) concluded that the disorder results from defects in ribosome synthesis. Calo et al. (2018) showed that ribosomal gene perturbations associated with Diamond-Blackfan anemia disrupted DDX21 (606357) localization. At the molecular level, Calo et al. (2018) demonstrated that impaired rRNA synthesis elicits a DNA damage response, and that ribosomal DNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Calo et al. (2018) concluded that these and other findings illustrated how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations. Mapping Gustavsson et al. (1997) reported a female patient with a de novo balanced translocation t(X;19)(p21;q13) who presented with constitutional erythroblastopenia as well as short stature and left kidney hypoplasia. By analysis of 26 families with DBA, Gustavsson et al. (1997) found linkage to chromosome 19q13 with a peak lod score at D19S197 (maximum lod = 7.08, theta = 0.00). Within this region, a submicroscopic de novo deletion of 3.3 Mb was identified in a patient with DBA. The deletion coincided with the translocation breakpoint observed in the patient mentioned earlier and, together with key recombinations, restricted the DBA gene to a 1.8-Mb region. Using polymorphic 19q13 markers, including a short-tandem repeat in the critical DBA locus region, Gustavsson et al. (1998) studied 29 multiplex DBA families and 50 families with sporadic DBA cases. In 26 of the 29 multiplex families, DNA analysis yielded results consistent with a DBA gene on 19q within a 4.1-cM interval restricted by D19S200 and D19S178; however, in 3 multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. This result suggested genetic heterogeneity for DBA, but indicated that the gene region on 19q segregates with the majority of familial cases. Among the 50 families comprising sporadic DBA cases, Gustavsson et al. (1998) identified 2 de novo and overlapping microdeletions on 19q13. In combination, the 3 known microdeletions associated with DBA restricted the critical gene region to approximately 1 Mb. ### Genetic Heterogeneity In 5 of 12 Italian families with DBA, Ramenghi et al. (1999) excluded the locus on 19q. Costa et al. (2002) described piebaldism in a patient with DBA who did not have a mutation in the RPS19, KIT, or SCF genes. RPS19 is involved in approximately 25% of patients with DBA, KIT is a basis for piebald trait, and SCF is the KIT ligand. Costa et al. (2002) suggested that DBA with piebaldism may represent a novel phenotype due to mutation in a gene not previously identified. Molecular Genetics In 10 of 40 probands with DBA, Draptchinskaia et al. (1999) identified 9 different heterozygous mutations in the RPS19 gene (see, e.g., 603474.0001-603474.0002). Twenty-one patients had a family history of the disorder and 19 were sporadic cases. Six of the patients with mutations had a family history of the disorder. No mutations were found in the 5-prime untranslated region sequence or in the coding sequence in the 30 other probands. Willig et al. (1999) identified heterozygous mutations in the RPS19 gene in 42 (24.4%) of 172 index patients with DBA. Mutations in the RPS19 gene were also found in some apparently unaffected individuals from DBA families who presented only with increased ADA levels. The authors found no genotype/phenotype correlations. For example, in 1 family, a pair of monozygotic twins had the same mutation, but only 1 of them had a thumb malformation. Gazda et al. (2006) stated that mutation in the RPS19 gene occurs in an estimated 25% of probands with DBA. The authors identified de novo nonsense and splice site mutations in another ribosomal protein, RPS24 (602412), in 3 families with DBA. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other ribosomal proteins or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA. Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia who were negative for mutation in 10 known DBA-associated ribosomal protein genes, and identified large deletions in 6 (7%) of the patients, including a deletion in the RPS19 gene (603474.0009) in a steroid-dependent male patient with a webbed neck. Large deletions were also identified in the RPS24, RPS17, RPS26, and RPL15 genes; Landowski et al. (2013) proposed screening of all 80 ribosomal protein genes for copy number changes in DBA patients. Genotype/Phenotype Correlations Gazda et al. (2008) screened 196 probands with DBA for mutations in 25 genes encoding ribosomal proteins and identified mutations in the RPL5 (603634), RPL11 (604175), and RPS7 (603658) genes that segregated with disease in multiplex families and were associated with defects in the maturation of ribosomal RNAs in vitro. Mutations in RPL5 were associated with craniofacial abnormalities, particularly cleft lip and/or palate, in 9 of 14 patients with known malformations; the authors noted that none of the 12 DBA patients with RPL11 mutations and associated malformations had craniofacial abnormalities (p = 0.007) nor did any of the 35 previously reported DBA patients with RPS19 mutations and associated malformations (p = 9.745 x 10(-7)). In addition, mutations in RPL5 appeared to cause a more severe phenotype compared to mutations in RPL11 or RPS19, with RPL11 mutations being predominantly associated with thumb abnormalities. Population Genetics In France, Willig et al. (1999) estimated the incidence of DBA to be 7.3 cases per million live births. Landowski et al. (2013) stated that the incidence of DBA is estimated to be 5 to 7 per million live births, equally distributed between genders. History Mentzer (2003) provided a biographic sketch of Louis Diamond (1902-1999) and a review of his contributions to pediatric hematology. Diamond and Blackfan (1938) described 'their' syndrome in an article on hypoplastic anemia. They reported 4 children with hypoplastic anemia beginning in infancy and requiring red cell transfusions at regular intervals. Similar cases had been reported earlier by Josephs (1936) at Johns Hopkins. Diamond's name is also associated with that of Shwachman in the syndrome of pancreatic insufficiency and bone marrow dysfunction, Shwachman-Diamond syndrome (260400). 'Congenital (erythroid) hypoplastic anemia' was the term used by Diamond et al. (1961) for the disorder subsequently called Diamond-Blackfan anemia. Confusingly, Estren and Dameshek (1947) had used the designation 'familial hypoplastic anemia' for the disorder in 2 families that were later shown to have Fanconi anemia (FA; 227650) (Li and Potter, 1978). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature Other \- Intrauterine growth retardation, mild \- Failure to thrive HEAD & NECK Head \- Microcephaly \- Delayed closure of fontanel Face \- Micrognathia \- Retrognathia Eyes \- Downslanting palpebral fissures \- Hypertelorism \- Strabismus Nose \- Flat nose Mouth \- Cleft lip \- Cleft palate \- High-arched palate Neck \- Webbed neck \- Short neck CARDIOVASCULAR Heart \- Atrial septal defect \- Ventricular septal defect Vascular \- Coarctation of the aorta \- Absent radial pulse CHEST External Features \- Narrow shoulders Ribs Sternum Clavicles & Scapulae \- 11 pairs of ribs \- Clavicle agenesis SKELETAL Skull \- Parietal foramina Spine \- Bifid thoracic vertebrae \- Hypoplastic sacral vertebrae \- Hypoplastic coccygeal vertebrae Pelvis \- Hypoplastic ilia Limbs \- Mild radial hypoplasia Hands \- Triphalangeal thumbs \- Bifid thumbs \- Hypoplastic thumbs \- Absent thumbs SKIN, NAILS, & HAIR Skin \- Pallor NEUROLOGIC Central Nervous System \- Mental retardation (in some patients) HEMATOLOGY \- Anemia, congenital hypoplastic, moderate-severe (normochromic, macrocytic) \- Reticulocytopenia \- Neutropenia, mild \- Thrombocytosis \- Thrombocytopenia \- Elevated fetal hemoglobin (HbF) \- Presence of i erythrocyte antigen \- Increased myeloid to erythroid ratio (M:E ratio) 10:1-200:1 NEOPLASIA \- Osteogenic sarcoma \- Myelodysplastic syndrome \- Colon cancer PRENATAL MANIFESTATIONS Delivery \- Premature birth LABORATORY ABNORMALITIES \- Elevated erythrocyte adenosine deaminase (eADA) MISCELLANEOUS \- Onset in infancy \- Age at diagnosis 2-4 months \- 40% patients have associated abnormalities \- Variable expressivity in families \- Most cases are sporadic MOLECULAR BASIS \- Caused by mutation in the ribosomal protein S19 gene (RPS19, 603474.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	DIAMOND-BLACKFAN ANEMIA 1	c1260899	4,658	omim	https://www.omim.org/entry/105650	2019-09-22T16:45:05	{"doid": ["1339"], "mesh": ["D029503"], "omim": ["105650"], "orphanet": ["124"], "synonyms": ["Alternative titles", "DBA", "BLACKFAN-DIAMOND SYNDROME", "ANEMIA, CONGENITAL HYPOPLASTIC, OF BLACKFAN AND DIAMOND", "ANEMIA, CONGENITAL ERYTHROID HYPOPLASTIC", "RED CELL APLASIA, PURE, HEREDITARY", "AREGENERATIVE ANEMIA, CHRONIC CONGENITAL", "ERYTHROGENESIS IMPERFECTA", "AASE-SMITH SYNDROME II", "AASE SYNDROME"], "genereviews": ["NBK7047"]}
Nocardiosis is a local (skin, lung, brain) or disseminated (whole body) acute, subacute, or chronic bacterial infection. ## Epidemiology Annual incidence in the United States is estimated at around 1/250,000 inhabitants, but may be underestimated. The exact incidence in Europe is unknown. Men are more frequently affected than women (sex ratio: 3:1). ## Clinical description Nocardiosis may occur in any age group, but it is more common in middle-aged adults. Clinical manifestations depend on the site of infection. Most patients present with pulmonary disease. Frequent signs are fatigue, fever, chills, coughing (similar to the cough in pneumonia or tuberculosis), dyspnea, pleural chest pain, and weight loss. Primary cutaneous nocardiosis may present as cutaneous, lymphocutaneous or subcutaneous infection. Cutaneous infection manifests as cellulitis, pustules, pyoderma, paronychia, ulcerations or localized abscesses. Similar lesions are present with lymphocutaneous infection but are associated with ascending regional lymphadenopathy. Subcutaneous infection manifests as the apparition of mycetoma (see this term), predominantly affecting the extremities. Disseminated nocardiosis typically affects immunocompromised hosts. Lesions in the brain or meninges are frequent. ## Etiology The disease is caused by Nocardia infections. Nocardia is an aerobic, Gram-positive branching filamentous bacteria found in soil, decaying vegetable matter, and aquatic environments. Infection may occur through direct inhalation or inoculation. At least 13 species of Nocardia are reported to cause human disease, with the most frequently identified causes being N. asteroids complex and N. brasiliensis. Nocardiosis is often associated with a patient history of trauma (puncture wounds or cat scratches), immunodeficiency, resistance to previous antibiotic therapy, or fever. ## Diagnostic methods The diagnosis is based on analysis of cultures of the causative organism from the infection site and on identification of Nocardia throughmolecular techniques (RFLP or PCR assays). Chest radiography may also be required. ## Differential diagnosis The differential diagnosis should include tuberculosis, aspergillosis, histoplasmosis, Kaposi sarcoma, sporotrichosis, non-Hodgkin lymphoma (see these terms), lung abscess and pneumonia. ## Management and treatment Management includes antibiotic therapy, in particular with trimethoprim-sulfamethoxazole (TMP-SMX). The duration of therapy (1 to 12 months) depends on the type of Nocardia infection. Surgical resection may be feasible for localized abscesses. ## Prognosis Prognosis is generally favorable, except in cases of disseminated nocardiosis in immunocompromised patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Nocardiosis	c0028242	4,659	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=31204	2021-01-23T17:52:52	{"gard": ["7210"], "mesh": ["D009617", "C536125"], "umls": ["C0028242"], "icd-10": ["A43.0", "A43.1", "A43.8", "A43.9"]}
Wikipedia list article This article needs attention from an expert on the subject. Please add a reason or a talk parameter to this template to explain the issue with the article. When placing this tag, consider associating this request with a WikiProject. (June 2015) List of types of malnutrition or list of nutritional disorders include diseases that results from excessive or inadequate intake of food and nutrients. ## Contents * 1 Overnutrition * 1.1 Metabolic * 1.2 Vitamins and micronutrients * 2 Deficiencies * 2.1 Proteins/fats/carbohydrates * 2.2 Dietary vitamins and minerals ## Overnutrition[edit] Main article: Overnutrition ### Metabolic[edit] Obesity is caused by eating too many calories compared to the amount of exercise the individual is performing, causing a distorted energy balance. It can lead to diseases such as cardiovascular disease and diabetes. Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, is increased to a point where it is associated with certain health conditions or increased mortality. The low-cost food that is generally affordable to the poor in affluent nations is low in nutritional value and high in fats, sugars and additives. In rich countries, therefore, obesity is often a sign of poverty and malnutrition while in poorer countries obesity is more associated with wealth and good nutrition. Other non-nutritional causes for obesity included: sleep deprivation, stress, lack of exercise, and heredity. Acute overeating can also be a symptom of an eating disorder. Goitrogenic foods can cause goitres by interfering with iodine uptake. ### Vitamins and micronutrients[edit] Vitamin poisoning is the condition of overly high storage levels of vitamins, which can lead to toxic symptoms. The medical names of the different conditions are derived from the vitamin involved: an excess of vitamin A, for example, is called "hypervitaminosis A". Iron overload disorders are diseases caused by the overaccumulation of iron in the body. Organs commonly affected are the liver, heart and endocrine glands in the mouth. ## Deficiencies[edit] ### Proteins/fats/carbohydrates[edit] * Protein malnutrition * Kwashiorkor * Marasmus ### Dietary vitamins and minerals[edit] * Calcium * Osteoporosis * Rickets * Tetany * Iodine deficiency * Goiter * Selenium deficiency * Keshan disease * Iron deficiency * Iron deficiency anemia * Zinc * Growth retardation * Thiamine (Vitamin B1) * Beriberi * Niacin (Vitamin B3) * Pellagra * Vitamin C * Scurvy * Vitamin D * Osteoporosis * Rickets * Vitamin A * Night Blindness * Vitamin K * Haemophilia * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	List of types of malnutrition	c3714509	4,660	wikipedia	https://en.wikipedia.org/wiki/List_of_types_of_malnutrition	2021-01-18T18:45:06	{"mesh": ["D009748"], "umls": ["C3714509"], "wikidata": ["Q1361144"]}
A number sign (#) is used with this entry because spinocerebellar ataxia-38 (SCA38) is caused by heterozygous mutation in the ELOVL5 gene (611805) on chromosome 6p12. Description Spinocerebellar ataxia-38 is an autosomal dominant neurologic disorder characterized by adult-onset of slowly progressive gait ataxia accompanied by nystagmus. Brain MRI shows cerebellar atrophy (summary by Di Gregorio et al., 2014). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Di Gregorio et al. (2014) reported 4 unrelated families, 3 Italian and 1 French, with a relatively pure form of autosomal dominant spinocerebellar ataxia. Patients presented with walking difficulties due to gait ataxia between 34 and 51 years of age. Additional features included nystagmus, slow saccades, dysarthria, and limb ataxia. The disorder was slowly progressive. Several patients had distal sensory impairment consistent with axonal neuropathy. Cognition was preserved. Inheritance The transmission pattern of SCA38 in the families reported by Di Gregorio et al. (2014) was consistent with autosomal dominant inheritance. Mapping By genomewide linkage analysis of a large Italian family with autosomal dominant SCA, Di Gregorio et al. (2014) found linkage to a 56.2-Mb interval on chromosome 6p22.2-q14.1 between markers D6S276 and D6S460 (Zmax of 3.08). Molecular Genetics In affected members of a large Italian family with autosomal dominant SCA38, Di Gregorio et al. (2014) identified a heterozygous missense mutation in the ELOVL5 gene (G230V; 611805.0001). The mutation was found by linkage analysis and candidate gene sequencing. Screening of the ELOVL5 gene in 456 European probands with SCA identified heterozygous mutations in 3 additional families (611805.0001 and 611805.0002). Arachidonic acid and docosahexaenoic acid, 2 final products of the enzyme, were reduced in the serum of affected individuals. Transfection of the mutations into several cell lines showed that the mutant proteins had a less diffuse ER signal compared to wildtype, and tended to accumulate in the Golgi apparatus. Transfected cells showed increased levels of CHOP (DDIT3; 126337), suggesting activation of the unfolded protein response that could lead to apoptosis. In a French man with SCA38, Di Gregorio et al. (2014) identified a heterozygous missense mutation (L72V; 611805.0002) in the ELOVL5 gene. Population Genetics Di Gregorio et al. (2014) identified the same ELOVL5 mutation (G230V; 611805.0001) in affected members of 3 unrelated Italian families with SCA38. Haplotype analysis indicated a founder effect. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus \- Slow saccades NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Gait ataxia \- Limb ataxia \- Dysarthria \- Cerebellar atrophy Peripheral Nervous System \- Axonal neuropathy (in some patients) MISCELLANEOUS \- Onset between 34 and 51 years of age \- Slowly progressive MOLECULAR BASIS \- Caused by mutation in the elongation of very long chain fatty acids-like 5 gene (ELOVL5, 611805.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	SPINOCEREBELLAR ATAXIA 38	c4518337	4,661	omim	https://www.omim.org/entry/615957	2019-09-22T15:50:29	{"doid": ["0050985"], "omim": ["615957"], "orphanet": ["423296"], "synonyms": ["SCA38"], "genereviews": ["NBK543515"]}
Idiopathic sclerosing mesenteritis Other namesMesenteric panniculitis Sclerosing mesenteritis - note the hemosiderin, chronic inflammation CausesNot known[1] Risk factorsAutoimmune disorder, abdominal trauma, history of infection[1] Diagnostic methodCT scan[2][3] TreatmentCorticosteroids may be used[1] Idiopathic sclerosing mesenteritis (ISM) is a rare disease of the small intestine, characterized by chronic inflammation and eventual fibrosis of the mesentery.[1] It has also been called mesenteric lipodystrophy, or retractile mesenteritis.[4] ## Contents * 1 Signs and symptoms * 2 Mechanism * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 Research * 7 See also * 8 References * 9 Further reading * 10 External links ## Signs and symptoms[edit] Sclerosing mesenteritis may present with no or nearly no signs or symptoms, but many people have chronic and severe pain in the abdomen as the most common chief complaint. Other people have chronic problems with bowel movements, resulting in diarrhea, bloating, gas, and cramping which can range from severe to mild.[4][5] The disorder is identified by histopathology showing fat necrosis, fibrosis and chronic inflammation of the small intestine. Examination of the mesentery may indicate a solitary mass, but diffuse mesentery thickening is common.[4][6] It often mimics other abdominal diseases such as pancreatic or disseminated cancer.[7] CT scanning is important for making the initial diagnosis.[8] ## Mechanism[edit] Several causes of sclerosing mesenteritis have been suggested such as trauma, prior surgical procedures, autoimmune diseases such as lupus, IgG4-related disease, rheumatoid arthritis, infections such as tuberculosis, cryptococcosis, schistosomiasis, HIV and medicines such as paroxetine and pergolide but their associations with sclerosing mesenteritis are largely speculative with high degree of bias.[9] ## Diagnosis[edit] CTscan In regards to the diagnosis of idiopathic sclerosing mesenteritis, a CT scan which creates cross-section pictures of the affected individuals body, can help in the assessment of the disease. “Misty mesentery” is often used to describe increase in mesenteric fat density in sclerosing mesenteritis. However, it is not specific and can be found in other conditions such as mesenteric oedema, lymphedema, haemorrhage, and presence of neoplastic and inflammatory cells must be excluded. Mesenteric lymph nodes are rarely larger than 10 mm in sclerosing mesenteritis. Larger lymph nodes should prompt further investigations with PET scan or biopsy.[9] MRI scan may show an intermediate T1 intensity and variable T2 intensity depending on degree of oedema and fibrosis. Presence of oedema causes high T2 signal while fibrosis causes low T2 signal.[9] ## Treatment[edit] In terms of possible treatment for the condition of idiopathic sclerosing mesenteritis, medications such as corticosteroids, tamoxifen and thalidomide have been used.[10] ## Epidemiology[edit] The epidemiology of Idiopathic sclerosing mesenteritis disease is extremely rare and has only been diagnosed in about an estimated 300 patients worldwide to date (as of 2014), it is probably under diagnosed.[11] It can occur in children.[10] ## Research[edit] Tamoxifen The Mayo Clinic in Rochester reported a large study of 92 patients, with widely ranging severity of their symptoms. The majority were male, with an average age of 65 years. They commonly had abdominal pain (70%), diarrhea (25%), and weight loss (23%). Depending on the stage of the scarring and fibrosis, several different treatments, including surgery for bowel obstruction, or drugs were used to halt the progression of the disease.[5] In that case series, 56% of patients received only pharmacological therapy, most often receiving tamoxifen with a reducing dose of reducing prednisone, or also had colchicine, azathioprine or thalidomide.[5] Their findings suggest that sclerosing mesenteritis can be debilitating although relatively benign. Symptomatic patients benefited from medical therapy, usually tamoxifen and prednisone, but further follow-up information would strengthen these results.[5] ## See also[edit] * Small intestine ## References[edit] 1. ^ a b c d "Sclerosing mesenteritis \| Disease \| Overview \| Office of Rare Diseases Research (ORDR-NCATS)". rarediseases.info.nih.gov. Retrieved 2015-08-12. 2. ^ Akram, Salma; Pardi, Darrell S.; Schaffner, John A.; Smyrk, Thomas C. (May 2007). "Sclerosing Mesenteritis: Clinical Features, Treatment, and Outcome in Ninety-Two Patients". Clinical Gastroenterology and Hepatology. 5 (5): 589–596. doi:10.1016/j.cgh.2007.02.032. PMID 17478346. 3. ^ "CT Scans: MedlinePlus". NIH.gov. NIH. Retrieved 23 July 2016. 4. ^ a b c Emory TS, Monihan JM, Carr NJ, Sobin LH (1997). "Sclerosing mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy: a single entity?". Am J Surg Pathol. 21 (4): 392–8. doi:10.1097/00000478-199704000-00004. PMID 9130985. 5. ^ a b c d Akram S, Pardi DS, Schaffner JA, Smyrk TC (2007). "Sclerosing mesenteritis: clinical features, treatment, and outcome in ninety-two patients". Clin Gastroenterol Hepatol. 5 (5): 589–96. doi:10.1016/j.cgh.2007.02.032. PMID 17478346. 6. ^ Fletcher, Christopher D. M. (2007-03-29). Diagnostic Histopathology of Tumors: 2-Volume Set with CD-ROMs. Elsevier Health Sciences. ISBN 9780702032059. 7. ^ Scudiere JR, Shi C, Hruban RH, Herman JM, Fishman EK, Schulick RD, et al. (2010). "Sclerosing mesenteritis involving the pancreas: a mimicker of pancreatic cancer". Am J Surg Pathol. 34 (4): 447–53. doi:10.1097/PAS.0b013e3181d325c0. PMC 2861335. PMID 20351487. 8. ^ Horton KM, Lawler LP, Fishman EK (2003). "CT findings in sclerosing mesenteritis (panniculitis): spectrum of disease". Radiographics. 23 (6): 1561–7. doi:10.1148/rg.1103035010. PMID 14615565. 9. ^ a b c Danford, Christopher J.; Lin, Steven C.; Wolf, Jacqueline L. (June 2019). "Sclerosing Mesenteritis". The American Journal of Gastroenterology. 114 (6): 867–873. doi:10.14309/ajg.0000000000000167. ISSN 0002-9270. PMID 30829677. 10. ^ a b Viswanathan, Vijay; Murray, Kevin J (2010). "Idiopathic sclerosing mesenteritis in paediatrics: Report of a successfully treated case and a review of literature". Pediatric Rheumatology. 8 (5): 5. doi:10.1186/1546-0096-8-5. PMC 2825191. PMID 20205836. 11. ^ Federle, Michael P.; Raman, Siva P. (2015-07-29). Diagnostic Imaging: Gastrointestinal. Elsevier Health Sciences. ISBN 9780323400404. ## Further reading[edit] * Federle, Michael P.; Raman, Siva P. (2015-07-29). Diagnostic Imaging: Gastrointestinal. Elsevier Health Sciences. ISBN 9780323400404. * Vlachos, Konstantinos; Archontovasilis, Fotis; Falidas, Evangelos; Mathioulakis, Stavros; Konstandoudakis, Stefanos; Villias, Constantinos (2011-06-02). "Sclerosing Mesenteritis: Diverse clinical presentations and dissimilar treatment options. A case series and review of the literature". International Archives of Medicine. 4: 17. doi:10.1186/1755-7682-4-17. ISSN 1755-7682. PMC 3128041. PMID 21635777. * Issa, Iyad; Baydoun, Hassan (14 August 2009). "Mesenteric panniculitis: Various presentations and treatment regimens". World Journal of Gastroenterology. 15 (30): 3827–3830. doi:10.3748/wjg.15.3827. ISSN 1007-9327. PMC 2726466. PMID 19673029. ## External links[edit] Classification D * ICD-10: K65.4 Scholia has a topic profile for Idiopathic sclerosing mesenteritis. * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Idiopathic sclerosing mesenteritis	c0267770	4,662	wikipedia	https://en.wikipedia.org/wiki/Idiopathic_sclerosing_mesenteritis	2021-01-18T18:29:25	{"gard": ["8169"], "mesh": ["D015436"], "umls": ["C0267770", "C0025470"], "orphanet": ["238593"], "wikidata": ["Q17048348"]}
A number sign (#) is used with this entry because nonprogressive cerebellar ataxia with mental retardation (CANPMR) is caused by heterozygous disruption of the CAMTA1 gene (611501) on chromosome 1p36. Description Nonprogressive cerebellar ataxia with mental retardation is an autosomal dominant neurodevelopmental disorder characterized by mildly delayed psychomotor development, early onset of cerebellar ataxia, and intellectual disability later in childhood and adult life. Other features may include neonatal hypotonia, dysarthria, and dysmetria. Brain imaging in some patients shows cerebellar atrophy. Dysmorphic facial features are variable (summary by Thevenon et al., 2012). Clinical Features Thevenon et al. (2012) reported 2 unrelated families and an unrelated single patient with mild mental retardation and ataxia apparent from infancy. In the first family, 2 adult half sisters had mild mental retardation, attended schools for special needs, and worked at simple jobs. Both had ataxic gait with static instability; 1 had mild intention tremor. Brain MRI of both women showed mild hippocampal atrophy, simplified gyration of the dentate gyri, posterior cortical atrophy, and cerebellar atrophy. PET scan of 1 woman showed hypometabolism of several cerebral brain regions. Detailed neuropsychologic testing showed defects of rehearsal processing in episodic visual memory. One of the women had 2 affected sons, and the other had 3 affected children. All patients had mental retardation, usually with delayed psychomotor development, and all had gait instability or frank ataxia. More variable features included strabismus, infantile hypotonia, delayed speech, and myoclonic seizures of the upper arm (1 patient). Some patients had mild dysmorphic facial features, such as long face with pointed chin, bulbous nose, long philtrum, and thick lower lip. The mother of the women reportedly had mild intellectual disability. In a second family, a mother and her son and daughter were affected. All had mild intellectual disability, and the mother and daughter had ataxic gait. The 2 children had delayed psychomotor development with speech delay. One had neonatal hypotonia and the other had autistic features, poor interactive skills, and bursts of aggression. Mild facial dysmorphism was noted, including large forehead, palpebral edema, wide flat nose, short ears, small mouth, and abnormally implanted teeth. In a third family, a girl had delayed psychomotor development and features of ataxia, including ataxic gait, dysmetria, instability, and dysarthria. Shinawi et al. (2015) reported 3 patients from 2 unrelated families with CANPMR. The probands in both families were 12-year-old boys with delayed development, intellectual disability/learning disabilities, attention-deficit hyperactivity disorder, ataxia, dysarthria, and poor fine motor skills. The affected mother of 1 patient had mild intellectual disability, but could drive, cook, and manage her bills. They had some mild and variable dysmorphic features, including short stature, broad forehead, hypertelorism, downslanting palpebral fissures, strabismus, high-arched palate, small mouth, and low-set ears. The other proband had onset of seizures in infancy that continued throughout childhood and were partially responsive to medication. EEG showed focal epilepsy with secondary generalization. He also had aggressive behavior. Dysmorphic features included tall and broad forehead, broad nasal tip, narrow chin, and prominent ears. This patient had a family history of intellectual disability and epilepsy, but his father did not carry a CAMTA1 mutation, and DNA from the mother was unavailable. All 3 patients also had gastrointestinal problems, including reflux and constipation. Brain imaging of all 3 patients showed mild cerebellar atrophy. Inheritance The transmission pattern in 2 families with nonprogressive cerebellar ataxia with mental retardation reported by Thevenon et al. (2012) was consistent with autosomal dominant inheritance. Molecular Genetics Using array CGH, Thevenon et al. (2012) identified a heterozygous intragenic deletion in the CAMTA1 gene (611501.0001) in affected members of a large family with early-onset nonprogressive cerebellar ataxia and mild mental retardation. Another family with a similar phenotype had a heterozygous intragenic duplication in the CAMTA1 gene (611501.0002). Both of these disruptions were predicted to lead to a frameshift and premature termination. An unrelated child with ataxia but milder cognitive involvement had a different in-frame deletion within the gene (611501.0003). All of the rearrangements affected the CG1 domain of the protein. DNA sequencing analysis of the CAMTA1 gene in a cohort of 197 patients with intellectual disability or nonprogressive cerebellar ataxia did not identify any point mutations, suggesting that microrearrangements of the CAMTA1 are the most frequent mutations. In 3 patients from 2 unrelated families with CANPMR, Shinawi et al. (2015) identified heterozygous intragenic deletions in the CAMTA1 gene. The deletions were similar in size, 247.7 and 247.9 kb, respectively, but had different breakpoints. The 2 deletions removed amino acids 147-971 of the protein and introduced a frameshift that was predicted to result in premature termination or be subject to nonsense-mediated mRNA decay, consistent with haploinsufficiency. The deletions were identified by microarray analysis and FISH studies. Functional studies of the variant and additional studies of patient cells were not performed. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Large forehead \- Broad forehead Face \- Long face \- Pointed chin \- Long philtrum Ears \- Short ears \- Low-set ears \- Prominent ears Eyes \- Strabismus (in some patients) \- Palpebral edema (in 1 family) \- Hypertelorism \- Downslanting palpebral fissures Nose \- Wide flat nose \- Bulbous nose \- Anteverted nostrils Mouth \- Thick lower lip \- Small mouth Teeth \- Abnormally implanted teeth (in 1 family) ABDOMEN Gastrointestinal \- Constipation \- Gastroesophageal reflux MUSCLE, SOFT TISSUES \- Hypotonia, neonatal NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation, mild \- Intellectual disability \- Speech delay \- Unsteady gait \- Ataxia \- Dysmetria, mild \- Dysarthria \- Poor motor coordination, fine and gross \- Seizures (uncommon) \- Cerebellar hypoplasia \- Hippocampal atrophy (in 2 siblings) \- Cortical atrophy (in 2 siblings) Behavioral Psychiatric Manifestations \- Behavioral difficulties (in some patients) \- Attention-deficit \- Hyperactivity \- Aggressive behavior MISCELLANEOUS \- Dysmorphic facial features are variable \- Ataxia is nonprogressive MOLECULAR BASIS \- Caused by disruption of the calmodulin-binding transcription activator 1 gene (CAMTA1, 611501.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	CEREBELLAR ATAXIA, NONPROGRESSIVE, WITH MENTAL RETARDATION	c3553661	4,663	omim	https://www.omim.org/entry/614756	2019-09-22T15:54:17	{"doid": ["0050998"], "omim": ["614756"], "orphanet": ["314647"], "synonyms": []}
A rare hematologic disease characterized by symptoms of mast cell activation in the absence of cutaneous findings, as well as absence of diagnostic criteria of systemic mastocytosis with tryptase levels of less than 20 ng/ml and normal to low burden of mast cells. Bone marrow biopsy reveals the presence of monoclonal mast cells carrying the KIT D816V mutation and/or expressing CD25. Patients present with recurrent episodes of flushing, headache, hypotension, abdominal cramping, nausea, diarrhea, cardiac arrhythmias, bronchoconstriction, and bleeding diathesis, among others. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Monoclonal mast cell activation syndrome	c4267893	4,664	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=529468	2021-01-23T17:12:25	{"synonyms": ["Monoclonal MCAD"]}
Ochoa syndrome is a disorder characterized by urinary problems and unusual facial expressions. The urinary problems associated with Ochoa syndrome typically become apparent in early childhood or adolescence. People with this disorder may have difficulty controlling the flow of urine (incontinence), which can lead to bedwetting. Individuals with Ochoa syndrome may be unable to completely empty the bladder, often resulting in vesicoureteral reflux, a condition in which urine backs up into the ducts that normally carry it from each kidney to the bladder (the ureters). Urine may also accumulate in the kidneys (hydronephrosis). Vesicoureteral reflux and hydronephrosis can lead to frequent infections of the urinary tract and kidney inflammation (pyelonephritis), causing damage that may eventually result in kidney failure. Individuals with Ochoa syndrome also exhibit a characteristic frown-like facial grimace when they try to smile or laugh, often described as inversion of facial expression. While this feature may appear earlier than the urinary tract symptoms, perhaps as early as an infant begins to smile, it is often not brought to medical attention. Approximately two-thirds of individuals with Ochoa syndrome also experience problems with bowel function, such as constipation, loss of bowel control, or muscle spasms of the anus. ## Frequency Ochoa syndrome is a rare disorder. About 150 cases have been reported in the medical literature. ## Causes Ochoa syndrome can be caused by mutations in the HPSE2 gene. This gene provides instructions for making a protein called heparanase 2. The function of this protein is not well understood. Mutations in the HPSE2 gene that cause Ochoa syndrome result in changes in the heparanase 2 protein that likely prevent it from functioning. The connection between HPSE2 gene mutations and the features of Ochoa syndrome are unclear. Because the areas of the brain that control facial expression and urination are in close proximity, some researchers have suggested that the genetic changes may lead to an abnormality in this brain region that may account for the symptoms of Ochoa syndrome. Other researchers believe that a defective heparanase 2 protein may lead to problems with the development of the urinary tract or with muscle function in the face and bladder. Some people with Ochoa syndrome do not have mutations in the HPSE2 gene. In these individuals, the cause of the disorder is unknown. ### Learn more about the gene associated with Ochoa syndrome * HPSE2 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Ochoa syndrome	c0403555	4,665	medlineplus	https://medlineplus.gov/genetics/condition/ochoa-syndrome/	2021-01-27T08:25:20	{"gard": ["104"], "mesh": ["C536480"], "omim": ["236730"], "synonyms": []}
Footballer's Ankle is a pinching or impingement of the ligaments or tendons of the ankle between the bones, particularly the talus and tibia. This results in pain, inflammation and swelling. ## Contents * 1 Causes * 2 Symptoms * 3 Treatment * 4 External links ## Causes[edit] A common cause of anterior impingement is a bone spur on anklebone (talus) or the shinbone (tibia). Repeated kicking actions can cause the anklebone to hit the bottom of the shinbone, which can lead to a lump of bone (or bone spur) developing. This bone spur may then begin to impact on the soft tissue at the front of the ankle, causing inflammation and swelling. The condition is most common in athletes who repeatedly bend the ankle upward (dorsiflexion), such as footballers, hence the name. ## Symptoms[edit] \- pain and tenderness over anterior ankle joint \- pain on dorsiflexion and plantar flexion \- band of pain across anterior ankle when kicking a ball \- palpable bony lump on distal tibia or superior talus ## Treatment[edit] \- soft tissue techniques to stretch muscles crossing the ankle to relieve tension \- mobilisation of ankle joint \- steroid injection to reduce inflammation \- surgery to remove bony spurs ## External links[edit] * [1] What is Footballer's Ankle? * [2] Simon Moyes: Anterior Impingement (Footballer's Ankle) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Footballer's ankle	c3267036	4,666	wikipedia	https://en.wikipedia.org/wiki/Footballer%27s_ankle	2021-01-18T18:58:11	{"umls": ["C3267036"], "wikidata": ["Q5466445"]}
Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome is characterized by neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis. ## Epidemiology It has been described in four patients: two sisters and their female cousin belonging to a consanguineous Pakistani family, and one unrelated case (also born to consanguineous parents). ## Clinical description Patients also present with facial dysmorphism (a triangular face, small chin, low set ears), flexion contractures of the arms and legs, very little subcutaneous fat, and optic nerve hypoplasia. One of the patients had pancreatic agenesis, and the others were suspected of having pancreatic hypoplasia. ## Etiology The syndrome is caused by mutations in the PTF1A gene (10p12.3). ## Antenatal diagnosis Prenatal diagnosis is possible by demonstration of the absence of the cerebellum and severe intra-uterine growth retardation. ## Genetic counseling The syndrome is transmitted as an autosomal recessive disorder. ## Prognosis All patients died in the neonatal period. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	c1836780	4,667	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=65288	2021-01-23T18:04:18	{"mesh": ["C563796"], "omim": ["609069"], "umls": ["C1836780"], "synonyms": ["Pancreatic and cerebellar agenesis"]}
Adrenal gland disorders (or diseases) are conditions that interfere with the normal functioning of the adrenal glands.[1] Adrenal disorders may cause hyperfunction or hypofunction, and may be congenital or acquired. The adrenal gland produces hormones that affects growth, development and stress, and also helps to regulate kidney function. There are two parts of the adrenal glands, the adrenal cortex and the adrenal medulla. The adrenal cortex produces mineralocorticoids, which regulate salt and water balance within the body, glucocorticoids (including cortisol) which have a wide number of roles within the body, and androgens, hormones with testosterone-like function.[2] The adrenal medulla produces epinephrine (adrenaline) and norepinephrine (noradrenaline).[2] Disorders of the adrenal gland may affect the production of one or more of these hormones. ## Contents * 1 Tumors of the adrenal gland * 1.1 Hereditary disorders associated with adrenal tumors * 2 Notable people with adrenal gland disorders * 3 Disorders of hormone over/under-production * 4 References ## Tumors of the adrenal gland[edit] * Adrenal adenoma, a benign tumor of the adrenal gland which may result in overproduction of one or more adrenal hormones, or may be inactive. * Adrenocortical carcinoma, cancer of the adrenal cortex * Adrenal incidentaloma, an adrenal tumor (of any type) discovered accidentally during a scan which performed for an unrelated reason * Pheochromocytoma, a catecholamine-producing tumor of the adrenal medulla, which may or may not be cancerous ### Hereditary disorders associated with adrenal tumors[edit] * Von Hippel–Lindau disease, a mutation of the VHL1 tumor-suppression gene associated with many types of tumor, including pheochromocytoma * Multiple Endocrine Neoplasia, a family of syndromes in which genetic abnormalities contribute to the development of endocrine tumors ## Notable people with adrenal gland disorders[edit] * John F. Kennedy, the 35th president of the United States was diagnosed with Addison’s disease.[3] * Some have suggested Jane Austen was an avant la lettre case of Addison's Disease, but others have disputed this.[4] * Scientist Eugene Merle Shoemaker, co-discoverer of the Comet Shoemaker-Levy 9 had Addison's Disease.[5] ## Disorders of hormone over/under-production[edit] * Addison's disease, also known as primary adrenal insufficiency, a disease in which the adrenal glands do not produce sufficient glucocorticoids (sometimes also mineralocorticoids) for a reason directly related to the adrenal gland itself, such as auto-immune damage to the adrenal gland or adrenal gland atrophy due to medication use * Adrenal crisis, a life-threatening medical emergency resulting from insufficient levels of cortisol * Adrenal insufficiency, a condition in which the adrenal glands do not produce sufficient glucocorticoids (or sometimes mineralocorticoids. This is often due to another adrenal disorder, such as Addison's Disease or Congenital Adrenal Hyperplasia, however it may also result from a problem elsewhere in the body (such as the hypothalamus or pituitary gland) that leads to abnormalities in the production of hormones regulating adrenal function * Congenital Adrenal Hyperplasia, a hereditary disorder in which one of the enzymes involved in cortisol synthesis does not function properly. This disorder is also often associated with an over-production of androgen hormones. * Cushing's disease, a disorder in which cortisol levels are abnormally high * Hyperaldosteronism (including Conn's syndrome), a condition in which aldosterone is over-produced * Hypoaldosteronism, a condition in which aldosterone is under-produced ## References[edit] 1. ^ "Overview of the Adrenal Glands: Adrenal Gland Disorders: Merck Manual Home Health Handbook". Retrieved 2009-03-28. 2. ^ a b Adrenal Glands, Johns Hopkins Medicine Health Library. 3. ^ Mandel, Lee R. (September 2009). "Endocrine and Autoimmune Aspects of the Health History of John F. Kennedy". Annals of Internal Medicine. 151 (5): 350–354. doi:10.7326/0003-4819-151-5-200909010-00011. PMID 19721023. 4. ^ Upfal, Annette (2005). "Jane Austen's lifelong health problems and final illness: New evidence points to a fatal Hodgkin's disease and excludes the widely accepted Addison's". Medical Humanities. BMJ Publishing Group. 31 (1): 3–11. doi:10.1136/jmh.2004.000193. PMID 23674643. 5. ^ Marsden, Brian (1997-07-18). "Eugene Shoemaker (1928-1997)". Comet Shoemaker-Levy Collision with Jupiter. Jet Propulsion Laboratory. Archived from the original on 11 July 2007. Retrieved 2007-07-25. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Adrenal gland disorder	c0001621	4,668	wikipedia	https://en.wikipedia.org/wiki/Adrenal_gland_disorder	2021-01-18T18:37:22	{"mesh": ["D000307"], "umls": ["C0001621", "C4021794"], "wikidata": ["Q4684717"]}
Familial dysautonomia is a genetic disorder that affects the development and survival of certain nerve cells. The disorder disturbs cells in the autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. Familial dysautonomia is also called hereditary sensory and autonomic neuropathy, type III. Problems related to this disorder first appear during infancy. Early signs and symptoms include poor muscle tone (hypotonia), feeding difficulties, poor growth, lack of tears, frequent lung infections, and difficulty maintaining body temperature. Older infants and young children with familial dysautonomia may hold their breath for prolonged periods of time, which may cause a bluish appearance of the skin or lips (cyanosis) or fainting. This breath-holding behavior usually stops by age 6. Developmental milestones, such as walking and speech, are usually delayed, although some affected individuals show no signs of developmental delay. Additional signs and symptoms in school-age children include bed wetting, episodes of vomiting, reduced sensitivity to temperature changes and pain, poor balance, abnormal curvature of the spine (scoliosis), poor bone quality and increased risk of bone fractures, and kidney and heart problems. Affected individuals also have poor regulation of blood pressure. They may experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. They can also have episodes of high blood pressure when nervous or excited, or during vomiting incidents. About one-third of children with familial dysautonomia have learning disabilities, such as a short attention span, that require special education classes. By adulthood, affected individuals often have increasing difficulties with balance and walking unaided. Other problems that may appear in adolescence or early adulthood include lung damage due to repeated infections, impaired kidney function, and worsening vision due to the shrinking size (atrophy) of optic nerves, which carry information from the eyes to the brain. ## Frequency Familial dysautonomia occurs primarily in people of Ashkenazi (central or eastern European) Jewish descent. It affects about 1 in 3,700 individuals in Ashkenazi Jewish populations. Familial dysautonomia is extremely rare in the general population. ## Causes Mutations in the ELP1 gene cause familial dysautonomia. The ELP1 gene provides instructions for making a protein that is found in a variety of cells throughout the body, including brain cells. Nearly all individuals with familial dysautonomia have two copies of the same ELP1 gene mutation in each cell. This mutation can disrupt how information in the ELP1 gene is pieced together to make a blueprint for the production of ELP1 protein. As a result of this error, a reduced amount of normal ELP1 protein is produced. This mutation behaves inconsistently, however. Some cells produce near normal amounts of the protein, and other cells—particularly brain cells—have very little of the protein. Critical activities in brain cells are probably disrupted by reduced amounts or the absence of ELP1 protein, leading to the signs and symptoms of familial dysautonomia. ### Learn more about the gene associated with Familial dysautonomia * ELP1 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Familial dysautonomia	c0013364	4,669	medlineplus	https://medlineplus.gov/genetics/condition/familial-dysautonomia/	2021-01-27T08:25:31	{"gard": ["7581"], "mesh": ["D004402"], "omim": ["223900"], "synonyms": []}
