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Injury of the brain from an external source
Traumatic brain injury
Other namesIntracranial injury, physically induced brain injury[1]
CT scan showing cerebral contusions, hemorrhage within the hemispheres, subdural hematoma, and skull fractures[2]
SpecialtyNeurosurgery, pediatrics
SymptomsPhysical, cognitive, sensory, social, emotional, and behavioral symptoms
TypesMild to severe[3]
CausesTrauma to the head[3]
Risk factorsOld age,[3] alcohol
Diagnostic methodBased on neurological exam, medical imaging[4]
TreatmentBehavioral therapy, speech therapy
A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury [mTBI/concussion] to severe traumatic brain injury), mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area).[5] Head injury is a broader category that may involve damage to other structures such as the scalp and skull. TBI can result in physical, cognitive, social, emotional and behavioral symptoms, and outcomes can range from complete recovery to permanent disability or death.
Causes include falls, vehicle collisions and violence. Brain trauma occurs as a consequence of a sudden acceleration or deceleration within the cranium or by a complex combination of both movement and sudden impact. In addition to the damage caused at the moment of injury, a variety of events following the injury may result in further injury. These processes include alterations in cerebral blood flow and pressure within the skull. Some of the imaging techniques used for diagnosis include computed tomography (CT) and magnetic resonance imaging (MRIs).
Prevention measures include use of seat belts and helmets, not drinking and driving, fall prevention efforts in older adults and safety measures for children.[6] Depending on the injury, treatment required may be minimal or may include interventions such as medications, emergency surgery or surgery years later. Physical therapy, speech therapy, recreation therapy, occupational therapy and vision therapy may be employed for rehabilitation. Counseling, supported employment and community support services may also be useful.
TBI is a major cause of death and disability worldwide, especially in children and young adults.[7] Males sustain traumatic brain injuries around twice as often as females.[8] The 20th century saw developments in diagnosis and treatment that decreased death rates and improved outcomes.
## Contents
* 1 Classification
* 1.1 Severity
* 1.2 Pathological features
* 2 Signs and symptoms
* 3 Causes
* 4 Mechanism
* 4.1 Physical forces
* 4.2 Primary and secondary injury
* 5 Diagnosis
* 6 Prevention
* 7 Treatment
* 7.1 Acute stage
* 7.2 Chronic stage
* 8 Prognosis
* 9 Complications
* 10 Epidemiology
* 10.1 Mortality
* 10.2 Demographics
* 11 History
* 12 Research directions
* 12.1 Medications
* 12.2 Procedures
* 12.3 Psychological
* 12.4 Monitoring pressure
* 13 References
* 14 Cited texts
* 15 External links
## Classification
Traumatic brain injury is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile.[9] Brain function is temporarily or permanently impaired and structural damage may or may not be detectable with current technology.[10]
TBI is one of two subsets of acquired brain injury (brain damage that occur after birth); the other subset is non-traumatic brain injury, which does not involve external mechanical force (examples include stroke and infection).[11][12] All traumatic brain injuries are head injuries, but the latter term may also refer to injury to other parts of the head.[13][14][15] However, the terms head injury and brain injury are often used interchangeably.[16] Similarly, brain injuries fall under the classification of central nervous system injuries[17] and neurotrauma.[18] In neuropsychology research literature, in general the term "traumatic brain injury" is used to refer to non-penetrating traumatic brain injuries.
TBI is usually classified based on severity, anatomical features of the injury, and the mechanism (the causative forces).[19] Mechanism-related classification divides TBI into closed and penetrating head injury.[9] A closed (also called nonpenetrating, or blunt)[13] injury occurs when the brain is not exposed.[14] A penetrating, or open, head injury occurs when an object pierces the skull and breaches the dura mater, the outermost membrane surrounding the brain.[14]
### Severity
Severity of traumatic brain injury[20] GCS PTA LOC
Mild 13–15 <1
day 0–30
minutes
Moderate 9–12 >1 to <7
days >30 min to
<24 hours
Severe 3–8 >7 days >24
hours
Brain injuries can be classified into mild, moderate, and severe categories.[19] The Glasgow Coma Scale (GCS), the most commonly used system for classifying TBI severity, grades a person's level of consciousness on a scale of 3–15 based on verbal, motor, and eye-opening reactions to stimuli.[21] In general, it is agreed that a TBI with a GCS of 13 or above is mild, 9–12 is moderate, and 8 or below is severe.[10][15][22] Similar systems exist for young children.[15] However, the GCS grading system has limited ability to predict outcomes. Because of this, other classification systems such as the one shown in the table are also used to help determine severity. A current model developed by the Department of Defense and Department of Veterans Affairs uses all three criteria of GCS after resuscitation, duration of post-traumatic amnesia (PTA), and loss of consciousness (LOC).[20] It also has been proposed to use changes that are visible on neuroimaging, such as swelling, focal lesions, or diffuse injury as method of classification.[9] Grading scales also exist to classify the severity of mild TBI, commonly called concussion; these use duration of LOC, PTA, and other concussion symptoms.[23]
### Pathological features
Main article: Focal and diffuse brain injury
CT scan Spread of the subdural hematoma (single arrows), midline shift (double arrows)
Systems also exist to classify TBI by its pathological features.[19] Lesions can be extra-axial, (occurring within the skull but outside of the brain) or intra-axial (occurring within the brain tissue).[24] Damage from TBI can be focal or diffuse, confined to specific areas or distributed in a more general manner, respectively.[25] However, it is common for both types of injury to exist in a given case.[25]
Diffuse injury manifests with little apparent damage in neuroimaging studies, but lesions can be seen with microscopy techniques post-mortem,[25][26] and in the early 2000s, researchers discovered that diffusion tensor imaging (DTI), a way of processing MRI images that shows white matter tracts, was an effective tool for displaying the extent of diffuse axonal injury.[27][28] Types of injuries considered diffuse include edema (swelling), concussion and diffuse axonal injury, which is widespread damage to axons including white matter tracts and projections to the cortex.[29][30]
Focal injuries often produce symptoms related to the functions of the damaged area.[17] Research shows that the most common areas to have focal lesions in non-penetrating traumatic brain injury are the orbitofrontal cortex (the lower surface of the frontal lobes) and the anterior temporal lobes, areas that are involved in social behavior, emotion regulation, olfaction, and decision-making, hence the common social/emotional and judgment deficits following moderate-severe TBI.[31][32][33][34] Symptoms such as hemiparesis or aphasia can also occur when less commonly affected areas such as motor or language areas are, respectively, damaged.[35][36]