A number sign (#) is used with this entry because ovarian cancer has been associated with somatic changes in several genes, including OPCML (600632), PIK3CA (171834), AKT1 (164730), CTNNB1 (116806), RRAS2 (600098), CDH1 (192090), ERBB2 (164870), and PARK2 (602544). See also 607893 for an ovarian cancer susceptibility locus (OVCAS1) that has been mapped to chromosome 3p25-p22. Familial ovarian cancer may be part of other cancer syndromes. See susceptibility to familial breast-ovarian cancer 1 and 2 (604370 and 612555), due to mutations in the BRCA1 (113705) and BRCA2 (600185) genes, respectively; and Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1; 120435), due to mutations in DNA mismatch repair genes such as MSH2 (609309), MSH3 (600887), MSH6 (600678), and MLH1 (120436). Description Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008). Inheritance There are several early reports of familial ovarian cancer showing autosomal dominant inheritance. Some of these families may have had the breast-ovarian cancer syndrome or Lynch syndrome. Liber (1950) described a family with histologically proven papillary adenocarcinoma of the ovary in 5 sisters and their mother. Jackson (1967) reported a Jamaican family in which grandmother, mother, and daughter developed ovarian tumors; 2 tumors were known to have been dysgerminomas (see 603737). Lewis and Davison (1969) described a family in which 5 of 6 sisters and their mother had ovarian cancer. One of the 5 had a malignant ovarian cyst but subsequently died of colon cancer. Prophylactic oophorectomy was performed in the sixth sister and in 5 females of the following generation. Li et al. (1970) reported a family in which 7 women, including 4 sisters, had ovarian carcinoma. Ovarian cancer was suspected in 3 other women of the family. Philipp (1979) described a family with multiple cases of poorly differentiated cystadenocarcinoma of the ovary. The 4 relatives with ovarian carcinoma were the proband's mother, maternal aunt, that woman's daughter, and the daughter of another maternal aunt. Cytogenetics Whang-Peng et al. (1984) performed cytogenetic studies on ovarian tumor tissue from 44 patients with various forms of epithelial ovarian cancer. All 44 samples had numerical abnormalities, and 39 had structural abnormalities involving multiple chromosomes. Clone formation and the number of chromosomes involved in structural abnormalities increased with duration of disease and were more extensive in patients treated with chemotherapy compared to patients treated with surgery alone. Aneuploidy was observed in all patients and there was considerable variation in the chromosome numbers, often ranging from diploidy to triploidy to tetraploidy. Mapping ### Chromosome 2q22.1 Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, Song et al. (2009) evaluated 11 of the most significant loci from a previously reported breast cancer genomewide association study for association with invasive ovarian cancer (Easton et al., 2007). The 11 SNPs were initially genotyped in 2,927 invasive ovarian cancer cases and 4,143 controls from 6 ovarian cancer case-control studies. Only rs4954956 located less than 7.0 kb upstream of the NXPH2 gene (604635) was significantly associated with ovarian cancer risk both in the replication study and in combined analysis of 5,353 patients and 8,453 controls. This association was stronger for the serous histologic subtype (p = 0.0004; OR, 1.14) than for all types of ovarian cancer (p = 0.05; OR, 1.07). ### Chromosome 6q25 Saito et al. (1992) examined loss of heterozygosity (LOH) in 70 ovarian tumors using 9 RFLP markers located at chromosome 6q24-q27. Among 33 informative serous cancers, 17 (52%) showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors showed LOH. A detailed deletion map delineated a 1.9-cM region, within which the authors postulated the existence of a tumor suppressor gene involved in ovarian carcinoma. In 54 fresh and paraffin-embedded invasive ovarian epithelial tumor tissues, Colitti et al. (1998) used tandem repeat markers on chromosome 6q25 to delineate a 4-cM minimal region of LOH of 6q25.1-q25.2 between markers D6S473 and D6S448. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). LOH at D6S473 correlated significantly both with serous compared to non-serous ovarian tumors (p = 0.040), and with high-grade compared to low-grade specimens (p = 0.023). ### Chromosome 9p24 By transfection of NIH-3T3 cells with genomic DNA from a human ovarian adenocarcinoma tumor cell line, Halverson et al. (1990) identified a rearranged human DNA sequence that was generated during transfection and induced both morphologic transformation and tumorigenesis. One fragment mapped to human chromosome 9p24 and the other to human chromosome 8. Because rat ovarian surface epithelial cells transformed spontaneously in vitro have been found to have homozygous deletions of the interferon alpha gene (IFNA; 147660) on 9p22, suggesting inactivation of a tumor-suppressor gene in that region may be crucial for the development of ovarian cancer, Chenevix-Trench et al. (1994) used microsatellite markers and Southern analysis to examine the homologous region in humans, 9p, for deletions in sporadic ovarian adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity occurred in 34 (37%) of 91 informative sporadic tumors, including some benign, low-malignant-potential and early-stage tumors, suggesting that it is an early event in the development of ovarian adenocarcinoma. Furthermore, homozygous deletions on 9p were found in 2 of 10 independent cell lines. Deletion mapping of the tumors and cell lines indicated that the candidate suppressor gene inactivated as a consequence lies between D9S171 and the IFNA locus. This region is deleted in several other tumors and contains a melanoma predisposition locus (155601). In a note added in proof, Chenevix-Trench et al. (1994) suggested that the target of these 9p deletions might be CDKN2 (600160) as described by Kamb et al. (1994). ### Chromosome 11q25 Loss of heterozygosity studies indicated that a tumor suppressor gene associated with sporadic ovarian cancer may reside at chromosome 11q25 (Gabra et al., 1996; Launonen et al., 1998). In tumor tissue from 118 individuals with epithelial ovarian cancer, Sellar et al. (2003) observed a peak LOH rate of 49% (36 of 74 informative cases) across 11q25 at D11S4085. Conversely, LOH analysis of 39 pairs of DNA from individuals with colorectal cancer (see 114500) and normal DNA showed an LOH rate at D11S4085 of only 23% (6 of 26 informative cases), with no evidence of complete LOH. ### Chromosome 17p Eccles et al. (1990) found LOH of chromosome 17p in 69% of 16 epithelial ovarian cancer tumors. Schultz et al. (1996) identified 2 genes, OVCA1 (DPH1; 603527) and OVCA2 (607896), within a minimum region of allelic loss on chromosome 17p13.3 in a cohort of ovarian tumors. Expression of OVCA1 and OVCA2 was reduced or undetectable in ovarian tumor tissue and cell lines compared with normal ovarian epithelial cells. The findings provided evidence for 1 or more possible tumor suppressor genes on chromosome 17p distinct from the TP53 gene (191170). Phillips et al. (1996) also identified the DPH1 (OVCA1) gene within the region on chromosome 17p13.3 that is deleted in 80% of all ovarian epithelial malignancies. They suggested that it may act as a tumor suppressor gene. ### Chromosome 17q Chromosome 17q contains several genes implicated in ovarian cancer: the BRCA1 gene (113705) on 17q21, the ERBB2 gene (164870) on 17q21.1, and the SEPT9 gene (604061) on 17q25. Eccles et al. (1990) found LOH of 17q in 77% of 16 epithelial ovarian cancer tumors. Godwin et al. (1994) examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of epithelial ovarian tumors. Evaluation of a set of markers positioned telomeric to BRCA1 on chromosome 17q21 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to the BRCA1 gene. Russell et al. (2000) isolated the SEPT9 gene, which they designated ovarian/breast (Ov/Br) septin, as a candidate for the ovarian tumor suppressor gene that had been indirectly identified by up to 70% LOH for a marker at chromosome 17q25 in a bank of malignant ovarian tumors. Two splice variants were demonstrated within the 200-kb contig, which differed only at exon 1. The septins are a family of genes involved in cytokinesis and cell cycle control, whose known functions are consistent with the hypothesis that the human 17q25 septin gene may be a candidate for the ovarian tumor suppressor gene. Rafnar et al. (2011) performed a genomewide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders and imputed genotypes to 41,675 Icelanders using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer in 656 affected individuals. Rafnar et al. (2011) discovered a rare (0.41% allelic frequency) frameshift mutation, 2040_2041insTT, in the BRIP1 (also known as FANCJ; 605882) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, p = 2.8 x 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced life span by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, 1702_1703del, was seen in 2 of 144 subjects with ovarian cancer and 1 of 1,780 control subjects (p = 0.016). This allele was also associated with breast cancer (seen in 6 of 927 cases; p = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation showed loss of the wildtype allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer. Molecular Genetics ### Germline Mutations Stratton et al. (1999) conducted a population-based study to determine the contribution of germline mutations in known candidate genes to epithelial ovarian cancer diagnosed before the age of 30 years. Two of 101 women with invasive ovarian cancer had germline mutations in the MLH1 gene (120436), which is involved in hereditary nonpolyposis colorectal cancer-2 (HNPCC2; 609310). In addition to colon cancer, ovarian cancer may be a manifestation of this syndrome. No germline mutations were identified in any of the other genes analyzed, including BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of BRCA2, and MSH2. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or HNPCC. There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk = 1.6, P = 0.01), but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had an increased risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Liede et al. (1998) raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, the 185delAG mutation in the BRCA1 gene (113705.0003) segregated with the cancer. Liede et al. (1998) concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. ### Somatic Mutations Cesari et al. (2003) identified the complete PARK2 gene (602544) within an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%), both of which are located within the PARK2 gene. Expression of the PARK2 gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, Cesari et al. (2003) found 2 somatic truncating deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian cancers. The data suggested that PARK2 may act as a tumor suppressor gene. Because PARK2 maps to FRA6E, one of the most active common fragile sites in the human genome (Smith et al., 1998), it may represent another example of a large tumor suppressor gene, like FHIT (601153) and WWOX (605131), located at a common fragile site. An Editorial Expression of Concern was published regarding the article by Cesari et al. (2003) because it appeared that Figures 2a and 2b, beta-actin panel, had duplicated bands. The authors stated that 'because this issue was first raised more than 10 years after publication, the original data are not available to confirm whether an error was made in the figure construction' but that 'any error in figure construction does not affect their scientific conclusions.' Denison et al. (2003) found that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian tumors were heterozygous for the duplication or deletion of 1 or more exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian tumor-derived cell lines were found to have a duplication or deletion of 1 or more parkin exons. Diminished or absent parkin expression was observed in most of the ovarian cancer cell lines when studies with antibodies were performed. Denison et al. (2003) suggested that parkin may represent a tumor suppressor gene. Sellar et al. (2003) determined that D11S4085 on 11q25 is located in the second intron of the OPCML gene (600632). OPCML was frequently somatically inactivated in epithelial ovarian cancer tissue by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with tumor suppressor gene properties both in vitro and in vivo. A somatic missense mutation from an individual with epithelial ovarian cancer showed clear evidence of loss of function (600632.0001). These findings suggested that OPCML was an excellent candidate for an ovarian cancer tumor suppressor gene located on 11q25. By examining DNA copy number of 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. The Cancer Genome Atlas Research Network (2011) reported that high-grade serous ovarian cancer is characterized by TP53 (191170) mutations in almost all tumors (96% of 489 high-grade serous ovarian adenocarcinomas); low prevalence but statistically recurrent somatic mutations in 9 further genes including NF1 (613113), BRCA1 (113705), BRCA2 (600185), RB1 (614041), and CDK12 (615514); 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated 4 ovarian cancer transcriptional subtypes, 3 microRNA subtypes, 4 promoter methylation subtypes, and a transcriptional signature associated with survival duration, and shed new light on the impact that tumors with BRCA1/2 and CCNE1 (123837) aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumors analyzed, and that NOTCH (190198) and FOXM1 (602341) signaling are involved in serous ovarian cancer pathophysiology. ### Modifier Genes Quaye et al. (2009) used microcell-mediated chromosome transfer approach and expression microarray analysis to identify candidate genes that were associated with neoplastic suppression in ovarian cancer cell lines. In over 1,600 ovarian cancer patients from 3 European population-based studies, they genotyped 68 tagging SNPs from 9 candidate genes and found a significant association between survival and 2 tagging SNPs in the RBBP8 gene (604124), rs4474794 (hazard ratio, 0.85; 95% CI, 0.75-0.95; p = 0.007) and rs9304261 (hazard ratio, 0.83; 95% CI, 0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging SNPs in 314 ovarian tumors identified associations between somatic gene deletions and survival. Thirty-five percent of tumors in 101 informative cases showed LOH for the RBBP8 gene, which was associated with a significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p = 0.001). Quaye et al. (2009) concluded that germline genetic variation and somatic alterations of the RBBP8 gene in tumors are associated with survival in ovarian cancer patients. Clinical Management Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors from 60 patients with epithelial ovarian cancer and 51 with gastric cancer (137215) and found that those with tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. Chien et al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance. Pathogenesis Using a PCR-based differential display method, Mok et al. (1994) identified a gene, termed DOC2 (601236), that was expressed in normal ovarian epithelial cells, but downregulated or absent from ovarian carcinoma cell lines. The DOC2 gene maps to chromosome 5p13. Mok et al. (1998) reported that transfection of the DOC2 gene into an ovarian carcinoma cell line resulted in significantly reduced growth rate and ability to form tumors in nude mice. Among 48 primary ovarian cancer tumors and corresponding metastases, Blechschmidt et al. (2008) found a significant association (p = 0.008) between reduced E-cadherin (CDH1) expression in the primary cancer tissue and shorter overall survival. Patients with decreased E-cadherin expression and increased SNAIL (SNAI1; 604238) expression in the primary tumor showed a higher risk of death (p = 0.002). There was no significant difference in expression of E-cadherin or SNAIL between primary tumors and metastases. The findings were consistent with a role for E-cadherin and SNAIL in the behavior of metastatic cancer. Merritt et al. (2008) observed decreased mRNA and protein expression of the RNAse III enzymes DICER1 (606241) and DROSHA (RNASEN; 608828) in 60 and 51%, respectively, of 111 invasive epithelial ovarian cancer specimens. Low DICER1 expression was significantly associated with advanced tumor stage (p = 0.007), and low DROSHA expression with suboptimal surgical cytoreduction (p = 0.02). Cancer specimens with both high DICER1 expression and high DROSHA expression were associated with increased median survival (greater than 11 years vs 2.66 years for other subgroups; p less than 0.001). Statistical analysis revealed 3 independent predictors of reduced disease-specific survival: low DICER1 expression (hazard ratio, 2.10; p = 0.02), high-grade histologic features (hazard ratio, 2.46; p = 0.03), and poor response to chemotherapy (hazard ratio, 3.95; p less than 0.001). Poor clinical outcomes among patients with low DICER1 expression were validated in an additional cohort of patients. Although rare missense variants were found in both genes, the presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low DICER1 expression. The findings implicated a component of the RNA-interference machinery, which regulates gene expression, in the pathogenesis of ovarian cancer. Merritt et al. (2009) noted that 109 of the 111 samples used in the 2008 study had serous histologic features, of which 93 were high-grade and 16 low-grade tumors. To explore the genetic origin of ovarian clear cell carcinoma, Jones et al. (2010) determined the exomic sequences of 8 tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, Jones et al. (2010) identified 4 genes that were mutated in at least 2 tumors. PIK3CA (171834), which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS (190070), which encodes a well-known oncoprotein, had previously been implicated in ovarian clear cell carcinoma. The other 2 mutated genes were previously unknown to be involved in ovarian clear cell carcinoma: PPP2R1A (605983) encodes a regulatory subunit of serine/threonine phosphatase-2, and ARID1A (603024) encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggested that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 ovarian clear cell carcinomas, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. Jones et al. (2010) concluded that their results suggested that aberrant chromatin remodeling contributes to the pathogenesis of ovarian clear cell carcinoma. Flesken-Nikitin et al. (2013) identified the hilum region of the mouse ovary, the transitional (or junction) area between the ovarian surface epithelium, mesothelium, and tubal (oviductal) epithelium, as a stem cell niche of the ovarian surface epithelium (OSE). They found that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1 (100640), LGR5 (606667), LEF1 (153245), CD133 (604365), and CK6B (148042). These cells display long-term stem cell properties ex vivo and in vivo, as shown by serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells showed increased transformation potential after inactivation of tumor suppressor genes Trp53 (191170) and Rb1 (614041), whose pathways are altered frequently in the most aggressive and common type of human epithelial ovarian cancer, high-grade serous adenocarcinoma. Flesken-Nikitin et al. (2013) concluded that their study supported experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in these areas. To better understand the drivers of clinical phenotypes of high-grade serous ovarian cancer, Patch et al. (2015) used whole-genome sequencing of tumor and germline DNA samples from 92 patients with primary refractory, resistant, sensitive, and matched acquired resistant disease. The authors showed that gene breakage commonly inactivates the tumor suppressors RB1, NF1 (613113), RAD51B (602948), and PTEN (601728) in high-grade serous ovarian cancer, contributing to acquired chemotherapy resistance. CCNE1 (123837) amplification was common in primary resistant and refractory disease. Patch et al. (2015) observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 (113705) or BRCA2 (600185) mutations in individual patients; loss of BRCA1 promoter methylation; an alteration in molecular subtype; and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1 (171050). Genotype/Phenotype Correlations Grindedal et al. (2010) performed a retrospective survival study of 144 women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had a mutation in MSH6. The mean age of onset was 44.7 years, compared to 51.2 years in carriers of BRCA1 mutations with ovarian cancer and 57.5 in carriers of BRCA2 mutations with ovarian cancer (Risch et al., 2001). Most (81.5%) women with MMR mutations were diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-, 20- and 30-year survival specific for deaths due to ovarian cancers were 82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The 5-, 10-, 20-, and 30-year survival specific for deaths due to HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and 47.3%, respectively. Overall, the survival for women with ovarian cancer due to MMR mutations was better than for those with ovarian cancer due to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime risk of ovarian cancer in MMR mutation carriers was about 10% and the risk of dying from ovarian cancer was 20%, yielding an overall risk of dying from ovarian cancer of about 2% in MMR mutation carriers. Grindedal et al. (2010) suggested that mutations in the MMR and BRCA1/2 genes may predispose to biologically different types of tumors. Animal Model Dinulescu et al. (2005) developed a mouse model of ovarian cancer. A recombinant adenoviral vector expressing an oncogenic Kras (190070) allele within the ovarian surface epithelium resulted in the development of benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma; 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary. INHERITANCE \- Somatic mutation NEOPLASIA \- Ovarian cancer \- Dysgerminoma \- Ovarian papillary adenocarcinoma \- Serous ovarian cystadenocarcinoma \- Breast cancer LABORATORY ABNORMALITIES \- Frequent loss of heterozygosity at 6q24-q27 ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	OVARIAN CANCER	c0677886	4,670	omim	https://www.omim.org/entry/167000	2019-09-22T16:36:48	{"doid": ["2394"], "mesh": ["D000077216"], "omim": ["167000"], "icd-9": ["183.0"], "icd-10": ["C56"]}
Proteopathy Micrograph of a section of the cerebral cortex from a person with Alzheimer's disease, immunostained with an antibody to amyloid beta (brown), a protein fragment that accumulates in senile plaques and cerebral amyloid angiopathy. 10X microscope objective. In medicine, proteopathy (/proʊtiːˈɒpəθiː/; from proteo- [pref. protein]; -pathy [suff. disease]; proteopathies pl.; proteopathic adj) refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body.[1][2] Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way (a toxic gain-of-function) or they can lose their normal function.[3] The proteopathies (also known as proteinopathies, protein conformational disorders, or protein misfolding diseases) include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders.[2][4][5][6][7][8] The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.[1] The concept of proteopathy can trace its origins to the mid-19th century, when, in 1854, Rudolf Virchow coined the term amyloid ("starch-like") to describe a substance in cerebral corpora amylacea that exhibited a chemical reaction resembling that of cellulose. In 1859, Friedreich and Kekulé demonstrated that, rather than consisting of cellulose, "amyloid" actually is rich in protein.[9] Subsequent research has shown that many different proteins can form amyloid, and that all amyloids show birefringence in cross-polarized light after staining with the dye Congo red, as well as a fibrillar ultrastructure when viewed with an electron microscope.[9] However, some proteinaceous lesions lack birefringence and contain few or no classical amyloid fibrils, such as the diffuse deposits of amyloid beta (Aβ) protein in the brains of people with Alzheimer's.[10] Furthermore, evidence has emerged that small, non-fibrillar protein aggregates known as oligomers are toxic to the cells of an affected organ, and that amyloidogenic proteins in their fibrillar form may be relatively benign.[11][12] Micrograph of amyloid in a section of liver that has been stained with the dye Congo red and viewed with crossed polarizing filters, yielding a typical orange-greenish birefringence. 20X microscope objective; the scale bar is 100 microns (0.1mm). ## Contents * 1 Pathophysiology * 2 Seeded induction * 3 List of proteopathies * 4 Management * 5 Additional images * 6 See also * 7 References * 8 External links ## Pathophysiology[edit] In most, if not all proteopathies, a change in 3-dimensional folding (conformation) increases the tendency of a specific protein to bind to itself.[5] In this aggregated form, the protein is resistant to clearance and can interfere with the normal capacity of the affected organs. In some cases, misfolding of the protein results in a loss of its usual function. For example, cystic fibrosis is caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR) protein,[3] and in amyotrophic lateral sclerosis / frontotemporal lobar degeneration (FTLD), certain gene-regulating proteins inappropriately aggregate in the cytoplasm, and thus are unable to perform their normal tasks within the nucleus.[13][14] Because proteins share a common structural feature known as the polypeptide backbone, all proteins have the potential to misfold under some circumstances.[15] However, only a relatively small number of proteins are linked to proteopathic disorders, possibly due to structural idiosyncrasies of the vulnerable proteins. For example, proteins that are normally unfolded or relatively unstable as monomers (that is, as single, unbound protein molecules) are more likely to misfold into an abnormal conformation.[5][15][16] In nearly all instances, the disease-causing molecular configuration involves an increase in beta-sheet secondary structure of the protein.[5][15][17][18] The abnormal proteins in some proteopathies have been shown to fold into multiple 3-dimensional shapes; these variant, proteinaceous structures are defined by their different pathogenic, biochemical, and conformational properties.[19] They have been most thoroughly studied with regard to prion disease, and are referred to as protein strains.[20][21] Micrograph of immunostained α-synuclein (brown) in Lewy bodies (large clumps) and Lewy neurites (thread-like structures) in the cerebral cortex of a patient with Lewy body disease, a synucleinopathy. 40X microscope objective. The likelihood that proteopathy will develop is increased by certain risk factors that promote the self-assembly of a protein. These include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance.[1][5][15] Advancing age is a strong risk factor,[1] as is traumatic brain injury.[22][23] In the aging brain, multiple proteopathies can overlap.[24] For example, in addition to tauopathy and Aβ-amyloidosis (which coexist as key pathologic features of Alzheimer's disease), many Alzheimer patients have concomitant synucleinopathy (Lewy bodies) in the brain.[25] It is hypothesized that chaperones and co-chaperones (proteins that assist protein folding) may antagonize proteotoxicity during aging and in protein misfolding-diseases to maintain proteostasis.[26][27][28] ## Seeded induction[edit] Some proteins can be induced to form abnormal assemblies by exposure to the same (or similar) protein that has folded into a disease-causing conformation, a process called 'seeding' or 'permissive templating'.[29][30] In this way, the disease state can be brought about in a susceptible host by the introduction of diseased tissue extract from an afflicted donor. The best known form of such inducible proteopathy is prion disease,[31] which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation.[32][33] There is now evidence that other proteopathies can be induced by a similar mechanism, including Aβ amyloidosis, amyloid A (AA) amyloidosis, and apolipoprotein AII amyloidosis,[30][34] tauopathy,[35] synucleinopathy,[36][37][38][39] and the aggregation of superoxide dismutase-1 (SOD1),[40][41] polyglutamine,[42][43] and TAR DNA-binding protein-43 (TDP-43).[44] In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. In some cases, the deposition of one type of protein can be experimentally induced by aggregated assemblies of other proteins that are rich in β-sheet structure, possibly because of structural complementarity of the protein molecules. For example, AA amyloidosis can be stimulated in mice by such diverse macromolecules as silk, the yeast amyloid Sup35, and curli fibrils from the bacterium Escherichia coli.[45] AII amyloid can be induced in mice by a variety of β-sheet rich amyloid fibrils,[46] and cerebral tauopathy can be induced by brain extracts that are rich in aggregated Aβ.[47] There is also experimental evidence for cross-seeding between prion protein and Aβ.[48] In general, such heterologous seeding is less efficient than is seeding by a corrupted form of the same protein. ## List of proteopathies[edit] Proteopathy Major aggregating protein Alzheimer's disease[16] Amyloid β peptide (Aβ); Tau protein (see tauopathies) Cerebral β-amyloid angiopathy[49] Amyloid β peptide (Aβ) Retinal ganglion cell degeneration in glaucoma[50] Amyloid β peptide (Aβ) Prion diseases (multiple)[51] Prion protein Parkinson's disease and other synucleinopathies (multiple)[52] α-Synuclein Tauopathies (multiple)[53] Microtubule-associated protein tau (Tau protein) Frontotemporal lobar degeneration (FTLD) (Ubi+, Tau-)[54] TDP-43 FTLD–FUS[54] Fused in sarcoma (FUS) protein Amyotrophic lateral sclerosis (ALS)[55][56] Superoxide dismutase, TDP-43, FUS, C9ORF72, ubiquilin-2 (UBQLN2) Huntington's disease and other trinucleotide repeat disorders (multiple)[57][58] Proteins with tandem glutamine expansions Familial British dementia[49] ABri Familial Danish dementia[49] ADan Hereditary cerebral hemorrhage with amyloidosis (Icelandic) (HCHWA-I)[49] Cystatin C CADASIL[59] Notch3 Alexander disease[60] Glial fibrillary acidic protein (GFAP) Pelizaeus-Merzbacher disease proteolipid protein (PLP) Seipinopathies[61] Seipin Familial amyloidotic neuropathy, Senile systemic amyloidosis Transthyretin[62] Serpinopathies (multiple)[63] Serpins AL (light chain) amyloidosis (primary systemic amyloidosis) Monoclonal immunoglobulin light chains[62] AH (heavy chain) amyloidosis Immunoglobulin heavy chains[62] AA (secondary) amyloidosis Amyloid A protein[62] Type II diabetes[64] Islet amyloid polypeptide (IAPP; amylin) Aortic medial amyloidosis Medin (lactadherin)[62] ApoAI amyloidosis Apolipoprotein AI[62] ApoAII amyloidosis Apolipoprotein AII[62] ApoAIV amyloidosis Apolipoprotein AIV[62] Familial amyloidosis of the Finnish type (FAF) Gelsolin[62] Lysozyme amyloidosis Lysozyme[62] Fibrinogen amyloidosis Fibrinogen[62] Dialysis amyloidosis Beta-2 microglobulin[62] Inclusion body myositis/myopathy[65] Amyloid β peptide (Aβ) Cataracts[66] Crystallins Retinitis pigmentosa with rhodopsin mutations[67] rhodopsin Medullary thyroid carcinoma Calcitonin[62] Cardiac atrial amyloidosis Atrial natriuretic factor[62] Pituitary prolactinoma Prolactin[62] Hereditary lattice corneal dystrophy Keratoepithelin[62] Cutaneous lichen amyloidosis[68] Keratins Mallory bodies[69] Keratin intermediate filament proteins Corneal lactoferrin amyloidosis Lactoferrin[62] Pulmonary alveolar proteinosis Surfactant protein C (SP-C)[62] Odontogenic (Pindborg) tumor amyloid Odontogenic ameloblast-associated protein[62] Seminal vesicle amyloid Semenogelin I[62] Apolipoprotein C2 amyloidosis Apolipoprotein C2 (ApoC2)[62] Apolipoprotein C3 amyloidosis Apolipoprotein C3 (ApoC3)[62] Lect2 amyloidosis Leukocyte chemotactic factor-2 (Lect2)[62] Insulin amyloidosis Insulin[62] Galectin-7 amyloidosis (primary localized cutaneous amyloidosis) Galectin-7 (Gal7)[62] Corneodesmosin amyloidosis Corneodesmosin[62] Enfuvirtide amyloidosis[70] Enfuvirtide[62] Cystic fibrosis[71] cystic fibrosis transmembrane conductance regulator (CFTR) protein Sickle cell disease[72] Hemoglobin ## Management[edit] The development of effective treatments for many proteopathies has been challenging.[73][74] Because the proteopathies often involve different proteins arising from different sources, treatment strategies must be customized to each disorder; however, general therapeutic approaches include maintaining the function of affected organs, reducing the formation of the disease-causing proteins, preventing the proteins from misfolding and/or aggregating, or promoting their removal.[75][73][76] For example, in Alzheimer's disease, researchers are seeking ways to reduce the production of the disease-associated protein Aβ by inhibiting the enzymes that free it from its parent protein.[74] Another strategy is to use antibodies to neutralize specific proteins by active or passive immunization.[77] In some proteopathies, inhibiting the toxic effects of protein oligomers might be beneficial.[78] Amyloid A (AA) amyloidosis can be reduced by treating the inflammatory state that increases the amount of the protein in the blood (referred to as serum amyloid A, or SAA).[73] In immunoglobulin light chain amyloidosis (AL amyloidosis), chemotherapy can be used to lower the number of the blood cells that make the light chain protein that forms amyloid in various bodily organs.[79] Transthyretin (TTR) amyloidosis (ATTR) results from the deposition of misfolded TTR in multiple organs.[80] Because TTR is mainly produced in the liver, TTR amyloidosis can be slowed in some hereditary cases by liver transplantation.[81] TTR amyloidosis also can be treated by stabilizing the normal assemblies of the protein (called tetramers because they consist of four TTR molecules bound together). Stabilization prevents individual TTR molecules from escaping, misfolding, and aggregating into amyloid.[82][83] Several other treatment strategies for proteopathies are being investigated, including small molecules and biologic medicines such as small interfering RNAs, antisense oligonucleotides, peptides, and engineered immune cells.[82][79][84][85] In some cases, multiple therapeutic agents may be combined to improve effectiveness.[79][86] ## Additional images[edit] * Micrograph of tauopathy (brown) in a neuronal cell body (arrow) and process (arrowhead) in the cerebral cortex of a patient with Alzheimer's disease. Bar = 25 microns (0.025mm). ## See also[edit] * Amyloidosis * Neurofibrillary tangles * Protein toxicity * Prion ## References[edit] 1. ^ a b c d Walker LC, LeVine H (2000). "The cerebral proteopathies". Neurobiology of Aging. 21 (4): 559–61. doi:10.1016/S0197-4580(00)00160-3. PMID 10924770. 2. ^ a b Walker LC, LeVine H (2000). 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Phil Trans R Soc Lond B. 356: 203–211. doi:10.1098/rstb.2000.0766. PMC 1088426. PMID 11260801. 76. ^ Walker LC, LeVine H 3rd (2002). "Proteopathy: the next therapeutic frontier?". Curr Opin Investig Drugs. 3 (5): 782–7. PMID 12090553. 77. ^ Braczynski AK, Schulz JB, Bach JP (2017). "Vaccination strategies in tauopathies and synucleinopathies". J Neurochem. 143 (5): 467–488. doi:10.1111/jnc.14207. PMID 28869766. 78. ^ Klein WL (2013). "Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer's disease?". J Alzheimers Dis. 33 (Suppl 1): S49-65. doi:10.3233/JAD-2012-129039. PMID 22785404. 79. ^ a b c Badar T, D'Souza A, Hari P (2018). "Recent advances in understanding and treating immunoglobulin light chain amyloidosis". F1000Res. 7: 1348. doi:10.12688/f1000research.15353.1. PMC 6117860. PMID 30228867. 80. ^ Carvalho A, Rocha A, Lobato L (2015). "Liver transplantation in transthyretin amyloidosis: issues and challenges". Liver Transpl. 21 (3): 282–292. doi:10.1002/lt.24058. PMID 25482846. 81. ^ Suhr OB, Herlenius G, Friman S, Ericzon BG (2000). "Liver transplantation for hereditary transthyretin amyloidosis". Liver Transpl. 6 (3): 263–276. doi:10.1053/lv.2000.6145. PMID 10827225. 82. ^ a b Suhr OB, Larsson M, Ericzon BG, Wilczek HE, et al. (2016). "Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry". Transplantation. 100 (2): 373–381. doi:10.1097/TP.0000000000001021. PMC 4732012. PMID 26656838. 83. ^ Coelho T, et al. (2016). "Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis". Neurol Ther. 5 (1): 1–25. doi:10.1007/s40120-016-0040-x. PMC 4919130. PMID 26894299. 84. ^ Yu D, et al. (2012). "Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression". Cell. 150 (5): 895–908. doi:10.1016/j.cell.2012.08.002. PMC 3444165. PMID 22939619. 85. ^ Nuvolone M, Merlini G (2017). "Emerging therapeutic targets currently under investigation for the treatment of systemic amyloidosis". Expert Opin Ther Targets. 21 (12): 1095–1110. doi:10.1080/14728222.2017.1398235. PMID 29076382. 86. ^ Joseph NS, Kaufman JL (2018). "Novel Approaches for the Management of AL Amyloidosis". Curr Hematol Malig Rep. 13 (3): 212–219. doi:10.1007/s11899-018-0450-1. PMID 29951831. ## External links[edit] * Amyloidosis * Prion-Related Diseases [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Proteopathy	None	4,671	wikipedia	https://en.wikipedia.org/wiki/Proteopathy	2021-01-18T18:37:41	{"wikidata": ["Q2113512"]}
Familial exudative vitreoretinopathy is a hereditary disorder that can cause progressive vision loss. This condition affects the retina, the specialized light-sensitive tissue that lines the back of the eye. The disorder prevents blood vessels from forming at the edges of the retina, which reduces the blood supply to this tissue. The signs and symptoms of familial exudative vitreoretinopathy vary widely, even within the same family. In many affected individuals, the retinal abnormalities never cause any vision problems. In others, a reduction in the retina's blood supply causes the retina to fold, tear, or separate from the back of the eye (retinal detachment). This retinal damage can lead to vision loss and blindness. Other eye abnormalities are also possible, including eyes that do not look in the same direction (strabismus) and a visible whiteness (leukocoria) in the normally black pupil. Some people with familial exudative vitreoretinopathy also have reduced bone mineral density, which weakens bones and increases the risk of fractures. ## Frequency The prevalence of familial exudative vitreoretinopathy is unknown. It appears to be rare, although affected people with normal vision may never come to medical attention. ## Causes Mutations in the FZD4, LRP5, and NDP genes can cause familial exudative vitreoretinopathy. These genes provide instructions for making proteins that participate in a chemical signaling pathway that affects the way cells and tissues develop. In particular, the proteins produced from the FZD4, LRP5, and NDP genes appear to play critical roles in the specialization of retinal cells and the establishment of a blood supply to the retina and the inner ear. The LRP5 protein also helps regulate bone formation. Mutations in the FZD4, LRP5, or NDP gene disrupt chemical signaling during early development, which interferes with the formation of blood vessels at the edges of the retina. The resulting abnormal blood supply to this tissue leads to retinal damage and vision loss in some people with familial exudative vitreoretinopathy. The eye abnormalities associated with familial exudative vitreoretinopathy tend to be similar no matter which gene is altered. However, affected individuals with LRP5 gene mutations often have reduced bone mineral density in addition to vision loss. Mutations in the other genes responsible for familial exudative vitreoretinopathy do not appear to affect bone density. In some cases, the cause of familial exudative vitreoretinopathy is unknown. Researchers believe that mutations in several as-yet-unidentified genes are responsible for the disorder in these cases. ### Learn more about the genes associated with Familial exudative vitreoretinopathy * FZD4 * LRP5 * NDP ## Inheritance Pattern Familial exudative vitreoretinopathy has different inheritance patterns depending on the gene involved. Most commonly, the condition results from mutations in the FZD4 or LRP5 gene and has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Most people with autosomal dominant familial exudative vitreoretinopathy inherit the altered gene from a parent, although the parent may not have any signs and symptoms associated with this disorder. Familial exudative vitreoretinopathy caused by LRP5 gene mutations can also have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with autosomal recessive familial exudative vitreoretinopathy each carry one copy of the mutated gene, but they do not have the disorder. When familial exudative vitreoretinopathy is caused by mutations in the NDP gene, it has an X-linked recessive pattern of inheritance. The NDP gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Familial exudative vitreoretinopathy	c0035344	4,672	medlineplus	https://medlineplus.gov/genetics/condition/familial-exudative-vitreoretinopathy/	2021-01-27T08:25:17	{"gard": ["1613"], "mesh": ["D012178"], "omim": ["133780", "305390", "605750", "601813"], "synonyms": []}
A rare myeloproliferative neoplasm characterized by stem-cell derived clonal over proliferation of mature myeloid lineages, such as erythrocytes, leukocytes, and megakaryocytes, with variable degrees of megakaryocyte atypia, associated with reticulin and/or collagen bone marrow fibrosis, osteosclerosis, ineffective erythropoiesis, angiogenesis, extramedullary hematopoiesis, and abnormal cytokine expression. ## Epidemiology The annual incidence of primary myelofibrosis (PMF) is approximately 1 case per 100,000 individuals, although an increased prevalence is noted in Ashkenazi Jews. ## Clinical description Age at diagnosis is usually in adulthood, around the sixth decade of life. Clinical manifestations depend on the type of blood cell(s) affected and may include severe anemia, pallor, petechiae, ecchymosis, bleeding, thrombosis, pancytopenia, pruritus, hypermetabolic state, marked hepato/splenomegaly, and/or constitutional symptoms, such as fatigue, fever, and night sweats. Symtomatic portal hypertension and non hepatoslenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients. ## Etiology Evidence strongly suggests that PMF is attributed to the dysregulation of the JAK2-STAT5 signaling pathway. The mutation JAK2V617F on the JAK2 gene is the most prevalent mutation reported. Additionally, mutations in the MPL gene, which encodes the thrombopoietin receptor, and CALR. Furthermore, the megakaryocyte lineage contributes to the pathogenesis as these cells produce various profibrotic, angiogenic and pro-inflammatory cytokines, which are believed to play a role in bone marrow fibrosis, osteosclerosis and angiogenesis. ## Diagnostic methods The diagnosis is based on the presence of major and minor criteria. It requires meeting all three major criteria, and at least one minor criterion. Major criteria include megakaryocytic proliferation and presence of reticulin and/or collagen fibrosis grades 2 or 3. The absence of other sign of blood and bone marrow cells proliferation and tumour (WHO classification). The mutations test for JAK2, CALR or MPL. Minor criteria include blood test for anemia, Leukocytosis, LDH level and Leukoerythroblastosis. ## Differential diagnosis Differential diagnosis of PMF includes other closely related myeloid neoplasms, such as chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelodysplastic syndromes, chronic myelomonocytic leukemia, acute panmyelosis with myelofibrosis and acute megakaryoblastic leukemia. ## Genetic counseling The pathology is not inherited although it is linked with important gene mutations which occur at any time in life. Although most cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles. ## Management and treatment Historically, splenectomy and hematopoietic stem cell transplantation (HSCT) have been the treatment for PMF, with the latter being the only treatment modality which prolongs survival or potentially cures PMF. HSCT, however, is associated with important morbidity and high transplant-related death therefore, individual patient risk-benefit assessment is necessary. Drug therapy with JAK inhibitors improves symptoms and splenomegaly but has not been shown to favorably modify disease natural history or prolong survival and therefore risk-benefit should also be carefully evaluated. ## Prognosis Severity and prognosis are variable depending on the affected genes and symptoms. Risk assessment using the International Prognostic Scoring System (IPSS) and the Dynamic IPSS (DIPSS) has proven useful in classifying patients into risk categories at diagnosis and later time points. A more recent score (MIPSS70) is particularly useful for risk stratification for transplantation-age patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Primary myelofibrosis	c0001815	4,673	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=824	2021-01-23T18:16:10	{"gard": ["8618"], "mesh": ["D055728"], "omim": ["254450"], "umls": ["C0001815", "C0026987"], "icd-10": ["D47.4"], "synonyms": ["Agnogenic myeloid metaplasia", "Idiopathic myelofibrosis", "Myelofibrosis with myeloid metaplasia", "Osteomyelofibrosis"]}
Beare et al. (1966) described an Irish family in which 4 persons in 3 generations suffered from annular erythema. Inheritance \- Autosomal dominant Skin \- Annular erythema ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	ANNULAR ERYTHEMA	c0234906	4,674	omim	https://www.omim.org/entry/106500	2019-09-22T16:44:59	{"mesh": ["C562461"], "omim": ["106500"]}
Superficial spreading melanoma Other namesSuperficially spreading melanoma[1] SpecialtyDermatology Superficial spreading melanoma (SSM) is usually characterized as the most common form of cutaneous melanoma[2] in Caucasians. The average age at diagnosis is in the fifth decade, and it tends to occur on sun-exposed skin, especially on the backs of males and lower limbs of females. ## Contents * 1 Signs and symptoms * 2 Histopathology * 3 Treatment * 4 See also * 5 References * 6 External links ## Signs and symptoms[edit] Often, this disease evolves from a precursor lesion, usually a dysplastic nevus. Otherwise it arises in previously normal skin. A prolonged radial growth phase, where the lesion remains thin, may eventually be followed by a vertical growth phase where the lesion becomes thick and nodular. As the risk of spread varies with the thickness, early SSM is more frequently cured than late nodular melanoma. ## Histopathology[edit] The microscopic hallmarks are: * Large melanocytic cells with nest formation along the dermo-epidermal junction. * Invasion of the upper epidermis in a pagetoid fashion (discohesive single cell growth). * The pattern of rete ridges is often effaced. * Invasion of the dermis by atypical, pleomorphic melanocytes * Absence of the 'maturation' typical of naevus cells * Mitoses ## Treatment[edit] Treatment is by excisional biopsy, wide local excision and possibly sentinel node biopsy. Spread of disease to local lymph nodes or distant sites (typically brain, bone, skin and lung) marks a decidedly poor prognosis. ## See also[edit] * Melanoma * List of cutaneous conditions ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 2. ^ Forman SB, Ferringer TC, Peckham SJ, et al. (June 2008). "Is superficial spreading melanoma still the most common form of malignant melanoma?". J. Am. Acad. Dermatol. 58 (6): 1013–20. doi:10.1016/j.jaad.2007.10.650. PMID 18485983. ## External links[edit] Classification D * ICD-10: C43 (ILDS C43.L20) * ICD-O: M8743/3 * Fact File from the Royal College of Pathologists of Australasia (pdf) * 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Superficial spreading melanoma	c0334438	4,675	wikipedia	https://en.wikipedia.org/wiki/Superficial_spreading_melanoma	2021-01-18T18:54:37	{"gard": ["9960"], "umls": ["C0334438"], "icd-10": ["C43"], "wikidata": ["Q7643331"]}
Toyama (1972) described 3 affected males, all first cousins, each in a different sibship. The relevant parents were 2 brothers and a sister, all affected. Presumably there was no consanguinity in the family. Autosomal dominant inheritance with reduced penetrance seems possible. Collaboration of a structural predisposition and repeated minor trauma may be involved in causation. Limbs \- Popliteal cyst Inheritance \- Autosomal dominant with reduced penetrance ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	POPLITEAL CYST	c0032650	4,676	omim	https://www.omim.org/entry/175750	2019-09-22T16:35:57	{"mesh": ["D011151"], "omim": ["175750"], "icd-9": ["727.51"], "icd-10": ["M71.20", "M71.2"], "synonyms": ["Alternative titles", "BAKER CYST"]}
Pseudohypoaldosteronism type 2 (PHA2) is caused by problems that affect regulation of the amount of sodium and potassium in the body. Sodium and potassium are important in the control of blood pressure, and their regulation occurs primarily in the kidneys. People with PHA2 have high blood pressure (hypertension) and high levels of potassium in their blood (hyperkalemia) despite having normal kidney function. The age of onset of PHA2 is variable and difficult to pinpoint; some affected individuals are diagnosed in infancy or childhood, and others are diagnosed in adulthood. Hyperkalemia usually occurs first, and hypertension develops later in life. Affected individuals also have high levels of chloride (hyperchloremia) and acid (metabolic acidosis) in their blood (together, referred to as hyperchloremic metabolic acidosis). People with hyperkalemia, hyperchloremia, and metabolic acidosis can have nonspecific symptoms like nausea, vomiting, extreme tiredness (fatigue), and muscle weakness. People with PHA2 may also have high levels of calcium in their urine (hypercalciuria). ## Frequency PHA2 is a rare condition; however, the prevalence is unknown. ## Causes PHA2 can be caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 gene. These genes play a role in the regulation of blood pressure. The proteins produced from the WNK1 and WNK4 genes help control the amount of sodium and potassium in the body by regulating channels in the cell membrane that control the transport of sodium or potassium into and out of cells. This process primarily occurs in the kidneys. Mutations in either of these genes disrupt control of these channels, leading to abnormal levels of sodium and potassium in the body. As a result, affected individuals develop hypertension and hyperkalemia. The proteins produced from the CUL3 gene (called cullin-3) and the KLHL3 gene help control the amount of WNK1 and WNK4 protein available. Cullin-3 and KLHL3 are two pieces of a complex, called an E3 ubiquitin ligase, that tags certain other proteins with molecules called ubiquitin. This molecule acts as a signal for the tagged protein to be broken down when it is no longer needed. E3 ubiquitin ligases containing cullin-3 and KLHL3 are able to tag the WNK1 and WNK4 proteins with ubiquitin, leading to their breakdown. Mutations in either the CUL3 or KLHL3 gene impair breakdown of the WNK4 protein. (The effect of these mutations on the WNK1 protein is unclear.) An excess of WNK4 likely disrupts control of sodium and potassium levels, resulting in hypertension and hyperkalemia. ### Learn more about the genes associated with Pseudohypoaldosteronism type 2 * CUL3 * KLHL3 * WNK1 * WNK4 ## Inheritance Pattern This condition is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases caused by mutations in the WNK1, WNK4, or KLHL3 gene, an affected person inherits the mutation from one affected parent. While some cases caused by CUL3 gene mutations can be inherited from an affected parent, many result from new mutations in the gene and occur in people with no history of the disorder in their family. Some cases caused by mutations in the KLHL3 gene are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Pseudohypoaldosteronism type 2	c1840389	4,677	medlineplus	https://medlineplus.gov/genetics/condition/pseudohypoaldosteronism-type-2/	2021-01-27T08:25:16	{"gard": ["4553"], "mesh": ["C564160"], "omim": ["145260", "614491", "614492", "614495", "614496"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-34 (DFNA34) with or without inflammation is caused by heterozygous mutation in the NLRP3 gene (606416) on chromosome 1q44. Heterozygous mutation in the NLRP3 gene can also cause several autoinflammatory disorders, including familial cold autoinflammatory syndrome-1 (FCAS1; 120100), Muckle-Wells syndrome (MWS; 191900), and CINCA syndrome (CINCA; 607115). Description DFNA34 is an autosomal dominant form of postlingual, slowly progressive sensorineural hearing loss with variable severity and variable additional features. Some patients have pure hearing loss without significant additional features, whereas some patients have features of an autoinflammatory disorder with systemic manifestations, including periodic fevers, arthralgias, and episodic urticaria. The disorder results from abnormally increased activation of the inflammatory pathway, and treatment with an IL1 receptor antagonist (see 147679) may be effective if started early (summary by Nakanishi et al., 2017). Clinical Features Kurima et al. (2000) reported a family (LMG113) with autosomal dominant postlingual nonsyndromic sensorineural hearing loss. The hearing loss became clinically detectable during the third or fourth decade of life and was slowly progressive. Nakanishi et al. (2017) reported follow-up of family LMG113, which was a North American Caucasian family in which 3 generations were affected. Patients had onset of bilateral, symmetric, and progressive hearing loss between the late second and fourth decades of life. There were no consistent additional features, but 3 patients had some notable features as adults. One (subject 1285) developed multiple sclerosis, another (subject 1189) had episodic edema of her lower extremities, and a third (subject 1236) had a remote history of self-limited arthritis of unknown etiology. Laboratory investigations in subjects 1189 and 1236, both in their sixties with hearing loss, had serologic evidence of inflammation and pathologic enhancement of the cochlea on imaging. Another mutation carrier (subject 1238) in her thirties, who did not have hearing loss, had normal levels of inflammatory markers and normal cochlear imaging. However, peripheral blood cells from all 3 individuals secreted abnormally high levels of IL1B in response to stimulation with LPS. ### Clinical Variability Nakanishi et al. (2017) reported another family (LMG446) of North American descent with DFNA34 associated with a systemic inflammatory disorder. The patients included a 35-year-old father and his 3 children, 13, 10, and 6 years of age. The father had progressive hearing loss, episodic urticaria, periodic fevers, conjunctivitis, oral ulcers, cervical lymphadenopathy, arthralgias, and migraine headaches. All 3 children had similar inflammatory features, including periodic fevers, conjunctivitis, oral ulcers, cervical lymphadenopathy, episodic urticaria, and headaches, although only the 2 older children had evidence of mild hearing loss. Imaging showed variable abnormal cochlear signals in all 4 patients. Laboratory studies showed normal levels of inflammatory markers, but peripheral blood cells in all 3 children showed abnormally high secretion of IL1B in response to stimulation. Cells from the father were not tested. Clinical Management Nakanishi et al. (2017) found variably effective treatment of DFNA34 using anakinra, an IL1-receptor antagonist, if started early in the disease course. A 59-year-old woman from family LMG113 with hearing loss did not have subjective improvement of her hearing loss after treatment, but her serum markers of inflammation normalized. Treatment of 2 children from family LMG446 with anakinra resulted in significant improvement in hearing loss, whereas treatment of their father resulted in partial improvement. These improvements corresponded with decreased cochlear enhancement on imaging and improvement or resolution of signs and symptoms of autoinflammation. Mapping By genomewide linkage analysis of a family (LMG113) with autosomal dominant deafness, Kurima et al. (2000) found linkage to a 14-cM region on chromosome 1q44 between markers D1S102 and D1S3739 (maximum lod score of 3.33 at D1S2836). The locus was designated DNFA34. Kurima et al. (2000) noted that the locus overlapped that of Muckle-Wells syndrome (191900), and suggested that they may be allelic disorders. Molecular Genetics In affected members of 2 unrelated families from North America with DFNA34, Nakanishi et al. (2017) identified a heterozygous missense mutation in the NLRP3 gene (R918Q; 606416.0011). The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in both families. Haplotype analysis suggested a founder effect for the 2 families. Direct functional studies of the variant were not performed, but Nakanishi et al. (2017) postulated a gain-of-function effect because patient cells showed increased IL1B secretion in response to stimulation. Mouse cochlea showed expression of Nlrp3, Il1b, and other members of the Nlrp3 inflammasome, and Nlrp3 was specifically expressed in macrophage-like cells in the cochlea. Stimulation with LPS resulted in increased IL1B secretion in cochlear tissue, indicating that innate activation of the Nlrp3 inflammasome can occur specifically in the cochlea and theoretically result in local cochlear damage and hearing loss. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Sensorineural hearing loss, postlingual \- Abnormal fluid signals suggestive of inflammation in the cochlea seen on imaging Eyes \- Conjunctivitis Mouth \- Oral ulcers SKELETAL \- Arthralgia \- Arthritis SKIN, NAILS, & HAIR Skin \- Urticaria, episodic NEUROLOGIC Central Nervous System \- Headache IMMUNOLOGY \- Systemic autoinflammation \- Periodic fever \- Lymphadenopathy \- Peripheral blood cells secrete abnormally high levels of IL-1B in response to stimulation with LPS LABORATORY ABNORMALITIES \- Increased serum markers of systemic inflammation (in some patients) MISCELLANEOUS \- Variable severity \- Variable phenotype \- Onset of hearing loss range first to fourth decade \- Slowly progressive \- Treatment with an IL-1 receptor antagonist may be effective if started early \- Two unrelated families have been reported (last curated November 2017) MOLECULAR BASIS \- Caused by mutation in the NLR family, pyrin domain-containing 3 gene (NLRP3, 606416.0011 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	DEAFNESS, AUTOSOMAL DOMINANT 34, WITH OR WITHOUT INFLAMMATION	c4521680	4,678	omim	https://www.omim.org/entry/617772	2019-09-22T15:44:48	{"omim": ["617772"]}
A rare X-linked syndromic intellectual disability characterized by intellectual impairment of variable severity, progressive lower limb spasticity, and diffuse palmoplantar hyperkeratosis. Additional manifestations include pes cavus, extensor plantar responses, hand tremor, and mild dysmorphic facial features. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Paraplegia-intellectual disability-hyperkeratosis syndrome	c2745996	4,679	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2824	2021-01-23T18:16:35	{"gard": ["2344"], "mesh": ["C537058"], "omim": ["309560"], "umls": ["C2745996"], "icd-10": ["G82.1"], "synonyms": ["Fitzsimmons-McLachlan-Gilbert syndrome"]}
Part of a series on Doping in sport Substances and types * Anabolic steroids * Blood doping * Gene doping * Cannabinoids * Diuretics * Painkillers * Sedatives * Stem cell doping * Stimulants * Beta2-adrenergic agonist * Clenbuterol * Ephedrine * EPO * Human growth hormone * Methylhexanamine * SARMs * Stanozolol * Tetrahydrogestrinone Terminology * Abortion doping * Biological passport * Blood-spinning * Doping test * Performance-enhancing drugs * Repoxygen * Stem cell doping * Whizzinator History * Olympics * Tour de France (1998, 1999, 2007) * Auto racing * BALCO scandal * Clemson University steroid scandal * U of South Carolina steroid scandal * Dubin Inquiry * Association Football * China * East Germany * Russia * United States * Festina affair * Floyd Landis case * Game of Shadows * Juiced * L.A. Confidentiel * Lance Armstrong * History of allegations * Doping case * Operación Puerto * Operation Aderlass * Doping in American football * Steroid use in baseball * Barry Bonds perjury case * Mitchell Report * Biogenesis scandal Doping-related lists * Doping cases in Sport * Athletics * Cycling * Doping at the Olympic Games * Doping at the World Championships in Athletics * Stripped Olympic medals * Stripped European Athletics C'ships medals * Drugs banned from the Olympics * MLB players suspended for doping * MLB players in the Mitchell Report Anti-doping bodies * World Anti-Doping Agency * International Testing Agency * List of national anti-doping organizations * Australian Sports Anti-Doping Authority * French Anti-Doping Agency * National Anti-Doping Agency * Russian Anti-Doping Agency * UK Anti-Doping * United States Anti-Doping Agency * v * t * e In competitive sports, doping is the use of banned athletic performance-enhancing drugs by athletic competitors. The term doping is widely used by organizations that regulate sporting competitions. The use of drugs to enhance performance is considered unethical, and therefore prohibited, by most international sports organizations, including the International Olympic Committee. Furthermore, athletes (or athletic programs) taking explicit measures to evade detection exacerbate the ethical violation with overt deception and cheating. The origins of doping in sports go back to the very creation of sport itself. From ancient usage of substances in chariot racing to more recent controversies in baseball and cycling, popular views among athletes have varied widely from country to country over the years. The general trend among authorities and sporting organizations over the past several decades has been to strictly regulate the use of drugs in sport. The reasons for the ban are mainly the health risks of performance-enhancing drugs, the equality of opportunity for athletes, and the exemplary effect of drug-free sport for the public. Anti-doping authorities state that using performance-enhancing drugs goes against the "spirit of sport". ## Contents * 1 History * 2 Prevalence * 2.1 Goldman's dilemma * 3 Substance * 3.1 Steroids * 3.1.1 Strychnine at the Olympics * 3.2 Stimulants * 3.3 Anabolic steroids * 3.3.1 1988 Seoul Olympics * 4 Countries * 4.1 East Germany * 4.2 Soviet Union * 4.3 West Germany * 4.4 China * 4.5 Russia * 5 Association football * 6 Ultimate Fighting Championship (UFC) * 7 Endurance sports * 7.1 Cycling * 7.1.1 The Convicts of the Road * 7.1.2 Festina affair * 7.1.3 Floyd Landis * 7.1.4 Lance Armstrong case * 7.2 Other endurance sports * 8 Non-endurance sports * 8.1 Side effects in men * 8.2 Side effects in women * 9 Reaction from sports organizations * 10 The influence of popular culture * 10.1 Social pressures * 10.2 Physical pressures * 10.3 Psychological motivations * 11 Anti-doping organizations and legislation * 12 Test methods * 12.1 Urine test * 12.2 Blood test * 12.3 Gas chromatography-combustion-IRMS * 12.4 Athlete biological passport * 12.5 Re-testing of samples * 12.6 Cheating the tests * 12.7 Validity * 13 Defense * 14 Legal * 15 See also * 16 References * 17 Further reading * 18 External links ## History[edit] The use of drugs in sports goes back centuries, about all the way back to the very invention of the concept of sports.[1] In ancient times, when the fittest of a nation were selected as athletes or combatants, they were fed diets and given treatments considered beneficial to help increase muscle. For instance, Scandinavian mythology says Berserkers could drink a mixture called "butotens", to greatly increase their physical power at the risk of insanity. One theory is that the mixture was prepared from the Amanita muscaria mushroom, though this has been disputed. The ancient Olympics in Greece have been alleged to have had forms of doping. In ancient Rome, where chariot racing had become a huge part of their culture, athletes drank herbal infusions to strengthen them before chariot races.[1] More recently, a participant in an endurance walking race in Britain, Abraham Wood, said in 1807 that he had used laudanum (which contains opiates) to keep him awake for 24 hours while competing against Robert Barclay Allardyce.[2] By April 1877, walking races had stretched to 500 miles and the following year, also at the Agricultural Hall in Islington, London, to 520 miles. The Illustrated London News chided: It may be an advantage to know that a man can travel 520 miles in 138 hours, and manage to live through a week with an infinitesimal amount of rest, though we fail to perceive that anyone could possibly be placed in a position where his ability in this respect would be of any use to him [and] what is to be gained by a constant repetition of the fact.[3] The event proved popular, however, with 20,000 spectators attending each day.[4] Encouraged, the promoters developed the idea and soon held similar races for cyclists. "...and much more likely to endure their miseries publicly; a tired walker, after all, merely sits down – a tired cyclist falls off and possibly brings others crashing down as well. That's much more fun".[4] The fascination with six-day bicycle races spread across the Atlantic and the same appeal brought in the crowds in America as well. And the more spectators paid at the gate, the higher the prizes could be and the greater was the incentive of riders to stay awake—or be kept awake—to ride the greatest distance. Their exhaustion was countered by soigneurs (the French word for "healers"), helpers akin to seconds in boxing. Among the treatments they supplied was nitroglycerine, a drug used to stimulate the heart after cardiac attacks and which was credited with improving riders' breathing.[5] Riders suffered hallucinations from the exhaustion and perhaps the drugs. The American champion Major Taylor refused to continue the New York race, saying: "I cannot go on with safety, for there is a man chasing me around the ring with a knife in his hand."[6] Public reaction turned against such trials, whether individual races or in teams of two. One report said: An athletic contest in which the participants 'go queer' in their heads, and strain their powers until their faces become hideous with the tortures that rack them, is not sport, it is brutality. It appears from the reports of this singular performance that some of the bicycle riders have actually become temporarily insane during the contest... Days and weeks of recuperation will be needed to put the racers in condition, and it is likely that some of them will never recover from the strain.[7] The father of anabolic steroids in the United States was John Ziegler (1917–1983), a physician for the U.S. weightlifting team in the mid-20th century. In 1954, on his tour to Vienna with his team for the world championship, Ziegler learned from his Russian colleague that the Soviet weightlifting team's success was due to their use of testosterone as a performance-enhancing drug. Deciding that U.S. athletes needed chemical assistance to remain competitive, Ziegler worked with the CIBA Pharmaceutical Company to develop an oral anabolic steroid. This resulted in the creation of methandrostenolone, which appeared on the market in 1960 under the brand name Dianabol. During the Olympics that year, the Danish cyclist Knud Enemark Jensen collapsed and died while competing in the 100-kilometer (62-mile) race. An autopsy later revealed the presence of amphetamines and a drug called nicotinyl tartrate in his system. The American specialist in doping, Max M. Novich, wrote: "Trainers of the old school who supplied treatments which had cocaine as their base declared with assurance that a rider tired by a six-day race would get his second breath after absorbing these mixtures."[8] John Hoberman, a professor at the University of Texas in Austin, Texas, said six-day races were "de facto experiments investigating the physiology of stress as well as the substances that might alleviate exhaustion."[9] ## Prevalence[edit] Over 30% of athletes participating in 2011 World Championships in Athletics admitted having used banned substances during their careers. According to a study commissioned by the World Anti-Doping Agency (WADA), actually 44% of them had used them. Nevertheless, only 0.5% of those tested were caught.[10][11] The entire Russian track and field team was banned from the 2016 Olympic Games, as the Russian State had sponsored and essentially sanctioned their doping program.[11] ### Goldman's dilemma[edit] Main article: Goldman's dilemma Goldman's dilemma, or the Goldman dilemma, is a question that was posed to elite athletes by physician, osteopath and publicist Bob Goldman, asking whether they would take a drug that would guarantee them success in sport, but cause them to die after five years. In his research, as in previous research by Mirkin, approximately half the athletes responded that they would take the drug,[12] but modern research by James Connor and co-workers has yielded much lower numbers, with athletes having levels of acceptance of the dilemma that were similar to the general population of Australia.[13][14] ## Substance[edit] ### Steroids[edit] Over the last 20 years the appearance of steroids in sports has been seen as an epidemic. Research and limited tests have been conducted only to find short-term, reversible effects on athletes that are both physical and mental. These side effects would be alleviated if athletes were allowed the use of controlled substances under proper medical supervision. These side-effects include intramuscular abscesses and other microbial bacteria that can cause infections, from counterfeited products the user decides to purchase on the black market, high blood pressure and cholesterol, as well as infertility, and dermatological conditions like severe acne. Mental effects include increased aggression and depression, and in rare cases suicide has been seen as well. Most studies on the effects of steroids have shown to be improper and lacking credible tests as well as performing studies in a skewed fashion to predetermine the world's view on the use of steroids in sports. Long-term effects have not been identified due to the recency of testing, but are expected to show up as early steroid users reach the age of 50 and older. [15][16][17][18] #### Strychnine at the Olympics[edit] Hicks and supporters at the 1904 Summer Olympics These "de facto experiments investigating the physiology of stress as well as the substances that might alleviate exhaustion" were not unknown outside cycling. Thomas Hicks, an American born in England on 7 January 1875, won the Olympic marathon in 1904. He crossed the line behind a fellow American Fred Lorz, who had been transported for 11 miles of the course by his trainer, leading to his disqualification. However, Hicks's trainer Charles Lucas, pulled out a syringe and came to his aid as his runner began to struggle. I therefore decided to inject him with a milligram of sulphate of strychnine and to make him drink a large glass brimming with brandy. He set off again as best he could [but] he needed another injection four miles from the end to give him a semblance of speed and to get him to the finish.[19] The use of strychnine, at the time, was thought necessary to survive demanding races, according to sports historians Alain Lunzenfichter[20] and historian of sports doping, Dr Jean-Pierre de Mondenard, who said: It has to be appreciated that at the time the menace of doping for the health of athletes or of the purity of competition had yet to enter the morals because, after this marathon, the official race report said: The marathon has shown from a medical point of view how drugs can be very useful to athletes in long-distance races.[2] Hicks was, in the phrase of the time, "between life and death" but recovered, collected his gold medal a few days later, and lived until 1952. Nonetheless, he never again took part in athletics.[21] ### Stimulants[edit] Stimulants are drugs that usually act on the central nervous system to modulate mental function and behavior, increasing an individual's sense of excitement and decreasing the sensation of fatigue. In the World Anti-Doping Agency list of prohibited substances, stimulants are the second largest class after the anabolic steroids.[22] Examples of well known stimulants include caffeine, cocaine, amphetamine, modafinil, and ephedrine. Caffeine, although a stimulant, has not been banned by the International Olympic Committee or the World Anti Doping Agency since 2004.[23] Benzedrine is a trade name for amphetamine. The Council of Europe says it first appeared in sport at the Berlin Olympics in 1936.[24] It was produced in 1887 and the derivative, Benzedrine, was isolated in the U.S. in 1934 by Gordon Alles. Its perceived effects gave it the street name "speed". British troops used 72 million amphetamine tablets in the Second World War[2] and the RAF got through so many that "Methedrine won the Battle of Britain" according to one report.[25] The problem was that amphetamine leads to a lack of judgement and a willingness to take risks, which in sport could lead to better performances but in fighters and bombers led to more crash landings than the RAF could tolerate. The drug was withdrawn but large stocks remained on the black market. Amphetamine was also used legally as an aid to slimming and also as a thymoleptic before being phased out by the appearance of newer agents in the 1950s. Everton, one of the top clubs in the English football league, were champions of the 1962–63 season, and it was done, according to a national newspaper investigation, with the help of Benzedrine. Word spread after Everton's win that the drug had been involved. The newspaper investigated, cited where the reporter believed it had come from, and quoted the goalkeeper, Albert Dunlop, as saying: I cannot remember how they first came to be offered to us. But they were distributed in the dressing rooms. We didn't have to take them but most of the players did. The tablets were mostly white but once or twice they were yellow. They were used through the 1961–62 season and the championship season which followed it. Drug-taking had previously been virtually unnamed in the club. But once it had started we could have as many tablets as we liked. On match days they were handed out to most players as a matter of course. Soon some of the players could not do without the drugs.[26] The club agreed that drugs had been used but that they "could not possibly have had any harmful effect." Dunlop, however, said he had become an addict.[26] In November 1942, the Italian cyclist Fausto Coppi took "seven packets of amphetamine" to beat the world hour record on the track.[27] In 1960, the Danish rider Knud Enemark Jensen collapsed during the 100 km team time trial at the Olympic Games in Rome and died later in hospital. The autopsy showed he had taken amphetamine and another drug, Ronicol, which dilates the blood vessels. The chairman of the Dutch cycling federation, Piet van Dijk, said of Rome that "dope – whole cartloads – [were] used in such royal quantities."[28] The 1950s British cycling professional Jock Andrews would joke: "You need never go off-course chasing the peloton in a big race – just follow the trail of empty syringes and dope wrappers."[29] The Dutch cycling team manager Kees Pellenaars told of a rider in his care: I took him along to a training camp in Spain. The boy changed then into a sort of lion. He raced around as though he was powered by rockets. I went to talk to him. He was really happy he was riding well and he told me to look out for him. I asked if he wasn't perhaps "using something" and he jumped straight up, climbed on a chair and from deep inside a cupboard he pulled out a plastic bag full of pills. I felt my heart skip a beat. I had never seen so many fireworks together. With a soigneur we counted the pills: there were 5,000 of them, excluding hormone preparations and sleeping pills. I took them away, to his own relief. I let him keep the hormones and the sleeping pills. Later he seemed to have taken too many at once and he slept for a couple of days on end. We couldn't wake him up. We took him to hospital and they pumped out his stomach. They tied him to his bed to prevent anything going wrong again. But one way or another he had some stimulant and fancied taking a walk. A nurse came across him in the corridor, walking along with the bed strapped to his back.[30] Currently modafinil is being used throughout the sporting world, with many high-profile cases attracting press coverage as prominent United States athletes have failed tests for this substance. Some athletes who were found to have used modafinil protested as the drug was not on the prohibited list at the time of their offence, however, the World Anti-Doping Agency (WADA) maintains it is a substance related to those already banned, so the decisions stand. Modafinil was added to the list of prohibited substances on 3 August 2004, ten days before the start of the 2004 Summer Olympics. One approach of athletes to get around regulations on stimulants is to use new designer stimulants, which have not previously been officially prohibited, but have similar chemical structures or biological effects. Designer stimulants that attracted media attention in 2010 included mephedrone, ephedrone, and fluoroamphetamines, which have chemical structures and effects similar to ephedrine and amphetamine. ### Anabolic steroids[edit] Main articles: Ergogenic use of anabolic steroids and Anabolic steroid Anabolic-androgenic steroids (AAS) were first isolated, identified and synthesized in the 1930s, and are now used therapeutically in medicine to induce bone growth, stimulate appetite, induce male puberty, and treat chronic wasting conditions, such as cancer and AIDS. Anabolic steroids also increase muscle mass and physical strength, and are therefore used in sports and bodybuilding to enhance strength or physique. Known side effects include harmful changes in cholesterol levels (increased low density lipoprotein and decreased high density lipoprotein), acne, high blood pressure, and liver damage. Some of these effects can be mitigated by taking supplemental drugs.[31] AAS use in sports began in October 1954 when John Ziegler, a doctor who treated American athletes, went to Vienna with the American weightlifting team. There he met a Russian physician who, over "a few drinks", repeatedly asked "What are you giving your boys?" When Ziegler returned the question, the Russian said that his own athletes were being given testosterone. Returning to America, Ziegler tried low doses of testosterone on himself, on the American trainer Bob Hoffman and on two lifters, Jim Park and Yaz Kuzahara. All gained more weight and strength than any training programme would produce but there were side-effects.[32] Ziegler sought a drug without after-effects and hit upon the anabolic steroid methandrostenolone, first made in the US in 1958 by Ciba and marketed as Dianabol (colloquially known as "d-bol").[33][34] The results were so impressive that lifters began taking more, and steroids spread to other sports. Paul Lowe, a former running back with the San Diego Chargers American football team, told a California legislative committee on drug abuse in 1970: "We had to take them [steroids] at lunchtime. He [an official] would put them on a little saucer and prescribed them for us to take them and if not he would suggest there might be a fine." Olympic statistics show the weight of shot putters increased 14 percent between 1956 and 1972, whereas steeplechasers weight increased 7.6 per cent. The gold medalist pentathlete Mary Peters said: "A medical research team in the United States attempted to set up extensive research into the effects of steroids on weightlifters and throwers, only to discover that there were so few who weren't taking them that they couldn't establish any worthwhile comparisons."[35] In 1984, Jay Silvester, a former four-time Olympian and 1972 silver medalist in the discus, who was then with the physical education department of Brigham Young University in the U.S., questioned competitors at that year's Olympics.[36] The range of steroid use he found ranged from 10 mg a day to 100 mg. Responses to questionnaire[citation needed] Question Yes (%) No (%) Other (%) Have you taken anabolic steroids within the past six months? 61 39 0 Have you ever taken anabolic steroids? 68 32 0 Ethically, do you approve of anabolic steroids in athletics? 50 27 23 If a test could positively identify steroid users, would you favour banishment of the drug in sport? 48 35 17 Are you aware of any specific reason why athletes who have not attained full maturity should avoid anabolic steroid usage? 42 48 10 If you were a coach, would you commend anabolic steroid usage to (mature) athletes in your event? 45 35 20 Do you feel anabolic steroids have positively affected the performance of athletes in your event? 65 16 19 Do you feel that steroids have negatively affected the performance of athletes in your event? 6 61 33 Do you feel that steroids enable a person to gain strength faster than otherwise possible? 84 3 13 Do you believe that steroids enable a person to gain cardio-respiratory endurance more quickly than otherwise possible? 13 42 45 Do you believe that steroids enable a person to gain greater cardio-respiratory endurance than otherwise possible? 6 45 49 Have you ever gained localised muscular endurance faster when taking anabolic steroids? 48 42 10 Have you gained greater local muscular endurance faster when taking anabolic steroids? 32 22 46 Do steroids enhance mental attitude? Do you feel more in control of your life? Do you feel you will perform better in your event? 68 10 22 Has steroid usage appeared to contribute to injury problems? 26 32 42 Are you aware of the undesirable side-effects? 74 19 7 Do steroids increase body weight? 55 16 29 Are steroids difficult to obtain? 22 61 17 [37][38] Brand name Dianabol is no longer produced but the drug methandrostenolone itself is still made in many countries and other, similar drugs are made elsewhere. The use of anabolic steroids is now banned by all major sporting bodies, including the ATP, WTA, ITF, International Olympic Committee, FIFA, UEFA, all major professional golf tours, the National Hockey League, Major League Baseball, the National Basketball Association, the European Athletic Association, WWE, the NFL, and the UCI. However, drug testing can be wildly inconsistent and, in some instances, has gone unenforced. A number of studies measuring anabolic steroid use in high school athletes found that out of all 12th grade students, 6.6 percent of them had used anabolic steroids at some point in their high school careers or were approached and counseled to use them. Of those students who acknowledged doping with anabolic–androgenic steroids, well over half participated in school-sponsored athletics, including football, wrestling, track and field, and baseball. A second study showed 6.3 percent of high school student Football players admitted to current or former AAS use. At the collegiate level, surveys show that AAS use among athletes range from 5 percent to 20 percent and continues to rise. The study found that skin changes were an early marker of steroid use in young athletes, and underscored the important role that dermatologists could play in the early detection and intervention in these athletes.[39] #### 1988 Seoul Olympics[edit] A famous case of AAS use in a competition was Canadian Ben Johnson's victory in the 100 m at the 1988 Summer Olympics.[40] He subsequently failed the drug test when stanozolol was found in his urine. He later admitted to using the steroid as well as Dianabol, testosterone, Furazabol, and human growth hormone amongst other things. Johnson was stripped of his gold medal as well as his world-record performance. Carl Lewis was then promoted one place to take the Olympic gold title. Lewis had also run under the current world record time and was therefore recognized as the new record holder.[41] Johnson was not the only participant whose success was questioned: Lewis had tested positive at the Olympic Trials for pseudoephedrine, ephedrine and phenylpropanolamine. Lewis defended himself, claiming that he had accidentally consumed the banned substances. After the supplements that he had taken were analyzed to prove his claims, the USOC accepted his claim of inadvertent use, since a dietary supplement he ingested was found to contain "Ma huang", the Chinese name for Ephedra (ephedrine is known to help weight loss).[42] Fellow Santa Monica Track Club teammates Joe DeLoach and Floyd Heard were also found to have the same banned stimulants in their systems, and were cleared to compete for the same reason.[43][44] The highest level of the stimulants Lewis recorded was 6 ppm, which was regarded as a positive test in 1988 but is now regarded as negative test. The acceptable level has been raised to ten parts per million for ephedrine and twenty-five parts per million for other substances.[42] According to the IOC rules at the time, positive tests with levels lower than 10 ppm were cause of further investigation but not immediate ban. Neal Benowitz, a professor of medicine at UC San Francisco who is an expert on ephedrine and other stimulants, agreed that "These [levels] are what you'd see from someone taking cold or allergy medicines and are unlikely to have any effect on performance."[42] Following Exum's revelations the IAAF acknowledged that at the 1988 Olympic Trials the USOC indeed followed the correct procedures in dealing with eight positive findings for ephedrine and ephedrine-related compounds in low concentration. Linford Christie of Great Britain was found to have metabolites of pseudoephedrine in his urine after a 200m heat at the same Olympics, but was later cleared of any wrongdoing.[45][46] Of the top five competitors in the race, only former world record holder and eventual bronze medalist Calvin Smith of the US never failed a drug test during his career. Smith later said: "I should have been the gold medalist."[47][48] The CBC radio documentary, Rewind, "Ben Johnson: A Hero Disgraced" broadcast on September 19, 2013, for the 25th anniversary of the race, stated 20 athletes tested positive for drugs but were cleared by the IOC at this 1988 Seoul Olympics. An IOC official stated that endocrine profiles done at those games indicated that 80 percent of the track and field athletes tested showed evidence of long-term steroid use, although not all were banned. ## Countries[edit] ### East Germany[edit] Main article: Doping in East Germany In 1977, one of East Germany's best sprinters, Renate Neufeld, fled to the West with the Bulgarian she later married. A year later she said that she had been told to take drugs supplied by coaches while training to represent East Germany at the 1980 Summer Olympics. At 17, I joined the East Berlin Sports Institute. My speciality was the 80m hurdles. We swore that we would never speak to anyone about our training methods, including our parents. The training was very hard. We were all watched. We signed a register each time we left for dormitory and we had to say where we were going and what time we would return. One day, my trainer, Günter Clam, advised me to take pills to improve my performance: I was running 200m in 24 seconds. My trainer told me the pills were vitamins, but I soon had cramp in my legs, my voice became gruff and sometimes I couldn't talk any more. Then I started to grow a moustache and my periods stopped. I then refused to take these pills. One morning in October 1977, the secret police took me at 7am and questioned me about my refusal to take pills prescribed by the trainer. I then decided to flee, with my fiancé.[49][50] She brought with her to the West grey tablets and green powder she said had been given to her, to members of her club, and to other athletes. The West German doping analyst Manfred Donike reportedly identified them as anabolic steroids. She said she stayed quiet for a year for the sake of her family. But when her father then lost his job and her sister was expelled from her handball club, she decided to tell her story.[49] Ilona Slupianek in 1981. East Germany closed itself to the sporting world in May 1965.[2] In 1977, the shot-putter Ilona Slupianek, who weighed 93 kg, failed a test for anabolic steroids at the European Cup meeting in Helsinki and thereafter athletes were tested before they left the country. At the same time, the Kreischa testing laboratory near Dresden passed into government control, which was reputed to make around 12,000 tests a year on East German athletes but without any being penalised.[2] The International Amateur Athletics Federation (IAAF) suspended Slupianek for 12 months, a penalty that ended two days before the European championships in Prague. In the reverse of what the IAAF hoped, sending her home to East Germany meant she was free to train unchecked with anabolic steroids, if she wanted to, and then compete for another gold medal, which she won. After that, almost nothing emerged from the East German sports schools and laboratories. A rare exception was the visit by the sports writer and former athlete, Doug Gilbert of the Edmonton Sun, who said: Dr (Heinz) Wuschech knows more about anabolic steroids than any doctor I have ever met, and yet he cannot discuss them openly any more than Geoff Capes or Mac Wilkins can openly discuss them in the current climate of amateur sports regulation. What I did learn in East Germany was that they feel there is little danger from anabolica, as they call it, when the athletes are kept on strictly monitored programmes. Although the extremely dangerous side-effects are admitted, they are statistically no more likely to occur than side-effects from the birth control pill. If, that is, programmes are constantly medically monitored as to dosage.[51] Other reports came from the occasional athlete who fled to the West. There were 15 between 1976 and 1979. One, the ski-jumper Hans-Georg Aschenbach, said: "Long-distance skiers start having injections to their knees from the age 14 because of their intensive training."[2] He said: "For every Olympic champion, there are at least 350 invalids. There are gymnasts among the girls who have to wear corsets from the age of 18 because their spine and their ligaments have become so worn... There are young people so worn out by the intensive training that they come out of it mentally blank [lessivés – washed out], which is even more painful than a deformed spine."[52] After German reunification, on 26 August 1993 the records were opened and the evidence was there that the Stasi, the state secret police, supervised systematic doping of East German athletes from 1971 until reunification in 1990. Doping existed in other countries, says the expert Jean-Pierre de Mondenard, both communist and capitalist, but the difference with East Germany was that it was a state policy.[53] The Sportvereinigung Dynamo (English:Dynamo Sports Club)[54] was especially singled out as a center for doping in the former East Germany.[55] Many former club officials and some athletes found themselves charged after the dissolution of the country. A special page on the internet was created by doping victims trying to gain justice and compensation, listing people involved in doping in the GDR.[56] State-endorsed doping began with the Cold War when every Eastern Bloc gold was an ideological victory. From 1974, Manfred Ewald, the head of East Germany's sports federation, imposed blanket doping. At the 1968 Summer Olympics in Mexico City, the country of 17 million collected nine gold medals. Four years later the total was 20 and in 1976 it doubled again to 40.[57] Ewald was quoted as having told coaches, "They're still so young and don't have to know everything." He was given a 22-month suspended sentence, to the outrage of his victims.[58] Often, doping was carried out without the knowledge of the athletes, some of them as young as ten years of age. It is estimated that around 10,000 former athletes bear the physical and mental scars of years of drug abuse,[59] one of them is Rica Reinisch, a triple Olympic champion and world record-setter at the 1980 Summer Olympics, has since suffered numerous miscarriages and recurring ovarian cysts.[59] Two former Dynamo Berlin club doctors, Dieter Binus, chief of the national women's team from 1976 to 1980, and Bernd Pansold, in charge of the sports medicine center in East Berlin, were committed for trial for allegedly supplying 19 teenagers with illegal substances.[60] Binus was sentenced in August,[61] Pansold in December 1998 after both being found guilty of administering hormones to underage female athletes from 1975 to 1984.[62] Virtually no East German athlete ever failed an official drugs test, though Stasi files show that many did produce failed tests at Kreischa, the Saxon laboratory (German:Zentrales Dopingkontroll-Labor des Sportmedizinischen Dienstes) that was at the time approved by the International Olympic Committee (IOC),[63] now called the Institute of Doping Analysis and Sports Biochemistry (IDAS).[64] In 2005, 15 years after the end of East Germany, the manufacturer of the drugs, Jenapharm, still found itself involved in numerous lawsuits from doping victims, being sued by almost 200 former athletes.[65] Former Sport Club Dynamo athletes who publicly admitted to doping, accusing their coaches:[66] * Daniela Hunger * Andrea Pollack Former Sport Club Dynamo athletes disqualified for doping: * Ilona Slupianek[67] (Ilona Slupianek failed a test along with three Finnish athletes at the 1977 European Cup, becoming the only East German athlete ever to be convicted of doping) Based on the admission by Pollack, the United States Olympic Committee asked for the redistribution of gold medals won in the 1976 Summer Olympics.[68] Despite court rulings in Germany that substantiate claims of systematic doping by some East German swimmers, the IOC executive board announced that it has no intention of revising the Olympic record books. In rejecting the American petition on behalf of its women's medley relay team in Montreal and a similar petition from the British Olympic Association on behalf of Sharron Davies, the IOC made it clear that it wanted to discourage any such appeals in the future.[69] ### Soviet Union[edit] See also: Doping at the Olympic Games § 1980 Moscow According to British journalist Andrew Jennings, a KGB colonel stated that the agency's officers had posed as anti-doping authorities from the IOC to undermine doping tests and that Soviet athletes were "rescued with [these] tremendous efforts".[70] On the topic of the 1980 Summer Olympics, a 1989 Australian study said "There is hardly a medal winner at the Moscow Games, certainly not a gold medal winner, who is not on one sort of drug or another: usually several kinds. The Moscow Games might as well have been called the Chemists' Games."[70] A member of the IOC Medical Commission, Manfred Donike, privately ran additional tests with a new technique for identifying abnormal levels of testosterone by measuring its ratio to epitestosterone in urine. Twenty percent of the specimens he tested, including those from sixteen gold medalists would have resulted in disciplinary proceedings had the tests been official.[citation needed] The results of Donike's unofficial tests later convinced the IOC to add his new technique to their testing protocols.[71] The first documented case of "blood doping" occurred at the 1980 Summer Olympics as a runner was transfused with two pints of blood before winning medals in the 5000 m and 10,000 m.[72] Documents obtained in 2016 revealed the Soviet Union's plans for a statewide doping system in track and field in preparation for the 1984 Summer Olympics in Los Angeles. Dated prior to the country's decision to boycott the Games, the document detailed the existing steroids operations of the program, along with suggestions for further enhancements. The communication, directed to the Soviet Union's head of track and field, was prepared by Dr. Sergey Portugalov of the Institute for Physical Culture. Portugalov was also one of the main figures involved in the implementation of the Russian doping program prior to the 2016 Summer Olympics.[73] ### West Germany[edit] This section needs expansion. You can help by adding to it. (November 2020) The 800-page "Doping in Germany from 1950 to today" study details how the West German government helped fund a wide-scale doping programme. West Germany encouraged and covered up a culture of doping across many sports for decades.[74][75][76][77][78][79] Clemens Prokop, head of Germany’s athletics federation, told Reuters Television in an interview, "It is a bit of a problem that there is a short version that has been published and that names have not been named."[80] Immediately after the 1954 FIFA World Cup Final, rumors emerged that the West German team had taken performance-enhancing substances. Several members of the team fell ill with jaundice, presumably from a contaminated needle. Members of the team later claimed they had been injected glucose,[81] and the team physician Franz Loogen said in 2004 that the players had only been given Vitamin C before the game.[82] A Leipzig University study in 2010 posited that the West German players had been injected with the banned substance methamphetamine.[83] According to the German Olympic Sports Association (DOSB), doping was common in the West German athletes of the 1980s. West German heptathlete Birgit Dressel died at age 26 due to sudden multiple organ failure, which was at least partly triggered by long-term steroid abuse.[84] In the newly emerging doping discussion in 2013 after submission of the final report of the anti-doping commission, the former German sprinter Manfred Ommer accused the Freiburg physician Armin Klümper: "Klümper was the largest doper on this planet."[85] ### China[edit] Main article: Doping in China China conducted a state sanctioned doping programme on athletes in the 1980s and 1990s.[86] In a July 2012 interview published by the Sydney Morning Herald newspaper, Chen Zhangho, the lead doctor for the Chinese Olympic team at the Los Angeles, Seoul and Barcelona Olympics told of how he had tested hormones, blood doping and steroids on about fifty elite athletes.[87] Chen also accused the United States, the Soviet Union and France of using performance-enhancing drugs at the same time as China.[87] ### Russia[edit] Main articles: Doping in Russia, McLaren Report, Russia at the 2016 Summer Olympics, and Olympic Athletes from Russia at the 2018 Winter Olympics The Olympic flag, which is used for independent athletes The doping history of Russia is big and over the years, Russia has had 47 Olympic medals stripped for doping violations. No other country has more stripped medals than Russia. After the release of the McLarren report in 2016, the IOC decided that Russian athletes had to participate under a neutral flag at the Olympic games in Rio 2016 and 2018 at the Winter Olympic Games. The reason for this decision was because Russia manipulated doping tests at the Olympic winter games in Sochi. Russian athletes who participated in Rio and Pyoengchang had to participate under a neutral flag with very strict criteria. Furthermore, government officials were not allowed to visit the event and the Olympic anthem was played instead of the Russian anthem.[88] In November 2019 Russia's representatives circumvented WADA rules and deleted data's from Russian doping tests handed over to the WADA. Russian athletics officials tried to block doping investigations of a high jumper. They also forged documents from indoor gold medalist Danil Lysenko to explain his whereabouts violations. The WADA recommends a ban from the Olympic and Paralympic Games in Tokyo for Russia. However, the final decision is not made yet, but it could include a ban from the Olympic Games, soccer World Cup and the world championships from wrestling, archery and other sports. IOC President Thomas Bach is against a complete ban of Russian athletes. Another point to consider is, that some people criticise, that the WADA is paid by the IOC, which makes an independent decision impossible.[89] ## Association football[edit] There have been few incidents of doping in football, mainly due to FIFA's belief that education and prevention with constant in and out-of-competition controls play a key role in making high-profile competitions free of performance-enhancing drugs.[90] The FIFA administration work alongside team physicians to fight for dope free competitions, having them sign a joint declaration that states they agree with having routine blood testing to check for blood doping before any FIFA World Cup.[91] In 2014, the biological passport was introduced in the 2014 FIFA World Cup; blood and urine samples from all players before the competition and from two players per team and per match are analysed by the Swiss Laboratory for Doping Analyses.[92] ## Ultimate Fighting Championship (UFC)[edit] In December 2013, the UFC began a campaign to drug test their entire roster randomly all year-round. Random testing, however, became problematic for the promotion as it began to affect revenue, as fighters who had tested positive would need to be taken out of fights, which adversely affected fight cards, and therefore pay-per-view sales. If the UFC were not able to find a replacement fighter fights would have to be cancelled. According to Steven Marrocco of MMAjunkie.com, about 31% of UFC fighters subjected to random testing since the program first started have failed due to using performance-enhancing drugs. That is approximately five failed tests for every sixteen random screenings.[93] From July 2015, the UFC has advocated to all commissions that every fighter be tested in competition for every card. Lorenzo Feritta, who at the time was one of the presidents of the UFC, said, "We want 100 percent of the fighters tested the night they compete". Also, in addition to the drug testing protocols in place for competitors on fight night, the UFC conducts additional testing for main event fighters or any fighters that are due to compete in championship matches. This includes enhanced, random 'out of competition' testing for performance-enhancing drugs, with both urine and blood samples being taken. The UFC also announced that all potential UFC signees would be subject to mandatory pre-contract screening for performance-enhancing drugs prior to being offered a contract with the promotion.[94] ## Endurance sports[edit] The use of performance-enhancing drugs in sport has become an increasing problem across a wide range of sports.[95] It is defined as any substance or drug that, when taken, gives an athlete an unfair advantage relative to a "clean" athlete.[95] The banning of these drugs promotes a level playing field and equality among athletes.[96] The use of 'the suit' in swimming, which gives athletes an advantage in the way of hydrodynamics, has been banned from international competition due to the unfair advantage it delivered.[97] The drugs taken by athletes differ widely based on the performance needs of the sport. Erythropoietin (EPO) is largely taken by endurance athletes who seek a higher level of red blood cells, which leads to more oxygenated blood, and a higher VO2 max. An athlete's VO2 max is highly correlated with success within endurance sports such as swimming, long-distance running, cycling, rowing, and cross-country skiing. EPO has recently become prevalent amongst endurance athletes due to its potency and low degree of detectability when compared to other methods of doping such as blood transfusion. While EPO is believed to have been widely used by athletes in the 1990s, there was not a way to directly test for the drug until 2002 as there was no specific screening process to test athletes . Athletes at the Olympic Games are tested for EPO through blood and urine tests. Stringent guidelines and regulations can lessen the danger of doping that has existed within some endurance sports. ### Cycling[edit] See also: List of doping cases in cycling, Doping at the Tour de France, and Doping at the 2007 Tour de France #### The Convicts of the Road[edit] In 1924, a journalist Albert Londres followed the Tour de France for the French newspaper Le Petit Parisien. At Coutances he heard that the previous year's winner, Henri Pélissier, his brother Francis and a third rider, Maurice Ville, had resigned from the competition after an argument with the organiser Henri Desgrange. Pélissier explained the problem—whether or not he had the right to take off a jersey—and went on to talk of drugs, reported in Londres' race diary, in which he invented the phrase Les Forçats de la Route (The Convicts of the Road): "You have no idea what the Tour de France is," Henri said. "It's a Calvary. Worse than that, because the road to the Cross has only 14 stations and ours has 15. We suffer from the start to the end. You want to know how we keep going? Here..." He pulled a phial from his bag. "That's cocaine, for our eyes. This is chloroform, for our gums." "This," Ville said, emptying his shoulder bag "is liniment to put warmth back into our knees." "And pills. Do you want to see pills? Have a look, here are the pills." Each pulled out three boxes. "The truth is," Francis said, "that we keep going on dynamite." Henri spoke of being as white as shrouds once the dirt of the day had been washed off, then of their bodies being drained by diarrhea, before continuing: "At night, in our rooms, we can't sleep. We twitch and dance and jig about as though we were doing St Vitus's Dance..." "There's less flesh on our bodies than on a skeleton," Francis said.[98] Francis Pélissier said much later: "Londres was a famous reporter but he didn't know about cycling. We kidded him a bit with our cocaine and our pills. Even so, the Tour de France in 1924 was no picnic."[2][99] The acceptance of drug-taking in the Tour de France was so complete by 1930, when the race changed to national teams that were to be paid for by the organisers, that the rule book distributed to riders by the organiser, Henri Desgrange, reminded them that drugs were not among items with which they would be provided.