One type of focal injury, cerebral laceration, occurs when the tissue is cut or torn.[37] Such tearing is common in orbitofrontal cortex in particular, because of bony protrusions on the interior skull ridge above the eyes.[31] In a similar injury, cerebral contusion (bruising of brain tissue), blood is mixed among tissue.[22] In contrast, intracranial hemorrhage involves bleeding that is not mixed with tissue.[37]
Hematomas, also focal lesions, are collections of blood in or around the brain that can result from hemorrhage.[10] Intracerebral hemorrhage, with bleeding in the brain tissue itself, is an intra-axial lesion. Extra-axial lesions include epidural hematoma, subdural hematoma, subarachnoid hemorrhage, and intraventricular hemorrhage.[38] Epidural hematoma involves bleeding into the area between the skull and the dura mater, the outermost of the three membranes surrounding the brain.[10] In subdural hematoma, bleeding occurs between the dura and the arachnoid mater.[22] Subarachnoid hemorrhage involves bleeding into the space between the arachnoid membrane and the pia mater.[22] Intraventricular hemorrhage occurs when there is bleeding in the ventricles.[38]
## Signs and symptoms
Unequal pupil size is potentially a sign of a serious brain injury.[39]
Symptoms are dependent on the type of TBI (diffuse or focal) and the part of the brain that is affected.[40] Unconsciousness tends to last longer for people with injuries on the left side of the brain than for those with injuries on the right.[14] Symptoms are also dependent on the injury's severity. With mild TBI, the patient may remain conscious or may lose consciousness for a few seconds or minutes.[41] Other symptoms of mild TBI include headache, vomiting, nausea, lack of motor coordination, dizziness, difficulty balancing,[42] lightheadedness, blurred vision or tired eyes, ringing in the ears, bad taste in the mouth, fatigue or lethargy, and changes in sleep patterns.[41] Cognitive and emotional symptoms include behavioral or mood changes, confusion, and trouble with memory, concentration, attention, or thinking.[41] Mild TBI symptoms may also be present in moderate and severe injuries.[41]
A person with a moderate or severe TBI may have a headache that does not go away, repeated vomiting or nausea, convulsions, an inability to awaken, dilation of one or both pupils, slurred speech, aphasia (word-finding difficulties), dysarthria (muscle weakness that causes disordered speech), weakness or numbness in the limbs, loss of coordination, confusion, restlessness, or agitation.[41] Common long-term symptoms of moderate to severe TBI are changes in appropriate social behavior, deficits in social judgment, and cognitive changes, especially problems with sustained attention, processing speed, and executive functioning.[34][43][44][45][46] Alexithymia, a deficiency in identifying, understanding, processing, and describing emotions occurs in 60.9% of individuals with TBI.[47] Cognitive and social deficits have long-term consequences for the daily lives of people with moderate to severe TBI, but can be improved with appropriate rehabilitation.[46][48][49][50]
When the pressure within the skull (intracranial pressure, abbreviated ICP) rises too high, it can be deadly.[51] Signs of increased ICP include decreasing level of consciousness, paralysis or weakness on one side of the body, and a blown pupil, one that fails to constrict in response to light or is slow to do so.[51] Cushing's triad, a slow heart rate with high blood pressure and respiratory depression is a classic manifestation of significantly raised ICP.[10] Anisocoria, unequal pupil size, is another sign of serious TBI.[39] Abnormal posturing, a characteristic positioning of the limbs caused by severe diffuse injury or high ICP, is an ominous sign.[10]
Small children with moderate to severe TBI may have some of these symptoms but have difficulty communicating them.[52] Other signs seen in young children include persistent crying, inability to be consoled, listlessness, refusal to nurse or eat,[52] and irritability.[10]
## Causes
The most common causes of TBI in the U.S. include violence, transportation accidents, construction, and sports.[42][53] Motor bikes are major causes, increasing in significance in developing countries as other causes reduce.[54] The estimates that between 1.6 and 3.8 million traumatic brain injuries each year are a result of sports and recreation activities in the US.[55] In children aged two to four, falls are the most common cause of TBI, while in older children traffic accidents compete with falls for this position.[56] TBI is the third most common injury to result from child abuse.[57] Abuse causes 19% of cases of pediatric brain trauma, and the death rate is higher among these cases.[58] Although men are twice as likely to have a TBI. Domestic violence is another cause of TBI,[59] as are work-related and industrial accidents.[60] Firearms[14] and blast injuries from explosions[61] are other causes of TBI, which is the leading cause of death and disability in war zones.[62] According to Representative Bill Pascrell (Democrat, NJ), TBI is "the signature injury of the wars in Iraq and Afghanistan."[63] There is a promising technology called activation database-guided EEG biofeedback, which has been documented to return a TBI's auditory memory ability to above the control group's performance[64][65]
## Mechanism
### Physical forces
Ricochet of the brain within the skull may account for the coup-contrecoup phenomenon.[66]
The type, direction, intensity, and duration of forces all contribute to the characteristics and severity TBI.[9] Forces that may contribute to TBI include angular, rotational, shear, and translational forces.[37]
Even in the absence of an impact, significant acceleration or deceleration of the head can cause TBI; however in most cases, a combination of impact and acceleration is probably to blame.[37] Forces involving the head striking or being struck by something, termed contact or impact loading, are the cause of most focal injuries, and movement of the brain within the skull, termed noncontact or inertial loading, usually causes diffuse injuries.[19] The violent shaking of an infant that causes shaken baby syndrome commonly manifests as diffuse injury.[67] In impact loading, the force sends shock waves through the skull and brain, resulting in tissue damage.[37] Shock waves caused by penetrating injuries can also destroy tissue along the path of a projectile, compounding the damage caused by the missile itself.[22]
Damage may occur directly under the site of impact, or it may occur on the side opposite the impact (coup and contrecoup injury, respectively).[66] When a moving object impacts the stationary head, coup injuries are typical,[68] while contrecoup injuries are usually produced when the moving head strikes a stationary object.[69]
### Primary and secondary injury
MRI scan showing damage due to brain herniation after TBI[2]
Main article: Primary and secondary brain injury
A large percentage of the people killed by brain trauma do not die right away but rather days to weeks after the event;[70] rather than improving after being hospitalized, some 40% of TBI patients deteriorate.[71] Primary brain injury (the damage that occurs at the moment of trauma when tissues and blood vessels are stretched, compressed, and torn) is not adequate to explain this deterioration; rather, it is caused by secondary injury, a complex set of cellular processes and biochemical cascades that occur in the minutes to days following the trauma.[72] These secondary processes can dramatically worsen the damage caused by primary injury[62] and account for the greatest number of TBI deaths occurring in hospitals.[39]