[100] The use of Pot Belge by road cyclists in continental Europe exemplifies a cross-over between recreational and performance-enhancing abuse of drugs by sportsman. #### Festina affair[edit] Main articles: Festina affair and Doping at the 1998 Tour de France In 1998, the entire Festina team were excluded from the Tour de France following the discovery of a team car containing large amounts of various performance-enhancing drugs. The team director later admitted that some of the cyclists were routinely given banned substances. Six other teams pulled out in protest including Dutch team TVM who left the tour still being questioned by the police. The Festina scandal overshadowed cyclist Marco Pantani's tour win, but he himself later failed a test. The infamous "Pot Belge" or "Belgian mix" has a decades-long history in pro cycling, among both riders and support staff. David Millar, the 2003 World-Time Trial Champion, admitted using EPO, and was stripped of his title and suspended for two years. Roberto Heras was stripped of his victory in the 2005 Vuelta a España and suspended for two years after testing positive for EPO. #### Floyd Landis[edit] Main article: Floyd Landis doping case Controversial athlete Floyd Landis, shown here at the 2006 Tour of California, triggered a public scandal when caught doping to help his cycling. Floyd Landis was the initial winner of the 2006 Tour de France. However, a urine sample taken from Landis immediately after his Stage 17 win has twice tested positive for banned synthetic testosterone as well as a ratio of testosterone to epitestosterone nearly three times the limit allowed by World Anti-Doping Agency rules.[101] The International Cycling Union stripped him of his 2006 Tour de France title. Second place finisher Óscar Pereiro was officially declared the winner.[102] #### Lance Armstrong case[edit] Main article: History of Lance Armstrong doping allegations Lance Armstrong was world number one in 1996. In the same year he recovered from severe testicular cancer and continued to break records and win his seventh Tour de France in 2005. After beating cancer and breaking records he was accused of doping.[citation needed] Teammates of Lance had been caught taking EPO (Erythropoietin) which made the accusations against Armstrong stronger.[103] On 22 October 2012 Lance Armstrong was stripped of his Tour de France titles since 1998.[104] As a response to the decisions of the USADA and UCI, Armstrong resigned from the Lance Armstrong Foundation[105] On 14 January 2013, Armstrong confessed to doping in an interview with Oprah Winfrey which was aired on 17 January on the Oprah Winfrey Network. ### Other endurance sports[edit] In triathlon, 2004 Hawaii Ironman winner Nina Kraft, was disqualified for a positive test to EPO. She remains the only Hawaii Ironman winner to be disqualified for doping offences. Sports lawyer Michelle Gallen has said that the pursuit of doping athletes has turned into a modern-day witch-hunt.[106] ## Non-endurance sports[edit] This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Doping in sport" – news · newspapers · books · scholar · JSTOR (July 2015) In sports where physical strength is favored, athletes have used anabolic steroids, known for their ability to increase physical strength and muscle mass.[107] The drugs mimic the effect of testosterone and dihydrotestosterone in the body.[107] They were developed after Eastern Bloc countries demonstrated success in weightlifting during the 1940s.[107] At the time they were using testosterone, which carried with it negative side effects, and anabolic steroids were developed as a solution. The drugs have been used across a wide range of sports from football and basketball to weightlifting and track and field. While not as life-threatening as the drugs used in endurance sports, anabolic steroids have negative side effects, including: ### Side effects in men[edit] * Acne * Impaired liver function * Impotency * Breast formation (Gynecomastia) * Increase in oestrogen * Suppression of spermatogenesis: As endogenous testosterone is the major regulator of the HPG axis, the exogenous testosterone and androgen anabolic steroids exert a suppressive effect of LH and FSH, leading to a decrease in intratesticular and secreted testosterone, decrease in spermatogenesis and sperm production.[108] * Lack of libido and erectile dysfunction: especially occurs in those men abusing aromatisable androgen anabolic steroids, resulting in high oestrogen levels. Although physiological levels of oestrogens are necessary for normal sexual function, the high doses and the imbalance between testosterone and estradiol appear to be the cause of sexual dysfunction.[109] * Increased sex drive * Male pattern baldness * Risk of heart failure ### Side effects in women[edit] * Hair loss * Male pattern baldness * Hypertrophy of the clitoris * Increased sex drive * Irregularities of the menstrual cycle * Development of masculine facial traits * Increased coarseness of the skin * Premature closure of the epiphysis * Deepening of the voice In countries where the use of these drugs is controlled, there is often a black market trade of smuggled or counterfeit drugs. The quality of these drugs may be poor and can cause health risks. In countries where anabolic steroids are strictly regulated, some have called for regulatory relief. Anabolic steroids are available over-the-counter in some countries such as Thailand and Mexico. Sports that are members of the IOC also enforce drug regulations; for example bridge.[110] ## Reaction from sports organizations[edit] Many sports organizations have banned the use of performance-enhancing drugs and have very strict rules and penalties for people who are caught using them. The International Amateur Athletic Federation, now World Athletics, was the first international governing body of sport to take the situation seriously. In 1928 they banned participants from doping, but with little in the way of testing available they had to rely on the word of the athlete that they were clean.[111] It was not until 1966 that FIFA and Union Cycliste Internationale (cycling) joined the IAAF in the fight against drugs, followed by the International Olympic Committee the following year.[112] Progression in pharmacology has always outstripped the ability of sports federations to implement rigorous testing procedures but since the creation of the World Anti-Doping Agency in 1999, it has become more effective to catch athletes who use drugs.[113] The first tests for athletes were at the 1966 European Championships and two years later the IOC implemented their first drug tests at both the Summer and Winter Olympics.[114] Anabolic steroids became prevalent during the 1970s and after a method of detection was found they were added to the IOC's prohibited substances list in 1975,[115] after which the 1976 Summer Olympics in Montreal were the first Olympic games which tested for them. Over the years, different sporting bodies have evolved differently in the struggle against doping. Some, such as athletics and cycling, are becoming increasingly vigilant against doping. However, there has been criticism that sports such as football (soccer) and baseball are doing nothing about the issue, and letting athletes implicated in doping away unpunished. Some commentators maintain that, as outright prevention of doping is an impossibility, all doping should be legalised. However, most disagree with this, pointing out the claimed harmful long-term effects of many doping agents. Opponents claim that with doping legal, all competitive athletes would be compelled to use drugs, and the net effect would be a level playing field but with widespread health consequences. A common rebuttal to this argument asserts that anti-doping efforts have been largely ineffective due to both testing limitations and lack of enforcement, and so sanctioned steroid use would not be markedly different from the situation already in existence. Another point of view is that doping could be legalized to some extent using a drug whitelist and medical counseling, such that medical safety is ensured, with all usage published. Under such a system, it is likely that athletes would attempt to cheat by exceeding official limits to try to gain an advantage; this could be considered conjecture as drug amounts do not always correlate linearly with performance gains. ## The influence of popular culture[edit] ### Social pressures[edit] Social pressure is one of the factors that leads to doping in sport.[116] The media and society work together to construct a view of what masculinity and femininity should look like. Adolescent athletes are constantly influenced by what they see on the media, and some go to extreme measures to achieve the ideal image since society channels Judith Butler's definition of gender as a performative act.[42] Examples of social pressures were given in a study done on an online bodybuilding community where bodybuilders doped because they felt like it was a rite of passage to be accepted into the community, and to feel validated.[116] Both men and women are being materialized in the context of doping in sport; in an interview involving 140 men, it was concluded that "bodily practices are essential for masculine identity," and it was determined that the media highly publicizes female athletes who were strong, and thin.[42] This leads to the issue of the consumption of performance enhancement drugs to achieve muscular or thin figures, and the assumption that the opponents are also taking performance-enhancing drugs, deeming it as an acceptable behavior to conform to.[117][118][119] In addition, society's embracement of the "winning is everything" spirit leads many athletes to participate in doping, hoping that they will not be caught.[120] ### Physical pressures[edit] Elite athletes have financial competitive motivations that cause them to dope and these motivations differ from that of recreational athletes.[116] The common theme among these motivations is the pressure to physically perform. In a study of 101 individuals, 86% responded that their use of performance enhancement drugs were influenced by the potential athletic success, 74% by the economic aspect, and 30% by self-confidence and social recognition related reasons.[121] In another study of 40 people, it was concluded that athletes used performance enhancement drugs for healing purposes so that they were an able competitor for the economic rewards involved with elite sports.[122] Physical pressures often overlap with social pressures to have a certain body build. This is the case with muscle dysmorphia, where an athlete wants a more muscular physique for functionality and self- image purposes.[42] The most popular motive for athletes to take supplements is to prevent any nutrient deficiencies and to strengthen the immune system.[118] These factors all focus on improving the body for performance. ### Psychological motivations[edit] Psychology is another factor to take into consideration in doping in sport. It becomes a behavioral issue when the athlete acknowledges the health risks associated with doping, yet participates in it anyway.[123] This has to do with the psychological thinking that the drug will make one feel invincible.[120] The individuals are very egotistic in their way of thinking and their motivation is dependent on the performance enhancement drug since they believe that it delivers the results.[117] On a study on health psychology, Quirk points out three different psychological aspects that lead one to dope: social cognition, stress and strain, and addiction.[123] The social and physical pressures can alter an athlete's way of thinking, leading them to believe that they must take performance enhancement drugs since everyone else is doing it, known as “the doping dilemma.”[120] * ## Anti-doping organizations and legislation[edit] This section needs expansion. You can help by adding to it. (July 2015) Further information: World Anti-Doping Agency * In 1999, initiated by the International Olympic Committee to fight against doping in sport, the World Anti-Doping Agency had been founded. After the doping scandal in cycling in the summer 1998 the International Olympic Committee (IOC) decided to establish the WADA to promote, coordinate and monitor the fight of against doping in sport. The headquarters for WADA is in Montreal, Canada. The WADA is the supreme international authority and is allowed to do doping tests and can determine which substances are illegal.[124] * In February 2011, the United States Olympic Committee and the Ad Council launched an anti-steroid campaign called Play Asterisk Free aimed at teens. The campaign first launched in 2008 under the name "Don't Be An Asterisk!".[125] * In October 2012, the USADA released evidence to corroborate their doping claim against cyclist Lance Armstrong. According to USADA CEO Travis T. Tygart, the evidence against Armstrong includes, "...scientific data and laboratory test results that further prove the use, possession and distribution of performance enhancing drugs".[126] * On 1 November 1989, US Senator Joseph Biden introduced S. 1829, The Steroid Trafficking Act of 1989. The purpose of the act was simple: It would "amend the Controlled Substances Act to further restrict the use of steroids. By designating anabolic steroids as a Schedule II controlled substance, the bill would crack down on illegal steroid use". (Senate Judiciary Committee, 2002, p. 282).[127] ## Test methods[edit] ### Urine test[edit] Under established doping control protocols, the athlete will be asked to provide a urine sample, which will be divided into two, each portion to be preserved within sealed containers bearing the same unique identifying number and designation respectively as A- and B-samples.[128] An athlete whose A-sample has tested positive for a prohibited substance is requested an analysis of his or her B-sample after a confirmation test on sample A that delivered the same results. If the B-sample test results match the A-sample results, then the athlete is considered to have a positive test, otherwise, the test results are negative.[129] This confirmation process ensures the safety of the individual.[130] ### Blood test[edit] see also: blood doping The blood test detects illegal performance enhancement drugs through the measurement of indicators that change with the use of recombinant human erythropoietin:[129] 1. Hematocrit 2. Reticulocytes 3. Level of Iron ### Gas chromatography-combustion-IRMS[edit] The gas chromatography-combustion-IRMS is a way to detect any variations in the isotopic composition of an organic compound from the standard. This test is used to detect whether or not synthetic testosterone was consumed, leading to an increased abnormal testosterone/epitestosterone (T/E) level.[129] Assumptions:[129] * 98.9% of the carbon atoms in nature are 12C * the remaining 1.1% are 13C The lower the 13C to 12C ratio, the more likely that synthetic testosterone was used.[131] ### Athlete biological passport[edit] The athlete biological passport is a program that tracks the location of an athlete to combat doping in sports.[132] This means that the athlete can be monitored and drug tested wherever they are and this data can be compared to the history of their doping test results.[133] There is an ongoing discussion about how this measure can be seen as a violation of an individual's privacy.[133] ### Re-testing of samples[edit] According to Article 6.5 in the World Anti-Doping Code samples may be re-tested later. Samples from high-profile events, such as the Olympic Games, are now re-tested up to eight years later to take advantage of new techniques for detecting banned substances.[134][135] ### Cheating the tests[edit] Athletes seeking to avoid testing positive use various methods. The most common methods include: * Urine replacement, which involves replacing dirty urine with clean urine from someone who is not taking banned substances. Urine replacement can be done by catheterization or with a prosthetic penis such as The Original Whizzinator. * Diuretics, used to cleanse the system before having to provide a sample. * Blood transfusions, which increase the blood's oxygen carrying capacity, in turn increasing endurance without the presence of drugs that could trigger a positive test result. * To avoid being tested during training periods, athletes can make themselves unavailable. To mitigate this, athletes have to report their location at any time. If intended doping tests could not be done because the athlete could not be found, three times during a year, it's considered a doping violation, same as refusing a test.[136] There is a web site and a phone app, called ADAMS, in which athletes are expected to report their location.[137][138] ### Validity[edit] Donald Berry, writing in the journal Nature, has called attention to potential problems with the validity of ways in which many of the standardised tests are performed;[139][subscription required] in his article, as described in an accompanying editorial, Berry > argues that anti-doping authorities have not adequately defined and publicized how they arrived at the criteria used to determine whether or not a test result is positive [which are] ...calibrated in part by testing a small number of volunteers taking the substance in question. [Berry argues] ...that individual labs need to verify these detection limits in larger groups that include known dopers and non-dopers under blinded conditions that mimic what happens during competition.[140] The editorial closes, saying "Nature believes that accepting 'legal limits' of specific metabolites without such rigorous verification goes against the foundational standards of modern science, and results in an arbitrary test for which the rate of false positives and false negatives can never be known."[140] ## Defense[edit] G. Pascal Zachary argues in a Wired essay that legalizing performance-enhancing substances, as well as genetic enhancements once they became available, would satisfy society's need for übermenschen and reverse the decline in public interest in sports.[141] Sports scholar Verner Moller argues that society is hypocritical when it holds athletes to moral standards, but do not conform to those morals themselves.[142] Fox Sports writer Jen Floyd Engel stated in an article, "We live in a pharmacological society. We live in a society of short cuts, of fake this and enhanced that, and somehow we keep trying to sell the line that sports has become this evil empire of cheating. The reality is athletes are merely doing what so many of us do and celebrate and watch every single day of our lives."[143] Sociologist Ellis Cashmore argues that what is considered doping is too arbitrary: transfusing blood cells is not allowed, but other methods of boosting blood cell count, such as hypobaric chambers, are allowed.[144] Other scholars have advanced similar arguments.[145] ## Legal[edit] Anti-doping policies instituted by individual sporting governing bodies may conflict with local laws. A notable case includes the National Football League (NFL)'s inability to suspend players found with banned substances, after it was ruled by a federal court that local labor laws superseded the NFL's anti-doping regime. The challenge was supported by the National Football League Players Association.[146][147] Athletes caught doping may be subject to penalties from their local, as well from the individual sporting, governing body. The legal status of anabolic steroids varies from country to country. Fighters found using performance-enhancing drugs in mixed martial arts competitions (e.g. the UFC) could face civil and/or criminal charges once Bill S-209 passes.[148] Under certain circumstances, when athletes need to take a prohibited substance to treat a medical condition, a therapeutic use exemption may be granted.[149] ## See also[edit] * Sports portal * Olympics portal * Drug test * Doping at the Olympic Games * Doping in Russia * BALCO scandal * Caffeine use for sport * Concussions in sport * Doping in pigeon racing * Equine drug testing * Gene doping * Mechanical doping * Mitchell Report * Stem cell doping * Technology doping ## References[edit] 1. ^ a b Kumar, R (2010). "Competing against doping". British Journal of Sports Medicine. 44: i8. doi:10.1136/bjsm.2010.078725.23. 2. ^ a b c d e f g Jean-Pierre de Mondenard (2000). Dopage : L'imposture des performances. Wilmette, Ill: Chiron. 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Pascal (April 2004). "Steroids for Everyone!". WIRED. Retrieved 9 June 2016. 142. ^ https://web.archive.org/web/20160304034820/http://www.practicalethics.ox.ac.uk/latest_news/2013/?a=28410. Archived from the original on 4 March 2016. Retrieved 9 June 2016. Missing or empty `\|title=` (help) 143. ^ Engel, Jen Floyd (29 August 2012). "Engel: Enough with the fake steroid outrage". Retrieved 9 June 2016. 144. ^ Cashmore, Ellis (24 February 2006). "The Olympics Meets the War on Drugs". StoptheDrugWar.org. The Drug Reform Coordination Network. Retrieved 26 October 2016. 145. ^ Collins, Rory (2017). "Lowering Restrictions on Performance Enhancing Drugs in Elite Sports". Inquiries Journal. 9 (3). Retrieved 7 July 2017. 146. ^ "Congress to review blocked doping suspensions". 8 October 2009. Retrieved 9 June 2016. 147. ^ Belson, Ken (4 November 2009). "N.F.L. Seeks Congressional Help on Drug Policy". The New York Times. Retrieved 27 May 2010. 148. ^ Magraken, Erik (9 March 2013). "Legal Ramifications for Using PEDs in MMA?". TopMMANews.com. Retrieved 9 March 2013. 149. ^ "Therapeutic Use Exemptions". World Anti-Doping Agency. 20 May 2014. ## Further reading[edit] * Collins, Rory (2017). "Lowering Restrictions on Performance Enhancing Drugs in Elite Sports". Inquiries Journal. 9 (3). Retrieved 7 July 2017. * Franke WW, Berendonk B (July 1997). "Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government". Clinical Chemistry. 43 (7): 1262–79. doi:10.1093/clinchem/43.7.1262. PMID 9216474. * Mottram, David (2005); Drugs in Sport, Routledge. ISBN 978-0-415-37564-1. * Murray, Thomas H. (2008); "Sports Enhancement", in From Birth to Death and Bench to Clinic: The Hastings Center Bioethics Briefing Book for Journalists, Policymakers, and Campaigns. * Pope J, Harrison G, Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S (2014). "Adverse health consequences of performance-enhancing drugs: An endocrine society scientific statement". Endocrine Reviews. 35 (3): 341–375. doi:10.1210/er.2013-1058. PMC 4026349. PMID 24423981. * Waddington and Smith (2008); An Introduction to Drugs in Sport, Routledge. ISBN 978-0-415-43125-5. ## External links[edit] Wikimedia Commons has media related to doping. * Anti-Doping Sciences Institute * Banned Substances Control Group * World Anti-Doping Agency * Anti-Doping at the International Association of Athletics Federations * v * t * e Sport * History * Clubs * Doping * Equipment * Industry * Medicine * Philosophy * Regulation * Science * Sociology * Women * Africa * Australia * Asia * Europe * North America * Oceania * South America * Category * Portal * Outline Authority control * GND: 4126002-8 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Doping in sport	None	4,680	wikipedia	https://en.wikipedia.org/wiki/Doping_in_sport	2021-01-18T18:57:20	{"mesh": ["D004300"], "umls": ["C0013039"], "wikidata": ["Q166376"]}
Congenital insensitivity to pain is a condition that inhibits the ability to perceive physical pain. From birth, affected individuals never feel pain in any part of their body when injured. People with this condition can feel the difference between sharp and dull and hot and cold, but cannot sense, for example, that a hot beverage is burning their tongue. This lack of pain awareness often leads to an accumulation of wounds, bruises, broken bones, and other health issues that may go undetected. Young children with congenital insensitivity to pain may have mouth or finger wounds due to repeated self-biting and may also experience multiple burn-related injuries. These repeated injuries often lead to a reduced life expectancy in people with congenital insensitivity to pain. Many people with congenital insensitivity to pain also have a complete loss of the sense of smell (anosmia). Congenital insensitivity to pain is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain. ## Frequency Congenital insensitivity to pain is a rare condition; about 20 cases have been reported in the scientific literature. ## Causes Mutations in the SCN9A gene cause congenital insensitivity to pain. The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. Sodium channels transport positively charged sodium atoms (sodium ions) into cells and play a key role in a cell's ability to generate and transmit electrical signals. NaV1.7 sodium channels are found in nerve cells called nociceptors that transmit pain signals to the spinal cord and brain. The NaV1.7 channel is also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain. The SCN9A gene mutations that cause congenital insensitivity to pain result in the production of nonfunctional alpha subunits that cannot be incorporated into NaV1.7 channels. As a result, the channels cannot be formed. The absence of NaV1.7 channels impairs the transmission of pain signals from the site of injury to the brain, causing those affected to be insensitive to pain. Loss of this channel in olfactory sensory neurons likely impairs the transmission of smell-related signals to the brain, leading to anosmia. ### Learn more about the gene associated with Congenital insensitivity to pain * SCN9A ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Congenital insensitivity to pain	c1855739	4,681	medlineplus	https://medlineplus.gov/genetics/condition/congenital-insensitivity-to-pain/	2021-01-27T08:25:03	{"gard": ["12267"], "mesh": ["C565467"], "omim": ["243000"], "synonyms": []}
Fetal hydantoin syndrome Phenytoin SpecialtyMedical genetics Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, commonly used in the treatment of epilepsy. It may also be called congenital hydantoin syndrome,[1] fetal hydantoin syndrome, dilantin embryopathy, or phenytoin embryopathy. Association with EPHX1 has been suggested.[2] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Signs and symptoms[edit] About one third of children whose mothers are taking this drug during pregnancy typically have intrauterine growth restriction with a small head and develop minor dysmorphic craniofacial features (microcephaly and mental retardation) and limb defects including hypoplastic nails and distal phalanges (birth defects). Heart defects including ventricular septal defect, atrial septal defect, patent ductus arteriosus and coarctation of the aorta may occur in these children. A smaller population will have growth problems and developmental delay, or intellectual disability. Methemoglobinemia is a rarely seen side effect. Heart defects and cleft lip[3] may also be featured. ## Diagnosis[edit] There is no diagnostic testing that can identify fetal hydantoin syndrome. A diagnosis is made clinically based upon identification of characteristic symptoms in an affected infant in conjunction with a history of phenytoin exposure during gestation. It is important to note that the majority of infants born to women who take phenytoin during pregnancy will not develop fetal hydantoin syndrome. [4] ## Treatment[edit] The treatment of fetal hydantoin syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, oral surgeons, plastic surgeons, neurologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Infants with fetal hydantoin syndrome can benefit from early developmental intervention to ensure that affected children reach their potential. Affected children may benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services may be necessary. Psychosocial support for the entire family is essential as well. [4] When cleft lip and/or palate are present, the coordinated efforts of a team of specialists may be used to plan an affected child’s treatment and rehabilitation. Cleft lip may be surgically corrected. Generally surgeons repair the lip when the child is still an infant. A second surgery is sometimes necessary for cosmetic purposes when the child is older. Cleft palate may be repaired by surgery or covered by an artificial device (prosthesis) that closes or blocks the opening. Surgical repair can be carried out in stages or in a single operation, according to the nature and severity of the defect. The first palate surgery is usually scheduled during the toddler period. [4] ## References[edit] 1. ^ Nicolai J, Vles JS, Aldenkamp AP (August 2008). "Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: a critical review directed at structural study-bias". J. Neurol. Sci. 271 (1–2): 1–14. doi:10.1016/j.jns.2008.03.004. PMID 18479711. 2. ^ Online Mendelian Inheritance in Man (OMIM): 132810 3. ^ Easton JD (December 1972). "Potential hazards of hydantoin use". Ann. Intern. Med. 77 (6): 998–9. doi:10.7326/0003-4819-77-6-998. PMID 4644176. 4. ^ a b c "Fetal Hydantoin Syndrome". NORD (National Organization for Rare Disorders). Retrieved 2019-02-15. ## External links[edit] Classification D * ICD-10: Q86.1 * ICD-9-CM: 760.77 * OMIM: 132810 * MeSH: C537922 * DiseasesDB: 33179 * v * t * e Congenital malformation due to substance exposure * Fetal alcohol spectrum disorder * Fetal hydantoin syndrome * Fetal warfarin syndrome * Prenatal amphetamine exposure * Prenatal cannabis exposure * Prenatal cocaine exposure * Prenatal nicotine exposure Other * Substance use disorder [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Fetal hydantoin syndrome	c0265372	4,682	wikipedia	https://en.wikipedia.org/wiki/Fetal_hydantoin_syndrome	2021-01-18T18:49:20	{"gard": ["6435"], "mesh": ["C537922"], "umls": ["C0265372"], "icd-9": ["760.77"], "icd-10": ["Q86.1"], "orphanet": ["1912"], "wikidata": ["Q5445904"]}
A rare, genetic, renal ciliopathy characterized by reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, cystic renal disease and progression to end stage renal disease (ESRD). The three clinical subtypes are characterized by the age of onset of ESRD which includes infantile, juvenile and late onset. ## Epidemiology The prevalence is unknown; however, at birth it is estimated at 1: 80,000 in Finland. Nephronophthisis (NPHP) is responsible for 2.4 to 15% of ESRD in children. ## Clinical description Three main forms have been described. Juvenile NPHP, the most frequent form, progresses to end-stage renal failure at median age of 13 and is responsible for 15% of cases of childhood ESRD. Infantile NPHP can present in utero with oligohydramnios sequence or postnatally with reduced kidney function and progresses to ESRD before age 3. Late-onset NPHP is a rare form of the disease and presents clinical and histological signs similar to the juvenile form but with ESRD occurring later (median age of 19 years). The typical clinical symptoms include polyuria, polydipsia with regular fluid intake, impaired sodium reabsorption that cause hypovolemia and hyponatremia, anemia and growth delay. Renal ultrasonography in early stages is normal or shows unspecific changes with increased renal echogenicity, with advancing kidney disease poor cortico-medullary differentiation is described; corticomedullary cysts are present in the 70% of patients. Renal histopathology in NPHP is characterized by the triad of tubular cysts, tubular basement membrane disruption, and interstitial fibrosis with interstitial cell infiltration. Retinal degeneration is the most frequent extrarenal findings (10%), cerebellar vermis aplasia, liver fibrosis and skeletal defects could be also present. Extrarenal phenotypes are distinct but they overlap in some syndromic forms of NPHP (such as Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome). ## Etiology To date, mutations in 14 genes have been identified in affected individuals. The majority of these genes encode for ciliary proteins that cluster to distinct subcellular localizations. The NPHP1 gene, that encodes for nephrocystin-1, is deleted or mutated in 25% of juvenile NPHP. Mutations in the gene INVS (9q31.1), coding for inversin, is frequently responsible for infantile NPHP. Mutations in NPHP3 (3q22.1), NPHP4 (1p36.31), NEK8 (17q11.2) genes give rise to late-onset nephronophthisis, however these genes are associated also with the Senior-Loken syndrome and Meckel-Gruber syndrome and predispose to multiorgan polycystic disease. ## Diagnostic methods The diagnosis is suggested by clinical features and confirmed by genetic testing. ## Differential diagnosis Differential diagnosis includes early onset autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease and congenital anomalies of kidney and urinary tract (CAKUT). Furthermore, juvenile NPHP forms part of a spectrum of NPHP-related ciliopathies which includes Joubert syndrome, Senior-Loken syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome and Skeletal Ciliopathies (Oral-facial-digital syndrome, Cranioectodermal dysplasia, Short-rib thoracic dysplasia). The infantile form should also be distinguished from renal hypodysplasia. ## Antenatal diagnosis Once the pathogenic variants have been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis can be considered. ## Genetic counseling The pattern of inheritance is autosomal recessive, with homozygous or compound heterozygous mutations possible. The parents are obligate heterozygotes (carriers) and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has a 50% risk of being an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Offspring of an affected individual will be obligate carriers. ## Management and treatment The management is supportive to maintain fluid and metabolic balance including: correction of water and electrolyte imbalances; anemia treatment, and proteinuria treatment if necessary. For the ESRD management, dialysis or renal transplantation are necessary. ## Prognosis The prognosis is dependent on the age of ESRD onset. Despite the risk of complications, transplant outcomes are excellent with no recurrence of tubular injury. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Nephronophthisis	c0687120	4,683	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=655	2021-01-23T18:14:11	{"gard": ["206"], "omim": ["256100", "602088", "604387", "606966", "611498", "613159", "613820", "613824", "614377", "615382", "615862", "617271"], "umls": ["C0687120"], "icd-10": ["Q61.5"]}
Cleft lip and alveolus is a fissure type embryopathy that involves the upper lip, nasal base and alveolar ridge in variable degrees. ## Epidemiology The annual incidence varies from 1/4,000 to 1/10,000 births with major variation among geographic regions and ethnic groups. Cleft lip/alveolus is twice as common in boys as girls and is seen more frequently on the left side. ## Clinical description The cleft is paramedian and is located at the philtrum level for the lip and nasal base and at the level of the upper lateral incisor for the alveolar ridge. It involves a cutaneous, muscular and mucosal interruption in the lip, in addition to nostril and nasal septum deformations and an interruption in the alveolar bone and dental arch. The maxillary lateral incisor, at the site of the alveolar cleft, can present with anomalies in shape, number (duplication or agenesis) and position. There is no correlation seen between temporary (primary) and permanent dentition. ## Etiology Cleft lip/alveolus is an embropathy that appears in the 5th to 7th week of pregnancy, following an error in fusion of the frontal processes (fronto-nasal process, medial and lateral nasal processes, maxillary process). Cleft lip and alveolus are isolated, non-syndromic anomalies in 70% of cases. The remaining 30% of cases are seen in about 300 syndromes where cleft lip/alveolus is just one of the featured anomalies. Non-syndromic clefts are believed to be caused by a combination of genetic and environmental factors. Factors such as the exposure to teratogenic substances during pregnancy (alcohol, tobacco or drugs) can influence genetic susceptibility. ## Diagnostic methods Diagnosis is clinical. ## Differential diagnosis The presence of associated malformations allows for differentiation between isolated and syndromic forms. ## Antenatal diagnosis Antenatal diagnosis is often made during prenatal ultrasound. The case is submitted to a multidisciplinary center for prenatal diagnosis in order to establish if it is an isolated anomaly. ## Management and treatment Management requires multidisciplinary medical and surgical intervention from birth until the end of development. It involves primary surgery followed by secondary maxilla-facial surgery along with plastic surgery. An initial treatment timeline is established during the neonatal period. Management is adapted to the child and based on morphological and functional problems that may arise during growth and development. Orthodontic management aims to correct the dental alignment problems, sometimes during the early primary teeth stage and then in the mixed and permanent stage. Treatment of the alveolar cleft requires a maxillary bone graft and a dental implant can correct permanent lateral incisor agenesis, if present after growth has stopped. The capacity to chew properly depends on the bucco-facial clinical history of the patient and any dental alignment problems. Breathing difficulties can occur due to the nostril anomaly as well as deviation of the vomer and nasal septum and turbinate hypertrophy. Secondary surgery of the nose can be performed to improve nasal appearance and function if necessary. ## Prognosis The prognosis depends on the quality of initial management and the regular follow-up by an experienced interdisciplinary team until the child is fully grown. Cleft lip/alveolus can have functional (morphological, respiratory), esthetic and psychological consequences that require management in a specialized health center. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Cleft lip and alveolus	c1298692	4,684	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=141291	2021-01-23T17:35:33	{"omim": ["119530", "129400", "225060", "600757", "602966", "608371", "608874", "610361", "612858"], "umls": ["C1298692"], "icd-10": ["Q36.0", "Q36.1", "Q36.9"]}
## Description Collagen has a triple-stranded rope-like coiled structure. The major collagen of skin, tendon, and bone is the same protein containing 2 alpha-1 polypeptide chains and 1 alpha-2 chain. Although these are long (the procollagen chain has a molecular mass of about 120 kD, before the 'registration peptide' is cleaved off; see 225410), each messenger RNA is monocistronic (Lazarides and Lukens, 1971). Differences in the collagens from these 3 tissues are a function of the degree of hydroxylation of proline and lysine residues, aldehyde formation for cross-linking, and glycosylation. The alpha-1 chain of the collagen of cartilage and that of the collagen of basement membrane are determined by different structural genes. The collagen of cartilage contains only 1 type of polypeptide chain, alpha-1, and this is determined by a distinct locus. The fetus contains collagen of distinctive structure. The genes for types I, II, and III collagens, the interstitial collagens, exhibit an unusual and characteristic structure of a large number of relatively small exons (54 and 108 bp) at evolutionarily conserved positions along the length of the triple-helical gly-X-Y portion (Boedtker et al., 1983). The family of collagen proteins consists of a minimum of 9 types of collagen molecules whose constituent chains are encoded by a minimum of 17 genes (Ninomiya and Olsen, 1984). Cloning and Expression Tromp et al. (1988) characterized a full-length cDNA clone for the COL1A1 gene. Mapping Sundar Raj et al. (1977) used the methods of cell hybridization and microcell hybridization to assign a collagen I gene to chromosome 17. Solomon and Sykes (1979) concluded, incorrectly as it turned out, that both the alpha-1 and the alpha-2 genes of collagen I are on chromosome 7. Solomon and Sykes (1979) also presented evidence that the alpha-1 chains of collagen III are also coded by chromosome 7. Church et al. (1981) assigned a structural gene for corneal type I procollagen to chromosome 7 by somatic cell hybridization involving corneal stromal fibroblasts. Because they had previously assigned a gene for skin type I procollagen to chromosome 17, they wondered whether skin and corneal type I collagen may be under separate control. Huerre et al. (1982) used a cDNA probe in both mouse-man and Chinese hamster-man somatic cell hybrids to demonstrate cosegregation with human chromosome 17. In situ hybridization using the same probe indicated that the gene is in the middle third of the long arm, probably in band 17q21 or 17q22. By chromosome-mediated gene transfer (CMGT), Klobutcher and Ruddle (1979) transferred the genes for thymidine kinase, galactokinase (604313), and type I procollagen (gene for alpha-1 polypeptide). The data indicated the following gene order: centromere--GALK--(TK1-COL1A1). Later studies (Ruddle, 1982) put the growth hormone gene cluster (see 139250) between GALK and (TK1-COL1A1). A HindIII restriction site polymorphism in the alpha-1(I) gene was described by Driesel et al. (1982), who probably unjustifiably stated that the gene is on chromosome 7. By in situ hybridization, Retief et al. (1985) concluded that the alpha-1(I) and alpha-2(I) genes are located in bands 17q21.31-q22.05 and 7q21.3-q22.1, respectively. Sippola-Thiele et al. (1986) commented on the limited number of informative RFLPs in the collagen genes, especially COL1A1. They proposed a method for assessing RFLPs that were otherwise undetectable in total human genomic DNA. Using the centromere-based locus D17Z1, Tsipouras et al. (1988) found a recombination fraction of 0.20 with COL1A1. Furthermore, they demonstrated that COL1A1 and GH1 (139250) show a recombination fraction of 0.10. They proposed that the most likely order is D17Z1--COL1A1--GH1. Byrne and Church (1983) had concluded that both subunits of type I collagen, alpha-1 and alpha-2, are coded by chromosome 16 in the mouse. SOD1 (147450), which in man is on chromosome 21, is also carried by mouse 16. It may have been type VI collagen (120220, 120240) that they dealt with; both COL6A1 and COL6A2 are coded by human chromosome 21. (In fact, the Col6a1 and Col6a2 genes are carried by mouse chromosome 10 (Justice et al., 1990).) Munke et al. (1986) showed that the alpha-1 gene of type I collagen is located on mouse chromosome 11; the Moloney murine leukemia virus is stably integrated into this site when microinjected into the pronuclei of fertilized eggs. This insertion results in a lethal mutation through blockage of the developmentally regulated expression of the gene (Schnieke et al., 1983). Molecular Genetics ### Osteogenesis Imperfecta Pope et al. (1985) described a substitution of cysteine in the C-terminal end of the alpha-1 collagen chain in a 9-year-old boy with mild osteogenesis imperfecta (OI) of Sillence type I. They assumed that this was a substitution for either arginine or serine (which could be accomplished by a single base change) because substitution of cysteine for glycine produced a much more drastic clinical picture. In a neonatal lethal case of OI congenita, Barsh and Byers (1981) demonstrated a defect in pro-alpha-1 chains (see OI type II, 166210). Byers et al. (1988) found an insertion in one COL1A1 allele in an infant with OI II. One alpha-1 chain was normal in length, whereas the other contained an insertion of approximately 50-70 amino acid residues within the triple-helical domain defined by amino acids 123-220. The structure of the insertion was consistent with duplication of an approximately 600-bp segment in 1 allele. Brookes et al. (1989) used an S1 nuclease directed cleavage of heteroduplex DNA molecules formed between genomic material and cloned sequences to search for mutations in the COL1A1 gene in 5 cases in which previous linkage studies had shown the mutation to be located in the COL1A1 gene and in 4 cases in which a COL1A1 null allele had been identified by protein and RNA studies. No abnormality was found in the complete 18 kb COL1A1 gene or in 2 kb of 5-prime flanking sequence. The method used was known to permit the detection of short length variations of the order of 4 bp in heterozygous subjects but not single basepair alterations. Thus, Brookes et al. (1989) suggested that single basepair alterations may be the predominant category of mutation in type I OI. COL1A1 and NGFR (162010) are in the same restriction fragment. In a 3-generation family with OI type I, Willing et al. (1990) found that all affected members had one normal COL1A1 allele and another from which the intragenic EcoRI restriction site near the 3-prime end of the gene was missing. They found, furthermore, a 5-bp deletion at the EcoRI site which changed the translational reading frame and predicted the synthesis of a pro-alpha-1(I) chain that extended 84 amino acids beyond the normal termination. Although the mutant chain was synthesized in an in vitro translation system, they were unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways. Cohn et al. (1990) demonstrated a clear instance of paternal germline mosaicism as the cause of 2 offspring with OI type I by different women. Both affected infants had a G-to-A change that resulted in substitution of aspartic acid for glycine at position 883 of the alpha-1 chain of type I collagen. Although not detected in the father's skin fibroblasts, the mutation was detected in somatic DNA from the father's hair root bulbs and lymphocytes. It was also found in the father's sperm where about 1 in 8 sperm carried the mutation, suggesting that at least 4 progenitor cells populate the germline in human males. The father was clinically normal. In an infant with perinatal lethal OI (OI type II), Wallis et al. (1990) demonstrated both normal and abnormal type I procollagen molecules. The abnormal molecules had substitution of arginine for glycine at position 550 of the triple-helical domain as a result of a G-to-A transition in the first base of the glycine codon. The father was shown to be mosaic for this mutation, which accounted for about 50% of the COL1A1 alleles in his fibroblasts, 27% of those in blood cells, and 37% of those in sperm. The father was short of stature; he had bluish sclerae, grayish discoloration of the teeth (which were small), short neck, barrel-shaped chest, right inguinal hernia, and hyperextensible fingers and toes. A triangular-shaped head had been noted at birth and he was thought to have hydrocephalus. No broken bones had been noted at that time. He had had only 1 fracture, that of the clavicle at age 8 years. Cole et al. (1990) reported the clinical features of 3 neonates with lethal perinatal OI resulting from a substitution of glycine by arginine in the COL1A1 gene product. The mutations were gly391-to-arg, gly667-to-arg, and gly976-to-arg. All 3 were small, term babies who died soon after birth. The ribs were broad and continuously beaded in the first, discontinuously beaded in the second, and slender with few fractures in the third. The overall radiographic classifications were type IIA, IIA/IIB, and IIB, respectively (based on an old classification by Sillence et al., 1984; see HISTORY in 166210). The findings suggested that there was a gradient of bone modeling capacity from the slender and overmodeled bones associated with the mutation nearest the C-terminal end of the molecule to absence of modeling with that nearest the N-terminal end. Dermal fibroblasts from most persons with OI type I produce about half the normal amount of type I procollagen as a result of decreased synthesis of one of its constituent chains, namely, the alpha-1 chain. Willing et al. (1992) used a polymorphic MnlI restriction endonuclease site in the 3-prime untranslated region of COL1A1 to distinguish the transcripts of the 2 alleles in 23 heterozygotes from 21 unrelated families with OI type I. In each case there was marked diminution in steady-state mRNA levels from one COL1A1 allele. They demonstrated that loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Primer extension with nucleotide-specific chain termination allowed identification of the mutant allele in cell strains that were heterozygous for an expressed polymorphism. Willing et al. (1992) suggested that the method is applicable to sporadic cases, to small families, and to large families in which key persons are uninformative at the polymorphic sites used in linkage analysis. Willing et al. (1993) pointed out that the abnormally low ratio of COL1A1 mRNA to COL1A2 (120160) mRNA in fibroblasts cultured from OI type I patients is an indication of a defect in the COL1A1 gene in the great majority of patients with this form of OI. Byers (1993) counted a total of approximately 70 point mutations identified in the helical portion of the alpha-1 peptide, approximately 10 exon skipping mutations, and about 6 point mutations in the C-propeptide. Steady state amounts of COL1A1 mRNA are reduced in both the nucleus and cytoplasm of dermal fibroblasts from most subjects with type I osteogenesis imperfecta (166200). Willing et al. (1995) investigated whether mutations involving key regulatory sequences in the COL1A1 promoter, such as the TATAAA and CCAAAT boxes, are responsible for the reduced levels of mRNA. They used PCR-amplified genomic DNA in conjunction with denaturing gradient gel electrophoresis and SSCP to screen the 5-prime untranslated domain, exon 1, and a small portion of intron 1 of the COL1A1 gene. In addition, direct sequence analysis was performed on an amplified genomic DNA fragment that included the TATAAA and CCAAAT boxes. In a survey of 40 unrelated probands with OI type I in whom no causative mutation was known, Willing et al. (1995) identified no mutations in the promoter region and there was 'little evidence of sequence diversity among any of the 40 subjects.' Whereas most cases of severe osteogenesis imperfecta result from mutations in the coding region of the COL1A1 or COL1A2 genes yielding an abnormal collagen alpha-chain, many patients with mild OI show evidence of a null allele due to a premature stop mutation in the mutant RNA transcript. As indicated in 120150.0046, mild OI in one case resulted from a null allele arising from a splice donor mutation where the transcript containing the included intron was sequestered in the nucleus. Nuclear sequestration precluded its translation and thus rendered the allele null. Using RT-PCR and SSCP of COL1A1 mRNA from patients with mild OI, Redford-Badwal et al. (1996) identified 3 patients with distinct null-producing mutations identified from the mutant transcript within the nuclear compartment. In a fourth patient with a gly-to-arg expressed point mutation, they found the mutant transcript in both the nucleus and the cytoplasm. Willing et al. (1996) analyzed the effects of nonsense and frameshift mutations on steady state levels of COL1A1 mRNA. Total cellular and nuclear RNA was analyzed. They found that mutations which predict premature termination reduce steady-state amounts of COL1A1 mRNA from the mutant allele in both nuclear and cellular mRNA. The investigators concluded that premature termination mutations have a predictable and uniform effect on COL1A1 gene expression which ultimately leads to decreased production of type I collagen and to the mild phenotype associated with OI type I. Willing et al. (1996) reported that mutations which lead to premature translation termination appear to be the most common molecular cause of OI type I. They identified 21 mutations, 15 of which lead to premature termination as a result of translational frameshifts or single-nucleotide substitutions. Five