Secondary injury events include damage to the blood–brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria.[62] Injured axons in the brain's white matter may separate from their cell bodies as a result of secondary injury,[62] potentially killing those neurons. Other factors in secondary injury are changes in the blood flow to the brain; ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); cerebral edema (swelling of the brain); and raised intracranial pressure (the pressure within the skull).[73] Intracranial pressure may rise due to swelling or a mass effect from a lesion, such as a hemorrhage.[51] As a result, cerebral perfusion pressure (the pressure of blood flow in the brain) is reduced; ischemia results.[39][74] When the pressure within the skull rises too high, it can cause brain death or herniation, in which parts of the brain are squeezed by structures in the skull.[51] A particularly weak part of the skull that is vulnerable to damage causing extradural haematoma is the pterion, deep in which lies the middle meningeal artery, which is easily damaged in fractures of the pterion. Since the pterion is so weak, this type of injury can easily occur and can be secondary due to trauma to other parts of the skull where the impact forces spreads to the pterion.
## Diagnosis
CT scan showing epidural hematoma (arrow)
Diagnosis is suspected based on lesion circumstances and clinical evidence, most prominently a neurological examination, for example checking whether the pupils constrict normally in response to light and assigning a Glasgow Coma Score.[22] Neuroimaging helps in determining the diagnosis and prognosis and in deciding what treatments to give.[75] DSM-5 can be utilized to diagnose TBI and its psychiatric sequelae.[76][77][78]
The preferred radiologic test in the emergency setting is computed tomography (CT): it is quick, accurate, and widely available.[79] Follow-up CT scans may be performed later to determine whether the injury has progressed.[9]
Magnetic resonance imaging (MRI) can show more detail than CT, and can add information about expected outcome in the long term.[22] It is more useful than CT for detecting injury characteristics such as diffuse axonal injury in the longer term.[9] However, MRI is not used in the emergency setting for reasons including its relative inefficacy in detecting bleeds and fractures, its lengthy acquisition of images, the inaccessibility of the patient in the machine, and its incompatibility with metal items used in emergency care.[22] A variant of MRI since 2012 is High definition fiber tracking (HDFT).[80]
Other techniques may be used to confirm a particular diagnosis. X-rays are still used for head trauma, but evidence suggests they are not useful; head injuries are either so mild that they do not need imaging or severe enough to merit the more accurate CT.[79] Angiography may be used to detect blood vessel pathology when risk factors such as penetrating head trauma are involved.[9] Functional imaging can measure cerebral blood flow or metabolism, inferring neuronal activity in specific regions and potentially helping to predict outcome.[81] Electroencephalography and transcranial doppler may also be used. The most sensitive physical measure to date is the quantitative EEG, which has documented an 80% to 100% ability in discriminating between normal and traumatic brain-injured subjects.[82][83]
Neuropsychological assessment can be performed to evaluate the long-term cognitive sequelae and to aid in the planning of the rehabilitation.[75] Instruments range from short measures of general mental functioning to complete batteries formed of different domain-specific tests.
## Prevention
Protective sports equipment such as helmets can help to protect athletes from head injury.
Since a major cause of TBI are vehicle accidents, their prevention or the amelioration of their consequences can both reduce the incidence and gravity of TBI. In accidents, damage can be reduced by use of seat belts, child safety seats[55] and motorcycle helmets,[84] and presence of roll bars and airbags.[37] Education programs exist to lower the number of crashes.[75] In addition, changes to public policy and safety laws can be made; these include speed limits, seat belt and helmet laws, and road engineering practices.[62]
Changes to common practices in sports have also been discussed. An increase in use of helmets could reduce the incidence of TBI.[62] Due to the possibility that repeatedly "heading" a ball practicing soccer could cause cumulative brain injury, the idea of introducing protective headgear for players has been proposed.[85] Improved equipment design can enhance safety; softer baseballs reduce head injury risk.[86] Rules against dangerous types of contact, such as "spear tackling" in American football, when one player tackles another head first, may also reduce head injury rates.[86]
Falls can be avoided by installing grab bars in bathrooms and handrails on stairways; removing tripping hazards such as throw rugs; or installing window guards and safety gates at the top and bottom of stairs around young children.[55] Playgrounds with shock-absorbing surfaces such as mulch or sand also prevent head injuries.[55] Child abuse prevention is another tactic; programs exist to prevent shaken baby syndrome by educating about the dangers of shaking children.[58] Gun safety, including keeping guns unloaded and locked, is another preventative measure.[87] Studies on the effect of laws that aim to control access to guns in the United States have been insufficient to determine their effectiveness preventing number of deaths or injuries.[88]
Recent clinical and laboratory research by neurosurgeon Julian Bailes, M.D., and his colleagues from West Virginia University, has resulted in papers showing that dietary supplementation with omega-3 DHA offers protection against the biochemical brain damage that occurs after a traumatic injury.[89] Rats given DHA prior to induced brain injuries suffered smaller increases in two key markers for brain damage (APP and caspase-3), as compared with rats given no DHA.[90] “The potential for DHA to provide prophylactic benefit to the brain against traumatic injury appears promising and requires further investigation. The essential concept of daily dietary supplementation with DHA, so that those at significant risk may be preloaded to provide protection against the acute effects of TBI, has tremendous public health implications.”[91]
Furthermore, acetylcysteine has been confirmed, in a recent double-blind placebo-controlled trial conducted by the US military, to reduce the effects of blast induced mild traumatic brain and neurological injury in soldiers.[92] Multiple animal studies have also demonstrated its efficacy in reducing the damage associated with moderate traumatic brain or spinal injury, and also ischemia-induced brain injury. In particular, it has been demonstrated through multiple studies to significantly reduce neuronal losses and to improve cognitive and neurological outcomes associated with these traumatic events. Acetylcysteine has been safely used to treat paracetamol overdose for over forty years and is extensively used in emergency medicine.