mutations were splicing defects leading to cryptic splicing or intron retention within the mature mRNA. Both of these alternative splicing pathways indirectly lead to frameshifts and premature termination in downstream exons. In 4 apparently unrelated patients with OI, Korkko et al. (1997) found 2 new recurrent nucleotide mutations in the COL1A1 gene, using a protocol whereby 43 exons and exon-flanking sequences were amplified by PCR and scanned for mutations by denaturing gradient gel electrophoresis. From an analysis of previous publications, they concluded that up to one-fifth of mutations causing OI are recurrent in the sense that they are identical in apparently unrelated probands. About 80% of these identical mutations were found to be in CpG dinucleotide sequences. Korkko et al. (1997) tabulated reported cases of recurrent mutations causing OI. The most frequent recurrent mutation was gly352ser (120150.0042), reported in 4 unrelated patients. They also reported a nonsense mutation in the codon for arginine-963 (120150.0055). Since collagen I consists of 2 alpha-1 chains and 1 alpha-2 chain, a mutation in the COL1A1 gene might affect the function of the collagen molecule more than would a similar substitution in the COL1A2 gene, thereby causing more severe OI, for example. Lund et al. (1997) tested this hypothesis by comparing patients with identical substitutions in different alpha chains. They presented a G586V substitution in the alpha-1 gene (120150.0056) and compared it with a G586V substitution in the alpha-2 gene (120160.0023). Their patient had lethal OI type II. Patients with the same substitution in the alpha-2 chain had either OI type IV (166220) or type III (259420). Lund et al. (1997) pointed out that identical biochemical alterations in the same chain are known to have different phenotypic effects, both within families and between unrelated patients. They took this into account in their cautious proposal that substitutions in the alpha-1 chain may have more serious consequences than similar substitutions in the alpha-2 chain. Kuivaniemi et al. (1997) summarized the data on 278 different mutations found in genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. Most mutations (217; 78% of the total) were single-base and either changed the codon of a critical amino acid (63%) or led to abnormal RNA splicing (13%). Most (155; 56%) of the amino acid substitutions were those of a bulkier amino acid replacing the obligatory glycine of the repeating Gly-X-Y sequence of the collagen triple helix. Altogether, 26 different mutations (9.4%) occurred in more than 1 unrelated individual. The 65 patients in whom the 26 mutations were characterized constituted almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in these 6 collagens caused a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV (130050) and VII (130060) Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familiar aneurysms. (The amino acid numbering system for collagen involves assigning number 1 to the first glycine of the triple-helical domain of an alpha chain. The numbers for the alpha-1 chain of type I collagen can be converted to positions in the pro-alpha-1 chain by adding 156, and the numbers for the alpha-2 chain can be converted to the human pro-alpha-2 chain by adding 68.) Dalgleish (1997) described a mutation database for the COL1A1 and COL1A2 genes. Mutations in the COL1A2 gene appear to be very rare causes of type I osteogenesis imperfecta. Korkko et al. (1998) developed a method for analysis of the COL1A1 and COL1A2 genes in 15 patients with type I OI and found only COL1A1 mutations. They described their protocols for PCR amplification of the exon and exon boundaries of all 103 exons in the COL1A1 and COL1A2 genes. As previously pointed out, most mutations found in patients with OI type I introduce either premature termination codons or aberrant RNA splicing and thereby reduce the expression of the COL1A1 gene. The mutations tend to occur in common sequence context. All 9 mutations, found by Korkko et al. (1998) to convert the arginine codon CGA to the premature-termination codon TGA, occurred in the sequence context of G/CCC CGA GG/T of the COL1A1 gene. None was found in 7 CGA codons for arginine in other sequence contexts of the COL1A1 gene. The COL1A1 gene has 6 such sequences, whereas the COL1A2 gene has none. Triple helix formation is a prerequisite for the passage of type I procollagen from the endoplasmic reticulum and secretion from the cell to form extracellular fibrils that will support mineral deposition in bone. In an analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta, Pace et al. (2001) found 11 novel, short in-frame deletions or duplications of 3, 9, or 18 nucleotides in the helical coding regions of the COL1A1 or COL1A2 collagen genes. Triple helix formation was impaired, type I collagen alpha chains were posttranslationally overmodified, and extracellular secretion was markedly reduced. With one exception, the obligate Gly-Xaa-Yaa repeat pattern of amino acids in the helical domains was not altered, but the Xaa and Yaa position residues were out of register relative to the amino acid sequences of adjacent chains in the triple helix. Thus, the identity of these amino acids, in addition to third position glycines, is important for normal helix formation. These findings expanded the repertoire of uncommon in-frame deletions and duplications in OI, and provided insight into normal collagen biosynthesis and collagen triple helix formation. Cabral et al. (2001) reported a 13-year-old girl with severe type III OI in whom they identified heterozygosity for a gly76-to-glu substitution in the COL1A1 gene (120150.0065). The authors stated that this was the first delineation of a glutamic acid substitution in the alpha-1(I) chain causing nonlethal osteogenesis imperfecta. Chamberlain et al. (2004) used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 collagen genes in mesenchymal stem cells, also known as marrow stromal cells, from individuals with severe OI, demonstrating successful gene targeting in adult human stem cells. ### Ehlers-Danlos Syndromes In 2 unrelated patients with classic EDS (EDSCL1; 130000), Nuytinck et al. (2000) identified an arg134-to-cys mutation (120150.0059) in the COL1A1 gene. Cabral et al. (2005) identified 7 children with the combination of skeletal fragility and characteristics of Ehlers-Danlos syndrome. In each child they identified a mutation in the first 90 residues of the helical region of alpha-1(I) collagen. These mutations prevented or delayed removal of the procollagen N-propeptide by purified N-proteinase (ADAMTS2; 604539) in vitro and in pericellular assays. The mutant pN-collagen which resulted was efficiently incorporated into matrix by cultured fibroblasts and osteoblasts and was prominently present in newly incorporated and immaturely cross-linked collagen. Dermal collagen fibrils had significantly reduced cross-sectional diameters, corroborating incorporation of pN-collagen into fibrils in vivo. The mutations disrupted disrupted a distinct folding region of high thermal stability in the first 90 residues at the amino end of type I collagen and altered the secondary structure of the adjacent N-proteinase cleavage site. Thus, these mutations are directly responsible for the bone fragility of OI and indirectly responsible for EDS symptoms, by interference with N-propeptide removal. Cabral et al. (2005) hypothesized that the nature of EDS-like symptoms in OI/EDS patients is similar to type VII EDS derived primarily by deletions of the N-propeptide cleavage site in alpha-1(I) and alpha-2(I) (120160) chains, in EDS VIIA (EDSARTH1; 130060) and VIIB (EDSARTH2; 617821), respectively, or by N-proteinase deficiency in EDS VIIC (EDSDRMS; 225410). It remained unclear why alpha-1(I)-OI/EDS patients had a somewhat different EDS phenotype (e.g., pronounced early scoliosis and no bilateral hip dysplasia) and why their collagen fibrils had more rounded cross-section under electron microscopy investigation. Makareeva et al. (2006) demonstrated that 85 N-terminal amino acids of the alpha1(I) chain participate in a highly stable folding domain, acting as the stabilizing anchor for the amino end of the type I collagen triple helix. This anchor region is bordered by a microunfolding region, 15 amino acids in each chain, which includes no proline or hydroxyproline residues and contains a chymotrypsin cleavage site. Glycine substitutions and amino acid deletions within the N-anchor domain induced its reversible unfolding above 34 degrees C. The overall triple helix denaturation temperature was reduced by 5 to 6 degrees C, similar to complete N-anchor removal. N-propeptide partially restored the stability of mutant procollagen but not sufficiently to prevent N-anchor unfolding and a conformational change at the N-propeptide cleavage site. The ensuing failure of N-proteinase to cleave at the misfolded site led to incorporation of pN-collagen into fibrils. As in EDS VIIA/B, fibrils containing pN-collagen are thinner and weaker causing EDS-like laxity of large and small joints and paraspinal ligaments. Makareeva et al. (2006) concluded that distinct structural consequences of N-anchor destabilization result in a distinct alpha1(I)-OI/EDS phenotype. ### Caffey Disease In affected individuals and obligate carriers from 3 unrelated families with Caffey disease (114000), Gensure et al. (2005) identified heterozygosity for an arg836-to-cys mutation (R836C; 120150.0063) in the COL1A1 gene. Kamoun-Goldrat et al. (2008) identified heterozygosity for the R836C mutation in the COL1A1 gene in the pulmonary tissue of a fetus with a severe form of prenatal cortical hyperostosis (see 114000) from a terminated pregnancy at 30 weeks' gestation. The authors speculated that mutation in another gene might also be involved. ### Susceptibility to Osteoporosis Osteoporosis (166710) is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COL1A1. Grant et al. (1996) described a novel G-to-T transversion at the first base of a binding site for the transcription factor Sp1 (189906) in intron 1 of COL1A1 (rs1800012; 120150.0051). They found that the polymorphism was associated with low bone density and increased appearance of osteoporotic vertebral fractures in 299 British women. In a study of 1,778 postmenopausal Dutch women, Uitterlinden et al. (1998) confirmed the association of the Sp1-binding site polymorphism and bone mineral density. Lohmueller et al. (2003) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations. For 8 of the 25 associations, strong evidence of replication of the initial report was available. One of these 8 was the association between COL1A1 and osteoporotic fracture as first reported by Grant et al. (1996). Of a G/T SNP in intron 1, osteoporotic fractures showed association with the T allele. In 1,873 Caucasian subjects from 405 nuclear families, Long et al. (2004) examined the relationship between 3 SNPs in the COL1A1 gene and bone size at the spine, hip, and wrist. They found suggestive evidence for an association with wrist size at SNP2 (p = 0.011): after adjusting for age, sex, height, and weight, subjects with the T allele of SNP2 had, on average, a 3.05% smaller wrist size than noncarriers. Long et al. (2004) concluded that the COL1A1 gene may have some effect on bone size variation at the wrist, but not at the spine or hip, in these families. Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains. Genotype/Phenotype Correlations Di Lullo et al. (2002) stated that binding sites on type I collagen had been elucidated for approximately half of the almost 50 molecules that had been found to interact with it. In addition, more than 300 mutations in type I collagen associated with human connective tissue disorders had been described. However, the spatial relationships between the ligand-binding sites and mutation positions had not been examined. Di Lullo et al. (2002) therefore created a map of type I collagen that included all of its ligand-binding sites and mutations. The map revealed several hotspots for ligand interactions on type I collagen and showed that most of the binding sites locate to its C-terminal half. Moreover, some potentially relevant relationships between binding sites were observed on the collagen fibril, including the following: fibronectin- and certain integrin-binding regions are near neighbors, which may mechanistically relate to fibronectin-dependent cell-collagen attachment; proteoglycan binding may influence collagen fibrillogenesis, cell-collagen attachment, and collagen glycation seen in diabetes and aging; and mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype. A missense mutation leading to the replacement of 1 Gly in the (Gly-Xaa-Yaa)n repeat of the collagen triple helix can cause a range of heritable connective tissue disorders that depend on the gene in which the mutation occurs. Persikov et al. (2004) found that the spectrum of amino acids replacing Gly was not significantly different from that expected for the COL7A1 (120120)-encoded collagen chains, suggesting that any Gly replacement will cause dystrophic epidermolysis bullosa (604129). On the other hand, the distribution of residues replacing Gly was significantly different from that expected for all other collagen chains studied, with a particularly strong bias seen for the collagen chains encoded by COL1A1 and COL3A1 (120180). The bias did not correlate with the degree of chemical dissimilarity between gly and the replacement residues, but in some cases a relationship was observed with the predicted extent of destabilization of the triple helix. Of the COL1A1-encoded chains, the most destabilizing residues (valine, glutamic acid, and aspartic acid) and the least destabilizing residue (alanine) were underrepresented. This bias supported the hypothesis that the level of triple-helix destabilization determines clinical outcome. In an extensive review of published and unpublished sources, Marini et al. (2007) identified and assembled 832 independent mutations in the type I collagen genes (493 in COL1A1 and 339 in COL1A2). There were 682 substitutions of glycine residues within the triple-helical domains of the proteins (391 in COL1A1 and 291 in COL1A2) and 150 splice site mutations (102 in COL1A1 and 48 in COL1A2). One-third of the mutations that result in glycine substitutions in COL1A1 were lethal, whereas substitutions in the first 200 residues were nonlethal and had variable outcomes unrelated to folding or helix stability domains. Two exclusively lethal regions, helix positions 691-823 and 910-964, aligned with major ligand binding regions. Mutations in COL1A2 were predominantly nonlethal (80%), but lethal regions aligned with proteoglycan bindings sites. Splice site mutations accounted for 20% of helical mutations, were rarely lethal, and often led to a mild phenotype. Rauch et al. (2010) compared the results of genotype analysis and clinical examination in 161 patients who were diagnosed as having OI type I, III, or IV according to the Sillence classification (median age: 13 years) and had glycine mutations in the triple-helical domain of alpha-1(I) (n = 67) or alpha-2(I) (n = 94). There were 111 distinct mutations, of which 38 affected the alpha-1(I) chain and 73 the alpha-2(I) chain. Serine substitutions were the most frequently encountered type of mutation in both chains. Overall, the majority of patients had a phenotypic diagnosis of OI type III or IV, had dentinogenesis imperfecta and blue sclera, and were born with skeletal deformities or fractures. Compared with patients with serine substitutions in alpha-2(I) (n = 40), patients with serine substitutions in alpha-1(I) (n = 42) on average were shorter (median height z-score -6.0 vs -3.4; P = 0.005), indicating that alpha-1(I) mutations cause a more severe phenotype. Height correlated with the location of the mutation in the alpha-2(I) chain but not in the alpha-1(I) chain. Patients with mutations affecting the first 120 amino acids at the N-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta. Among patients from different families sharing the same mutation, about 90% and 75% were concordant for dentinogenesis imperfecta and blue sclera, respectively. Takagi et al. (2011) reported 4 Japanese patients, including 2 unrelated patients with what the authors called 'classic OI IIC' and 2 sibs with features of 'OI IIC' but less distortion of the tubular bones (OI dense bone variant). No consanguinity was reported in their parents. In both sibs and 1 sporadic patient, they identified heterozygous mutations in the C-propeptide region of COL1A1 (120150.0069 and 120150.0070, respectively), whereas no mutation in this region was identified in the other sporadic patient. Familial gene analysis revealed somatic mosaicism of the mutation in the clinically unaffected father of the sibs, whereas their mother and healthy older sister did not have the mutation. Histologic examination in the 2 sporadic cases showed a network of broad, interconnected cartilaginous trabeculae with thin osseous seams in the metaphyseal spongiosa. Thick, cartilaginous trabeculae (cartilaginous cores) were also found in the diaphyseal spongiosa. Chondrocyte columnization appeared somewhat irregular. These changes differed from the narrow and short metaphyseal trabeculae found in other lethal or severe cases of OI. Takagi et al. (2011) concluded that heterozygous C-propeptide mutations in the COL1A1 gene may result in OI IIC with or without twisting of the long bones and that OI IIC appears to be inherited as an autosomal dominant trait. Cytogenetics ### COL1A1/PDGFB Fusion Gene Dermatofibrosarcoma protuberans (DFSP; 607907), an infiltrative skin tumor of intermediate malignancy, presents specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary ring chromosomes derived from t(17;22). Simon et al. (1997) characterized the breakpoints from translocations and rings in dermatofibrosarcoma protuberans and its juvenile form, giant cell fibroblastoma, on the genomic and RNA levels. They found that these rearrangements fuse the PDGFB gene (190040) and the COL1A1 gene. Simon et al. (1997) commented that PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes was not fully understood. They noted that neither COL1A1 nor PDGFB had hitherto been implicated in tumor translocations. The gene fusions deleted exon 1 of PDGFB and released this growth factor from its normal regulation; see 190040.0002. Nakanishi et al. (2007) used RT-PCR to examine the COL1A1/PDGFB transcript using frozen biopsy specimens from 3 unrelated patients with DFSP and identified fusion of COL1A1 exon 25, exon 31, and exon 46, respectively, to exon 2 of the PDGFB gene. Clinical features and histopathology did not demonstrate any specific characteristics associated with the different transcripts. Biochemical Features Gauba and Hartgerink (2008) reported the design of a novel model system based upon collagen-like heterotrimers that can mimic the glycine mutations present in either the alpha-1 or alpha-2 chains of type I collagen. The design utilized an electrostatic recognition motif in 3 chains that can force the interaction of any 3 peptides, including AAA (all same), AAB (2 same and 1 different), or ABC (all different) triple helices. Therefore, the component peptides could be designed in such a way that glycine mutations were present in zero, 1, 2, or all 3 chains of the triple helix. They reported collagen mutants containing 1 or 2 glycine substitutions with structures relevant to native forms of OI. Gauba and Hartgerink (2008) demonstrated the difference in thermal stability and refolding half-life times between triple helices that vary only in the frequency of glycine mutations at a particular position. By differential scanning calorimetry and circular dichroism, Makareeva et al. (2008) measured and mapped changes in the collagen melting temperature (delta-T(m)) for 41 different glycine substitutions from 47 OI patients. In contrast to peptides, they found no correlation of delta-T(m) with the identity of the substituting residue but instead observed regular variations in delta-T(m) with the substitution location on different triple helix regions. To relate the delta-T(m) map to peptide-based stability predictions, the authors extracted the activation energy of local helix unfolding from the reported peptide data and constructed the local helix unfolding map and tested it by measuring the hydrogen-deuterium exchange rate for glycine NH residues involved in interchain hydrogen bonds. Makareeva et al. (2008) delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the delta-T(m) map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the alpha-1(I) chain. Animal Model Pereira et al. (1993) established a line of transgenic mice that expressed moderate levels of an internally deleted human COL1A1 gene. The gene construct was modeled after a sporadic in-frame deletion that produced a lethal variant of OI. About 6% of the transgenic mice had a lethal phenotype with extensive fractures at birth, and 33% had fractures but were viable. The remaining 61% of the transgenic mice had no apparent fractures as assessed by x-ray examination on the day of birth. Brother-sister matings produced 8 litters in which approximately 40% of the mice had the lethal phenotype, indicating that expression of the transgene was more lethal in homozygous mice. The shortened collagen polypeptide chains synthesized from the human transgene were thought to bind to and produce degradation of the normal collagen genes synthesized from the normal mouse alleles. Khillan et al. (1994) extended these studies using an antisense gene. The strategy of specifically inhibiting expression of a gene with antisense RNA generated from an inverted gene was introduced in 1984 (Izant and Weintraub, 1984; Mizuno et al., 1984; and Pestka et al., 1984). Khillan et al. (1994) assembled an antisense gene that was similar to the internally deleted COL1A1 minigene used by Pereira et al. (1993) except that the 3-prime half of the gene was inverted so as to code for an antisense RNA. Transgenic mice expressing the antisense gene had a normal phenotype, apparently because the antisense gene contained human sequences instead of mouse sequences. Two lines of mice expressing the antisense gene were bred to 2 lines of transgenic mice expressing the minigene. In mice that inherited both genes, the incidence of the lethal fragile bone phenotype was reduced from 92 to 27%. The effect of the antisense gene was directly demonstrated by an increase in the ratio of normal mouse pro-alpha-1(I) chains to human mini-chains in tissues from mice that inherited both genes and had a normal phenotype. The results raised the possibility that chimeric gene constructs that contain intron sequences and in which only the first half of a gene is inverted may be particularly effective as antisense genes. Pereira et al. (1994) used an inbred strain of transgenic mice expressing a mutated COL1A1 gene to demonstrate interesting features concerning phenotypic variability and incomplete penetrance. These phenomena are striking in families with osteogenesis imperfecta and are usually explained by differences in genetic background or in environmental factors. The inbred strain of transgenic mice expressing an internally deleted COL1A1 gene was bred to wildtype mice of the same strain so that the inheritance of proneness to fracture could be examined in a homogeneous genetic background. To minimize the effects of environmental factors, the phenotype was evaluated in embryos that were removed from the mother one day before term. Examination of stained skeletons from 51 transgenic embryos from 11 separate litters demonstrated that approximately 22% had a severe phenotype with extensive fractures of both long bones and ribs, approximately 51% had a mild phenotype with fractures of ribs only, and approximately 27% had no fractures. The ratio of steady-state levels of the mRNA from the transgene to the level of mRNA from the endogenous gene was the same in all transgenic embryos. The results demonstrated that the phenotypic variability and incomplete penetrance were not explained by variation in genetic background or levels in gene expression. Pereira et al. (1994) concluded from these results that phenotypic variation may be an inherent characteristic of the mutated collagen gene. Pereira et al. (1998) studied a transgenic model of osteogenesis imperfecta (OI) in mice who expressed a mini-COL1A1 gene containing a large in-frame deletion. Marrow stromal cells from wildtype mice were infused into OI-transgenic mice. In mice that were irradiated with potentially lethal levels or sublethal levels, DNA from the donor marrow stromal cells was detected consistently in marrow, bone, cartilage, and lung at either 1 or 2.5 months after the infusion. The DNA also was detected, but less frequently, in the spleen, brain, and skin. There was a small but statistically significant increase in both collagen content and mineral content of bone 1 month after the infusion. In experiments in which male marrow stromal cells were infused into a female OI-transgenic mouse, fluorescence in situ hybridization assays for the Y chromosome indicated that after 2.5 months, donor male cells accounted for 4 to 19% of the fibroblasts or fibroblast-like cells obtained from primary cultures of the lung, calvaria, cartilage, long bone, tail, and skin. The results supported previous suggestions that marrow stromal cells or related cells in marrow serve as a source for continual renewal of cells in a number of nonhematopoietic tissues. Aihara et al. (2003) evaluated intraocular pressure (IOP) in transgenic mice with a targeted mutation in the Col1a1 gene and found that the mice had ocular hypertension. The authors suggested an association between IOP regulation and fibrillar collagen turnover. The mouse mutation 'abnormal gait-2' (Aga2) was identified in an N-ethyl-N- nitrosourea mutagenesis screen. Lisse et al. (2008) identified the Aga2 mutation as a T-to-A transversion within intron 50 of the Col1a1 gene, which introduced a novel 3-prime splice acceptor site that resulted in a frameshift. The mutant protein was predicted to have a novel C terminus that lacked a critical cysteine. Homozygosity for Aga2 was embryonic lethal. Heterozygous Aga2 (Aga2/+) animals showed early lethality, and surviving heterozygotes had widely variable phenotypes that included loss of bone mass, fractures, deformity, osteoporosis, and disorganized trabecular and collagen structures. Abnormal pro-Col1a1 chains accumulated intracellularly in Aga2/+ dermal fibroblasts and were poorly secreted. Intracellular accumulation of Col1a1 was associated with induction of an endoplasmic reticulum stress response and apoptosis characterized by caspase-12 (CASP12; 608633) and caspase-3 (CASP3; 600636) activation in vitro and in vivo. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	COLLAGEN, TYPE I, ALPHA-1	c1852924	4,685	omim	https://www.omim.org/entry/120150	2019-09-22T16:43:08	{"mesh": ["C565178"], "omim": ["120150"], "synonyms": ["Alternative titles", "COLLAGEN OF SKIN, TENDON, AND BONE, ALPHA-1 CHAIN"]}
2q33.1 microdeletion syndrome is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 2, with a highly variable phenotype typically characterized by severe intellectual disability, moderate to severe developmental delay (particularly speech), feeding difficulties, failure to thrive, hypotonia, thin, sparse hair, various dental abnormalities and cleft/high-arched palate. Typical dysmorphic features inlcude high, prominent forehead, down-slanting palpebral fissures and prominent nasal bridge with beaked nose. Various behavioral problems (e.g. hyperactivity, chaotic/repetitive behavior, touch avoidance) are also associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	SATB2-associated syndrome due to a chromosomal rearrangement	c2676739	4,686	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251028	2021-01-23T19:09:36	{"mesh": ["C567350"], "omim": ["612313"], "icd-10": ["Q93.5"], "synonyms": ["2q33.1 microdeletion syndrome", "Del(2)(q33.1)", "Monosomy 2q33.1"]}
Idiopathic recurrent pericarditis is a rare autoinflammatory syndrome defined as recurrence of pericardial inflammation of unknown origin following the first episode of acute pericarditis and a symptom-free interval of 4-6 weeks or longer. Recurrent attacks of chest pain may be the sole presentation or the chest pain may be accompanied by pericardial friction rub, electrocardiographic or echocardiographic changes, pericardial effusion and increased C-reactive protein. Cardiac tamponade is a rare, life-threatening complication. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Idiopathic recurrent pericarditis	c4707790	4,687	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251307	2021-01-23T18:15:43	{"icd-10": ["I09.2"], "synonyms": ["Idiopathic relapsing pericarditis"]}
A number sign (#) is used with this entry because osteogenesis imperfecta type IV (OI4) is caused by heterozygous mutation in the COL1A1 gene (120150) or the COL1A2 gene (120160). Description Osteogenesis imperfecta (OI) is a connective tissue disorder that is caused by an abnormality of type I collagen in over 90% of cases. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes: OI type I with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclera (259420); and OI type IV, with normal sclerae. Levin et al. (1978) suggested that OI subtypes could be further divided into types A and B based on the absence or presence of dentinogenesis imperfecta. Clinical Features On the basis of a study in Australia, Sillence et al. (1979) concluded that in addition to dominantly inherited osteogenesis imperfecta with blue sclerae (OI type I) there is a variety with normal sclerae. This agreed with the distinction made by Bauze et al. (1975) and Francis et al. (1975) between 'blue-eyed' and 'white-eyed' OI, and supported by a biochemical difference. Sillence et al. (1979) found only 2 families with the 'white-eyed' type as contrasted with the many 'blue-eyed' families. They suggested that the family reported by Holcomb (1931) fell into the 'blue-eyed' category. Neither blue sclerae nor deafness was noted in the families reported by Ekman (1788) or by Lobstein (1835). Johnson et al. (2002) reported a 35-year-old woman and 2 of her children with what the authors termed a 'variant' of OI type IVB. The woman had shown shortening of the limbs with severe angular malformations of the femora at birth. From 3 months to 1 year, her legs were maintained in plaster casts, which slightly improved the bowing. After starting to walk, her lower limbs showed significant improvement that lasted throughout adulthood. She had pale blue sclerae, which can occur in up to 10% of cases of OI type IV, easy bruising, 3 broken bones in her lifetime, recent development of lumbar spondylolisthesis, and dentinogenesis imperfecta. A son and daughter were shown to be severely affected during gestation. Johnson et al. (2002) noted that the proband had originally been classified as having kyphomelic dysplasia (211350), but molecular analysis showed a mutation in the COL1A2 gene (120160.0050). Biochemical Features From the cultured skin fibroblasts in a patient with type IV OI, Wenstrup et al. (1986) found that 2 populations of type I procollagen molecules were synthesized. The total amount of type I procollagen and the ratio of alpha-1 to alpha-2 chains were normal. The difference was shown to be due to excessive posttranslational modification in the case of one molecule. It appeared, furthermore, that incorporation of an abnormal chain into the triple helix resulted in excessive modification of all three chains; whether the alpha-1 or the alpha-2 chain was the site of mutation was not identified. The change was thought to involve the COOH-propeptide of the molecule. The biochemical abnormality had been found previously only in perinatal lethal OI type II. In a large kindred in which linkage studies indicated abnormality of the alpha-2 chain of type 1 collagen, Wenstrup et al. (1986) found that fibroblasts from 2 affected persons synthesized 2 populations of alpha-2 chains: one normal population and one with a deletion of about 10 amino acids from the middle of the triple helical domain. Diagnosis Byers et al. (2006) published practice guidelines for the genetic evaluation of suspected OI. ### Prenatal Diagnosis In a family with type IV OI genetically linked to the COL1A2 gene, Tsipouras et al. (1987) showed by linkage analysis that a fetus was unaffected, having inherited the normal COL1A2 allele from her affected parent. De Vos et al. (2000) reported the achievement of healthy twins by preimplantation genetic diagnosis in a couple in which the male partner carried a G-to-A substitution in exon 19 of the COL1A2 gene which resulted in a gly247-to-ser (G247S) missense change. Clinical Management Plotkin et al. (2000) studied 9 severely affected OI patients under 2 years of age (2.3 to 20.7 months at entry), 8 of whom had type III OI and 1 of whom had type IV OI, for a period of 12 months. Pamidronate was administered intravenously in cycles of 3 consecutive days. Patients received 4 to 8 cycles during the treatment period, with cumulative doses averaging 12.4 mg/kg. Clinical changes were evaluated regularly during treatment, and radiologic changes were assessed after 6 to 12 months of treatment. The control group consisted of 6 age-matched, severely affected OI patients who had not received pamidronate treatment. During treatment bone mineral density (BMD) increased between 86% and 227%. The deviation from normal, as indicated by the z-score, diminished from -6.5 +/- 2.1 to -3.0 +/- 2.1 (P less than 0.001). In the control group, the BMD z-score worsened significantly. Vertebral coronal area increased in all treated patients (11.4 +/- 3.4 to 14.9 +/- 1.8 cm2; P less than 0.001), but decreased in the untreated group (P less than 0.05). In the treated patients, fracture rate was lower than in control patients (2.6 +/- 2.5 vs 6.3 +/- 1.6 fractures/year; P less than 0.01). No adverse side effects were noted, apart from the well-known acute phase reaction during the first infusion cycle. The authors concluded that pamidronate treatment in severely affected OI patients under 3 years of age is safe, increases BMD, and decreases fracture rate. Astrom and Soderhall (2002) performed a prospective observational study using disodium pamidronate (APD) in 28 children and adolescents (aged 0.6 to 18 years) with severe OI or a milder form of the disease, but with spinal compression fractures. All bone metabolism variables in serum (alkaline phosphatase, osteocalcin, procollagen-1 C-terminal peptide, collagen-1 teleopeptide) and urine (deoxypyridinoline) indicated that there was a decrease in bone turnover. All patients experienced beneficial effects, and the younger patients showed improvement in well-being, pain, and mobility without significant side effects. Vertebral remodeling was also seen. They concluded that APD seemed to be an efficient symptomatic treatment for children and adolescents with OI. Rauch et al. (2002) compared parameters of iliac bone histomorphometry in 45 patients (23 girls, 22 boys) with OI type I, III, or IV before and after 2.4 +/- 0.6 years of treatment with cyclical intravenous pamidronate (age at the time of the first biopsy, 1.4 to 17.5 years). There was an increase in bone mass due to increases in cortical width and trabecular number. The bone surface-based indicators of cancellous bone remodeling, however, were decreased. There was no evidence of a mineralization defect in any of the patients. Lindsay (2002) reviewed the mechanism, effects, risks, and benefits of bisphosphonate therapy in children with OI. He stated that the clinical course and attendant morbidity for many children with severe OI is clearly improved with its judicious use. Nevertheless, since bisphosphonates accumulate in the bone and residual levels are measurable after many years, the long-term safety of this approach was unknown. He recommended that until long-term safety data were available, pamidronate intervention be reserved for those for whom the benefits clearly outweighed the risks. Rauch et al. (2003) evaluated the effect of intravenous therapy with pamidronate on bone and mineral metabolism in 165 patients with OI types I, III, and IV. All patients received intravenous pamidronate infusions on 3 successive days, administered at age-dependent intervals of 2 to 4 months. During the 3 days of the first infusion cycle, serum concentrations of ionized calcium dropped and serum PTH levels transiently almost doubled. Two to 4 months later, ionized calcium had returned to pretreatment levels. During 4 years of pamidronate therapy, ionized calcium levels remained stable, but PTH levels increased by about 30%. In conclusion, serum calcium levels can decrease considerably during and after pamidronate infusions, requiring close monitoring especially at the first infusion cycle. In long-term therapy, bone turnover is suppressed to levels lower than those in healthy children. The authors stated that the consequences of chronically low bone turnover in children with OI were unknown. Zeitlin et al. (2003) analyzed longitudinal growth during cyclical intravenous pamidronate treatment in children and adolescents (ages 0.04 to 15.6 years at baseline) with moderate to severe forms of OI types I, III, and IV and found that 4 years of treatment led to a significant height gain. Rauch et al. (2006) studied the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 years). The intervention was discontinuation of pamidronate treatment for 2 years. The results indicated that bone mass gains continue after treatment is stopped, but that lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent. In a cohort of 540 individuals with OI studied longitudinally, Bellur et al. (2016) conducted a study to address whether cesarean delivery has an effect on at-birth fracture rates and whether an antenatal diagnosis of OI influences the choice of delivery method. They compared self-reported at-birth fracture rates among individuals with OI types I (166200), III (259420), and IV. When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was vaginal or by cesarean section. Increased birth weight conferred conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing cesarean delivery. The authors recommended that cesarean delivery should not be performed for the sole purpose of fracture prevention in OI, but only for other maternal or fetal indications. Mapping To study 10 families with mild OI, Tsipouras et al. (1985) used 3 RFLPs associated with the alpha-2(I) collagen gene (COL1A2) known to be on chromosome 7. The 4 families with type IV OI showed tight linkage: maximum lod = 3.91 at theta 0.0. The 6 OI type I families showed very low positive lod scores at high values of theta. Reporting on the same study, Falk et al. (1986) found linkage between type IV OI and RFLPs of the alpha-2(I) procollagen gene. Heterogeneity Kamoun-Goldrat et al. (2008) described a father and son from a consanguineous Algerian family who had typical features of OI type IV but an improving course of the disease: severe modification of the long bones with complete improvement during growth. Both had blue sclerae and the son had dentinogenesis imperfecta. The disorder did not segregate with the COL1A1 or COL1A2 genes, no mutations in the coding sequences of these genes were identified by DHLPC analysis and cDNA sequencing, and Northern blot analysis did not indicate quantitative or qualitative abnormalities in collagen I mRNAs. Sequencing showed no evidence of alterations in the CRTAP (605497) gene, and father and son were heterozygous for markers surrounding the LEPRE1 gene (610339). Kamoun-Goldrat et al. (2008) identified a region of high concordance of homozygosity between markers D11S4127 and D11S4094 on chromosome 11q23.3-q24.1 in the father and son. Molecular Genetics In a child with OI type IV, Marini et al. (1989) identified a mutation in the COL1A1 gene (120150.0012). See also de Vries and de Wet (1986) and 120150.0003. In a patient with OI type IV, Wenstrup et al. (1988) identified a mutation in the COL1A2 gene (120160.0004), which resulted in increased posttranslational modification along the triple-helical domain. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature, often below 5th percentile HEAD & NECK Ears \- Hearing loss \- Otosclerosis Eyes \- Normal-greyish sclerae \- Pale blue sclerae (10% of the cases) Teeth \- Dentinogenesis imperfecta SKELETAL \- Mild-moderate skeletal deformity \- Varying degree of multiple fractures Skull \- Wormian bones Spine \- Scoliosis \- Kyphosis \- Biconcave flattened vertebrae Limbs \- Femoral bowing present at birth, straightening with time \- Bowed limbs due to multiple fractures MISCELLANEOUS \- Often identified in newborn period \- Fractures can occur in utero, during labor and delivery, or in newborn period \- Fractures occur in first few months, then decrease in frequency and then occur with ambulation \- Fractures decrease after puberty but increase after menopause MOLECULAR BASIS \- Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A1, 120150.0003 ) \- Caused by mutation in the collagen I, alpha-2 polypeptide gene (COL1A2, 120160.0004 ) ▲ 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	OSTEOGENESIS IMPERFECTA, TYPE IV	c0268363	4,688	omim	https://www.omim.org/entry/166220	2019-09-22T16:37:02	{"doid": ["0110340"], "mesh": ["C536045"], "omim": ["166220"], "orphanet": ["216820", "666"], "synonyms": ["Alternative titles", "OI, TYPE IV", "OSTEOGENESIS IMPERFECTA WITH NORMAL SCLERAE"], "genereviews": ["NBK1295"]}
Townes–Brocks syndrome This condition is inherited in an autosomal dominant manner SpecialtyMedical genetics Townes–Brocks syndrome[1] (TBS) is a rare genetic disease that has been described in approximately 200 cases in the published literature. It affects both males and females equally.[2] The condition was first identified in 1972.[2] by Philip L. Townes, who was at the time a human geneticists and Professor of Pediatrics, and Eric Brocks, who was at the time a medical student, both at the University of Rochester. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Notes * 6 External links ## Signs and symptoms[edit] TBS patients may have the following symptoms:[3] * Abnormalities of the external ears (unusually large or small, unusually shaped, sometimes with sensorineural hearing loss or deafness due to lesions or dysfunctions of part of the internal ear or its nerve tracts and centers or conductive hearing loss from the external or middle ear), dysplastic ears, lop ear (over-folded ear helix), preauricular tags or pits (a rudimentary tag of ear tissue typically located just in front of the ear). * Anorectal malformations, including imperforate anus/absence of an anal opening, rectovaginal fistula, anal stenosis, unusually placed anus. * Kidney abnormalities, sometimes leading to impaired kidney function or kidney failure, including hypoplastic kidneys (underdeveloped), multicystic kidneys, dysplastic kidneys. * Heart abnormalities, including tetralogy of fallot and defects of the ventricular septum. * Hand and foot abnormalities, such as hypoplastic thumbs, fingerlike thumbs, syndactyly (webbed fingers/toes), fusion of the wrist bones, overlapping foot and/or toe bones. Learning difficulties have been reported in some children with TBS. For others, intelligence is within the normal range. These abnormalities, which are present prenatally, can range from minor to severe, and as with similar disorders, most individuals with this condition have some, but not all, of these traits. ## Causes[edit] TBS is an autosomal dominant involving the a mutation of the gene SALL1, which encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. The clinical features of TBS overlap with VATER and VACTERL associations, oculo-auriculo-vertebral (OAV) spectrum, branchio-oto-renal (BOR) syndrome, and Fanconi anemia and other 'anus-hand-ear' syndromes.[4] Although some symptoms can be life-threatening, many people diagnosed with Townes-Brocks Syndrome live a normal lifespan.[2] ## Diagnosis[edit] This section is empty. You can help by adding to it. (May 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (May 2017) ## Notes[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 894. ISBN 978-1-4160-2999-1. 2. ^ a b c Contact a Family Archived 2006-09-24 at the Wayback Machine 3. ^ National Organization for Rare Diseases 4. ^ GeneDX Archived 2006-10-16 at Archive.today ## External links[edit] * GeneReview/NCBI/NIH/UW entry on Townes-Brocks Syndrome Classification D * ICD-10: Q87.8 * OMIM: 107480 * MeSH: C536974 * DiseasesDB: 32163 * SNOMED CT: 24750000 External resources * Orphanet: 857 * v * t * e Genetic disorders relating to deficiencies of transcription factor or coregulators (1) Basic domains 1.2 * Feingold syndrome * Saethre–Chotzen syndrome 1.3 * Tietz syndrome (2) Zinc finger DNA-binding domains 2.1 * (Intracellular receptor): Thyroid hormone resistance * Androgen insensitivity syndrome * PAIS * MAIS * CAIS * Kennedy's disease * PHA1AD pseudohypoaldosteronism * Estrogen insensitivity syndrome * X-linked adrenal hypoplasia congenita * MODY 1 * Familial partial lipodystrophy 3 * SF1 XY gonadal dysgenesis 2.2 * Barakat syndrome * Tricho–rhino–phalangeal syndrome 2.3 * Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome * Denys–Drash syndrome * Duane-radial ray syndrome * MODY 7 * MRX 89 * Townes–Brocks syndrome * Acrocallosal syndrome * Myotonic dystrophy 2 2.5 * Autoimmune polyendocrine syndrome type 1 (3) Helix-turn-helix domains 3.1 * ARX * Ohtahara syndrome * Lissencephaly X2 * MNX1 * Currarino syndrome * HOXD13 * SPD1 synpolydactyly * PDX1 * MODY 4 * LMX1B * Nail–patella syndrome * MSX1 * Tooth and nail syndrome * OFC5 * PITX2 * Axenfeld syndrome 1 * POU4F3 * DFNA15 * POU3F4 * DFNX2 * ZEB1 * Posterior polymorphous corneal dystrophy * Fuchs' dystrophy 3 * ZEB2 * Mowat–Wilson syndrome 3.2 * PAX2 * Papillorenal syndrome * PAX3 * Waardenburg syndrome 1&3 * PAX4 * MODY 9 * PAX6 * Gillespie syndrome * Coloboma of optic nerve * PAX8 * Congenital hypothyroidism 2 * PAX9 * STHAG3 3.3 * FOXC1 * Axenfeld syndrome 3 * Iridogoniodysgenesis, dominant type * FOXC2 * Lymphedema–distichiasis syndrome * FOXE1 * Bamforth–Lazarus syndrome * FOXE3 * Anterior segment mesenchymal dysgenesis * FOXF1 * ACD/MPV * FOXI1 * Enlarged vestibular aqueduct * FOXL2 * Premature ovarian failure 3 * FOXP3 * IPEX 3.5 * IRF6 * Van der Woude syndrome * Popliteal pterygium syndrome (4) β-Scaffold factors with minor groove contacts 4.2 * Hyperimmunoglobulin E syndrome 4.3 * Holt–Oram syndrome * Li–Fraumeni syndrome * Ulnar–mammary syndrome 4.7 * Campomelic dysplasia * MODY 3 * MODY 5 * SF1 * SRY XY gonadal dysgenesis * Premature ovarian failure 7 * SOX10 * Waardenburg syndrome 4c * Yemenite deaf-blind hypopigmentation syndrome 4.11 * Cleidocranial dysostosis (0) Other transcription factors 0.6 * Kabuki syndrome Ungrouped * TCF4 * Pitt–Hopkins syndrome * ZFP57 * TNDM1 * TP63 * Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8 Transcription coregulators Coactivator: * CREBBP * Rubinstein–Taybi syndrome Corepressor: * HR (Atrichia with papular lesions) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Townes–Brocks syndrome	c0265246	4,689	wikipedia	https://en.wikipedia.org/wiki/Townes%E2%80%93Brocks_syndrome	2021-01-18T18:34:16	{"gard": ["7784"], "mesh": ["C536974"], "umls": ["CN034849", "C0265246"], "icd-10": ["Q87.8"], "orphanet": ["857"], "wikidata": ["Q385774"]}
"Cocaine syndrome" redirects here. For the substance, see cocaine. For other uses, see Cockayne (disambiguation). Cockayne syndrome Other namesNeill-Dingwall syndrome SpecialtyMedical genetics, neurology, dermatology Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging.[1][2][3] Failure to thrive and neurological disorders are criteria for diagnosis, while photosensitivity, hearing loss, eye abnormalities, and cavities are other very common features.[3] Problems with any or all of the internal organs are possible. It is associated with a group of disorders called leukodystrophies, which are conditions characterized by degradation of neurological white matter. The underlying disorder is a defect in a DNA repair mechanism.[4] Unlike other defects of DNA repair, patients with CS are not predisposed to cancer or infection.[5] Cockayne syndrome is a rare but destructive disease usually resulting in death within the first or second decade of life. The mutation of specific genes in Cockayne syndrome is known, but the widespread effects and its relationship with DNA repair is yet to be well understood.[5] It is named after English physician Edward Alfred Cockayne (1880–1956) who first described it in 1936 and re-described in 1946.[6] Neill-Dingwall syndrome was named after Mary M. Dingwall and Catherine A. Neill.[6] These two scientists described the case of two brothers with Cockayne syndrome and asserted it was the same disease described by Cockayne. In their article the two contributed to the signs of the disease through their discovery of calcifications in the brain. They also compared Cockayne syndrome to what is now known as Hutchinson–Gilford progeria syndrome (HGPS), then called progeria, due to the advanced aging that characterizes both disorders.[6] ## Contents * 1 Types * 2 Causes * 3 Genetics * 4 Mechanism * 5 Diagnosis * 5.1 Laboratory Studies * 5.2 Imaging Studies * 5.3 Other Tests * 5.4 Neurology * 6 Treatment * 7 Prognosis * 8 Epidemiology * 9 Recent research * 10 See also * 11 References * 12 External links ## Types[edit] * CS Type I, the "classic" form, is characterized by normal fetal growth with the onset of abnormalities in the first two years of life. Vision and hearing gradually decline.[7] The central and peripheral nervous systems progressively degenerate until death in the first or second decade of life as a result of serious neurological degradation. Cortical atrophy is less severe in CS Type I.[8] * CS Type II is present from birth (congenital) and is much more severe than CS Type 1.[7] It involves very little neurological development after birth. Death usually occurs by age seven. This specific type has also been designated as cerebro-oculo-facio-skeletal (COFS) syndrome or Pena-Shokeir syndrome Type II.[7] COFS syndrome is named so due to the effects it has on the brain, eyes, face, and skeletal system, as the disease frequently causes brain atrophy, cataracts, loss of fat in the face, and osteoporosis. COFS syndrome can be further subdivided into several conditions (COFS types 1, 2, 3 (associated with xeroderma pigmentosum) and 4).[9] Typically patients with this early-onset form of the disorder show more severe brain damage, including reduced myelination of white matter, and more widespread calcifications, including in the cortex and basal ganglia.[8] * CS Type III, characterized by late-onset, is typically milder than Types I and II.[7] Often patients with Type III will live into adulthood. * Xeroderma pigmentosum-Cockayne syndrome (XP-CS) occurs when an individual also suffers from xeroderma pigmentosum, another DNA repair disease. Some symptoms of each disease are expressed. For instance, freckling and pigment abnormalities characteristic of XP are present. The neurological disorder, spasticity, and underdevelopment of sexual organs characteristic of CS are seen. However, hypomyelination and the facial features of typical CS patients are not present.[10] ## Causes[edit] If hyperoxia or excess oxygen occurs in our body, our cellular metabolism produce several highly reactive forms of oxygen called free radicals. This can cause oxidative damage to cellular components including the DNA. In normal cells, our body repairs the damaged sections. In the case of this disease, Due to subtle defects in transcription, children's genetic machinery for synthesizing proteins needed by the body does not operate at normal capacity. That is, scientists believed that these children's genetic machinery for synthesizing proteins needed by the body does not operate at normal capacity. Over time, went this theory, results in developmental failure and death. Every minute, the body pumps 10 to 20 liters of oxygen through the blood, carrying it to billions of cells in our bodies. In its normal molecular form, oxygen is harmless. However, cellular metabolism involving oxygen can generate several highly reactive free radicals. These free radicals can cause oxidative damage to cellular components including the DNA. In an average human cell, several thousand lesions occur in the DNA every day. Many of these lesions result from oxidative damage. Each lesion -- a damaged section of DNA -- must be snipped out and the DNA repaired to preserve its normal function. Unrepaired DNA can lose its ability to code for proteins. Mutations also can result. These mutations can activate oncogenes or silence tumor suppressor genes. According to research, oxidative damage to active genes is not preferentially repaired, and in the most severe cases, the repair is slowed throughout the whole genome. The resulting accumulation of oxidative damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis). The children with this disease do not repair the active genes where oxidative damage occurs. Normally, oxidative damage repair is faster in the active genes (which make up less than five percent of the genome) than in inactive regions of the DNA. The resulting accumulation of oxidative damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis).[citation needed] ## Genetics[edit] Cockayne syndrome is classified genetically as follows: Type OMIM Gene A 216400 ERCC8 (also called CSA) B 133540 ERCC6 (also called CSB) C 216411 none known * Mutations in the ERCC8 (also known as CSA) gene or the ERCC6 (also known as CSB) gene are the cause of Cockayne syndrome.[7] Mutations in the ERCC6 gene mutation makes up ~70% of cases. The proteins made by these genes are involved in repairing damaged DNA via the transcription-coupled repair mechanism, particularly the DNA in active genes. DNA damage is caused by ultraviolet rays from sunlight, radiation, or free radicals in the body. A normal cell can repair DNA damage before it accumulates. If either the ERCC6 or the ERCC8 gene is altered (as in Cockayne Syndrome), DNA damage encountered during transcription isn't repaired, causing RNA polymerase to stall at that location, interfering with gene expression. As the unrepaired DNA damage accumulates, progressively more active gene expression is impeded, leading to malfunctioning cells or cell death, which likely contributes to the signs of Cockayne Syndrome such as premature aging and neuronal hypomyelination.[7] ## Mechanism[edit] In contrast to cells with normal repair capability, CSA and CSB deficient cells are unable to preferentially repair cyclobutane pyrimidine dimers induced by the action of ultraviolet (UV) light on the template strand of actively transcribed genes.[11] This deficiency reflects the loss of ability to perform the DNA repair process known as transcription coupled nucleotide excision repair (TC-NER).[citation needed] Within the damaged cell, the CSA protein normally localizes to sites of DNA damage, particularly inter-strand cross-links, double-strand breaks and some monoadducts.[12] CSB protein is also normally recruited to DNA damaged sites, and its recruitment is most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damage.[12] CSB protein forms a complex with another DNA repair protein, SNM1A (DCLRE1A), a 5' – 3' exonuclease, that localizes to inter-strand cross-links in a transcription dependent manner.[13] The accumulation of CSB protein at sites of DNA double-strand breaks occurs in a transcription dependent manner and facilitates homologous recombinational repair of the breaks.[14] During the G0/G1 phase of the cell cycle, DNA damage can trigger a CSB-dependent recombinational repair process that uses an RNA (rather than DNA) template.[15] The premature aging features of CS are likely due, at least in part, to the deficiencies in DNA repair (see DNA damage theory of aging).[citation needed] ## Diagnosis[edit] People with this syndrome have smaller than normal head sizes (microcephaly), are of short stature (dwarfism), their eyes appear sunken, and they have a ″aged″ look. They often have long limbs with joint contractures (inability to relax the muscle at a joint), a hunched back (kyphosis), and they may be very thin (cachetic), due to a loss of subcutaneous fat. Their small chin, large ears, and pointy, thin nose often give an aged appearance.[8] The skin of those with Cockayne syndrome is also frequently affected: hyperpigmentation, varicose or spider veins (telangiectasia),[8] and serious sensitivity to sunlight are common, even in individuals without XP-CS. Often patients with Cockayne Syndrome will severely burn or blister with very little heat exposure. The eyes of patients can be affected in various ways and eye abnormalities are common in CS. Cataracts and cloudiness of the cornea (corneal opacity) are common. The loss of and damage to nerves of the optic nerve, causing optic atrophy can occur.[3] Nystagmus, or involuntary eye movement, and pupils that fail to dilate demonstrate a loss of control of voluntary and involuntary muscle movement.[8] A salt and pepper retinal pigmentation is also a typical sign. Diagnosis is determined by a specific test for DNA repair, which measures the recovery of RNA after exposure to UV radiation. Despite being associated with genes involved in nucleotide excision repair (NER), unlike xeroderma pigmentosum, CS is not associated with an increased risk of cancer.[5] ### Laboratory Studies[edit] In Cockayne syndrome patients, UV-irradiated cells show decreased DNA and RNA synthesis. https://emedicine.medscape.com/article/1115866-workup#c5 Laboratory studies are mainly useful to eliminate other disorders. For example, skeletal radiography, endocrinologic tests, and chromosomal breakage studies can help in excluding disorders included in the differential diagnosis.[citation needed] ### Imaging Studies[edit] Brain CT scanning in Cockayne syndrome patients may reveal calcifications and cortical atrophy.[citation needed] ### Other Tests[edit] Prenatal evaluation is possible. Amniotic fluid cell culturing is used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation. ### Neurology[edit] Imaging studies reveal a widespread absence of the myelin sheaths of the neurons in the white matter of the brain, and general atrophy of the cortex.[5] Calcifications have also been found in the putamen, an area of the forebrain that regulates movements and aids in some forms of learning,[8] along with the cortex.[6] Additionally, atrophy of the central area of the cerebellum found in patients with Cockayne syndrome could also result in the lack of muscle control, particularly involuntary, and poor posture typically seen.[citation needed] ## Treatment[edit] There is no permanent cure for this syndrome, although patients can be symptomatically treated. Treatment usually involves physical therapy and minor surgeries to the affected organs, such as cataract removal.[3] Also wearing high-factor sunscreen and protective clothing is recommended because Cockayne Syndrome patients are very sensitive to UV radiation.[16] Optimal nutrition can also help. Genetic counseling for the parents is recommended, as the disorder has a 25% chance of being passed to any future children, and prenatal testing is also a possibility.[3] Another important aspect is the prevention of recurrence of CS in other siblings. Identification of gene defects involved makes it possible to offer genetic counseling and antenatal diagnostic testing to the parents who already have one affected child.[17] ## Prognosis[edit] The prognosis for those with Cockayne syndrome is poor, as death typically occurs by the age of 12. [18] The prognosis for Cockayne syndrome varies by the disease type. There are three types of Cockayne syndrome according to the severity and onset of the symptoms. However, the differences between the types are not always clear-cut, and some researchers believe the signs and symptoms reflect a spectrum instead of distinct types: Cockayne syndrome Type A (CSA) is marked by normal development until a child is 1 or 2 years old, at which point growth slows and developmental delays are noticed. Symptoms are not apparent until they are 1 year. Life expectancy for type A is approximately 10 to 20 years. This symptoms are seen in CS type 1 children. Cockayne syndrome type B (CSB), also known as "cerebro-oculo-facio-skeletal (COFS) syndrome" (or "Pena-Shokeir syndrome type B"), is the most severe subtype. Symptoms are present at birth and normal brain development stops after birth. Average lifespan for children with type B is up to 7 years of age. These symptoms are seen in CS type 2 children. Cockayne syndrome type C (CSC) appears later in childhood with milder symptoms than the other types and a slower progression of the disorder. People with this type of Cockayne syndrome live into adulthood, with an average lifespan of 40 to 50 years. These symptoms are seen in CS type 3.[citation needed] ## Epidemiology[edit] Cockayne syndrome is rare worldwide. No racial predilection is reported for Cockayne syndrome. No sexual predilection is described for Cockayne syndrome; the male-to-female ratio is equal. Cockayne syndrome I (CS-A) manifests in childhood. Cockayne syndrome II (CS-B) manifests at birth or in infancy, and it has a worse prognosis.[citation needed] ## Recent research[edit] The recent research on Jan 2018 mentions different CS features that are seen globally with similarities and differences: CS has an incidence of 1 in 250,000 live births, and a prevalence of 2.5 per million, which is remarkably consistent across various regions globally:[19] Affected parts Clinical features pathology Face Wizened faceies. Sunken eyes, large ears, thin pointy nose. Small chin. Dental caries, enamel hypoplasia Skin, hair, nails Photosensitivity. Wrinkled and aged appearing skin. Thin dry hair, prematurely gray hair. Poor venous access. Central nervous system Microcephaly usually beginning at age 2. Mental retardation with low IQ. Delayed milestones.Tremors, ataxia, seizures, strokes, and subdural hemorrhages. Demyelination – is patchy and segmental– “Metachromatic leukodystrophy". Both oligodendroglia and Schwann cells are affected. Affects cerebral white matter, corpus callosum, brainstem, spinal cord, and peripheral nerves. Neuronal loss at multiple sites, especially the cerebellum. Loss of anterior horn cells due to anterograde and/or retrograde degeneration. Calcification [55–95%] of the cerebral cortex (especially depths of sulci, basal ganglia, cerebellum, thalamus; also of the arteries, arterioles, and capillaries. Vascular changes - String vessels, especially in areas of Metachromatic leukodystrophy, calcification in leptomeningeal vessels, accelerated atherosclerosis and arteriolosclerosis. Gliosis is present. Astrocytes and microglia may show irregular cytoplasm, multiple nuclei. May be seen as a high-intensity white matter on FLAIR MRI sequences signals. No major brain malformations. Relative sparing of the cerebral cortex, slight thinning of cortical ribbon may be seen. Normal gyral pattern with widening of sulci. Lamination, neuronal size, and configuration of the neocortex are preserved. May show parietal occipital dominance. Severe cerebellar atrophy. Loss of Purkinje, granular neurons, and in some cases neurons in the dentate nucleus. Dendrites of Purkinje cells may be grossly deformed (“cactus flowers”), ferruginated dendrites. Dendrites have fewer higher order branches. Purkinje “axonal torpedoes” may be present. Ventricular enlargement, enlarged cisterna magna are seen. Amyloid plaques, neurofibrillary tangles, Hirano bodies not commonly seen, although ubiquitin reactivity of axons present Hearing and vestibular systems Sensorineural, high tone hearing loss [60–90%]. Mixed conductive and sensorineural hearing loss (44%) Most commonly bilateral, rarely unilateral Loss of hair cells in the cochlea, particularly in the basal turn. Loss of neurons in spiral ganglion. Atrophy of auditory pathways. Scala communis, thickened stapes curare, widened prototympanum. Loss of hair cells in pars superior. Loss of neurons in vestibular ganglion. Collapse of the endolymphatic duct of pars inferior Vision Corneal opacification. Cataracts [36–86%]. Usually bilateral, most develop by 4 years of age. Pigmentary retinopathy (“salt and pepper”)[43–89%]. Miotic pupils, Optic disk pallor, Enophthalmos, Narrow palpebral fissures. Patchy loss of melanin pigment granules. Lipofuscin deposition, large pigment laden cells in a perivascular distribution. Retinal pigment epithelial atrophy and hyperplasia. Loss of cells in ganglion and outer nuclear cell layers. Both the outer and inner segments of photoreceptors are affected. Optic nerve atrophy, with partial demyelination, axonal loss, and gliosis Musculoskeletal system Cachectic dwarfism. Contractures. Kyphosis, scoliosis. Stooped posture. Muscle wasting. Denervation myopathy, disuse atrophy Cardiovascular system Accelerated hypertension. Aortic root dilatation. Cardiomyopathy. Increased intima medial thickening. Atherosclerosis, arteriosclerosis. Gastrointestinal system Severe reflux. Abnormal gastrointestinal motility. Many have percutaneous gastrostomy tubes. Hepatomegaly, splenomegaly, elevated liver enzymes. Altered metabolism of drugs \- Renal system Renal failure Renal arteries show changes in advanced atherosclerosis and arteriolosclerosis. Unilateral or hypoplastic kidneys. Reproductive system - \- Males Micropenis, smaller testicular size \- Females Ovarian atrophy. A successful pregnancy has been reported. \- Endocrine systems Normal secondary sexual characteristics. Normal growth hormone, thyroid-stimulating hormone, calcium levels Normal pituitary gland and thyroid gland Eccrine systems Decreased production of sweat, tears, saliva \- ## See also[edit] * Accelerated aging disease * Biogerontology * Degenerative disease * Genetic disorder * CAMFAK syndrome — thought to be a form (or subset) of Cockayne syndrome[20] ## References[edit] 1. ^ Bertola; Cao, H; Albano, Lm; Oliveira, Dp; Kok, F; Marques-Dias, Mj; Kim, Ca; Hegele, Ra (2006). "Cockayne syndrome type A: novel mutations in eight typical patients". Journal of Human Genetics. 51 (8): 701–5. doi:10.1007/s10038-006-0011-7. PMID 16865293. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 575. ISBN 978-0-7216-2921-6. 3. ^ a b c d e Bender M, Potocki L, Metry D. What syndrome is this? Cockayne syndrome. Pediatric Dermatology [serial online]. November 2003;20(6):538-540. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed April 30, 2015. 4. ^ Hoeijmakers JH (October 2009). "DNA damage, aging, and cancer". N. Engl. J. Med. 361 (15): 1475–85. doi:10.1056/NEJMra0804615. PMID 19812404. 5. ^ a b c d Nance M, Berry S (1 January 1992). "Cockayne syndrome: review of 140 cases". American Journal of Medical Genetics. 42 (1): 68–84. doi:10.1002/ajmg.1320420115. PMID 1308368. 6. ^ a b c d Neill CA, Dingwall MM. A Syndrome Resembling Progeria: A Review of Two Cases. Archives of Disease in Childhood. 1950;25(123):213-223. 7. ^ a b c d e f Cockayne Syndrome. Genetics Home Reference http://ghr.nlm.nih.gov/condition/cockayne-syndrome Published April 28, 2015. Reviewed May 2010. Accessed April 30, 2015. 8. ^ a b c d e f Javadzadeh M. Cockayne Syndrome. Iran J Child Neurol. Autumn 2014;8;4(Suppl.1):18-19. 9. ^ Cerebrooculofacioskeletal Syndrome 2. Online Mendelian Inheritance in Man. https://omim.org/entry/610756. Published 2/12/2007. 10. ^ Laugel V. Cockayne Syndrome. 2000 Dec 28 [Updated 2012 Jun 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: [1] 11. ^ van Hoffen A, Natarajan AT, Mayne LV, van Zeeland AA, Mullenders LH, Venema J (1993). "Deficient repair of the transcribed strand of active genes in Cockayne's syndrome cells". Nucleic Acids Res. 21 (25): 5890–5. doi:10.1093/nar/21.25.5890. PMC 310470. PMID 8290349. 12. ^ a b Iyama T, Wilson DM (2016). "Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome". J. Mol. Biol. 428 (1): 62–78. doi:10.1016/j.jmb.2015.11.020. PMC 4738086. PMID 26616585. 13. ^ Iyama T, Lee SY, Berquist BR, Gileadi O, Bohr VA, Seidman MM, McHugh PJ, Wilson DM (2015). "CSB interacts with SNM1A and promotes DNA interstrand crosslink processing". Nucleic Acids Res. 43 (1): 247–58. doi:10.1093/nar/gku1279. PMC 4288174. PMID 25505141. 14. ^ Batenburg NL, Thompson EL, Hendrickson EA, Zhu XD (2015). "Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation". EMBO J. 34 (10): 1399–416. doi:10.15252/embj.201490041. PMC 4491999. PMID 25820262. 15. ^ Wei L, Nakajima S, Böhm S, Bernstein KA, Shen Z, Tsang M, Levine AS, Lan L (2015). "DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination". Proc. Natl. Acad. Sci. U.S.A. 112 (27): E3495–504. Bibcode:2015PNAS..112E3495W. doi:10.1073/pnas.1507105112. PMC 4500203. PMID 26100862. 16. ^ Kyllermen, Marten. Cockayne Syndrome. Swedish Information Centre for Rare Diseases. 2012: 4.0. http://www.socialstyrelsen.se/rarediseases/cockaynesyndrome#anchor_17 Archived 2015-09-24 at the Wayback Machine 17. ^ Title: Cockayne Syndrome Authors: Dr Nita R Sutay, Dr Md Ashfaque Tinmaswala, Dr Manjiri Karlekar, Dr Swati Jhahttp://jmscr.igmpublication.org/v3-i7/35%20jmscr.pdf 18. ^ "Cockayne syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". 19. ^ Karikkineth, A. C.; Scheibye-Knudsen, M.; Fivenson, E.; Croteau, D. L.; Bohr, V. A. (2016). "Cockayne syndrome: Clinical features, model systems and pathways". Ageing Research Reviews. 33: 3–17. doi:10.1016/j.arr.2016.08.002. PMC 5195851. PMID 27507608. 20. ^ "Orphanet: CAMFAK syndrome". ## External links[edit] * This article incorporates some public domain text from The U.S. National Library of Medicine Classification D * ICD-10: Q87.1 (ILDS Q87.110) * ICD-9-CM: 759.8 * OMIM: 216400 133540 216411 * MeSH: D003057 * DiseasesDB: 2907 * SNOMED CT: 21086008 External resources * eMedicine: ped/424 * GeneReviews: Cockayne Syndrome * Orphanet: 191 * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome * v * t * e Metabolic disease: DNA replication and DNA repair-deficiency disorder DNA replication * Separation/initiation: RNASEH2A * Aicardi–Goutières syndrome 4 * Termination/telomerase: DKC1 * Dyskeratosis congenita DNA repair Nucleotide excision repair * Cockayne syndrome/DeSanctis–Cacchione syndrome * Thymine dimer * Xeroderma pigmentosum * IBIDS syndrome MSI/DNA mismatch repair * Hereditary nonpolyposis colorectal cancer * Muir–Torre syndrome * Mismatch repair cancer syndrome MRN complex * Ataxia telangiectasia * Nijmegen breakage syndrome Other * RecQ helicase * Bloom syndrome * Werner syndrome * Rothmund–Thomson syndrome/Rapadilino syndrome * Fanconi anemia * Li-Fraumeni syndrome * Severe combined immunodeficiency * v * t * e Progeroid syndromes DNA repair RecQ-associated * Werner syndrome * Bloom syndrome * Rothmund–Thomson syndrome NER protein-associated * Cockayne syndrome * Xeroderma pigmentosum * Trichothiodystrophy Lamin A/C * Hutchinson–Gilford progeria syndrome * Restrictive dermopathy Other/related disorders * Li–Fraumeni syndrome * Rapadilino syndrome * Baller–Gerold syndrome * DeSanctis–Cacchione syndrome * Nijmegen breakage syndrome * Fanconi anemia * Dyskeratosis congenita * Ataxia telangiectasia * De Barsy syndrome * PIBI(D)S syndrome * BIDS syndrome * Marfanoid–progeroid–lipodystrophy syndrome See also: DNA replication and repair-deficiency disorder [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Cockayne syndrome	c0009207	4,690	wikipedia	https://en.wikipedia.org/wiki/Cockayne_syndrome	2021-01-18T19:03:16	{"gard": ["6122"], "mesh": ["D003057"], "umls": ["C0009207"], "orphanet": ["90322", "90324", "90321", "191"], "wikidata": ["Q914389"]}
Normochromic anemia This condition entails insufficient numbers of red blood cell SpecialtyHematology Normochromic anemia is a form of anemia in which the concentration of hemoglobin in the red blood cells is within the standard range, but there is an insufficient number of red blood cells. Conditions where this is found include aplastic, posthemorrhagic, and hemolytic anemias and anemia of chronic disease.[1] MCH (average amount of hemoglobin found in the red blood cells in the body) or MCHC (the average weight of that hemoglobin based on the volume of red blood cells) in these cells are normal. ## See also[edit] * Normocytic anemia ## References[edit] 1. ^ Stoelting's Anesthesia and Co-Existing Disease (7 ed.). Elsevier. 2018. pp. 477–506. * v * t * e Diseases of red blood cells ↑ Polycythemia * Polycythemia vera ↓ Anemia Nutritional * Micro-: Iron-deficiency anemia * Plummer–Vinson syndrome * Macro-: Megaloblastic anemia * Pernicious anemia Hemolytic (mostly normo-) Hereditary * enzymopathy: Glucose-6-phosphate dehydrogenase deficiency * glycolysis * pyruvate kinase deficiency * triosephosphate isomerase deficiency * hexokinase deficiency * hemoglobinopathy: Thalassemia * alpha * beta * delta * Sickle cell disease/trait * Hereditary persistence of fetal hemoglobin * membrane: Hereditary spherocytosis * Minkowski–Chauffard syndrome * Hereditary elliptocytosis * Southeast Asian ovalocytosis * Hereditary stomatocytosis Acquired AIHA * Warm antibody autoimmune hemolytic anemia * Cold agglutinin disease * Donath–Landsteiner hemolytic anemia * Paroxysmal cold hemoglobinuria * Mixed autoimmune hemolytic anemia * membrane * paroxysmal nocturnal hemoglobinuria * Microangiopathic hemolytic anemia * Thrombotic microangiopathy * Hemolytic–uremic syndrome * Drug-induced autoimmune * Drug-induced nonautoimmune * Hemolytic disease of the newborn Aplastic (mostly normo-) * Hereditary: Fanconi anemia * Diamond–Blackfan anemia * Acquired: Pure red cell aplasia * Sideroblastic anemia * Myelophthisic Blood tests * Mean corpuscular volume * normocytic * microcytic * macrocytic * Mean corpuscular hemoglobin concentration * normochromic * hypochromic Other * Methemoglobinemia * Sulfhemoglobinemia * Reticulocytopenia This article about a disease of the blood or immune 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Normochromic anemia	c0235983	4,691	wikipedia	https://en.wikipedia.org/wiki/Normochromic_anemia	2021-01-18T18:38:16	{"umls": ["C0235983"], "wikidata": ["Q3343910"]}
Organic mental disorder caused by late-stage syphilis This article is about the neuropsychiatric disorder. For the physical malady, paralysis, see paresis. 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: "General paresis of the insane" – news · newspapers · books · scholar · JSTOR (March 2014) (Learn how and when to remove this template message) General paresis Other namesGeneral paralysis of the insane, paralytic dementia SpecialtyInfectious disease SymptomsEarly: Neurasthenia, personality changes, mood swings, problems with memory, judgment and concentration Later: Delusions, dementia, tremors, hyperreflexia, seizures, cachexia Usual onset10-30 years after initial infection CausesMeningoencephalitis caused by syphilis Risk factorsUntreated syphilis infection General paresis, also known as general paralysis of the insane (GPI) or paralytic dementia, is a severe neuropsychiatric disorder, classified as an organic mental disorder and caused by the chronic meningoencephalitis that leads to cerebral atrophy in late-stage syphilis. Degenerative changes are associated primarily with the frontal and temporal lobar cortex. The disease affects approximately 7% of infected individuals. It is more common among men. GPI was originally considered to be a type of madness due to a dissolute character, when first identified in the early 19th century. The condition's connection with syphilis was discovered in the late 1880s. Progressively, with the discovery of organic arsenicals such as Salvarsan and Neosalvarsan (1910s), the development of pyrotherapy (1920s), and the widespread availability and use of penicillin in the treatment of syphilis (1940s), the condition was rendered avoidable and curable. Prior to this, GPI was inevitably fatal, and it accounted for as much as 25% of the primary diagnoses for residents in public psychiatric hospitals. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Prognosis * 4 History * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Symptoms of the disease first appear from 10 to 30 years after infection. Incipient GPI is usually manifested by neurasthenic difficulties, such as fatigue, headaches, insomnia, dizziness, etc. As the disease progresses, mental deterioration and personality changes occur. Typical symptoms include loss of social inhibitions, asocial behavior, gradual impairment of judgment, concentration and short-term memory, euphoria, mania, depression, or apathy. Subtle shivering, minor defects in speech and Argyll Robertson pupil may become noticeable. Delusions, common as the illness progresses, tend to be poorly systematized and absurd. They can be grandiose, melancholic, or paranoid. These delusions include ideas of great wealth, immortality, thousands of lovers, unfathomable power, apocalypsis, nihilism, self-guilt, self-blame, or bizarre hypochondriacal complaints. Later, the patient experiences dysarthria, intention tremors, hyperreflexia, myoclonic jerks, confusion, seizures and severe muscular deterioration. Eventually, the paretic dies bedridden, cachectic and completely disoriented, frequently in a state of status epilepticus. ## Diagnosis[edit] The diagnosis could be differentiated from other known psychoses and dementias by a characteristic abnormality in eye pupil reflexes (Argyll Robertson pupil), and, eventually, the development of muscular reflex abnormalities, seizures, memory impairment (dementia) and other signs of relatively pervasive neurocerebral deterioration. Definitive diagnosis is based on the analysis of cerebrospinal fluid and tests for syphilis. ## Prognosis[edit] Although there were recorded cases of remission of the symptoms, especially if they had not passed beyond the stage of psychosis, these individuals almost invariably experienced relapse within a few months to a few years. Otherwise, the patient was seldom able to return home because of the complexity, severity and unmanageability of the evolving symptom picture. Eventually, the patient would become completely incapacitated, bedfast, and would die, the process taking about three to five years on average. ## History[edit] While retrospective studies have found earlier instances of what may have been the same disorder, the first clearly identified examples of paresis among the insane were described in Paris after the Napoleonic Wars. General paresis of the insane was first described as a distinct disease in 1822 by Antoine Laurent Jesse Bayle. General paresis most often struck people (men far more frequently than women) between 20 and 40 years of age. By 1877, for example, the superintendent of an asylum for men in New York reported that in his institution this disorder accounted for more than 12% of admissions and more than 2% of deaths. Originally, the cause was believed to be an inherent weakness of character or constitution. While Friedrich von Esmarch and the psychiatrist Peter Willers Jessen had asserted as early as 1857 that syphilis caused general paresis (progressive Paralyse),[1] progress toward the general acceptance by the medical community of this idea was only accomplished later by the eminent 19th Century syphilographer Alfred Fournier (1832–1914). In 1913 all doubt about the syphilitic nature of paresis was finally eliminated when Hideyo Noguchi and J. W. Moore demonstrated the syphilitic spirochaetes in the brains of paretics. In 1917 Julius Wagner-Jauregg discovered that pyrotherapy involving infecting paretic patients with malaria could halt the progression of general paresis. He won a Nobel Prize for this discovery in 1927. After World War II the use of penicillin to treat syphilis made general paresis a rarity: even patients manifesting early symptoms of actual general paresis were capable of full recovery with a course of penicillin. The disorder is now virtually unknown outside third-world countries, and even there the epidemiology is substantially reduced. Theo Van Gogh, brother of painter Vincent Van Gogh, died six months after Vincent in 1891 from "dementia parylitica" or what is now called syphilitic paresis.[2] The Chicago gangster Al Capone died of syphilitic paresis, having contracted syphilis in a brothel prior to Prohibition and the Volstead Act and not having been treated for it in time to prevent the development of syphilitic paresis in himself. ## See also[edit] * Karolina Olsson * Neurosyphilis * Tuskegee experiment * Tabes dorsalis ## References[edit] 1. ^ Bangen, Hans: Geschichte der medikamentösen Therapie der Schizophrenie. Berlin 1992, ISBN 3-927408-82-4 2. ^ Voskuil, Piet H. A. (2009). "The cause of death of Theo van Gogh (1857-1891)". Nederlands Tijdschrift voor Geneeskunde. 153: B362. ISSN 1876-8784. PMID 20051145. ## External links[edit] Classification D * ICD-10: A52.1 * ICD-9-CM: 090.40 094.1 * MeSH: D009494 External resources * MedlinePlus: 000748 * v * t * e Bacterial diseases due to gram negative non-proteobacteria (BV4) Spirochaete Spirochaetaceae Treponema * Treponema pallidum * Syphilis/bejel * Yaws * Treponema carateum (Pinta) * Treponema denticola Borrelia * Borrelia burgdorferi/Borrelia afzelii * Lyme disease * Erythema migrans * Neuroborreliosis * Borrelia recurrentis (Louse borne relapsing fever) * Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever) Leptospiraceae Leptospira * Leptospira interrogans (Leptospirosis) Chlamydiaceae Chlamydia * Chlamydia psittaci (Psittacosis) * Chlamydia pneumoniae * Chlamydia trachomatis * Chlamydia * Lymphogranuloma venereum * Trachoma Bacteroidetes * Bacteroides fragilis * Tannerella forsythia * Capnocytophaga canimorsus * Porphyromonas gingivalis * Prevotella intermedia Fusobacteria * Fusobacterium necrophorum (Lemierre's syndrome) * Fusobacterium nucleatum * Fusobacterium polymorphum * Streptobacillus moniliformis (Rat-bite fever/Haverhill fever) * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	General paresis of the insane	c0205858	4,692	wikipedia	https://en.wikipedia.org/wiki/General_paresis_of_the_insane	2021-01-18T18:53:28	{"mesh": ["D009494"], "umls": ["C0205858"], "icd-9": ["094.1", "090.40"], "icd-10": ["A52.1"], "wikidata": ["Q1932655"]}
Infection by herpes simplex viruses of the genitals Genital herpes Other namesAnogenital herpesviral infection, herpes genitalis An outbreak of genital herpes affecting the vulva SpecialtyInfectious disease SymptomsNone, small blisters that break open to form painful ulcers, flu-like symptoms[1][2] ComplicationsAseptic meningitis, increased risk of HIV/AIDS if exposed, neonatal herpes[1] Usual onset2–12 days after exposure[1] DurationUp to 4 weeks (first outbreak)[1] CausesHerpes simplex virus (HSV-1, HSV-2)[1] Diagnostic methodTesting lesions, blood tests for antigen[1] Differential diagnosisSyphilis, chancroid, molluscum contagiosum, hidradenitis suppurativa[3] PreventionNot having sex, using condoms, only having sex with someone who is not infected[2] TreatmentAntiviral medication[1] Frequency846 million (2015)[4] Genital herpes is an infection by the herpes simplex virus (HSV) of the genitals.[1] Most people either have no or mild symptoms and thus do not know they are infected.[1] When symptoms do occur, they typically include small blisters that break open to form painful ulcers.[1] Flu-like symptoms, such as fever, aching, or swollen lymph nodes, may also occur.[2] Onset is typically around 4 days after exposure with symptoms lasting up to 4 weeks.[1] Once infected further outbreaks may occur but are generally milder.[1] The disease is typically spread by direct genital contact with the skin surface or secretions of someone who is infected.[1] This may occur during sex, including anal and oral sex.[1] Sores are not required for transmission to occur.[1] The risk of spread between a couple is about 7.5% over a year.[5] HSV is classified into two types, HSV-1 and HSV-2.[1] While historically HSV-2 was more common, genital HSV-1 has become more common in the developed world.[1][6] Diagnosis may occur by testing lesions using either PCR or viral culture or blood tests for specific antibodies.[1] Efforts to prevent infection include not having sex, using condoms, and only having sex with someone who is not infected.[2] Once infected, there is no cure.[2] Antiviral medications may, however, prevent outbreaks or shorten outbreaks if they occur.[1] The long-term use of antivirals may also decrease the risk of further spread.[1] In 2015 about 846 million people (12% of the world population) had genital herpes.[4] In the United States, more than one-in-six people have HSV-2.[7] Women are more commonly infected than men.[1] Rates of disease caused by HSV-2 have decreased in the United States between 1990 and 2010.[1] Complications may rarely include aseptic meningitis, an increased risk of HIV/AIDS if exposed to HIV-positive individuals, and spread to the baby during childbirth resulting in neonatal herpes.[1] ## Contents * 1 Signs and symptoms * 1.1 Recurrence * 2 Transmission * 3 Diagnosis * 4 Screening * 5 Treatment * 6 Epidemiology * 7 History * 8 Research * 9 References * 10 External links ## Signs and symptoms Genital herpes affecting the penis In males, the lesions occur on the glans penis, shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus. In females, lesions appear on or near the pubis, clitoris or other parts of the vulva, buttocks or anus.[2] Other common symptoms include pain, itching, and burning. Less frequent, yet still common, symptoms include discharge from the penis or vagina, fever, headache, muscle pain (myalgia), swollen and enlarged lymph nodes and malaise.[8] Women often experience additional symptoms that include painful urination (dysuria) and cervicitis. Herpetic proctitis (inflammation of the anus and rectum) is common for individuals participating in anal intercourse.[8] After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts.[8] In rare cases, involvement of the sacral region of the spinal cord can cause acute urinary retention and one-sided symptoms and signs of myeloradiculitis (a combination of myelitis and radiculitis): pain, sensory loss, abnormal sensations (paresthesia) and rash.[9][10] Historically, this has been termed Elsberg syndrome, although this entity is not clearly defined.[9] ### Recurrence After a first episode of herpes genitalis caused by HSV-2, there will be at least one recurrence in approximately 80% of people, while the recurrence rate for herpes genitalis caused by HSV-1 is approximately 50%.[11] Herpes genitalis caused by HSV-2 recurs on average four to six times per year, while that of HSV-1 infection occurs only about once per year.[11] People with recurrent genital herpes may be treated with suppressive therapy, which consists of daily antiviral treatment using acyclovir, valacyclovir or famciclovir.[12] Suppressive therapy may be useful in those who have at least four recurrences per year but the quality of the evidence is poor.[12] People with lower rates of recurrence will probably also have fewer recurrences with suppressive therapy.[13] Suppressive therapy should be discontinued after a maximum of one year to reassess recurrence frequency.[13] ## Transmission Genital herpes can be spread by viral shedding prior to and following the formation of ulcers. The risk of spread between a couple is about 7.5% over a year (for unprotected sex).[5] The likelihood of transferring genital herpes from one person to another is decreased by male condom use by 50%, by female condom by 50%, and refraining from sex during an active outbreak.[5] The longer a partner has had the infection, the lower the transmission rate.[5] An infected person may further decrease transmission risks by maintaining a daily dose of antiviral medications.[5] Infection by genital herpes occurs in about 1 in every 1,000 sexual acts.[5] ## Diagnosis This section is empty. You can help by adding to it. (March 2019) ## Screening Testing peoples' blood, including those who are pregnant, who do not have symptoms for HSV is not recommended.[14] This is due to concerns of greater harm than benefit, as there is a high false-positive rate and receiving a positive test result can cause other problems, such as relationship difficulties.[14] ## Treatment Once infected, there is no cure.[2] Antiviral medications, such as acyclovir, valacyclovir, may prevent outbreaks or shorten outbreaks if they occur.[1] The long-term use of antivirals may also decrease the risk of further spread.[1] The longer a person has the virus, the fewer outbreaks they experience and the harder it will be to transmit to others, due to these specialty antigens and a strengthened immune system response.[2] Acyclovir is an antiviral medication and reduces the pain and the number of lesions in the initial case of genital herpes. Furthermore, it decreases the frequency and severity of recurrent infections. It comes in capsules, tablets, suspension, injection, powder for injection, and ointment. The ointment is used topically and it decreases pain, reduces healing time, and limits the spread of the infection.[15] In people experiencing their first episode of genital herpes oral acyclovir may reduce the duration of symptoms and lesions but the risk of adverse effects is not certain.[16] There may also be little or no difference between topical acyclovir and placebo in terms of duration of symptoms and lesions and the risk of adverse effects.[16] Valacyclovir is a prodrug that is converted to acyclovir once in the body. It helps relieve the pain and discomfort and speeds healing of sores. It only comes in caplets and its advantage is that it has a longer duration of action than acyclovir.[17] An example usage is by mouth twice per day for ten days for primary lesion, and twice per day for three days for a recurrent episode.[18] Famciclovir is another antiviral drug that belongs to the same class. Famciclovir is a prodrug that is converted to penciclovir in the body. The latter is the one active against the viruses. It has a longer duration of action than acyclovir and it only comes in tablets.[19] ## Epidemiology About 16 percent of Americans between the ages of 14 and 49 are infected with genital herpes, making it one of the most common sexually transmitted diseases.[20] More than 80% of those infected are unaware of their infection.[21] Approximately 776,000 people in the United States get new herpes infections every year.[21] Tests for herpes are not routinely included among STD screenings. Performers in the pornography industry are screened for HIV, chlamydia, and gonorrhea with an optional panel of tests for hepatitis B, hepatitis C and syphilis, but not herpes. Testing for herpes is controversial since the results are not always accurate or helpful.[22] Most sex workers and performers will contract herpes at some point in their careers whether they use protection or not.[23] ## History Early 20th century public health legislation in the United Kingdom required compulsory treatment for sexually transmitted diseases but did not include herpes because it was not serious enough.[24] As late as 1975, nursing textbooks did not include herpes as it was considered no worse than a common cold.[24] After the development of acyclovir in the 1970s, the drug company Burroughs Wellcome launched an extensive marketing campaign that publicized the illness, including creating victim's support groups.[24] ## Research Main article: Herpes simplex research There are efforts to develop a vaccine for active outbreaks of the virus—despite most cases being asymptomatic—but the results thus far have not been able to do so or eliminate transmission.[25] ## References 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y "Genital Herpes – CDC Fact Sheet". 9 February 2017. Retrieved 20 December 2017. 2. ^ a b c d e f g h "STD Facts – Genital Herpes". 2017-12-11. Retrieved 30 October 2018. 3. ^ Ferri, Fred F. (2010). Ferri's Differential Diagnosis: A Practical Guide to the Differential Diagnosis of Symptoms, Signs, and Clinical Disorders. Elsevier Health Sciences. p. 230. ISBN 978-0323076999. 4. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. 5. ^ a b c d e f pmhdev (December 12, 2012). "Genital herpes: How can you prevent the spread of herpes in sexual relationships?". PubMed Health. 6. ^ Beigi, Richard H., ed. (2012-03-27). Sexually transmitted diseases. Chichester, West Sussex: John Wiley & Sons, Ltd. p. 139. ISBN 9781118314975. 7. ^ "STD Facts - Genital Herpes". www.cdc.gov. December 11, 2017. Retrieved September 22, 2018. "Genital herpes is common in the United States. More than one out of every six people aged 14 to 49 years have genital herpes." 8. ^ a b c Gupta R, Warren T, Wald A (December 2007). "Genital herpes". Lancet. 370 (9605): 2127–37. doi:10.1016/S0140-6736(07)61908-4. PMID 18156035. S2CID 40916450. 9. ^ a b Sakakibara R, Yamanishi T, Uchiyama T, Hattori T (August 2006). "Acute urinary retention due to benign inflammatory nervous diseases". Journal of Neurology. 253 (8): 1103–10. doi:10.1007/s00415-006-0189-9. PMID 16680560. S2CID 24474530. 10. ^ Vonk P (December 1993). "[Elsberg syndrome: acute urinary retention following a viral infection]". Nederlands Tijdschrift voor Geneeskunde (in Dutch). 137 (50): 2603–5. PMID 8277988. 11. ^ a b How the facts about Genital Herpes can help. By New Zealand Herpes Foundation. Retrieved June 2014 12. ^ a b Le Cleach L, Trinquart L, Do G, Maruani A, Lebrun-Vignes B, Ravaud P, Chosidow O (August 2014). "Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients". The Cochrane Database of Systematic Reviews. 8 (8): CD009036. doi:10.1002/14651858.CD009036.pub2. PMID 25086573. 13. ^ a b 2007 National Guideline for the Management of Genital Herpes. Archived 2015-09-23 at the Wayback Machine By Clinical Effectiveness Group at British Association for Sexual Health and HIV. 14. ^ a b Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, García FA, et al. (December 2016). "Serologic Screening for Genital Herpes Infection: US Preventive Services Task Force Recommendation Statement". JAMA. 316 (23): 2525–2530. doi:10.1001/jama.2016.16776. PMID 27997659. 15. ^ "Medications and Drugs". Retrieved 30 October 2018. 16. ^ a b Heslop, R; Roberts, H; Flower, D; Jordan, V (30 August 2016). "Interventions for men and women with their first episode of genital herpes". The Cochrane Database of Systematic Reviews (8): CD010684. doi:10.1002/14651858.CD010684.pub2. PMID 27575957. 17. ^ "Brand Name: Valtrex". Retrieved 30 October 2018. 18. ^ Canadian Guidelines on Sexually Transmitted Infections > Section 5 - Management and Treatment of Specific Infections > Genital Herpes simplex virus (HSV) Infections. from the Public Health Agency of Canada. Date Modified: 2013-02-01. 19. ^ "Brand Name: Famvir". Retrieved 30 October 2018. 20. ^ Allen J (2010-03-09). "U.S. herpes rates remain high - CDC". Reuters. Retrieved 2013-05-03. 21. ^ a b "Genital Herpes - CDC Fact Sheet". Retrieved 2013-06-03. 22. ^ "Prevent STDs like a porn star". CNN. 2011-05-19. Retrieved 2013-11-04. 23. ^ "Sore Subject: The Symptoms of Herpes Aren't Just Physical". 2012-01-09. Retrieved 2013-11-04. 24. ^ a b c Scott, Nigel (1 September 2011). "The courts should keep out of our sex lives". Spiked. Retrieved 30 October 2018. 25. ^ Hofstetter AM, Rosenthal SL, Stanberry LR (February 2014). "Current thinking on genital herpes". Current Opinion in Infectious Diseases. 27 (1): 75–83. doi:10.1097/qco.0000000000000029. PMID 24335720. S2CID 4910110. ## External links Classification D * ICD-10: A60 * ICD-9-CM: 054.1 * MeSH: D006558 External resources * MedlinePlus: 000857 * v * t * e Skin infections, symptoms and signs related to viruses DNA virus Herpesviridae Alpha HSV * Herpes simplex * Herpetic whitlow * Herpes gladiatorum * Herpes simplex keratitis * Herpetic sycosis * Neonatal herpes simplex * Herpes genitalis * Herpes labialis * Eczema herpeticum * Herpetiform esophagitis Herpes B virus * B virus infection VZV * Chickenpox * Herpes zoster * Herpes zoster oticus * Ophthalmic zoster * Disseminated herpes zoster * Zoster-associated pain * Modified varicella-like syndrome Beta * Human herpesvirus 6/Roseolovirus * Exanthema subitum * Roseola vaccinia * Cytomegalic inclusion disease Gamma * KSHV * Kaposi's sarcoma Poxviridae Ortho * Variola * Smallpox * Alastrim * MoxV * Monkeypox * CPXV * Cowpox * VV * Vaccinia * Generalized vaccinia * Eczema vaccinatum * Progressive vaccinia * Buffalopox Para * Farmyard pox: Milker's nodule * Bovine papular stomatitis * Pseudocowpox * Orf * Sealpox Other * Yatapoxvirus: Tanapox * Yaba monkey tumor virus * MCV * Molluscum contagiosum Papillomaviridae HPV * Wart/plantar wart * Heck's disease * Genital wart * giant * Laryngeal papillomatosis * Butcher's wart * Bowenoid papulosis * Epidermodysplasia verruciformis * Verruca plana * Pigmented wart * Verrucae palmares et plantares * BPV * Equine sarcoid Parvoviridae * Parvovirus B19 * Erythema infectiosum * Reticulocytopenia * Papular purpuric gloves and socks syndrome Polyomaviridae * Merkel cell polyomavirus * Merkel cell carcinoma RNA virus Paramyxoviridae * MeV * Measles Togaviridae * Rubella virus * Rubella * Congenital rubella syndrome ("German measles" ) * Alphavirus infection * Chikungunya fever Picornaviridae * CAV * Hand, foot, and mouth disease * Herpangina * FMDV * Foot-and-mouth disease * Boston exanthem disease Ungrouped * Asymmetric periflexural exanthem of childhood * Post-vaccination follicular eruption * Lipschütz ulcer * Eruptive pseudoangiomatosis * Viral-associated trichodysplasia * Gianotti–Crosti syndrome * 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 [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Genital herpes	c0019342	4,693	wikipedia	https://en.wikipedia.org/wiki/Genital_herpes	2021-01-18T19:05:20	{"mesh": ["D006558"], "umls": ["C0019342"], "icd-10": ["A60"], "wikidata": ["Q7476596"]}
A number sign (#) is used with this entry because this form of nonsyndromic X-linked mental retardation is caused by mutation in the gene encoding p21-activated kinase-3 (PAK3; 300142). Clinical Features Des Portes et al. (1997) reported a French family in which 6 males in 2 generations had nonsyndromic X-linked mental retardation. All affected males had moderate to severe mental retardation without seizures, statural growth deficiencies, or other physical abnormalities. Gedeon et al. (2003) reported an Australian family with nonsyndromic MRX affecting 19 males in 5 generations. Some of the patients had relatively long ears, but no other physical abnormalities. The mental deficit was borderline to mild, and most attended special schools, had menial jobs, and could perform activities of daily living independently. Four patients had histories of psychiatric problems, including features of schizophrenia. Carrier females had no abnormalities. Peippo et al. (2007) further characterized PAK3-related mental retardation in a Finnish family. The 5 affected males examined had a proportionately small head or microcephaly, large ears, thin upper lip, open mouth appearance, drooling, and inarticulate speech. Behavioral features included short attention span, anxiety, restlessness, and aggression. One affected male had paranoid psychosis. EEG recordings in 4 affected males and 1 carrier female demonstrated similar posterior slow wave activity without epileptic discharge. One affected male had epilepsy. Neuropsychologic testing in affected males and carrier females suggested a common profile of impaired spatial cognitive abilities and defects in attentional and executive functions. In contrast to the report by Gedeon et al. (2003), most carrier females manifested learning problems and mild mental disability. Skewed X-inactivation was observed in female carriers. Rejeb et al. (2008) reported a Tunisian family with PAK3-related mental retardation. The phenotype was relatively homogeneous and characterized by microcephaly, marked hypotonia, and oromotor dysfunction with drooling and speech difficulties. Affected individuals also had characteristic behavioral features, including aggression, hyperactivity, and agitation. Dysmorphic features consisted of microcephaly, flat face, low forehead, upslanting palpebral fissures, short nose with upturned nasal tips, large ears, large open mouth, and high palate. The findings suggested a specific phenotype. Mapping By linkage analysis of an Australian family with MRX, Donnelly et al. (1996) identified a candidate locus, termed MRX30, within a 28-cM region on chromosome Xq21.3-q24 between markers DXS990 and DXS424 (maximum multipoint lod score of 2.78). By linkage analysis of a French family with nonsyndromic X-linked mental retardation, des Portes et al. (1997) identified a candidate disease locus, termed MRX47, on chromosome Xq22.3-q24 (maximum 2-point lod score of 3.75 at marker DXS1059). Recombination events defined a 17-cM interval between DXS1105 and DXS8067. The region overlapped with that reported by Donnelly et al. (1996) for MRX30. Molecular Genetics Allen et al. (1998) identified a mutation in the PAK3 gene (300142.0001) in affected males of the Australian family with MRX30 reported by Donnelly et al. (1996). In affected members of the French family with MRX47 reported by des Portes et al. (1997), Bienvenu et al. (2000) identified a mutation in the PAK3 gene (300142.0002). Gedeon et al. (2003) identified a mutation in the PAK3 gene (300142.0003) that segregated with MRX in an Australian family. In 5 males with mental retardation in a Finnish family, Peippo et al. (2007) identified a novel missense mutation in the PAK3 gene (300142.0004). The mutation was absent in 2 unaffected male relatives. Each mother of an affected male was found to be a carrier of the mutation. Rejeb et al. (2008) identified a mutation in the PAK3 gene (300142.0005) in affected members of a Tunisian family with mental retardation. INHERITANCE \- X-linked recessive HEAD & NECK Head \- Microcephaly Face \- Flat face \- Low forehead Ears \- Relatively long ears Nose \- High-bridged nose \- Short nose \- Upturned nasal tips Mouth \- Open mouth appearance \- Thin upper lip \- High palate \- Drooling NEUROLOGIC Central Nervous System \- Mental retardation, mild to severe \- Mental retardation, borderline-mild in carrier females \- Delayed speech development \- Inarticulate speech Delayed gross motor skills \- Posterior slow-wave activity on EEG \- Epilepsy Behavioral Psychiatric Manifestations \- Schizophrenia-like symptoms (uncommon) \- Short attention span \- Anxiety \- Restlessness \- Agitation \- Hyperactivity \- Aggression \- Psychosis \- Impaired visuospatial perception \- Impaired attentional and executive function MISCELLANEOUS \- Variable severity \- Some patients can attend special school \- Some patients can hold menial jobs MOLECULAR BASIS \- Caused by mutation in the p21-activated kinase 3 gene (PAK3, 300142.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	MENTAL RETARDATION, X-LINKED 30	c2931498	4,694	omim	https://www.omim.org/entry/300558	2019-09-22T16:20:06	{"doid": ["0050776"], "mesh": ["C567906"], "omim": ["300558"], "orphanet": ["777"], "synonyms": ["Alternative titles", "MENTAL RETARDATION, X-LINKED 47"]}