## Treatment
It is important to begin emergency treatment within the so-called "golden hour" following the injury.[93] People with moderate to severe injuries are likely to receive treatment in an intensive care unit followed by a neurosurgical ward.[94] Treatment depends on the recovery stage of the patient. In the acute stage, the primary aim is to stabilize the patient and focus on preventing further injury. This is done because the initial damage caused by trauma cannot be reversed.[94] Rehabilitation is the main treatment for the subacute and chronic stages of recovery.[94] International clinical guidelines have been proposed with the aim of guiding decisions in TBI treatment, as defined by an authoritative examination of current evidence.[9]
### Acute stage
Tranexamic acid within three hours of a head injury decreases the risk of death.[95] Certain facilities are equipped to handle TBI better than others; initial measures include transporting patients to an appropriate treatment center.[51][96] Both during transport and in hospital the primary concerns are ensuring proper oxygen supply, maintaining adequate blood flow to the brain, and controlling raised intracranial pressure (ICP),[10] since high ICP deprives the brain of badly needed blood flow[97] and can cause deadly brain herniation. Other methods to prevent damage include management of other injuries and prevention of seizures.[22][75] Some data supports the use of hyperbaric oxygen therapy to improve outcomes.[98] Further research is required to determine the effectiveness and clinical importance of positioning the head at different angles (degrees of head-of-bed elevation) while the person is being treated in intensive care.[99]
Neuroimaging is helpful but not flawless in detecting raised ICP.[100] A more accurate way to measure ICP is to place a catheter into a ventricle of the brain,[39] which has the added benefit of allowing cerebrospinal fluid to drain, releasing pressure in the skull.[39] Treatment of raised ICP may be as simple as tilting the person's bed and straightening the head to promote blood flow through the veins of the neck. Sedatives, analgesics and paralytic agents are often used.[51] Propofol and midazol are equally effective as a sedative.[101]
Hypertonic saline can improve ICP by reducing the amount of cerebral water (swelling), though it is used with caution to avoid electrolyte imbalances or heart failure.[9][102][103] Mannitol, an osmotic diuretic,[9] appears to be equally effective at reducing ICP.[104][105][106][107] Some concerns, however, have been raised regarding some of the studies performed.[108] Diuretics, drugs that increase urine output to reduce excessive fluid in the system, may be used to treat high intracranial pressures, but may cause hypovolemia (insufficient blood volume).[39] Hyperventilation (larger and/or faster breaths) reduces carbon dioxide levels and causes blood vessels to constrict; this decreases blood flow to the brain and reduces ICP,[109] but it potentially causes ischemia[10][39][110] and is, therefore, used only in the short term.[10]
Giving corticosteroids is associated with an increased risk of death, and so their routine use is not recommended.[111][112] There is no strong evidence that the following pharmaceutical interventions should be recommended to routinely treat TBI: magnesium, monoaminergic and dopamine agonists, progesterone, aminosteroids, excitatory amino acid reuptake inhibitors, beta-2 antagonists (bronchodilators), haemostatic and antifibrinolytic drugs.[101][113][114][115][116]
Endotracheal intubation and mechanical ventilation may be used to ensure proper oxygen supply and provide a secure airway.[75] Hypotension (low blood pressure), which has a devastating outcome in TBI, can be prevented by giving intravenous fluids to maintain a normal blood pressure. Failing to maintain blood pressure can result in inadequate blood flow to the brain.[22] Blood pressure may be kept at an artificially high level under controlled conditions by infusion of norepinephrine or similar drugs; this helps maintain cerebral perfusion.[117] Body temperature is carefully regulated because increased temperature raises the brain's metabolic needs, potentially depriving it of nutrients.[118] Seizures are common. While they can be treated with benzodiazepines, these drugs are used carefully because they can depress breathing and lower blood pressure.[51] Anti-convulsant medications have only been found to be useful for reducing the risk of an early seizure.[101] Phenytoin and leviteracetam appear to have similar levels of effectiveness for preventing early seizures.[101] People with TBI are more susceptible to side effects and may react adversely to some medications.[94] During treatment monitoring continues for signs of deterioration such as a decreasing level of consciousness.[9][10]
Traumatic brain injury may cause a range of serious coincidental complications that include cardiac arrhythmias[119] and neurogenic pulmonary edema.[120] These conditions must be adequately treated and stabilised as part of the core care.
Surgery can be performed on mass lesions or to eliminate objects that have penetrated the brain. Mass lesions such as contusions or hematomas causing a significant mass effect (shift of intracranial structures) are considered emergencies and are removed surgically.[22] For intracranial hematomas, the collected blood may be removed using suction or forceps or it may be floated off with water.[22] Surgeons look for hemorrhaging blood vessels and seek to control bleeding.[22] In penetrating brain injury, damaged tissue is surgically debrided, and craniotomy may be needed.[22] Craniotomy, in which part of the skull is removed, may be needed to remove pieces of fractured skull or objects embedded in the brain.[121] Decompressive craniectomy (DC) is performed routinely in the very short period following TBI during operations to treat hematomas; part of the skull is removed temporarily (primary DC).[122] DC performed hours or days after TBI in order to control high intracranial pressures (secondary DC) has not been shown to improve outcome in some trials and may be associated with severe side-effects.[9][122]
### Chronic stage
Physical therapy will commonly include muscle strength exercise.