Abnormally large head size This article is in list format, but may read better as prose. You can help by converting this article, if appropriate. Editing help is available. (May 2020) Macrocephaly An MRI of a patient with benign familial macrocephaly (male with head circumference > 60cm) SpecialtyMedical genetics Macrocephaly is a condition in which the human head is abnormally large; this includes the scalp, the cranial bone, and the contents of the cranium. It may be pathological or benign, even a familial genetic characteristic. People diagnosed with macrocephaly will have further testing done to determine if the syndrome is accompanied by any other disorders. Those with benign or familial macrocephaly are considered to have megalencephaly, another form of macrocephaly that will not result in the development of neurological disorders in the patient. ## Contents * 1 Causes * 1.1 Hydrocephalus * 1.1.1 Noncommunicating * 1.1.2 Communicating * 1.1.3 Arachnoid cyst, supratentorial * 1.1.4 Meningeal fibrosis/obstruction * 1.1.5 Vascular * 1.1.6 Choroid plexus papilloma * 1.1.7 Neurocutaneous syndromes * 1.1.8 Destructive lesions * 1.1.9 Familial, autosomal-dominant, autosomal-recessive, X-linked * 1.2 Subdural fluid * 1.3 Brain edema (toxic-metabolic) * 1.4 Thick skull or scalp (hyperostosis) * 1.5 Megalencephaly and hemimegalencephaly * 2 Diagnosis * 2.1 Benign or familial macrocephaly * 3 Treatment * 4 Associated syndromes * 4.1 Include multiple major and or minor anomalies * 4.2 Secondary to a metabolic disorder * 4.3 Associated with a skeletal dysplasia * 4.4 With no obvious physical findings * 5 See also * 6 References * 7 External links ## Causes[edit] Many people with abnormally large heads or large skulls are healthy, but macrocephaly may be pathological. Pathologic macrocephaly may be due to megalencephaly (enlarged brain), hydrocephalus (abnormally increased cerebrospinal fluid), cranial hyperostosis (bone overgrowth), and other conditions. Pathologic macrocephaly is called "syndromic", when it is associated with any other noteworthy condition, and "nonsyndromic" otherwise. Pathologic macrocephaly may be caused by congenital anatomic abnormalities, genetic conditions, or by environmental events.[1] Many genetic conditions are associated with macrocephaly, including familial macrocephaly related to the holgate gene, autism, PTEN mutations such as Cowden disease, neurofibromatosis type 1, and tuberous sclerosis; overgrowth syndromes such as Sotos syndrome (cerebral gigantism), Weaver syndrome, Simpson-Golabi-Behmel syndrome (bulldog syndrome), and macrocephaly-capillary malformation (M-CMTC) syndrome; neurocardiofacial-cutaneous syndromes such as Noonan syndrome, Costello syndrome, Gorlin Syndrome,[2] (also known as Basal Cell Nevus Syndrome) and cardiofaciocutaneous syndrome; Fragile X syndrome; leukodystrophies (brain white matter degeneration) such as Alexander disease, Canavan disease, and megalencephalic leukoencephalopathy with subcortical cysts; and glutaric aciduria type 1 and D-2-hydroxyglutaric aciduria.[1] At one end of the genetic spectrum, duplications of chromosomes have been found to be related to autism and macrocephaly; at the other end, deletions of chromosomes have been found to be related to schizophrenia and microcephaly.[3][4][5] Environmental events associated with macrocephaly include infection, neonatal intraventricular hemorrhage (bleeding within the infant brain), subdural hematoma (bleeding beneath the outer lining of the brain), subdural effusion (collection of fluid beneath the outer lining of the brain), and arachnoid cysts (cysts on the brain surface).[1] In research, cranial height or brain imaging may be used to determine intracranial volume more accurately.[1] Below is a list of causes of macrocephaly from Swaiman's pediatric neurology: principles and practice noted in The Little Black Book of Neurology:[6][7] ### Hydrocephalus[edit] Dandy-Walker malformation #### Noncommunicating[edit] * Arnold-Chiari malformation * Aqueductal stenosis * X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) syndrome (L1CAM) * Dandy-Walker malformation * Galenic vein aneurysm or malformation * Neoplasms, supratentorial, and infratentorial * Arachnoid cyst, infratentorial * Holoprosencephaly with dorsal interhemispheric sac #### Communicating[edit] * External or extraventricular obstructive hydrocephalus (dilated subarachnoid space) #### Arachnoid cyst, supratentorial[edit] This section is empty. You can help by adding to it. (March 2020) #### Meningeal fibrosis/obstruction[edit] * Postinflammatory * Posthemorrhagic * Neoplastic infiltration Empyema #### Vascular[edit] * Arteriovenous malformation * Intracranial hemorrhage * Dural sinus thrombosis #### Choroid plexus papilloma[edit] This section is empty. You can help by adding to it. (March 2020) #### Neurocutaneous syndromes[edit] * Incontinentia pigmenti #### Destructive lesions[edit] * Hydranencephaly * Porencephaly #### Familial, autosomal-dominant, autosomal-recessive, X-linked[edit] This section is empty. You can help by adding to it. (March 2020) Hyperostosis ### Subdural fluid[edit] * Hematoma * Hygroma * Empyema ### Brain edema (toxic-metabolic)[edit] * Intoxication * Lead * Vitamin A * Tetracycline * Endocrine (hypoparathyroidism, hypoadrenocorticism) * Galactosemia * Idiopathic (pseudotumorcerebri) Hemimegalencephaly ### Thick skull or scalp (hyperostosis)[edit] * Familial variation * Anemia * Osteoporosis, severe precocious autosomal-recessive osteoporosis (CLCN7, TCIRG1) * Pycnodysostosis (CTSK) * Craniometaphyseal dysplasia (ANKH) * Craniodiaphyseal dysplasia * Pyle dysplasia * Sclerosteosis (SOST) * Juvenile Paget disease * Idiopathic hyperphosphatasia * Familial osteoectasia * Osteogenesis imperfecta * Rickets * Cleidocranial dysostosis * Hyperostosis corticalis generalisata (van Buchem disease) * Proteus syndrome ### Megalencephaly and hemimegalencephaly[edit] This section is empty. You can help by adding to it. (March 2020) ## Diagnosis[edit] Macrocephaly is customarily diagnosed if head circumference is greater than two standard deviations (SDs) above the mean.[8] Relative macrocephaly occurs if the measure is less than two SDs above the mean, but is disproportionately above that when ethnicity and stature are considered. Diagnosis can be determined in utero or can be determined within eighteen 18-24 months after birth in some cases where head circumference tends to stabilize in infants.[9] Diagnosis in infants includes measuring the circumference of the child's head and comparing how significant it falls above the 97.5 percentile of children similar to their demographic. If falling above the 97.5th percentile then the patient will be checked to determine if there is any intracranial pressure present and whether or not immediate surgery is needed.[10] If immediate surgery is not needed then further testing will be done to determine if the patient has either macrocephaly or benign macrocephaly. Diagnosis for macrocephaly involves the comparison of the infant's head circumference to that of other infants of the same age and ethnicity. If a patient is suspected of having macrocephaly molecular testing will be used to confirm diagnosis. Symptoms vary on the cause of macrocephaly on the child and if the child has any other accompanying syndromes which will be determined through molecular testing. ### Benign or familial macrocephaly[edit] Benign macrocephaly can occur without reason or be inherited by one or both parents (in which it is considered benign familial macrocephaly and is considered megalencephaly form of macrocephaly). Diagnoses for familial macrocephaly is determined by measuring the head circumference of both parents and comparing it to the child's. Benign and familial macrocephaly is not associated with neurological disorders.[10] While benign and familial macrocephaly does not result in neurological disorders, neurodevelopment will still be assessed. Although neurological disorders do not occur, temporary symptoms of benign and familial macrocephaly include: developmental delay, epilepsy, and mild hypotonia.[10] Neurodevelopment is assessed for all cases and suspected cases of macrocephaly to determine if and what treatments may be needed and whether or not other syndromes may be present or likely to develop. ## Treatment[edit] Treatment varies depending on whether or not it occurs with other medical conditions in the child and where cerebrospinal fluid is present.[9] * If benign and found between the brain and skull then no surgery is needed.[9][11] * If excess fluid is found between the ventricle spaces in the brain then surgery will be needed.[11] ## Associated syndromes[edit] Below is a list of syndromes associated with macrocephaly that are noted in Signs and Symptoms of Genetic Conditions: A Handbook.[12] Lujan-fryns syndrome ### Include multiple major and or minor anomalies[edit] * Acrocallosal Syndrome * Apert Syndrome * Bannayan-Riley-Ruvalcaba * Cardiofaciocutaneous syndrome * Chromosome 14 - maternal dismoy * Chromosome 22qter deletion * Cleidocranial dysostosis * Costello syndrome * Encephalocraniocutaneous lipomatosis * FG syndrome * Hailermann-streiff syndrome * Hydolethalus syndrome * Hypomelanosis syndrome * Hypomelanosis of Ito * Kelvin Peter anomaly plus syndrome * Lujan-fryns syndrome * Macrocephaly-CM (MCAP) * Marshall-Smith syndrome * Neuhauser megalocornea/MR syndrome * Neurofibromatosis I * Nevoid basal cell carcinoma syndrome * Noonan syndrome * Ocular-ectodermal syndrome * Osteopathia striata - cranial sclerosis * Perlman syndrome * Ricky * Ritscher - schinzel syndrome * Robinow syndrome * Simpson-golabi-behmel syndrome * Sotos syndrome * Sturge-Weber syndrome * Weaver syndrome * Wiedermann-rautenstrauch syndrome Sturge-Weber syndrome ### Secondary to a metabolic disorder[edit] * Glutaric aciduria type II * GM1 gangliosidosis * Hunter syndrome * Hurler syndrome * MPS VII * Sanfilippo syndrome * Zellweger syndrome Alexander disease ### Associated with a skeletal dysplasia[edit] * Achondroplasia * Camptomelic dysplasia * Craniodiaphyseal dysplasia * Craniometalphyseal dysplasia * Hypochondrogenesis * Hypochondroplasia * Kenny-caffey * Kniest syndrome * Lenz-majewski * Osteogenesis imperfecta III * Osteopetrosis, autosomal recessive form * Schneckenbecken dysplasia * Sclerosteosis * Short rib syndrome, beemer-langer type * Short rib-polydactyly 2 (majewski type) * Spondyleopiphyseal dysplasia congenita * Thanatophoric dysplasia Tay-sachs ### With no obvious physical findings[edit] * Alexander disease * Canavan * Cobalamin deficiency (combined methylmalonic aciduria and homocystinuria) * Dandy-Walker malformation * Glutaric aciduria I * L-2 hydroxglutaric aciduria * Megalencephalic leukoencephalopathy * Osteogenesis imperfecta IV * Osteopathia striata-cranial sclerosis * Periventricular heterotopia * Sandhoff disease * Tay-sachs ## See also[edit] * Microcephaly * Megalencephaly * Hydrocephalus ## References[edit] 1. ^ a b c d Williams CA, Dagli A, Battaglia A (2008). "Genetic disorders associated with macrocephaly". Am J Med Genet A. 146A (16): 2023–37. doi:10.1002/ajmg.a.32434. PMID 18629877. S2CID 205309800. 2. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2015-10-09. Retrieved 2015-05-04.CS1 maint: archived copy as title (link) 3. ^ Crespi; et al. (2010). "Comparative genomics of autism and schizophrenia". PNAS. 107: 1736–1741. doi:10.1073/pnas.0906080106. PMC 2868282. PMID 19955444. 4. ^ International Schizophrenia Consortium (September 2008). "Rare chromosomal deletions and duplications increase risk of schizophrenia; The International Schizophrenia Consortium;". Nature. 455 (7210): 237–241. doi:10.1038/nature07239. PMC 3912847. PMID 18668038. 5. ^ Dumas L.; Sikela J.M. (2009). "DUF1220 Domains, Cognitive Disease, and Human Brain Evolution". Cold Spring Harb. Symp. Quant. Biol. 74: 375–82. doi:10.1101/sqb.2009.74.025. PMC 2902282. PMID 19850849. 6. ^ Cooke, Rachel. "ProQuest Ebook Central". doi:10.5260/cca.199425. Cite journal requires `\|journal=` (help) 7. ^ Swaiman, Kenneth F.; Ashwal, Stephen; Ferriero, Donna M.; Schor, Nina F. (2012), "Preface to the Fifth Edition", Swaiman's Pediatric Neurology, Elsevier, pp. xiii–xiv, doi:10.1016/b978-1-4377-0435-8.00116-5, ISBN 978-1-4377-0435-8 8. ^ Fenichel, Gerald M. (2009). Clinical Pediatric Neurology: A Signs and Symptoms Approach (6th ed.). Philadelphia, PA: Saunders/Elsevier. p. 369. ISBN 978-1416061854. 9. ^ a b c "Macrocephaly \| Nicklaus Children's Hospital". www.nicklauschildrens.org. Retrieved 2020-04-11. 10. ^ a b c Signs and symptoms of genetic conditions : a handbook. Hudgins, Louanne,, Toriello, Helga V.,, Enns, Gregory M.,, Hoyme, H. Eugene. Oxford. 30 May 2014. ISBN 978-0-19-938869-1. OCLC 879421703.CS1 maint: others (link) 11. ^ a b "Macrocephaly or "Big Head"". Department of Neurosurgery. Retrieved 2020-04-27. 12. ^ Signs and symptoms of genetic conditions : a handbook. Hudgins, Louanne,, Toriello, Helga V.,, Enns, Gregory M.,, Hoyme, H. Eugene. Oxford. 30 May 2014. ISBN 978-0-19-938869-1. OCLC 879421703.CS1 maint: others (link) ## External links[edit] * GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS) * GeneReviews/NCBI/NIH/UW entry on 9q22.3 Microdeletion Classification D * ICD-10: Q75.3 * ICD-9-CM: 756.0 * OMIM: 248000 * MeSH: D058627 * DiseasesDB: 22519 * SNOMED CT: 9740002 External resources * MedlinePlus: 003305 * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category *[Rate]: ICU-care cases per confirmed cases in each category	Macrocephaly	c0220690	4,695	wikipedia	https://en.wikipedia.org/wiki/Macrocephaly	2021-01-18T18:49:11	{"gard": ["147"], "mesh": ["C537717"], "umls": ["C0220690"], "icd-9": ["756.0"], "icd-10": ["Q75.3"], "wikidata": ["Q635339"]}
Spectators' banner during the Tour de France 2006 Part of a series on Doping in sport Substances and types * Anabolic steroids * Blood doping * Gene doping * Cannabinoids * Diuretics * Painkillers * Sedatives * Stem cell doping * Stimulants * Beta2-adrenergic agonist * Clenbuterol * Ephedrine * EPO * Human growth hormone * Methylhexanamine * SARMs * Stanozolol * Tetrahydrogestrinone Terminology * Abortion doping * Biological passport * Blood-spinning * Doping test * Performance-enhancing drugs * Repoxygen * Stem cell doping * Whizzinator History * Olympics * Tour de France (1998, 1999, 2007) * Auto racing * BALCO scandal * Clemson University steroid scandal * U of South Carolina steroid scandal * Dubin Inquiry * Association Football * China * East Germany * Russia * United States * Festina affair * Floyd Landis case * Game of Shadows * Juiced * L.A. Confidentiel * Lance Armstrong * History of allegations * Doping case * Operación Puerto * Operation Aderlass * Doping in American football * Steroid use in baseball * Barry Bonds perjury case * Mitchell Report * Biogenesis scandal Doping-related lists * Doping cases in Sport * Athletics * Cycling * Doping at the Olympic Games * Doping at the World Championships in Athletics * Stripped Olympic medals * Stripped European Athletics C'ships medals * Drugs banned from the Olympics * MLB players suspended for doping * MLB players in the Mitchell Report Anti-doping bodies * World Anti-Doping Agency * International Testing Agency * List of national anti-doping organizations * Australian Sports Anti-Doping Authority * French Anti-Doping Agency * National Anti-Doping Agency * Russian Anti-Doping Agency * UK Anti-Doping * United States Anti-Doping Agency * v * t * e There have been allegations of doping in the Tour de France since the race began in 1903. Early Tour riders consumed alcohol and used ether, among other substances, as a means of dulling the pain of competing in endurance cycling.[1] Riders began using substances as a means of increasing performance rather than dulling the senses, and organizing bodies such as the Tour and the International Cycling Union (UCI), as well as government bodies, enacted policies to combat the practice. Use of performance-enhancing drugs in cycling predates the Tour de France. Cycling, having been from the start a sport of extremes, whether of speed by being paced by tandems, motorcycles and even cars, or of distance, the suffering involved encouraged the means to alleviate it. Not until after World War II were sporting or even particularly health issues raised. Those came shortly before the death of Tom Simpson in the Tour de France of 1967. Max Novich referred to the Tour de France in a 1973 issue of New York State Journal of Medicine as "a cycling nightmare".[2] Journalist Hans Halter wrote in 1998 that "For as long as the Tour has existed, since 1903, its participants have been doping themselves. For 60 years doping was allowed. For the past 30 years it has been officially prohibited. Yet the fact remains; great cyclists have been doping themselves, then and now."[3] ## Contents * 1 Early doping in cycling * 2 1903-1940s: Doping as acceptable means * 2.1 The Convicts of the Road * 3 1950s–1960s: Early anti-doping stance * 3.1 Malléjac incident * 3.2 Too drugged to pull on the brakes * 3.3 Wiel's affair * 4 1965: Criminalization of doping * 4.1 First anti-doping test and a strike * 4.2 Death of Tom Simpson * 4.3 Steroids and allied drugs * 4.4 Pollentier incident * 5 1990s: The era of EPO * 5.1 1998 Festina scandal * 5.2 Lance Armstrong * 5.3 2006 Tour de France * 5.3.1 Operación Puerto investigation * 5.3.2 Floyd Landis accusation * 5.4 2007 Tour de France * 6 2012 USADA report * 7 Testing * 8 Status of Tour de France winners since 1961 * 9 Doping histories of Top-10 finishers, 1997–2015 * 9.1 1997 Tour de France * 9.2 1998 Tour de France * 9.3 1999 Tour de France * 9.4 2000 Tour de France * 9.5 2001 Tour de France * 9.6 2002 Tour de France * 9.7 2003 Tour de France * 9.8 2004 Tour de France * 9.9 2005 Tour de France * 9.10 2006 Tour de France * 9.11 2007 Tour de France * 9.12 2008 Tour de France * 9.13 2009 Tour de France * 9.14 2010 Tour de France * 9.15 2011 Tour de France * 9.16 2012 Tour de France * 9.17 2013 Tour de France * 9.18 2014 Tour de France * 9.19 2015 Tour de France * 10 See also * 11 References * 12 Further reading * 13 External links ## Early doping in cycling[edit] See also: Use of performance-enhancing drugs in sport Major Taylor racing in Paris 1908 Drug-taking in cycling predates the Tour de France. "It existed, it has always existed", said the French reporter and author, Pierre Chany, who followed 49 Tours before his death in 1996.[4] The exhaustion of six-day races on the track was countered by the riders' soigneurs (the French word for "carer"), helpers akin to seconds in boxing. Among the treatments they supplied was nitroglycerine, a drug used to stimulate the heart after cardiac attacks and which was credited with improving riders' breathing.[5] Riders suffered hallucinations from the exhaustion and perhaps the drugs. The American champion Major Taylor refused to continue the New York race, saying: "I cannot go on with safety, for there is a man chasing me around the ring with a knife in his hand."[6] Also used was strychnine, which in small doses tightened tired muscles. A track rider of the era said he had developed such a tolerance to the drug that he took doses large enough to kill smaller men.[7] The use of strychnine, far from being banned, was thought necessary to survive demanding races, says the sports historian Alain Lunzenfichter.[8] The American specialist in doping, Max M. Novich, wrote: "Trainers of the old school who supplied treatments which had cocaine as their base declared with assurance that a rider tired by a six-day race would get his second breath after absorbing these mixtures."[9] John Hoberman, a professor at the University of Texas in Austin, Texas, said six-day races were "de facto experiments investigating the physiology of stress as well as the substances that might alleviate exhaustion."[10] The first backers of races on the road were newspapers. Although Le Vélocipède Illustré, which was behind the world's first long-distance road race in November 1869, said its purpose was "to further the good cause of the bicycle" because "it must be determined that the bicycle can be raced over considerable distances with incomparably less fatigue than running",[11] backing the race would also boost the newspaper's sales. In an era before radio and television, newspapers could build the drama of a race for weeks, rely on customers buying a further copy on the day to prepare for the riders to pass and then another next day to see what had become of them. Few people had travelled 130 km, at least not often, and the idea of doing it by bicycle and at as high a speed as possible when the roads were potholed and bicycles had wooden wheels and metal tyres was exciting. The result was that newspapers outdid each other in promotions. In 1891 came a race from Bordeaux to Paris. In the same year, Le Petit Journal went twice as far by running Paris–Brest–Paris over 1,200 km. During a meeting at L'Auto in Paris, journalist Géo Lefèvre suggested a race right round France, not just one day but six, "like the six-day races on the track."[12] The idea of bringing the excess of the indoors to the roads of the outdoors was born. And with it came the practices which had seen riders through their suffering. ## 1903-1940s: Doping as acceptable means[edit] The strongest drug in the early Tour de France was strychnine. Other than that, riders would take anything to survive the tedium, the pain and the exhaustion of stages that could last more than 300 km. That included alcohol, which was already strong in French culture and sometimes purer than water after World War I destroyed water pipes and polluted water tables, and ether. There are photographs of riders holding ether-soaked handkerchiefs to their mouths, or leaving them knotted under the chin so the fumes would deaden the pain in their legs.[13] The smell, enough to turn a man's stomach said Pierre Chany,[14] discouraged some but also showed the extent of suffering by others. Roger Lapébie, winner of the Tour in 1937, said he smelled ether "in the bunch near the finish; it used to be taken in a little bottle called a topette."[15] Its use lasted decades; riders were caught using it as late as 1963. The acceptance of drug-taking in the Tour de France was so complete by 1930, when the race changed to national teams that were to be paid for by the organisers, that the rule book distributed to riders by the organiser, Henri Desgrange, reminded them that drugs were not among items with which they would be provided.[16] In a 1949 interview with Fausto Coppi, the 1949 and 1952 Tour winner, he admitted to amphetamine use and said "those who claim [that cyclists do not take amphetamine], it's not worth talking to them about cycling".[17] ### The Convicts of the Road[edit] In 1924 the journalist Albert Londres followed the Tour de France for the French newspaper, Le Petit Parisien. At Coutances he heard that the previous year's winner, Henri Pélissier, his brother Francis and a third rider, Maurice Ville, had pulled out after a row with the organiser, Henri Desgrange. Henri Pélissier explained the problem – whether or not he had the right to take off a jersey – and went on to talk of drugs, reported in Londres' race diary, in which he coined the phrase Les Forçats de la Route (The Convicts of the Road): Henri Pelissier, 1919 "You have no idea what the Tour de France is", Henri said. "It's a Calvary. Worse than that, because the road to the Cross has only 14 stations and ours has 15. We suffer from the start to the end. You want to know how we keep going? Here..." He pulled a phial from his bag. "That's cocaine, for our eyes. This is chloroform, for our gums." "This", Ville said, emptying his shoulder bag "is liniment to put warmth back into our knees." "And pills. Do you want to see pills? Have a look, here are the pills." Each pulled out three boxes. "The truth is", Francis said, "that we keep going on dynamite." Henri spoke of being as white as shrouds once the dirt of the day had been washed off, then of their bodies being drained by diarrhoea, before continuing: "At night, in our rooms, we can't sleep. We twitch and dance and jig about as though we were doing St Vitus's Dance..." "There's less flesh on our bodies than on a skeleton", Francis said.[18] Francis Pélissier said much later: "Londres was a famous reporter but he didn't know about cycling. We kidded him a bit with our cocaine and our pills. Even so, the Tour de France in 1924 was no picnic."[19][20] ## 1950s–1960s: Early anti-doping stance[edit] Pierre Dumas was the first doctor to campaign for the testing and suppression of doping, both within cycling and then at international level at the Olympic Games. Dumas came to the Tour de France in 1952 when the original doctor pulled out. Dumas was a judoka rather than a cyclist and had none of the preconceptions established in cycling. He discovered a world in which "there were soigneurs, fakirs, who came from the six-days. Their value was in the contents of their case. Riders took anything they were given, even bee stings and toad extract." He spoke of "medicine from the heart of Africa... healers laying on hands or giving out irradiating balms, feet plunged into unbelievable mixtures which could lead to eczema, so-called magnetised diets and everything else you could imagine. In 1953 and 1954 it was all magic, medicine and sorcery. After that, they started reading Vidal [the French medicine directory]."[21] Such was the extent to which stronger drugs entered cycling that the French team manager, Marcel Bidot, was cited to an inquiry by the Council of Europe as saying: "Three-quarters of riders were doped. I am well placed to know that since I visited their rooms each evening during the Tour. I always left frightened after these visits."[19] At the 1956 Tour, it was evident how much drug-taking and the "care" of riders had changed. After stage 14, all members of the Belgian team chose to abandon the race following a "mystery illness". Insiders suspected doping usage as the real reason, while the team attributed the illness to a dinner of 'bad fish' they had eaten,[22] an excuse which was reused in both 1962 and 1991. In 1960, Pierre Dumas walked into a hotel bedroom on his nightly tour of teams to find eventual winner Gastone Nencini prone on his bed with a plastic tube running from each arm to a bottle containing hormones.[23] However, the hormone injection was not illegal at the time, and indeed only few were disqualified or sanctioned whenever they were found out to use doping.[22] ### Malléjac incident[edit] On stage 12 of the 1955 Tour, the riders went over Mount Ventoux. Ten kilometres from the summit, said the journalist Jacques Augendre, French rider Jean Malléjac was: "Streaming with sweat, haggard and comatose, he was zigzagging and the road wasn't wide enough for him... He was already no longer in the real world, still less in the world of cyclists and the Tour de France."[19] Malléjac collapsed, falling to the ground with one foot still trapped in a pedal. The other leg pedalled on in the air. He was, said Pierre Chany, "completely unconscious, his face the colour of a corpse, a freezing sweat ran on his forehead.[12] Malléjac was hauled to the side of the road by Sauveur Ducazeaux, an official of another team, and Dumas summoned. Georges Pahnoud of the Télégramme de Brest reported: He had to force [Malléjec's] jaws apart to try to make him drink and it was a quarter of an hour later, after he had received an injection of solucamphor and been given oxygen, that Malléjac regained consciousness. Taken by ambulance, he hadn't however completely recovered. He fought, he gesticulated, he shouted, demanded his bike, wanted to get out. Dumas had to strap Malléjac down for the journey to hospital at Avignon. Mallejac insisted that he had been given a drugged bottle from a soigneur, whom he did not name, and said that while his other belongings had reached the hospital intact, the bottle had been emptied and could not be analysed.[24] Malléjac insisted that he wanted to start legal proceedings, and Dumas said: "I'm prepared to call for a charge of attempted murder." The incident was never resolved, however, with Mallejac returning for subsequent Tours and denying any wrongdoing for the rest of his life. ### Too drugged to pull on the brakes[edit] In the 1960 Tour, Roger Rivière was second to the Italian Gastone Nencini, a rider he planned to beat by tagging along with him in the mountains and then speeding away on the flat. The problem was that Nencini was lighter and a better climber and that he was such a fast descender that, in the view of another French rider, Raphaël Géminiani, "the only reason to follow Nencini downhill is if you've got a death wish." A monument recording the fall of Rivière. Rivière was able to stay with Nencini on the climb to the Col de Perjuret, as the pair crossed the summit together. Then came a series of descending zigzags. Nencini took the perfect line and Rivière, trying to match him, overshot a bend, fell into a ravine, and broke his back. There he was found by his teammate, Louis Rostollan. Rivière quickly passed the blame for his fall and his broken back on the team mechanic, accusing him of leaving oil on the wheels and the brakes for not working. The mechanic was outraged, and the doctors soon found the real reason – that so much painkiller was in Rivière's blood that his hands were too slow to operate the brakes. He had taken a heavy dose of the opioid painkiller dextromoramide (Palfium), to help him stay with Nencini on Col de Perjuret.[22] Rivière later admitted to being a drug addict, telling a newspaper how he had doped to beat the world hour record,[25] and admitted downing thousands of tablets a year. ### Wiel's affair[edit] The stage from Luchon to Carcassonne in 1962 set off 10 minutes later than scheduled because the German rider, Hans Junkermann, had been ill most of the night. At first he was not going to start. When he said that after all he felt well enough, the organisers gave him the extra time to get ready. Junkermann was leader of the Wiel's-Groene Leeuw team and was allowed his privilege because he was in eighth position. Junkermann soon dropped to the back of the field and after 50 km he lost contact. On the first hill he got off his bike and sat by the roadside. "I ate bad fish at the hotel last night", he told onlookers. The same complaint came all day. A total twenty riders fell ill, and eleven others abandoned the Tour that day, including the former leader, Willy Schroeders, the 1960 winner Gastone Nencini and a future leader, Karl-Heinz Kunde. Jacques Goddet wrote that he suspected doping but nothing was proven – other than that none of the hotels the previous night had served fish, the hoteliers being anxious to clear their reputation. Pierre Dumas spoke of "certain preparations" and speculated the riders were given the same tainted drug by one of the soigneurs.[22] Team managers grew angry at the several days of newspaper reporting that followed and came close to calling for a strike. ## 1965: Criminalization of doping[edit] In 1960, the Danish rider Knud Enemark Jensen collapsed during the 100 km team time trial at the 1960 Olympic Games in Rome and died later in hospital. The autopsy showed he had taken amphetamine and another drug, Ronicol, which dilates the blood vessels. Pierre Dumas then led a committee of doctors demanding tests at the following Games. A national anti-doping law entered French legislation in June 1965.[26] Performance-enhancing drugs were now illegal in France, and the first anti-doping testing began at the 1966 Tour. That year, amphetamine use in France was running at almost a third of those tested.[20] Alec Taylor, team manager of rider Tom Simpson who died following doping usage in the 1967 Tour, said officials treated controls in fear, knowing what was there, afraid of what they might find. Race officials, federations, even the law on the Continent have been lax. Before Tom's death I saw on the Continent the overcautious way riders were tested for dope, as if the authorities feared to lift the veil, scared of how to handle the results; knowing all the while what they would be. They called on the law to act, enabling them to shelter under its wing and feel secure from interminable court actions and claims. They let the show carry on while the law acted light-heartedly, without vigour and purpose – and its deterrent had no effect.[27] ### First anti-doping test and a strike[edit] Testers arrived at the Tour de France for the first time in 1966, in Bordeaux, although only after word had spread and many riders had left their hotels. The first competitor they found was Raymond Poulidor, who became the first rider to be tested in the Tour. He said: "I was strolling down the corridor in ordinary clothes when I came across two guys in plain clothes. They showed me their cards and said to me: 'You're riding the Tour?' "I said: 'Yes'. 'You're a rider?' "I said: 'Yes'. 'OK, come with us.' "I swear it happened just like that. They made me go into a room, I pissed into some bottles and they closed them without sealing them. Then they took my name, my date of birth, without asking for anything to check my identity. I could have been anyone, and they could have done anything they liked with the bottles."[28] A few other riders were found, including Rik Van Looy; some obliged and others refused. Next morning, the race left the city on the way to the Pyrenees and stopped in the suburb of Gradignan, in the university area of La House. The riders climbed off and began walking, shouting protests in general and in particular abuse at Pierre Dumas, whom some demanded should also take a test to see if he had been drinking wine or taking aspirin to make his own job easier. ### Death of Tom Simpson[edit] Main article: Death of Tom Simpson Tom Simpson was the leader of the British team in the 1967 Tour de France. At the start of stage 13 on Thursday 13 July, he was still suffering the effects of a stomach bug he had endured earlier in the race. It was a blisteringly hot day, and he was seen to drink brandy during the early parts of the stage.[citation needed] In those years, the organisers limited each rider to four bottles of water each, about two litres – the effects of dehydration being poorly understood. During races, riders often raided roadside bars and cafes for drinks, and filled their bottles from fountains.[citation needed] About two kilometres from the summit of the day's main climb, Mont Ventoux, Simpson began to zig-zag across the road, eventually falling against an embankment.While his team-car helpers wanted him to retire from the race, Simpson insisted on being put back on his cycle and he continued for another 500 m or so before again beginning to falter; he toppled unconscious into the arms of his helpers, still gripping his handlebars.[citation needed] A motorcycle policeman summoned Pierre Dumas, who took over team officials' first attempts at saving Simpson, including mouth-to-mouth resuscitation.[citation needed] Dumas massaged Simpson's heart and gave him oxygen. A race helicopter then took Simpson to hospital but Simpson was declared dead soon after his arrival.[citation needed] Drug usage was only hinted at in the news coverage, particularly by Jacques Goddet, who referred in L'Équipe to Simpson's "errors in the way he looked after himself." Then a British reporter, J. L. Manning, broke the news that two empty tubes and a third full of amphetamines were found in the pocket of his jersey.[29] Manning was a serious and well-respected journalist. His exposure, the first time a formal connection had been made between drugs and Simpson's death, set off a wave of similar reporting in Britain and elsewhere. The following month, Manning went further, in a piece headed "Evidence in the case of Simpson who crossed the frontier of endurance without being able to know he had 'had enough'": The question of whether Tommy Simpson's death in the Tour de France might have been prevented has one clear answer. Yes, and it should have been. Three days after this year's race, the French authorities announced that next October and November a French and Italian rider would be prosecuted for alleged doping offences in last year's Tour. France had surrendered the need rigrously to prevent doping to the discreet requirement of not tackling it on a big tourist occasion until a year had safely passed. It takes two days at most to analyse samples: it took a year for France to authorise prosecutions. […] Is France trying to hush up the scandals of the Tour? I say yes. The first act of hushing up is not to attempt detection, let alone waiting a year before taking action. How much husher can you get? ### Steroids and allied drugs[edit] Merckx at the 1974 World Cycling Championships held in Montreal. During 1974, a number of riders failed tests for amphetamines, including Claude Tollet at the Tour. In 1977, a test for amphetamine-like drug Pemoline was perfected, catching five-time Tour de France winner Eddy Merckx among others. Far from abandoning drugs, riders and their helpers concentrated on finding alternatives that could not be detected. Five-time Tour de France winner Jacques Anquetil argued that stopping riders using amphetamine would not stop doping, but merely lead riders to use more dangerous drugs. In the 1970s, cycling moved into the steroid era. According to Dr Jean-Pierre de Mondenard, steroids were not used to build muscle bulk, but rather to improve recovery and thereby let competitors train harder and longer and with less rest. There is also a secondary stimulant effect. De Mondenard argued that such was the acceptance of steroids and then of corticoids that only the cost – which he put in prices of the time as between 35,000 and 50,000 French francs – was likely to restrict use. Only the richest or the most ambitious riders could afford that. And the rewards could be high: Bernard Thévenet won the 1975 and 1977 Tour de France editions by using cortisone. "I was doped with cortisone for three years and there were many like me", he said.[30] The experience had ruined his health, he said. Spanish rider Luis Ocaña failed tests in his last participation in the Tour de France in 1977 which was called the Tour of Doping.[31][32] Testing took time to adapt, but in 1978 Belgian rider Jean-Luc van den Broucke failed tests for steroid use, and said: In the Tour de France, I took steroids. That is not a stimulant, just a strengthener. If I hadn't, I would have had to give up. […] On the first rest day, before we went into the Pyrenees, I had a first hormone injection. I had another one on the second day, at the start of the last week. You can't call that medically harmful, not if it's done under a doctor's control and within reason. There was a mass of steroids used in the Tour, everyone will admit that. How can we stay at the top otherwise? Even at Munich [at the world track championship] it was used a lot. I hope the riders will get together next season and take action. Who can ride classics and long-distance Tours the whole year through without strengtheners?[33] ### Pollentier incident[edit] Riders became adept at circumventing controls. Their advisers learned to calculate how long it would take a drug to move from blood into urine, and therefore how much time a rider could risk waiting before going to a drugs test. Sometimes, riders simply cheated, as was revealed to the world in 1978. The rider was Michel Pollentier, who that year was the Belgian national champion and therefore wearing his national colours of red, yellow and black. By the end of the stage which finished on Alpe d'Huez he had taken the race lead and could change his champion's jersey for the yellow jersey as leader of the general classification. Pollentier was called to the drugs test with José Nazabal and Antoine Gutierrez. Nazabal gave his sample but left the race that night. When Gutierrez went to provide his sample, the doctor – a man called Le Calvez spending his first day with the race – grew suspicious and tugged up his jersey, revealing a system of tubes and a bottle of urine. He then pulled down Pollentier's shorts and found him similarly equipped. Reports in the press called the supply of urine – somebody else's urine – as being in a bottle. Riders called it a "pear". In fact it was a condom. The tube ran from there to the riders' shorts so that pressure on the condom, held under the armpit, would give the impression of urinating.[34] Pollentier's manager, Fred De Bruyne, who was in the test caravan, told a news conference: I congratulated Michel and then sat down. On my left was Gutierrez, trying to provide a sample for the doctor, while Pollentier was in the other corner. They both had difficulty in urinating... Suddenly, the doctor cried out: 'What are you doing?' to Gutierrez. I looked round and saw there was some urine in the Frenchman's test flask and a small plastic tube in his hand. He was confused and tried to say the tube had been in his pocket. I was overcome with surprise and thought 'I'm glad he isn't one of my team'. But then, about a minute later, panic returned when the doctor pulled down Pollentier's shorts and revealed this plastic tube which you all now know about.[34] The doctor said that Pollentier had not actually used the tube and so the test would go ahead as normal. At 8pm, the organiser, Félix Lévitan, told the press that the UCI had ruled that Pollentier would be fined 5,000 Swiss francs and start an immediate suspension of two months. The question was obvious: if a rider was prepared to take drugs and win a stage, knowing he would be tested, how many times had the ruse been shown to work before? ## 1990s: The era of EPO[edit] When other drugs became detectable, riders began achieving the effects of transfusion more effectively by using erythropoietin, known as EPO, a drug to increase red-cell production in anaemia sufferers. EPO became widespread, as a flurry of exposures and confessions revealed in 2006 and 2007. "When I saw riders with fat arses climbing cols like aeroplanes, I understood what was happening", said the Colombian rider, Luis Herrera. EPO's problem for testers was that like testosterone and, before that, cortisone, they could not distinguish it from what the body produced naturally. For the first time, said Jean-Pierre de Mondenard, authorities had to settle not for the presence of a drug but its presence in unusual quantities. Testers set a haematocrit limit of 50 per cent and "rested" riders who exceeded it. Bjarne Riis, the Danish rider who won the Tour in 1996, was known as "Mr 60 per cent" among riders.[35] On 25 May 2007, he admitted he had used EPO from 1993 to 1998, including 1996 when he won the Tour. Cynicism set in among both riders and officials. Jacques Goddet, organiser of the Tour from 1936 to 1987, said in 1999: I brought controls to the Tour in the wake of Tom Simpson's death in 1967 – and the riders went on strike. After the discoveries made [into the so-called 1998 Festina scandal, see below], I feel real resentment towards the medical and scientific powers who deceived us for 30 years. The controls are almost always negative, which means that the labs have been making serious mistakes, mistakes that have only served to speed up the growth of this evil. The controls we developed after Simpson's death were a lie, covered up by the highest scientific and medical authorities, and I condemn them.[36] Since 1997, the Swiss Laboratory for Doping Analyses is the testing laboratory of the Tour de France.[37] ### 1998 Festina scandal[edit] Main articles: Festina affair and Doping at the 1998 Tour de France See also: Doping at the 1999 Tour de France On 8 July 1998, French Customs arrested Willy Voet, a soigneur for the Festina team, for the possession of illegal drugs, including narcotics, erythropoietin (EPO), growth hormones, testosterone, and amphetamines. Voet later described many common doping practices in his book, Massacre à la Chaîne.[38] On 23 July 1998, French police raided several teams' hotels and found drugs in the possession of the TVM team. As news spread, riders staged a sit-down strike during the 17th stage. After mediation by Jean-Marie Leblanc, the director of the Tour, police agreed to limit the most heavy-handed tactics and riders agreed to continue. Many riders and teams had already abandoned the race and only 111 riders completed the stage. In a 2000 trial, it became clear that the management and health officials of Festina had organized drug-taking within the team. Richard Virenque, a top Festina rider, finally confessed after being ridiculed for maintaining that if he was doping he was somehow not consciously aware of it – as the satirical television programme, Les Guignols de l'Info, put it: "à l'insu de mon plein gré" ("of my own free will but without my knowing"). In the years following the 1998 Festina affair, anti-doping measures were put into effect by race organizers and the UCI, including more frequent testing and new tests for blood doping transfusions and EPO use. The World Anti-Doping Agency (WADA) was also created to help governments in anti-doping. Evidence of drugs persisted and in 2004 came new allegations. In January, Philippe Gaumont, a rider with the Cofidis team, told investigators and the press that steroids, human growth hormone, EPO, and amphetamines were endemic to the team. In June, British cyclist David Millar, also of Cofidis, and time trial world champion, was detained by French police, his apartment searched and two used EPO syringes found. Jesus Manzano, a Spanish rider then recently dismissed by the Kelme team, told the Madrid sports newspaper AS he had been forced by his former team to take banned substances and that they had taught him to evade detection. The Kelme team itself was ultimately a casualty of the disclosures, which Manzano judged to be "an eye for an eye and a tooth for a tooth."[39] ### Lance Armstrong[edit] See also: L. A. Confidentiel L'Équipe cover accusing Armstrong of doping. The title translates to "The Armstrong Lie". 23 August 2006. Lance Armstrong has become a symbol for doping at the Tour de France. Suspicions arose initially over his association with Italian physician Michele Ferrari and his extraordinary achievements on the road. In 1999, Armstrong failed tests for a glucocorticosteroid hormone. Armstrong explained he had used an external cortisone ointment to treat a saddle sore and produced a prescription for it. The amount detected was below the threshold and said to be consistent with the amount used for a topical skin cream, but UCI rules required that prescriptions be shown to sports authorities in advance of use. Armstrong's former assistant, Mike Anderson, stated that Armstrong used a substance with a trade name similar to "androstenine". This resulted in a lawsuit against Anderson and a countersuit against Armstrong.[40] In late August 2005, one month after Lance Armstrong's seventh consecutive Tour victory, the French sports newspaper L'Équipe claimed evidence that Armstrong had used EPO in the 1999 Tour de France.[41] The claim was based on urine samples archived by the French National Laboratory for Doping Detection (LNDD) for research. Armstrong denied using EPO and the UCI did not penalise him because of the lack of a duplicate sample. The UCI confirmed that its own doctor Mario Zorzoli leaked the 15 forms tying Armstrong to the failed tests to L'Équipe. In October 2012 Armstrong was banned for life and stripped of all his titles since 1 August 1998, including all his Tour de France victories, because an investigation by USADA concluded that he had been engaged in a massive doping scheme.[42] He later admitted to doping in an interview with Oprah Winfrey. Of the cyclists who finished on the podium in the era in which Lance Armstrong won the Tour de France seven times (1999–2005), Fernando Escartín is the sole rider not to be implicated in a doping scandal.[43] With "20 of the 21 podium finishers in the Tour de France from 1999 through 2005 directly tied to likely doping through admissions, sanctions, public investigations or exceeding the UCI hematocrit (a blood test to discover EPO use) threshold", Escartin's third-place finish in the 1999 Tour de France stands as the lone of the 21 podium finishes that was untainted, during the years (1999–2005) in which Lance Armstrong finished the Tour de France in first place. ### 2006 Tour de France[edit] #### Operación Puerto investigation[edit] Main article: Operación Puerto doping case An anti-doping banner displayed during the route of 2006 Tour de France prologue In 2006, several riders, including Jan Ullrich and Ivan Basso, were barred from the eve of the race amid allegations by Spanish police as a result of their Operación Puerto investigation.[44] The Astana-Würth team could not start because, despite a ruling by the Court of Arbitration for Sport, five of its nine Tour riders were barred after being officially named in the Operacion Puerto affair. With only four riders remaining (Alexander Vinokourov, Andrey Kashechkin, Carlos Barredo and Luis León Sanchez) the team did not have the minimum number of riders demanded by the rules to enter.[45] The cyclists excluded from 2006 Tour de France were: * Astana-Würth team: * Alberto Contador, cleared by Spanish court on 26 July 2006.[46] * Joseba Beloki, cleared by Spanish court on 26 July 2006.[46] * Allan Davis, cleared by Spanish court on 26 July 2006.[46] * Isidro Nozal, cleared by Spanish court on 26 July 2006.[46] * Sérgio Paulinho, cleared by Spanish court on 26 July 2006.[46] * Individuals: * Ivan Basso, (CSC) * Francisco Mancebo, (AG2R Prévoyance) * Jan Ullrich, (T-Mobile Team) * Óscar Sevilla, (T-Mobile Team) #### Floyd Landis accusation[edit] Main article: Floyd Landis doping case Floyd Landis at the 2006 Tour de France On 27 July 2006, the Phonak team announced that Floyd Landis, winner of the 2006 Tour, failed a test after stage 17 for an abnormally high ratio of the hormone testosterone to epitestosterone. On the day the allegations were made public, Landis denied doping.[47] Landis' personal doctor later revealed the test had found a ratio of 11:1 in Landis' blood; the permitted ratio is 4:1.[48] On 31 July 2006, The New York Times reported that tests on Landis' sample revealed some synthetic testosterone.[49] He was later stripped of his title and banned from cycling for two years.[50] ### 2007 Tour de France[edit] Main article: Doping at the 2007 Tour de France The 2007 Tour de France was dogged by controversies from the start. On 18 July, two German television companies pulled out of coverage[51] after T-Mobile's German rider, Patrik Sinkewitz, failed a test for testosterone on 8 June at a pre-Tour training camp. Alessandro Petacchi, a sprint specialist, failed a test for salbutamol at Pinerolo on 23 May in the 2007 Giro d'Italia, the day of the third of his five-stage wins in the event. Petacchi, an asthma sufferer, was suspended by Milram and forced to miss the Tour de France.