Once medically stable, people may be transferred to a subacute rehabilitation unit of the medical center or to an independent rehabilitation hospital.[94] Rehabilitation aims to improve independent functioning at home and in society, and to help adapt to disabilities.[94] Rehabilitation has demonstrated its general effectiveness when conducted by a team of health professionals who specialize in head trauma.[123] As for any person with neurologic deficits, a multidisciplinary approach is key to optimizing outcome. Physiatrists or neurologists are likely to be the key medical staff involved, but depending on the person, doctors of other medical specialties may also be helpful. Allied health professions such as physiotherapy, speech and language therapy, cognitive rehabilitation therapy, and occupational therapy will be essential to assess function and design the rehabilitation activities for each person.[124] Treatment of neuropsychiatric symptoms such as emotional distress and clinical depression may involve mental health professionals such as therapists, psychologists, and psychiatrists, while neuropsychologists can help to evaluate and manage cognitive deficits.[94][125] Social workers, rehabilitation support personnel, nutritionists, therapeutic recreationists, and pharmacists are also important members of the TBI rehabilitation team.[124] After discharge from the inpatient rehabilitation treatment unit, care may be given on an outpatient basis. Community-based rehabilitation will be required for a high proportion of people, including vocational rehabilitation; this supportive employment matches job demands to the worker's abilities.[126] People with TBI who cannot live independently or with family may require care in supported living facilities such as group homes.[126] Respite care, including day centers and leisure facilities for the disabled, offers time off for caregivers, and activities for people with TBI.[126]
Pharmacological treatment can help to manage psychiatric or behavioral problems.[127] Medication is also used to control post-traumatic epilepsy; however the preventive use of anti-epileptics is not recommended.[128] In those cases where the person is bedridden due to a reduction of consciousness, has to remain in a wheelchair because of mobility problems, or has any other problem heavily impacting self-caring capacities, caregiving and nursing are critical. The most effective research documented intervention approach is the activation database guided EEG biofeedback approach, which has shown significant improvements in memory abilities of the TBI subject that are far superior than traditional approaches (strategies, computers, medication intervention). Gains of 2.61 standard deviations have been documented. The TBI's auditory memory ability was superior to the control group after the treatment.[64]
## Prognosis
Prognosis worsens with the severity of injury.[8] Most TBIs are mild and do not cause permanent or long-term disability; however, all severity levels of TBI have the potential to cause significant, long-lasting disability.[129] Permanent disability is thought to occur in 10% of mild injuries, 66% of moderate injuries, and 100% of severe injuries.[130] Most mild TBI is completely resolved within three weeks. Almost all people with mild TBI are able to live independently and return to the jobs they had before the injury, although a small portion have mild cognitive and social impairments.[87] Over 90% of people with moderate TBI are able to live independently, although some require assistance in areas such as physical abilities, employment, and financial managing.[87] Most people with severe closed head injury either die or recover enough to live independently; middle ground is less common.[9] Coma, as it is closely related to severity, is a strong predictor of poor outcome.[10]
Prognosis differs depending on the severity and location of the lesion, and access to immediate, specialised acute management. Subarachnoid hemorrhage approximately doubles mortality.[131] Subdural hematoma is associated with worse outcome and increased mortality, while people with epidural hematoma are expected to have a good outcome if they receive surgery quickly.[75] Diffuse axonal injury may be associated with coma when severe, and poor outcome.[9] Following the acute stage, prognosis is strongly influenced by the patient's involvement in activity that promote recovery, which for most patients requires access to a specialised, intensive rehabilitation service. The Functional Independence Measure is a way to track progress and degree of independence throughout rehabilitation.[132]
Medical complications are associated with a bad prognosis. Examples of such complications include: hypotension (low blood pressure), hypoxia (low blood oxygen saturation), lower cerebral perfusion pressures, and longer times spent with high intracranial pressures.[9][75] Patient characteristics also influence prognosis. Examples of factors thought to worsen it include: abuse of substances such as illicit drugs and alcohol and age over sixty or under two years (in children, younger age at time of injury may be associated with a slower recovery of some abilities).[75] Other influences that may affect recovery include pre-injury intellectual ability, coping strategies, personality traits, family environment, social support systems and financial circumstances.[133]
Life satisfaction has been known to decrease for individuals with TBI immediately following the trauma, but evidence has shown that life roles, age, and depressive symptoms influence the trajectory of life satisfaction as time passes.[134] Many people with traumatic brain injuries have poor physical fitness following their acute injury and this may result with difficulties in day-to-day activities and increased levels of fatigue.[135]
## Complications
Main article: Complications of traumatic brain injury
The relative risk of post-traumatic seizures increases with the severity of traumatic brain injury.[136]
A CT of the head years after a traumatic brain injury showing an empty space where the damage occurred marked by the arrow.