[52] He was later cleared after the drug was deemed to be therapeutic use.[53] On 19 June it was revealed that the leader, Michael Rasmussen, was under suspicion for missing two out-of-competition doping tests. The Dane had been dropped by the Danish Cycling Union and his Olympic place was under review.[54] However, with information available at the time, Rasmussen had not committed an offence under UCI rules[55] and he remained in the yellow jersey. On 8 November Rasmussen admitted providing false information to the UCI.[56] Then on 24 July it was revealed that Alexander Vinokourov had failed a test for blood doping after the time trial in Albi, which he won by more than a minute[57] As a result, the Astana Team withdrew. Vinokourov's teammates Andreas Klöden and Andrey Kashechkin were fifth and seventh at the time. Vinokourov also failed tests for blood doping after winning Monday's stage 15. Following the Vinokourov announcement, Tour director Christian Prudhomme said professional cycling needed a "complete overhaul" to combat doping.[58] A day later, after winning the 16th stage on the Col d'Aubisque—a victory that assured he would be the overall winner—it was alleged that Rasmussen had lied to his Rabobank team about his whereabouts on 13 and 14 June, prior to the Tour. For breaching team rules, he was removed from the race. It was later revealed that the Tour organiser, Amaury Sport Organisation, had pressed Rabobank to remove Rasmussen. On the same day, Team Cofidis pulled out following the failed test on their rider Cristian Moreni.[59] The Tour continued to be embroiled in doping controversies even after it finished. It emerged that Spanish cyclist (and 16th placed rider) Iban Mayo had failed a test for EPO on the second rest day, on 24 July. He was suspended by his team Saunier Duval-Prodir.[60] Mayo had previously failed tests for synthetic testosterone during the 2007 Giro d'Italia,[61] but the UCI found that he had not breached any doping regulation.[62] Tour winner Alberto Contador also continued to be linked to doping allegations, focussing on his relationship with Eufemiano Fuentes and his role in Operación Puerto, but without new revelations.[63][64] Contador was tested in the Tour after stages 14, 17, and 18 and no discrepancies were reported. Several participants, such as Sébastien Hinault, implied that he is no better than Rasmussen.[65] On 30 July German doping expert Werner Franke accused him of having taken drugs in the past.[66] ## 2012 USADA report[edit] In October 2012 USADA released a report on the U.S. Postal Service cycling team and doping. The report contained affidavits from the following riders, each of whom described widespread use by Tour racers of banned substances such as Erythropoietin (EPO), transfused blood, and testosterone. The affidavits implicated Lance Armstrong,[67] who was consequently banned for life and stripped of all titles.[42] * Frankie Andreu * Michael Barry * Leonardo Bertagnolli * Volodymyr Bileka * Tom Danielson * Tyler Hamilton * George Hincapie * Jörg Jaksche * Floyd Landis * Levi Leipheimer * Filippo Simeoni * Stephen Swart * Christian Vande Velde * Jonathan Vaughters * David Zabriskie ## Testing[edit] After each stage, four riders are tested: the overall leader, the stage winner, and two riders at random. In addition, every rider is tested before the first day's stage, normally a short time-trial. Most teams are tested in their entirety at some point during the three-week race. Additional testing may take place during the off-season, and riders are expected to keep their national cycling federation informed of their whereabouts so they can be located. Many teams have their own drug testing programs to keep the team name clean. Teams, such as Quick-Step, have pulled riders before they compete in major competitions. Tom Boonen was pulled for cocaine before the 2008 Tour de France. ## Status of Tour de France winners since 1961[edit] 14 of the 25 most recent winners (56%) have either failed tests or have confessed to have used doping. Together with those who failed tests but never sanctioned, 68% of the winners evidently used doping as detailed in the table below. Years Name Status Details 2019 Egan Bernal Never failed tests 2018 Geraint Thomas Never failed tests 2014 Vincenzo Nibali Never failed tests 2013 2015 2016 2017 Chris Froome Failed tests Cleared of doping use Failed tests for salbutamol in 2017; however the UCI officially closed the investigation stating that the rider had supplied sufficient evidence to suggest that the sample results do not constitute an "Adverse Analytical Finding". 2012 Bradley Wiggins Never failed tests Implicated in the "Team Sky Jiffy Bag Scandal[68] 2011 Cadel Evans Never failed tests 2010 Andy Schleck Never failed tests Named as winner after Contador disqualified.[69] 2007 2009 2010 Alberto Contador Failed tests Banned for two years Named in Operación Puerto doping case, but later declared clean. Failed tests during 2010 Tour de France for the banned stimulant clenbuterol. Suspended for two years. 2008 Carlos Sastre Never failed tests 2006 Óscar Pereiro Never failed tests Named as winner after Landis disqualified. Took salbutamol in 2006, but had a Therapeutic Use Exemption (TUE) for the substance as part of asthma treatment.[70] Floyd Landis Failed tests Banned for two years Failed tests for high testosterone to epitestosterone ratio;[49] 1999–2005 No winner after Armstrong disqualified. Six of the seven overall runners-up to Armstrong (all except Joseba Beloki in 2002) have either admitted to or been found guilty of doping.[71] Lance Armstrong Banned for life. Retroactively stripped of all titles since August 1998. Confessed doping use Failed tests for glucocorticosteroid hormone without prescription given in advance.[72] Associated with Michele Ferrari, who is suspected of prescribing doping agents.[73] Allegations by former assistant for Androstenine use.[74] Alleged EPO use in 1999 Tour de France.[75] According to court testimony by former teammate, Frankie Andreu, Armstrong admitted to doping to his doctor when in hospital for cancer treatment.[76] Floyd Landis accused Armstrong of doping in 2002 and 2003, and claimed that U.S. Postal team director Johan Bruyneel had bribed former UCI president Hein Verbruggen to keep quiet about a failed test by Armstrong in 2002.[77][78][79] Landis also maintains that he witnessed Armstrong receiving multiple blood transfusions, and dispensing testosterone patches to his teammates on the United States Postal Service Team.[80] Former teammate Tyler Hamilton accused Armstrong of doping with testimony to a federal grand jury during an investigation of Armstrong.[81] Hamilton implicated that Armstrong had used EPO on the TV news show 60 Minutes.[82] Implicated in a massive doping scheme by findings by USADA in 2012. Consequently, banned for life and stripped of all career titles since August 1998.[42] Admitted to doping at all seven of his victorious Tours in a 2013 interview with Oprah Winfrey.[83] 1998 Marco Pantani Never failed tests Banned for six months Failed a blood test in 1999 Giro d'Italia. Insulin found in his hotel room in the 2001 Giro d'Italia, but later declared clean "for not having committed any infraction." Nonetheless, the UCI confirmed the suspension.[84][85][86] 1997 Jan Ullrich Failed tests Banned from the 2006 Tour Retroactively stripped of titles 2005–2007. Confessed doping use Failed tests for amphetamines (off season, not taken for athletic performance gain)[87] Involved in the Operacion Puerto case. DNA subsequently linked to blood bag discovered during Puerto investigation[88] Admitted to doping in a 2013 interview with the German magazine Focus.[89] 1996 Bjarne Riis Never failed tests Confessed doping use Confessed having used EPO in 1996[90] 1991–1995 Miguel Induráin Never failed tests Failed tests for salbutamol in 1994, however both the IOC and UCI allowed Indurain, and asthma sufferers to use salbutamol at the time.[91] 1986 1989–1990 Greg LeMond Never failed tests 1988 Pedro Delgado Never failed tests Failed tests for probenecid, a masking agent for anabolic steroids in the 1988 Tour de France but, although banned by the IOC, it was not on the UCI list of banned substances at the time.[92] 1987 Stephen Roche Never failed tests Accused of taking EPO in 1993 as part of an investigation in Italy into the practices of Francesco Conconi[93] 1978–1979 1981–1982 1985 Bernard Hinault Never failed tests. Refused to submit to a doping control at the 1982 Critérium de Callac and was fined and given a one-month conditional suspension.[94] 1983–1984 Laurent Fignon Failed tests In 1989 Fignon failed a test after a team time trial[95][96][97] failed tests for amphetamines at the Grand Prix de la Liberation in Eindhoven on 17 September 1989.[98][99] 1980 Joop Zoetemelk Failed tests Failed tests in the 1977 (pemoline[100]), 1979 (steroids[101]) and 1983 Tour de France (nandrolon, although that was retracted later[100]). Admitted a blood transfusion on TV interviews right after winning the 10th (and 9th) stage of the 1976 Tour de France, as in that era it was seen as just medical aid. 1975 1977 Bernard Thévenet Never failed tests Confessed doping use Admitted using steroids in the 1975 and 1977 Tour[30][102] 1976 Lucien Van Impe Never failed tests 1969–1972 1974 Eddy Merckx Failed tests Merckx has failed tests three times, but never at the Tour de France. He was expelled from the 1969 Giro d'Italia after testing positive for Reactivan.[103] He failed tests for Mucantil after winning the 1973 Giro di Lombardia. The drug was later taken off the banned list.[103] In the 1977 Flèche Wallonne, Merckx failed tests for Stimul (pemoline), along with Freddy Maertens and Michel Pollentier .[104] 1973 Luis Ocaña Failed tests Failed tests in the 1977 Tour de France (pemoline) 18th stage. 1968 Jan Janssen Never failed tests 1967 Roger Pingeon Never failed tests 1966 Lucien Aimar Failed tests Banned for one month Missed the 1969 Vuelta a España due to a one-month doping ban. 1965 Felice Gimondi Failed tests Failed tests in the 1968 Giro and 1975 Tour. 1957 1961–1964 Jacques Anquetil Confessed doping use Debated with French government minister on television, saying "Leave me in peace; everybody takes dope." After winning Liège–Bastogne–Liège in 1966, was temporarily disqualified after refusing a drug test, saying he had already been to the toilet. He was later reinstated after he engaged a lawyer as the case was never heard. ## Doping histories of Top-10 finishers, 1997–2015[edit] An overview of the top 10 finishers in the General classification in the Tour de France since 1998, along with their individual doping records. Riders' finishing positions are color-coded according to doping status, as explained in the legend below. Note that no distinction is made on whether a rider was doped before, during or after the particular race for which his name is listed, except if the rider was officially disqualified, such as Alberto Contador, Bernhard Kohl and Floyd Landis. Except in these circumstances, the color code for a rider is the same in all years, and does not imply or allege that the rider was doped during any particular edition of the Tour. Legend : Stripped of result in the current race due to doping. Failed tests and/or sanctioned for doping in another competition or out of competition at some point in their career. Admitted to doping without failed tests and/or sanction during career. Failed tests for doping but later acquitted. Accused of doping without failed tests, sanction or admittance in their career. Has never been: stripped of a title, failed tests or sanctioned for doping to date, with no known accusations. ### 1997 Tour de France[edit] Rank Name Team Time Notes 1 Jan Ullrich (GER) Telekom 100h 30' 35" Implicated in Telekom affair and Operación Puerto. Banned retroactively in 2011 for the period 2005-07.[105] 2 Richard Virenque (FRA) Festina-Lotus \+ 9' 09" Sanctioned for doping during the Festina affair. 3 Marco Pantani (ITA) Mercatone Uno \+ 14' 03" Forced to take a two-week break from racing in 1999 Giro for irregular blood values.[106] Implicated in the Operación Puerto doping case in 2006. Died of a cocaine overdose in 2004. 4 Abraham Olano (ESP) Banesto \+ 15' 55" Failed tests for Caffeine and suspended for 3 months in 1994. Named as a client of Francesco Conconi in the 1998 Giardini Margherita investigation.[107] 5 Fernando Escartín (ESP) Kelme-Costa Blanca \+ 20' 32" Named as a client of Francesco Conconi.[108] Client of Michele Ferrari. 6 Francesco Casagrande (ITA) Saeco \+ 22' 47" In 1998, Casagrande tested positive for doping with testosterone during the Tour de Romandie, and consequently was fired by his team Cofidis.[109] Casagrande was barred from competing in the 2004 Vuelta a España a day before its start due to a high hematocrit level, indicating the use of erythropoietin (EPO), a popular doping product.[110] 7 Bjarne Riis (DEN) Telekom \+ 26' 34" Riis confessed on 25 May 2007 to taking EPO, growth hormone and cortisone for 6 years, from 1993 to 1998, including during his victory in the 1996 Tour de France.[111] 8 José María Jiménez (ESP) Banesto \+ 31' 17" 9 Laurent Dufaux (SUI) Saeco \+ 31' 55" Sanctioned for doping during Festina affair. 10 Roberto Conti (ITA) Mercatone Uno \+ 32' 26" After the Giro d’Italia 2002, Conti was banned for six months for possessing various banned substances for doping.[112] ### 1998 Tour de France[edit] Rank Name Team Time Notes 1 Marco Pantani Mercatone Uno 92h 49' 46" Forced to take a two-week break from racing in 1999 Giro for irregular blood values.[113] Implicated in the Operación Puerto doping case in 2006. Died of a cocaine overdose in 2004. 2 Jan Ullrich Telekom +3' 21" Implicated in Telekom affair and Operación Puerto. Banned retroactively in 2011 for the period 2005-07.[114] 3 Bobby Julich Cofidis +4' 08" Accused of doping by teammate Philippe Gaumont in the book Prisonnier du dopage. Admitted to doping in October 2012.[115][116] 4 Christophe Rinero Cofidis +9' 16" Accused of doping by teammate Philippe Gaumont in the book Prisonnier du dopage. 5 Michael Boogerd Rabobank +11' 26" Accused by Floyd Landis of blood doping.[117] Allegedly involved in Humanplasma affair.[118] Admitted to use of cortisone, EPO and blood transfusions between 1997 and 2007.[119] Handed a two-year ban in 2016 for historical doping offences.[120] 6 Jean-Cyril Robin US Postal Service +14' 57" 7 Roland Meier Cofidis +15' 13" Tested positive for EPO in 2001.[121] 8 Daniele Nardello Mapei +16' 07" 9 Giuseppe Di Grande Mapei +17' 35" Sentenced to six months imprisonment for violating anti-doping laws in Italy in 2005.[122] 10 Axel Merckx Polti +17' 39" Named as a client of Francesco Conconi in the 1998 Giardini Margherita investigation.[123] Client of Michele Ferrari.[124] ### 1999 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) US Postal Service 91h 32' 16" Allegedly failed tests for EPO in 1999[125] in an unofficial test done in 2005 on frozen urine. Client of banned doping doctor Michele Ferrari. Accused by former team members, including Floyd Landis and Tyler Hamilton. Banned for life and stripped of all Tour de France titles in 2012.[42] Admitted using doping to win all tours on television in an interview with Oprah Winfrey held on 17 January 2013. 2 Alex Zülle (SUI) Banesto +7' 37" Admitted to taking EPO during the Festina trial. 3 Fernando Escartín (ESP) Kelme +10' 26" Named as a client of Francesco Conconi.[126] Client of Michele Ferrari. 4 Laurent Dufaux (SUI) Saeco +14' 43" Sanctioned for doping during Festina affair. 5 Ángel Casero (ESP) Vitalicio Seguros +15' 11" Implicated in Operación Puerto. 6 Abraham Olano (ESP) ONCE +16' 47" Failed tests for Caffeine and suspended for 3 months in 1994. Named as a client of Francesco Conconi in the 1998 Giardini Margherita investigation.[127] 7 Daniele Nardello (ITA) Mapei +17' 02" 8 Richard Virenque (FRA) Polti +17' 28" Sanctioned for doping during the Festina affair. 9 Wladimir Belli (ITA) Festina +17' 37" 10 Andrea Peron (ITA) ONCE +23' 10" ### 2000 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) US Postal Service 92h 33' 08" See #1999 Tour de France 2 Jan Ullrich (GER) Telekom +6' 02" See #1998 Tour de France 3 Joseba Beloki (ESP) Festina +10' 04" Implicated in the Operación Puerto doping case. Name later removed from the case by Spanish officials in 2006. 4 Christophe Moreau (FRA) Festina +10' 34" Failed tests for anabolic steroids in 1998.[128] Admitted to taking EPO during the Festina trial.[129] 5 Roberto Heras (ESP) Kelme +11' 50" Tested positive for EPO at the 2005 Vuelta a España.[130] 6 Richard Virenque (FRA) Polti +13' 26" See #1999 Tour de France 7 Santiago Botero (COL) Kelme +14' 18" Implicated in Operación Puerto and banned from 2006 Tour. Later cleared by Colombian officials. 8 Fernando Escartín (ESP) Kelme +17' 21" See #1999 Tour de France 9 Francisco Mancebo (ESP) Banesto +18' 09" Implicated in Operación Puerto and banned from the 2006 Tour de France. 10 Daniele Nardello (ITA) Mapei +18' 25" ### 2001 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) US Postal Service 86h 17' 28" See #1999 Tour de France 2 Jan Ullrich (GER) Telekom +6' 44" See #1998 Tour de France 3 Joseba Beloki (ESP) ONCE +9' 05" See #2000 Tour de France 4 Andrei Kivilev (KAZ) Cofidis +9' 53" 5 Igor González (ESP) ONCE +13' 28" Banned for six months in 2000 for nandrolone and again in 2002. 6 François Simon (FRA) Bonjour +17' 22" 7 Óscar Sevilla (ESP) Kelme +18' 30" Implicated in Telekom affair and Operación Puerto. Banned in 2010 after failing tests in the Vuelta a Colombia. 8 Santiago Botero (COL) Kelme +20' 55" See #2000 Tour de France 9 Marcos Antonio Serrano (ESP) ONCE +21' 45" Among the riders named in the Operación Puerto doping case.[131] 10 Michael Boogerd (NED) Rabobank +22' 38" See #1998 Tour de France ### 2002 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) US Postal Service 82h 05' 12" See #1999 Tour de France 2 Joseba Beloki (ESP) ONCE +7' 17" See #2000 Tour de France 3 Raimondas Rumšas (LIT) Lampre +8' 17" Failed tests for EPO in 2003. Given a four-month suspended prison sentence in 2006 for importing prohibited substances into France. 4 Santiago Botero (COL) Kelme +13' 10" See #2000 Tour de France 5 Igor González (ESP) ONCE +13' 54" See #2001 Tour de France 6 José Azevedo (POR) ONCE +15' 44" 7 Francisco Mancebo (ESP) iBanesto.com +16' 05" See #2000 Tour de France 8 Levi Leipheimer (USA) Rabobank +17' 11" Failed tests for ephedrine 1996 U.S. National Criterium Championships. Admitted to doping during the 2012 USADA investigation and later had all results voided from June 1999 to July 2006.[132] 9 Roberto Heras (ESP) US Postal Service +17' 12" See #2000 Tour de France 10 Carlos Sastre (ESP) Team CSC +19' 05" ### 2003 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) US Postal Service 83h 41' 12" See #1999 Tour de France 2 Jan Ullrich (GER) Bianchi +1' 01" see #1998 Tour de France 3 Alexander Vinokourov (KAZ) Telekom +4' 14" Blood doping at 2007 Tour de France, one-year ban. 4 Tyler Hamilton (USA) Team CSC +6' 17" Received a two-year ban for blood doping at the 2004 Olympics and the 2004 Vuelta a España. Implicated in the Operación Puerto doping case in 2006. Given an eight-year bad for failing a tests for DHEA in 2009. Admitted to doping during the 2012 USADA investigation. 5 Haimar Zubeldia (ESP) Euskaltel +6' 51" 6 Iban Mayo (ESP) Euskaltel +7' 06" Handed a two-year ban after testing positive for EPO at the 2007 Tour de France. 7 Ivan Basso (ITA) Fassa Bortolo +10' 12" Implicated in Operación Puerto and suspended in 2007 for two years for admitting to planning to use doping.[133] 8 Christophe Moreau (FRA) Crédit Agricole +12' 28" see #2000 Tour de France 9 Carlos Sastre (ESP) Team CSC +18' 49" 10 Francisco Mancebo (ESP) iBanesto.com +19' 15" See #2000 Tour de France ### 2004 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) US Postal Service 83h 36' 02" See #1999 Tour de France 2 Andreas Klöden (GER) T-Mobile +6' 19" Named among the riders to have received illegal blood transfusions in Freiburg in 2006.[134] 3 Ivan Basso (ITA) Team CSC +6' 40" See #2003 Tour de France 4 Jan Ullrich (GER) T-Mobile +8' 50" See #1998 Tour de France 5 José Azevedo (POR) US Postal Service +14' 30" 6 Francisco Mancebo (ESP) Illes Balears-Banesto-Santander +18' 01" See #2000 Tour de France 7 Georg Totschnig (AUT) Gerolsteiner +18' 27" Charged with lying under oath about his involvement in doping after receiving a blood transfusion during the 2005 Tour de France.[135] 8 Carlos Sastre (ESP) Team CSC +19' 51" 9 Levi Leipheimer (USA) Rabobank +20' 12" See #2002 Tour de France 10 Óscar Pereiro (ESP) Phonak +22' 54" Failed tests for Salbutamol in 2006, but later acquitted. ### 2005 Tour de France[edit] Rank Name Team Time Notes 1 Lance Armstrong (USA) Discovery Channel 86h 15' 02" See #1999 Tour de France 2 Ivan Basso (ITA) Team CSC +4' 40" See #2003 Tour de France 3 Jan Ullrich (GER) T-Mobile +6' 21" see #1998 Tour de France 4 Francisco Mancebo (ESP) Illes Balears-Caisse d'Epargne +9' 59" See #2000 Tour de France 5 Alexander Vinokourov (KAZ) T-Mobile +11' 01" See #2003 Tour de France 6 Levi Leipheimer (USA) Gerolsteiner +11' 21" See #2002 Tour de France 7 Michael Rasmussen (DEN) Rabobank +11' 33" Removed by his own team from the 2007 Tour de France after lying about whereabouts testing violations. Admitted to the use of EPO, human growth hormone, testosterone, DHEA, insulin, IGF-1, cortisone and blood transfusions between 1998 and 2010.[136] 8 Cadel Evans (AUS) Davitamon-Lotto +11' 55" Documented client of Michele Ferrari. 9 Floyd Landis (USA) Phonak +12' 44" See #2006 Tour de France 10 Óscar Pereiro (ESP) Phonak +16' 04" See #2004 Tour de France ### 2006 Tour de France[edit] Rank Name Team Time Notes 1 Floyd Landis (USA) Phonak 89h 39' 30" Failed tests for Testosterone during the 2006 Tour de France and was disqualified from the race. Later admitted to doping throughout his career.[137] 2 Óscar Pereiro (ESP) Caisse d'Epargne \+ 0' 57" 3 Andreas Klöden (GER) T-Mobile +0' 32" See #2004 Tour de France 4 Carlos Sastre (ESP) Team CSC +2' 16" 5 Cadel Evans (AUS) Davitamon-Lotto +4' 11" See #2005 Tour de France 6 Denis Menchov (RUS) Rabobank +6' 09" Client of Michele Ferrari.[138] Disqualified from the 2009, 2010 and 2012 Tours and received a two-year ban for adverse biological passport findings.[139] 7 Cyril Dessel (FRA) Ag2r +7' 44" 8 Christophe Moreau (FRA) Ag2r +8' 40" see #2000 Tour de France 9 Haimar Zubeldia (ESP) Euskaltel +11' 08" 10 Michael Rogers (AUS) T-Mobile +14' 10" Client of Michele Ferrari.[140] ### 2007 Tour de France[edit] Rank Name Team Time Notes 1 Alberto Contador (ESP) DSC 91h 00' 26" see #2010 Tour de France 2 Cadel Evans (AUS) Predictor–Lotto \+ 23" See #2005 Tour de France 3 Levi Leipheimer (USA) DSC \+ 31" See #2002 Tour de France 4 Carlos Sastre (ESP) Team CSC \+ 7' 08" 5 Haimar Zubeldia (ESP) Euskaltel–Euskadi \+ 8' 17" 6 Alejandro Valverde (ESP) Caisse d'Epargne \+ 11' 37" Convicted in 2009 of EPO use after link to Operación Puerto and handed a two-year ban.[141] 7 Kim Kirchen (LUX) T-Mobile Team \+ 12' 18" 8 Yaroslav Popovych (UKR) Discovery Channel \+ 12' 25" Client of Michele Ferrari. House raided by police, who found drugs and doping paraphernalia. Scored 10/10 on 2010 leaked UCI list of suspicious riders.[142] 9 Mikel Astarloza (ESP) Euskaltel–Euskadi \+ 14' 14" Tested positive for EPO in 2009 and given a two-year ban. 10 Óscar Pereiro (ESP) Caisse d'Epargne \+ 14' 25" See #2004 Tour de France ### 2008 Tour de France[edit] Rank Name Team Time Notes 1 Carlos Sastre (ESP) Team CSC 87h 52' 52" 2 Cadel Evans (AUS) Silence-Lotto +0' 58" See #2005 Tour de France 3 Bernhard Kohl (AUT) Gerolsteiner DQ Failed tests for CERA and was disqualified. 4 Denis Menchov (RUS) Rabobank +2' 10" See #2006 Tour de France 5 Christian Vande Velde (USA) Garmin +3' 05" Admitted to using doping on the US Postal team. All results from June 2004 through April 2006 voided.[143] 6 Fränk Schleck (LUX) Team CSC +4' 28" Removed from the 2012 Tour de France after testing positive for diuretic masking agent xipamide. Implicated in the Opération Puerto doping case for transferring 7000 euros into a bank account held by Dr Fuentes.[144] 7 Samuel Sánchez (ESP) Euskaltel +6' 25" Handed a two-year ban after testing positive for growth hormone GHRP-2. 8 Kim Kirchen (LUX) Team Columbia +6' 55" 9 Alejandro Valverde (ESP) Caisse d'Epargne +7' 12" See #2007 Tour de France 10 Tadej Valjavec (SLO) Ag2r +9' 05" Handed a two-year ban for irregular biological passport values. ### 2009 Tour de France[edit] Rank Name Team Time Notes 1 Alberto Contador (ESP) Astana 85h 48' 35" See #2010 Tour de France 2 Andy Schleck (LUX) Team Saxo Bank +4' 11" 3 Lance Armstrong (USA) Astana +5' 24" See #1999 Tour de France 4 Bradley Wiggins (GBR) Garmin +6' 01" Implicated in the Team Sky "Jiffy Bag" Scandal[68] 5 Fränk Schleck (LUX) Team Saxo Bank +6' 04" See #2008 Tour de France 6 Andreas Klöden (GER) Astana +6' 42" See #2004 Tour de France 7 Vincenzo Nibali (ITA) Liquigas +7' 35" 8 Christian Vande Velde (USA) Garmin +12' 04" See #2008 Tour de France 9 Roman Kreuziger (CZE) Liquigas +14' 16" Targeted on the basis of inconsistencies in his biological passport from 2011 to 2012 while part of the Astana Team.[145] Admitted to working with Michele Ferrari.[146] 10 Christophe Le Mével (FRA) Française des Jeux +14' 25" ### 2010 Tour de France[edit] Rank Name Team Time Notes 1 Alberto Contador (ESP) Astana 91h 58'48" Implicated in the Operación Puerto doping case; although his name was removed by prosecutors in 2006. Tested positive for clenbuterol in the 2010 Tour de France and was stripped of his title and given a two-year doping ban. 2 Andy Schleck (LUX) Team Saxo Bank \+ 39" 3 Denis Menchov (RUS) Rabobank +2' 01" See #2006 Tour de France 4 Samuel Sánchez (ESP) Euskaltel +3' 40" See #2008 Tour de France 5 Jurgen Van den Broeck (BEL) Omega Pharma – Lotto +6' 54" Implicated in a Belgian blood-doping scandal in 2014.[147] 6 Robert Gesink (NED) Rabobank +9' 31" 7 Ryder Hesjedal (CAN) Garmin +10' 15" Admitted to doping[148] 8 Joaquim Rodríguez (ESP) Katusha +11' 37" 9 Roman Kreuziger (CZE) Liquigas +11' 54" See #2009 Tour de France. 10 Chris Horner (USA) Team Radioshack +12' 02" ### 2011 Tour de France[edit] Rank Name Team Time Notes 1 Cadel Evans (AUS) BMC Racing Team 86h 12′ 22″ See #2005 Tour de France 2 Andy Schleck (LUX) Leopard Trek \+ 1′ 34″ 3 Fränk Schleck (LUX) Leopard Trek \+ 2′ 30″ See #2008 Tour de France 4 Thomas Voeckler (FRA) Team Europcar \+ 3′ 20″ 5 Samuel Sánchez (ESP) Euskaltel–Euskadi \+ 4′ 55″ See #2008 Tour de France 6 Damiano Cunego (ITA) Lampre–ISD \+ 6′ 05″ Indicted but later cleared in the Mantoba doping trial.[149] 7 Ivan Basso (ITA) Liquigas–Cannondale \+ 7′ 23″ See #2003 Tour de France 8 Tom Danielson (USA) Garmin–Cervélo \+ 8′ 15″ Admitted to doping on the US Postal team. Banned for six months with all results from March 2005 through 23 September 2006 voided.[150] 9 Jean-Christophe Péraud (FRA) Ag2r–La Mondiale \+ 10′ 11″ 10 Pierre Rolland (FRA) Team Europcar \+ 10′ 43″ ### 2012 Tour de France[edit] Rank Rider Team Time Notes 1 Bradley Wiggins (GBR) Team Sky 87h 34' 47" See #2009 Tour de France 2 Chris Froome (GBR) Team Sky \+ 3' 21″ Adverse analytical finding for salbutamol at the 2017 Vuelta a España. Was later cleared following an investigation. 3 Vincenzo Nibali (ITA) Liquigas–Cannondale \+ 6' 19″ 4 Jurgen Van den Broeck (BEL) Lotto–Belisol \+ 10' 15″ See #2010 Tour de France 5 Tejay van Garderen (USA) BMC Racing Team \+ 11' 04″ 6 Haimar Zubeldia (ESP) RadioShack–Nissan \+ 15' 41″ 7 Cadel Evans (AUS) BMC Racing Team \+ 15' 49″ See #2005 Tour de France 8 Pierre Rolland (FRA) Team Europcar \+ 16' 26″ 9 Janez Brajkovič (SLO) Astana \+ 16' 33″ Handed a ten-month ban in 2018 for testing positive for methylhexanamine. 10 Thibaut Pinot (FRA) FDJ–BigMat \+ 17' 17″ ### 2013 Tour de France[edit] Rank Rider Team Time Notes 1 Chris Froome (GBR) Team Sky 83h 56' 40" See #2012 Tour de France 2 Nairo Quintana (COL) Movistar Team \+ 4' 20" 3 Joaquim Rodríguez (ESP) Team Katusha \+ 5' 04" 4 Alberto Contador (ESP) Saxo–Tinkoff \+ 6' 27" See #2007 Tour de France 5 Roman Kreuziger (CZE) Saxo–Tinkoff \+ 7' 27" See #2009 Tour de France 6 Bauke Mollema (NED) Belkin Pro Cycling \+ 11' 42" 7 Jakob Fuglsang (DEN) Astana \+ 12' 17" Cycling Anti-Doping Federation (CADF) lead an internal investigation, where no links between Fuglsang and banned doctor Michele Ferrari were found. The case was never processed to UCI.[151] 8 Alejandro Valverde (ESP) Movistar Team \+ 15' 26" See #2007 Tour de France. 9 Daniel Navarro (ESP) Cofidis \+ 15' 52" 10 Andrew Talansky (USA) Garmin–Sharp \+ 17' 39" ### 2014 Tour de France[edit] Rank Rider Team Time Notes 1 Vincenzo Nibali (ITA) Astana 89h 59' 06" 2 Jean-Christophe Péraud (FRA) Ag2r–La Mondiale \+ 7' 39" 3 Thibaut Pinot (FRA) FDJ.fr \+ 8' 15" 4 Alejandro Valverde (ESP) Movistar Team \+ 9' 40" See #2007 Tour de France 5 Tejay van Garderen (USA) BMC Racing Team \+ 11' 24" 6 Romain Bardet (FRA) Ag2r–La Mondiale \+ 11' 26" 7 Leopold Konig (CZE) NetApp–Endura \+ 14' 32" 8 Haimar Zubeldia (ESP) Trek Factory Racing \+ 17' 57" 9 Laurens ten Dam (NED) Belkin Pro Cycling \+ 18' 12" 10 Bauke Mollema (NED) Belkin Pro Cycling \+ 21' 15" ### 2015 Tour de France[edit] Rank Rider Team Time Notes 1 Chris Froome (GBR) Team Sky 84h 46' 14" See #2012 Tour de France 2 Nairo Quintana (COL) Movistar Team \+ 1' 12" 3 Alejandro Valverde (ESP) Movistar Team \+ 5' 25" See #2007 Tour de France 4 Vincenzo Nibali (ITA) Astana \+ 8' 36" 5 Alberto Contador (ESP) Tinkoff–Saxo \+ 9' 48" See #2010 Tour de France 6 Robert Gesink (NED) LottoNL–Jumbo \+ 10' 47" 7 Bauke Mollema (NED) Trek Factory Racing \+ 15' 14" 8 Mathias Frank (SUI) IAM Cycling \+ 15' 39" 9 Romain Bardet (FRA) AG2R La Mondiale \+ 16' 00" 10 Pierre Rolland (FRA) Team Europcar \+ 17' 30" ## See also[edit] * Tour de France * Doping * List of doping cases in cycling ## References[edit] 1. ^ https://www.amazon.co.uk/exec/obidos/tg/feature/-/187085/202-7384003-1751816As[dead link] History, Drugs and the Tour de France by Tim Moore 2. ^ Novich, Max M: Drug abuse and drugs in sports, New York State Journal of Medicine, vol 73, no 21, 1 November 1973 3. ^ Halter, Hans: 'Alles verstehen, alles verzeihen', Der Spiegel, Germany 3 August 1998 4. ^ Penot, Christophe: Pierre Chany, l'homme aux 50 Tours de France, Éditions Cristel, France, 1996 5. ^ Novich, Max M., Abbotempo, UK, 1964 6. ^ Bearings, US, 24 December 1896, cited Ritchie, Andrew, Major Taylor, Bicycle Books, US, 1988 7. ^ Woodland, Les (1980) Dope, the use of drugs in sport, David and Charles, UK 8. ^ Lunzenfichter, Alain: C'est pas du Jeu!, L'Équipe, France, 10 December 2007 9. ^ Novich, ibid. 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The Australian. 14 July 2012. Retrieved 14 July 2012. 141. ^ "Alejandro Valverde loses global doping ban appeal". BBC Sports. 10 January 2011. Retrieved 13 July 2012. 142. ^ "UCI angry after doping index leak". Eurosport. Retrieved 14 July 2012. 143. ^ Hersh, Philip (10 October 2012). "Lemont cyclist Vande Velde admits to doping, gets 6-month ban". Chicago Tribune. Retrieved 11 October 2012. 144. ^ "Frank Schleck admits Fuentes payment". Bike Radar. 3 October 2008. Retrieved 13 July 2012. 145. ^ Kreuziger’s public defence raises further questions about doping case \| CyclingTips 146. ^ "Roman Kreuziger admits working with banned Dr Ferrari". Cycling Weekly. 16 May 2013. Retrieved 17 November 2015. 147. ^ "In the News: 19 athletes implicated in Belgian blood-doping scandal". Retrieved 18 April 2020. 148. ^ "Hesjedal admits to doping, says evidence was given to USADA". cyclingnews.com. 30 October 2013. Retrieved 18 April 2020. 149. ^ "Lampre riders, staff cleared in doping trial: reports". Canadian Cycling Magazine. 19 December 2015. Retrieved 18 April 2020. 150. ^ "Six Former Armstrong USPS Teammates Receive Bans From USADA". Cyclingnews. 10 October 2012. Retrieved 18 October 2012. 151. ^ Ballinger, Alex (5 February 2020). "Anti-doping investigators release statement on leaked Jakob Fuglsang and Michele Ferrari report". Cycling Weekly. Retrieved 18 April 2020. ## Further reading[edit] * McKay, Feargal (1 June 2015). "The Tour de France, by Christopher S Thompson". SB Nation Podium Cafe. Retrieved 1 June 2015. ## External links[edit] * WADA list of prohibited substances * Drugs and the Tour de France by Ramin Minovi (Association of British Cycling Coaches) * v * t * e Doping at the Tour de France By year * 1998 * 1999 * 2007 Related articles * Death of Tom Simpson * Festina affair * Floyd Landis doping case * Lance Armstrong * doping allegations * doping case Related media Books * L.A. Confidentiel * Rough Ride * Seven Deadly Sins: My Pursuit of Lance Armstrong * Wheelmen Films * The Armstrong Lie * The Program * Rough Rider * Tour de Pharmacy * v * t * e Tour de France By year * 1903 * 1904 * 1905 * 1906 * 1907 * 1908 * 1909 * 1910 * 1911 * 1912 * 1913 * 1914 * 1915 * 1916 * 1917 * 1918 * 1919 * 1920 * 1921 * 1922 * 1923 * 1924 * 1925 * 1926 * 1927 * 1928 * 1929 * 1930 * 1931 * 1932 * 1933 * 1934 * 1935 * 1936 * 1937 * 1938 * 1939 * 1940 · 1941 · 1942 · 1943 · 1944 · 1945 · 1946 * 1947 * 1948 * 1949 * 1950 * 1951 * 1952 * 1953 * 1954 * 1955 * 1956 * 1957 * 1958 * 1959 * 1960 * 1961 * 1962 * 1963 * 1964 * 1965 * 1966 * 1967 * 1968 * 1969 * 1970 * 1971 * 1972 * 1973 * 1974 * 1975 * 1976 * 1977 * 1978 * 1979 * 1980 * 1981 * 1982 * 1983 * 1984 * 1985 * 1986 * 1987 * 1988 * 1989 * 1990 * 1991 * 1992 * 1993 * 1994 * 1995 * 1996 * 1997 * 1998 * 1999 * 2000 * 2001 * 2002 * 2003 * 2004 * 2005 * 2006 * 2007 * 2008 * 2009 * 2010 * 2011 * 2012 * 2013 * 2014 * 2015 * 2016 * 2017 * 2018 * 2019 * 2020 * 2021 Classifications ("jerseys") Current General (maillot jaune) Points (maillot vert) Mountains (maillot à pois) Young rider (maillot blanc) Team (classement d'équipes) Combativity (prix de combativité) Former Combination (maillot du combiné) Intermediate sprints (maillot rouge) Directors * 1903–1935: Henri Desgrange * 1936–1961: Jacques Goddet * 1962–1986: Jacques Goddet and Félix Lévitan * 1987: Jean-François Naquet-Radiguet * 1988: Xavier Louy * 1989–2006: Jean-Marie Leblanc * 2007–present: Christian Prudhomme Finish locations * 1903–1967: Parc des Princes * 1968–1974: Vélodrome de Vincennes * 1975–present: Champs-Élysées * final stage Lists * General classification winners * Secondary classification winners * Grands Départs * Records and statistics * Mountain passes and hills * Highest points reached Additional topics * During World War II * Yellow jersey statistics * Lanterne rouge * Doping * Hors catégorie * Souvenir Jacques Goddet * Souvenir Henri Desgrange Related articles * Émilien Amaury * Amaury Sport Organisation * Pierre Dumas * Géo Lefèvre * Didi Senft * La Course by Le Tour de France * L'Étape du Tour * Grand Tour * v * t * e Tour de France general classification winners 1903–1919 * 1903: Maurice Garin * 1904: Henri Cornet * 1905: Louis Trousselier * 1906: René Pottier * 1907–08: Lucien Petit-Breton * 1909: François Faber * 1910: Octave Lapize * 1911: Gustave Garrigou * 1912: Odile Defraye * 1913–14: Philippe Thys * 1915–1918: World War I * 1919: Firmin Lambot 1920–1939 * 1920: Philippe Thys * 1921: Léon Scieur * 1922: Firmin Lambot * 1923: Henri Pélissier * 1924–25: Ottavio Bottecchia * 1926: Lucien Buysse * 1927–28: Nicolas Frantz * 1929: Maurice De Waele * 1930: André Leducq * 1931: Antonin Magne * 1932: André Leducq * 1933: Georges Speicher * 1934: Antonin Magne * 1935: Romain Maes * 1936: Sylvère Maes * 1937: Roger Lapébie * 1938: Gino Bartali * 1939: Sylvère Maes 1940–1959 * 1940–1946: World War II * 1947: Jean Robic * 1948: Gino Bartali * 1949: Fausto Coppi * 1950: Ferdinand Kübler * 1951: Hugo Koblet * 1952: Fausto Coppi * 1953–1955: Louison Bobet * 1956: Roger Walkowiak * 1957: Jacques Anquetil * 1958: Charly Gaul * 1959: Federico Bahamontes 1960–1979 * 1960: Gastone Nencini * 1961–1964: Jacques Anquetil * 1965: Felice Gimondi * 1966: Lucien Aimar * 1967: Roger Pingeon * 1968: Jan Janssen * 1969–1972: Eddy Merckx * 1973: Luis Ocaña * 1974: Eddy Merckx * 1975: Bernard Thévenet * 1976: Lucien Van Impe * 1977: Bernard Thévenet * 1978–79: Bernard Hinault 1980–1998 * 1980: Joop Zoetemelk * 1981–82: Bernard Hinault * 1983–84: Laurent Fignon * 1985: Bernard Hinault * 1986: Greg LeMond * 1987: Stephen Roche * 1988: Pedro Delgado * 1989–90: Greg LeMond * 1991–1995: Miguel Indurain * 1996: Bjarne Riis * 1997: Jan Ullrich * 1998: Marco Pantani 2006–present * 1999–2005: results voided because of doping * 2006: Óscar Pereiro * 2007: Alberto Contador * 2008: Carlos Sastre * 2009: Alberto Contador * 2010: Andy Schleck * 2011: Cadel Evans * 2012: Bradley Wiggins * 2013: Chris Froome * 2014: Vincenzo Nibali * 2015–2017: Chris Froome * 2018: Geraint Thomas * 2019: Egan Bernal * 2020: Tadej Pogačar [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Doping at the Tour de France	None	4,696	wikipedia	https://en.wikipedia.org/wiki/Doping_at_the_Tour_de_France	2021-01-18T18:52:56	{"wikidata": ["Q2153457"]}
## Clinical Features Capella et al. (1963) reported a family in which 12 persons in 4 generations had microphthalmia and congenital cataract; 3 affected individuals also had mental retardation. No instance of male-to-male transmission was noted, but the ratio of affected to unaffected was 1:1, consistent with autosomal dominant transmission. Zeiter (1963) described a family with bilateral microphthalmia, congenital cataract, and nystagmus in 7 members over 3 generations. Of the 4 affected family members in the youngest generation, 2 were mentally retarded and 1 of the latter also had congenital heart disease with presumed interventricular septal defect and patent ductus arteriosus as well as hydrocephalus and brain atrophy on ventriculogram. Temtamy and Shalash (1974) reported a 3-year-old Egyptian boy, born of first-cousin parents, with bilateral microphthalmia, cataracts, and nystagmus. An older sister, who died at age 3 of a 'severe chest infection,' was said to have had an identical phenotype. Cytogenetics Yokoyama et al. (1992) described a family in which autosomal dominant congenital cataract and microphthalmia were segregating together with a reciprocal translocation t(2;16)(p22.3;p13.3) through 3 generations. There were several instances of male-to-male transmission of the ocular abnormality. The family included 4 persons with balanced translocations, 3 with partial trisomy 2p derived from the translocation, and 2 with a normal karyotype. All the subjects with balanced or unbalanced translocations had congenital cataract and microphthalmia, whereas the 2 persons with normal karyotypes did not show any ocular abnormalities. Molecular genetic studies demonstrated that the breakpoint in chromosome 16 was in the 16p13.3 region, proximal to HBA1 (141800). Yokoyama et al. (1992) concluded that a gene at the breakpoint on 16p was disrupted in the formation of the translocation. Eyes \- Cataract \- Microphthalmia \- Nystagmus \- Miosis \- Strabismus Inheritance \- Autosomal dominant (16p13.3) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	MICROPHTHALMIA, ISOLATED, WITH CATARACT 1	c1855052	4,697	omim	https://www.omim.org/entry/156850	2019-09-22T16:38:12	{"mesh": ["C565377"], "omim": ["251600", "156850"], "orphanet": ["2542"], "synonyms": ["CATARACT, CONGENITAL, WITH MICROPHTHALMIA", "Microphthalmia-anophthalmia-coloboma spectrum", "Isolated anophthalmia-microphthalmia syndrome", "Alternative titles", "MAC spectrum"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (November 2015) Flaccid dysarthria SpecialtyNeurology Flaccid dysarthria is a motor speech disorder resulting from damage to peripheral nervous system (cranial or spinal nerves) or lower motor neuron system. Depending on which nerves are damaged, flaccid dysarthria affects respiration, phonation, resonance, and articulation. It also causes weakness, hypotonia (low-muscle tone), and diminished reflexes.[1][2] Perceptual effects of flaccid dysarthria can include hypernasality, imprecise consonant productions, breathiness of voice, and affected nasal emission.[3] ## Contents * 1 Causes * 2 Diagnosis * 3 Treatment * 4 References ## Causes[edit] Flaccid dysarthria is caused when damage occurs to the motor unit (one or more cranial or spinal nerves). Processes that can cause this include:[1] * Congenital disorders * Demyelinating disorders * Infectious/Inflammatory * Degenerative disorders * Metabolic * Neoplastic * Traumatic * Vascular Diseases * Flaccid Paralysis ## Diagnosis[edit] The hallmark of flaccid dysarthria is weakness, affecting different muscles, depending on where the damage has occurred. Some common signs include the following[4] Phonation and prosody: Damage to cranial nerve X can present as changes in voice quality. One or both vocal folds may be effectively paralyzed, or have diminished function. If a vocal fold is stuck in an adducted or closed position, the voice will be harsh and low in volume. A vocal fold stuck in an abducted or open position may cause breathiness and low volume. Listen for vocal flutter and diplophonia. Having both vocal folds stuck in an abducted position creates a breathy voice, with potential inspiratory stridor. Having both vocal folds stuck in an adducted or closed position compromises the airway significantly. In addition to these changes in phonation, someone may have issues changing their pitch or loudness. Or, they may speak in short phrases, as they release more air than normal through their larynx while speaking. Resonance: Damage to the cranial nerves innervating muscles that control the velum may result in hypernasal speech. This can sound like someone is saying things through their nose, making oral sounds like "b" or "d" sound more like "m" or "n", respectively. Or, there may be air release through the nose that is audible, as in an attempt to say "s". Articulation: Damage to the cranial nerves innervating the lips, tongue and other key muscles for making speech sounds may result in inaccurate or imprecise articulation. This may improve with rest. Other: Flaccid paralysis can cause muscles to atrophy or lose mass over time. Twitches in the affected muscle fibres (fasciculations) may be present. In the tongue, this resembles worms moving in the tissue. If the muscles of the face are affected (i.e. if there is damage to cranial nerve VII; V for the jaw in mastication), there may be drooping, sagging or drooling. When the tongue moves forward (as in a protrusion exercise), it will move to the stronger side. If the person is asked to move their jaw, it will be opposite (toward the weaker side). Other visible signs that accompany flaccid dysarthria include facial or soft palate droop, or nasal regurgitation with eating (again, if the velum is an affected area). Issues with eating are common, given the shared nature of the muscles for talking and those for chewing and swallowing. These require evaluation alongside any speech difficulties, and if present, may be medically serious (i.e. if material enters the lungs, or if not enough food is able to be eaten). ## Treatment[edit] Treatment may be carried out by a range of professionals (i.e. speech-language pathologists/therapists, rehabilitation specialists, or others with training in this area). Treatments may include direct work on the nerves and muscles involved (see below, organised by affected component of speech); counselling; partner training (i.e. to improve their ability to understand the affected person, or implement exercises); or, training aimed at helping the person themselves compensate for their condition (i.e. using gestures to supplement a message; using a device to talk; advocating for others to wait while they get their message across).[1][5] Note that treatment should be planned and supervised by a trained professional, and tailored to the individual's specific profile. Phonation and prosody: Behavioural treatments may include turning one's head to the affected side during speech or lateralizing the thyroid cartilage; making an effortful closure of the vocal folds or an abrupt glottal attack; or, producing intense high-level phonation. Medical treatments may include surgery such as medialization laryngoplasty; arytenoid adduction; or, fat/collagen injections. Prosthetic approaches may include artificial larynges; or abdominal binders/corsets (to provide best posture for speech, and support stronger exhalation, if affected muscles include those controlling breathing). Resonance: Behavioural treatments may include use of CPAP machines, supine positioning (lying down, to help train velum closure), or reducing pressure during held consonants (i.e. 's' or 'z' sounds). Again, some medical or prosthetic approaches may be utilised, including palatal lifts, or pharyngeal flap procedures. Articulation: Behavioural treatments may include various speech sound strengthening or accuracy re-training exercises. ## References[edit] 1. ^ a b c Duffy, Joseph (June 6, 2013). Motor Speech Disorders: Substrates, Differential Diagnosis, and Management. Elsevier Health Sciences. ISBN 9780323242646. 2. ^ Manasco, H. (2014). Introduction to neurogenic communication disorders. Burlington, MA: Jones & Bartlett Learning. 3. ^ University of Minnesota Duluth. (2014). Dysarthria. http://www.d.umn.edu/~mmizuko/2230/msd.htm 4. ^ "Dysarthria Characteristics". www.csuchico.edu. Retrieved 2019-08-01. 5. ^ Swigert, Nancy, B. (2010). The Source for Dysarthria: Second Edition. Austin, Texas: Pro-Ed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Flaccid dysarthria	c0454597	4,698	wikipedia	https://en.wikipedia.org/wiki/Flaccid_dysarthria	2021-01-18T18:43:43	{"mesh": ["D004401"], "wikidata": ["Q25111774"]}
Type of vaginal discharge 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: "Leukorrhea" – news · newspapers · books · scholar · JSTOR (January 2019) (Learn how and when to remove this template message) Leukorrhea Diagram showing leukorrhea infection SpecialtySynonyms = Fluor albus, Whites Leukorrhea or (leucorrhoea British English) is a thick, whitish, yellowish or greenish vaginal discharge.[1][2][3] There are many causes of leukorrhea, the usual one being estrogen imbalance.[citation needed] The amount of discharge may increase due to vaginal infection, and it may disappear and reappear from time to time. This discharge can keep occurring for years, in which case it becomes more yellow and foul-smelling. It is usually a non-pathological symptom secondary to inflammatory conditions of the vagina or cervix.[4] Leukorrhea can be confirmed by finding >10 WBC under a microscope when examining vaginal fluid.[5] Vaginal discharge is normal, and causes of change in discharge include infection, malignancy, and hormonal changes. It sometimes occurs before an adolescent female has her first period, and is considered a sign of puberty. ## Contents * 1 Etymology * 2 Types * 2.1 Physiologic leukorrhea * 2.2 Inflammatory leukorrhea * 2.3 Parasitic leukorrhea * 3 Treatment * 4 References * 5 External links ## Etymology[edit] The word leukorrhea comes from Greek λευκός (leukós, “white”) + ῥοία (rhoía, “flow, flux”). In Latin leukorrhea is fluor albus (fluor, "flow" & albus, "white"). ## Types[edit] ### Physiologic leukorrhea[edit] It is not a major issue but is to be resolved as soon as possible. It can be a natural defense mechanism that the vagina uses to maintain its chemical balance, as well as to preserve the flexibility of the vaginal tissue. The term "physiologic leukorrhea" is used to refer to leukorrhea due to estrogen stimulation.[6] Leukorrhea may occur normally during pregnancy. This is caused by increased bloodflow to the vagina due to increased estrogen. Female infants may have leukorrhea for a short time after birth due to their in-uterine exposure to estrogen. ### Inflammatory leukorrhea[edit] It may also result from inflammation or congestion of the vaginal mucosa. In cases where it is yellowish or gives off an odor, a doctor should be consulted since it could be a sign of several disease processes, including an organic bacterial infection (aerobic vaginitis) or STD.[7] After delivery, leukorrhea accompanied by backache and foul-smelling lochia (post-partum vaginal discharge, containing blood, mucus, and placental tissue) may suggest the failure of involution (the uterus returning to pre-pregnancy size) due to infection. A number of investigation such as wet smear, Gram stain, culture, pap smear and biopsy are suggested to diagnose the condition. ### Parasitic leukorrhea[edit] Leukorrhea is also caused by trichomonads, a group of parasitic protozoan, specifically Trichomonas vaginalis. Common symptoms of this disease are burning sensation, itching and discharge of frothy substance, thick, white or yellow mucous.[4][8] ## Treatment[edit] Leukorrhea may be caused by sexually transmitted diseases; therefore, treating the STD will help treat the leukorrhea. Treatment may include antibiotics, such as metronidazole. Other antibiotics common for the treatment of STIs include clindamycin or tinidazole.[9] Homeopatic method of treatment for leucorrhoea is Graphites 200. Source: 1\. Graphites 200 Homeopathy Uses, Benefits - Graphites Materia Medica https://www.homeopathicmedicine.info/en/graphites/ 2\. Leucorrhoea: Its Concomitant Symptoms, and Its Homoeopathic Treatment By Alvin Matthew Cushing (1882) https://books.google.ca/books?hl=en&lr=&id=qUVQj3zmDQoC&oi=fnd&pg=PA3&dq=Graphites,+leucorrhoea&ots=hWgIOFuZ4j&sig=CX63iFcF3KceviShFZnBYZq3ozA#v=onepage&q=Graphites%2C%20leucorrhoea&f=false ## References[edit] 1. ^ "leukorrhea" at Dorland's Medical Dictionary 2. ^ "Definition of LEUKORRHEA". www.merriam-webster.com. Retrieved 2015-12-20. 3. ^ "Hormonal effects in newborns: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2018-11-07. 4. ^ a b "leukorrhea \| medical disorder". Encyclopædia Britannica. Retrieved 2015-12-20. 5. ^ Workowski, Kimberly A., and Stuart Berman. "Sexually Transmitted Diseases Treatment Guidelines, 2010." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 17 Dec. 2010. Web. 28 Oct. 2014. <https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5912a1.htm>. 6. ^ Behrman, Richard E.; Kliegman, Robert; Karen Marcdante; Jenson, Hal B. (2006). Nelson essentials of pediatrics. St. Louis, Mo: Elsevier Saunders. p. 348. ISBN 978-1-4160-0159-1. 7. ^ "leukorrhea". Cite journal requires `\|journal=` (help) 8. ^ Dhami, P.S (2015). A Textbook of Biology. Jalandhar, Punjab: Pradeep Publications. pp. 1/79. 9. ^ "Treatments for Specific Types of Sexually Transmitted Diseases and Sexually Transmitted Infections (STDs/STIs)." Treatments for Specific Types of Sexually Transmitted Diseases and Sexually Transmitted Infections (STDs/STIs). Eunice Kennedy Shriver National Institute of Child Health and Human Development, n.d. Web. 28 Oct. 2014. <http://www.nichd.nih.gov/health/topics/stds/conditioninfo/Pages/specific.aspx>. ## External links[edit] Classification D * ICD-10: N89.8 * ICD-9-CM: 623.5 * MeSH: D007973 * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium *[CAN]: Canada	Leukorrhea	c0023533	4,699	wikipedia	https://en.wikipedia.org/wiki/Leukorrhea	2021-01-18T18:34:38	{"mesh": ["D007973"], "umls": ["C0023533"], "icd-9": ["623.5"], "wikidata": ["Q1144334"]}

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