Improvement of neurological function usually occurs for two or more years after the trauma. For many years it was believed that recovery was fastest during the first six months, but there is no evidence to support this. It may be related to services commonly being withdrawn after this period, rather than any physiological limitation to further progress.[9] Children recover better in the immediate time frame and improve for longer periods.[10]
Complications are distinct medical problems that may arise as a result of the TBI. The results of traumatic brain injury vary widely in type and duration; they include physical, cognitive, emotional, and behavioral complications. TBI can cause prolonged or permanent effects on consciousness, such as coma, brain death, persistent vegetative state (in which patients are unable to achieve a state of alertness to interact with their surroundings),[137] and minimally conscious state (in which patients show minimal signs of being aware of self or environment).[138][139] Lying still for long periods can cause complications including pressure sores, pneumonia or other infections, progressive multiple organ failure,[94] and deep venous thrombosis, which can cause pulmonary embolism.[22] Infections that can follow skull fractures and penetrating injuries include meningitis and abscesses.[94] Complications involving the blood vessels include vasospasm, in which vessels constrict and restrict blood flow, the formation of aneurysms, in which the side of a vessel weakens and balloons out, and stroke.[94]
Movement disorders that may develop after TBI include tremor, ataxia (uncoordinated muscle movements), spasticity (muscle contractions are overactive), myoclonus (shock-like contractions of muscles), and loss of movement range and control (in particular with a loss of movement repertoire).[94][140] The risk of post-traumatic seizures increases with severity of trauma (image at right) and is particularly elevated with certain types of brain trauma such as cerebral contusions or hematomas.[130] People with early seizures, those occurring within a week of injury, have an increased risk of post-traumatic epilepsy (recurrent seizures occurring more than a week after the initial trauma).[141] People may lose or experience altered vision, hearing, or smell.[10]
Hormonal disturbances may occur secondary to hypopituitarism, occurring immediately or years after injury in 10 to 15% of TBI patients. Development of diabetes insipidus or an electrolyte abnormality acutely after injury indicate need for endocrinologic work up. Signs and symptoms of hypopituitarism may develop and be screened for in adults with moderate TBI and in mild TBI with imaging abnormalities. Children with moderate to severe head injury may also develop hypopituitarism. Screening should take place 3 to 6 months, and 12 months after injury, but problems may occur more remotely.[142]
Cognitive deficits that can follow TBI include impaired attention; disrupted insight, judgement, and thought; reduced processing speed; distractibility; and deficits in executive functions such as abstract reasoning, planning, problem-solving, and multitasking.[143] Memory loss, the most common cognitive impairment among head-injured people, occurs in 20–79% of people with closed head trauma, depending on severity.[144] People who have suffered TBI may also have difficulty with understanding or producing spoken or written language, or with more subtle aspects of communication such as body language.[94] Post-concussion syndrome, a set of lasting symptoms experienced after mild TBI, can include physical, cognitive, emotional and behavioral problems such as headaches, dizziness, difficulty concentrating, and depression.[10] Multiple TBIs may have a cumulative effect.[139] A young person who receives a second concussion before symptoms from another one have healed may be at risk for developing a very rare but deadly condition called second-impact syndrome, in which the brain swells catastrophically after even a mild blow, with debilitating or deadly results. About one in five career boxers is affected by chronic traumatic brain injury (CTBI), which causes cognitive, behavioral, and physical impairments.[145] Dementia pugilistica, the severe form of CTBI, affects primarily career boxers years after a boxing career. It commonly manifests as dementia, memory problems, and parkinsonism (tremors and lack of coordination).[146]
TBI may cause emotional, social, or behavioral problems and changes in personality.[147][148][149][150] These may include emotional instability, depression, anxiety, hypomania, mania, apathy, irritability, problems with social judgment, and impaired conversational skills.[147][150][151][152] TBI appears to predispose survivors to psychiatric disorders including obsessive compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, and anxiety disorders.[153] In patients who have depression after TBI, suicidal ideation is not uncommon; the suicide rate among these persons is increased 2- to 3-fold.[154] Social and behavioral symptoms that can follow TBI include disinhibition, inability to control anger, impulsiveness, lack of initiative, inappropriate sexual activity, asociality and social withdrawal, and changes in personality.[147][149][150][155]
TBI also has a substantial impact on the functioning of family systems[156] Caregiving family members and TBI survivors often significantly alter their familial roles and responsibilities following injury, creating significant change and strain on a family system. Typical challenges identified by families recovering from TBI include: frustration and impatience with one another, loss of former lives and relationships, difficulty setting reasonable goals, inability to effectively solve problems as a family, increased level of stress and household tension, changes in emotional dynamics, and overwhelming desire to return to pre-injury status. In addition, families may exhibit less effective functioning in areas including coping, problem solving and communication. Psychoeducation and counseling models have been demonstrated to be effective in minimizing family disruption.[157]
## Epidemiology
Causes of TBI fatalities in the US[158]
TBI is a leading cause of death and disability around the globe[7] and presents a major worldwide social, economic, and health problem.[9] It is the number one cause of coma,[159] it plays the leading role in disability due to trauma,[75] and is the leading cause of brain damage in children and young adults.[14] In Europe it is responsible for more years of disability than any other cause.[9] It also plays a significant role in half of trauma deaths.[22]
Findings on the frequency of each level of severity vary based on the definitions and methods used in studies. A World Health Organization study estimated that between 70 and 90% of head injuries that receive treatment are mild,[160] and a US study found that moderate and severe injuries each account for 10% of TBIs, with the rest mild.[71]
The incidence of TBI varies by age, gender, region and other factors.[161] Findings of incidence and prevalence in epidemiological studies vary based on such factors as which grades of severity are included, whether deaths are included, whether the study is restricted to hospitalized people, and the study's location.[14] The annual incidence of mild TBI is difficult to determine but may be 100–600 people per 100,000.[62]
### Mortality
In the US, the case fatality rate is estimated to be 21% by 30 days after TBI.[96] A study on Iraq War soldiers found that severe TBI carries a mortality of 30–50%.[62] Deaths have declined due to improved treatments and systems for managing trauma in societies wealthy enough to provide modern emergency and neurosurgical services.[118] The fraction of those who die after being hospitalized with TBI fell from almost half in the 1970s to about a quarter at the beginning of the 21st century.[75] This decline in mortality has led to a concomitant increase in the number of people living with disabilities that result from TBI.[162]
Biological, clinical, and demographic factors contribute to the likelihood that an injury will be fatal.[158] In addition, outcome depends heavily on the cause of head injury. In the US, patients with fall-related TBIs have an 89% survival rate, while only 9% of patients with firearm-related TBIs survive.[163] In the US, firearms are the most common cause of fatal TBI, followed by vehicle accidents and then falls.[158] Of deaths from firearms, 75% are considered to be suicides.[158]
The incidence of TBI is increasing globally, due largely to an increase in motor vehicle use in low- and middle-income countries.[9] In developing countries, automobile use has increased faster than safety infrastructure could be introduced.[62] In contrast, vehicle safety laws have decreased rates of TBI in high-income countries,[9] which have seen decreases in traffic-related TBI since the 1970s.[54] Each year in the United States, about two million people suffer a TBI,[20] approximately 675,000 injuries are seen in the emergency department,[164] and about 500,000 patients are hospitalized.[161] The yearly incidence of TBI is estimated at 180–250 per 100,000 people in the US,[161] 281 per 100,000 in France, 361 per 100,000 in South Africa, 322 per 100,000 in Australia,[14] and 430 per 100,000 in England.[60] In the European Union the yearly aggregate incidence of TBI hospitalizations and fatalities is estimated at 235 per 100,000.[9]
### Demographics
TBI is present in 85% of traumatically injured children, either alone or with other injuries.[165] The greatest number of TBIs occur in people aged 15–24.[12][37] Because TBI is more common in young people, its costs to society are high due to the loss of productive years to death and disability.[9] The age groups most at risk for TBI are children ages five to nine and adults over age 80,[8] and the highest rates of death and hospitalization due to TBI are in people over age 65.[129] The incidence of fall-related TBI in First-World countries is increasing as the population ages; thus the median age of people with head injuries has increased.[9]
Regardless of age, TBI rates are higher in males.[37] Men suffer twice as many TBIs as women do and have a fourfold risk of fatal head injury,[8] and males account for two thirds of childhood and adolescent head trauma.[166] However, when matched for severity of injury, women appear to fare more poorly than men.[97]
Socioeconomic status also appears to affect TBI rates; people with lower levels of education and employment and lower socioeconomic status are at greater risk.[14] Approximately half of those incarcerated in prisons and jails in the United States have had TBIs.[167]
## History
The Edwin Smith Papyrus
Head injury is present in ancient myths that may date back before recorded history.[168] Skulls found in battleground graves with holes drilled over fracture lines suggest that trepanation may have been used to treat TBI in ancient times.[169] Ancient Mesopotamians knew of head injury and some of its effects, including seizures, paralysis, and loss of sight, hearing or speech.[170] The Edwin Smith Papyrus, written around 1650–1550 BC, describes various head injuries and symptoms and classifies them based on their presentation and tractability.[171] Ancient Greek physicians including Hippocrates understood the brain to be the center of thought, probably due to their experience with head trauma.[172]
Medieval and Renaissance surgeons continued the practice of trepanation for head injury.[172] In the Middle Ages, physicians further described head injury symptoms and the term concussion became more widespread.[173] Concussion symptoms were first described systematically in the 16th century by Berengario da Carpi.[172]
It was first suggested in the 18th century that intracranial pressure rather than skull damage was the cause of pathology after TBI. This hypothesis was confirmed around the end of the 19th century, and opening the skull to relieve pressure was then proposed as a treatment.[169]
In the 19th century it was noted that TBI is related to the development of psychosis.[174] At that time a debate arose around whether post-concussion syndrome was due to a disturbance of the brain tissue or psychological factors.[173] The debate continues today.
Phineas Gage with the tamping iron that entered his left cheek and emerged at the top of his head
Perhaps the first reported case of personality change after brain injury is that of Phineas Gage, who survived an accident in which a large iron rod was driven through his head, destroying one or both of his frontal lobes; numerous cases of personality change after brain injury have been reported since.[31][33][34][43][44][48][175][176]
The 20th century saw the advancement of technologies that improved treatment and diagnosis such as the development of imaging tools including CT and MRI, and, in the 21st century, diffusion tensor imaging (DTI). The introduction of intracranial pressure monitoring in the 1950s has been credited with beginning the "modern era" of head injury.[118][177] Until the 20th century, the mortality rate of TBI was high and rehabilitation was uncommon; improvements in care made during World War I reduced the death rate and made rehabilitation possible.[168] Facilities dedicated to TBI rehabilitation were probably first established during World War I.[168] Explosives used in World War I caused many blast injuries; the large number of TBIs that resulted allowed researchers to learn about localization of brain functions.[178] Blast-related injuries are now common problems in returning veterans from Iraq & Afghanistan; research shows that the symptoms of such TBIs are largely the same as those of TBIs involving a physical blow to the head.[179]
In the 1970s, awareness of TBI as a public health problem grew,[180] and a great deal of progress has been made since then in brain trauma research,[118] such as the discovery of primary and secondary brain injury.[169] The 1990s saw the development and dissemination of standardized guidelines for treatment of TBI, with protocols for a range of issues such as drugs and management of intracranial pressure.[118] Research since the early 1990s has improved TBI survival;[169] that decade was known as the "Decade of the Brain" for advances made in brain research.[181]
## Research directions
### Medications
No medication is approved to halt the progression of the initial injury to secondary injury.[62] The variety of pathological events presents opportunities to find treatments that interfere with the damage processes.[9] Neuroprotection methods to decrease secondary injury, have been the subject of interest follows TBI. However, trials to test agents that could halt these cellular mechanisms have met largely with failure.[9] For example, interest existed in cooling the injured brain; however, a 2020 Cochrane review did not find enough evidence to see if it was useful or not.[182] Maintaining a normal temperature in the immediate period after a TBI appeared useful.[183] One review found a lower than normal temperature was useful in adults but not children.[184] While two other reviews found it did not appear to be useful.[185][183]
Further research is necessary to determine if the vasoconstrictor indomethacin (indometacin) can be used to treat increased pressure in the skull following a TBI.[186]
In addition, drugs such as NMDA receptor antagonists to halt neurochemical cascades such as excitotoxicity showed promise in animal trials but failed in clinical trials.[118] These failures could be due to factors including faults in the trials' design or in the insufficiency of a single agent to prevent the array of injury processes involved in secondary injury.[118]
Other topics of research have included investigations into mannitol,[187] dexamethasone,[188] progesterone,[189] xenon,[190] barbiturates,[191] magnesium (no strong evidence),[192][193] calcium channel blockers,[194] PPAR-γ agonists,[195][196] curcuminoids,[197] ethanol,[198] NMDA antagonists,[118] caffeine.[199]
### Procedures
In addition to traditional imaging modalities, there are several devices that help to monitor brain injury and facilitate research. Microdialysis allows ongoing sampling of extracellular fluid for analysis of metabolites that might indicate ischemia or brain metabolism, such as glucose, glycerol, and glutamate.[200][201] Intraparenchymal brain tissue oxygen monitoring systems (either Licox or Neurovent-PTO) are used routinely in neurointensive care in the US.[202] A non invasive model called CerOx is in development.[203]
Research is also planned to clarify factors correlated to outcome in TBI and to determine in which cases it is best to perform CT scans and surgical procedures.[204]
Hyperbaric oxygen therapy (HBO) has been evaluated as an add on treatment following TBI. The findings of a 2012 Cochrane systematic review does not justify the routine use of hyperbaric oxygen therapy to treat people recovering from a traumatic brain injury.[205] This review also reported that only a small number of randomized controlled trials had been conducted at the time of the review, many of which had methodological problems and poor reporting.[205] HBO for TBI is controversial with further evidence required to determine if it has a role.[206][205]
### Psychological
Further research is required to determine the effectiveness of non-pharmacological treatment approaches for treating depression in children/adolescents and adults with TBI.[207]
As of 2010, the use of predictive visual tracking measurement to identify mild traumatic brain injury was being studied. In visual tracking tests, a head-mounted display unit with eye-tracking capability shows an object moving in a regular pattern. People without brain injury are able to track the moving object with smooth pursuit eye movements and correct trajectory. The test requires both attention and working memory which are difficult functions for people with mild traumatic brain injury. The question being studied, is whether results for people with brain injury will show visual-tracking gaze errors relative to the moving target.[208]
### Monitoring pressure
Pressure reactivity index is an emerging technology which correlates intracranial pressure with arterial blood pressure to give information about the state of cerebral perfusion.[209]
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165. ^ Carli P, Orliaguet G (February 2004). "Severe traumatic brain injury in children". Lancet. 363 (9409): 584–85. doi:10.1016/S0140-6736(04)15626-2. PMID 14987880. S2CID 28381295.
166. ^ Necajauskaite, O; Endziniene M; Jureniene K (2005). "The prevalence, course and clinical features of post-concussion syndrome in children" (PDF). Medicina (Kaunas). 41 (6): 457–64. PMID 15998982.
167. ^ "An Unrecognized Problem" (PDF). Centers for Disease Control and Prevention. Retrieved October 13, 2019.
168. ^ a b c Boake and Diller (2005). p. 3
169. ^ a b c d Granacher (2007). p. 1.
170. ^ Scurlock JA, Andersen BR (2005). Diagnoses in Assyrian and Babylonian Medicine: Ancient Sources, Translations, and Modern Medical Analyses. Urbana: University of Illinois Press. p. 307. ISBN 978-0-252-02956-1.
171. ^ Sanchez GM, Burridge AL (2007). "Decision making in head injury management in the Edwin Smith Papyrus". Neurosurgical Focus. 23 (1): E5. doi:10.3171/FOC-07/07/E5. PMID 17961064.
172. ^ a b c Levin HS, Benton AL, Grossman R (1982). "Historical review of head injury". Neurobehavioral Consequences of Closed Head Injury. Oxford [Oxfordshire]: Oxford University Press. pp. 3–5. ISBN 978-0-19-503008-2.
173. ^ a b Zillmer EA, Schneider J, Tinker J, Kaminaris CI (2006). "A history of sports-related concussions: A neuropsychological perspective". In Echemendia RJ (ed.). Sports Neuropsychology: Assessment and Management of Traumatic Brain Injury. New York: The Guilford Press. pp. 21–23. ISBN 978-1-57230-078-1.
174. ^ Corcoran C, McAlister TW, Malaspina D (2005). "Psychotic disorders". In Silver JM, McAllister TW, Yudofsky SC (eds.). Textbook of Traumatic Brain Injury. Washington, DC: American Psychiatric Association. p. 213. ISBN 978-1-58562-105-7.
175. ^ Eslinger, P. J.; Damasio, A. R. (1985). "Severe disturbance of higher cognition after bilateral frontal lobe ablation: patient EVR". Neurology. 35 (12): 1731–41. doi:10.1212/wnl.35.12.1731. PMID 4069365. S2CID 22373825.
176. ^ Devinsky, O.; D'Esposito, M. (2004). Neurology of Cognitive and Behavioral Disorders (Vol. 68). New York: Oxford University Press. ISBN 978-0-19-513764-4.
177. ^ Marion (1999). p. 3.
178. ^ Jones E, Fear NT, Wessely S (November 2007). "Shell shock and mild traumatic brain injury: A historical review". The American Journal of Psychiatry. 164 (11): 1641–45. doi:10.1176/appi.ajp.2007.07071180. PMID 17974926.
179. ^ Belanger, H.G.; Kretzmer, T.; Yoash-Gantz, R.; Pickett, T; Tupler, L.A (2009). "Cognitive sequelae of blast-related versus other mechanisms of brain trauma". Journal of the International Neuropsychological Society. 15 (1): 1–8. doi:10.1017/S1355617708090036. PMID 19128523.
180. ^ Boake and Diller (2005). p. 8
181. ^ Bush, George H.W. (July 1990). "Project on the Decade of the Brain". Retrieved October 22, 2013.
182. ^ Lewis, Sharon R.; Baker, Philip E.; Andrews, Peter Jd; Cheng, Andrew; Deol, Kiran; Hammond, Naomi; Saxena, Manoj (October 31, 2020). "Interventions to reduce body temperature to 35 ⁰C to 37 ⁰C in adults and children with traumatic brain injury". The Cochrane Database of Systematic Reviews. 10: CD006811. doi:10.1002/14651858.CD006811.pub4. ISSN 1469-493X. PMID 33126293.
183. ^ a b Watson, HI; Shepherd, AA; Rhodes, JKJ; Andrews, PJD (March 29, 2018). "Revisited: A Systematic Review of Therapeutic Hypothermia for Adult Patients Following Traumatic Brain Injury". Critical Care Medicine. 46 (6): 972–979. doi:10.1097/CCM.0000000000003125. hdl:20.500.11820/fae8c4d4-8286-42db-b08d-1369e9092e06. PMID 29601315. S2CID 4495428.
184. ^ Crompton, EM; Lubomirova, I; Cotlarciuc, I; Han, TS; Sharma, SD; Sharma, P (December 9, 2016). "Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients". Critical Care Medicine. 45 (4): 575–583. doi:10.1097/CCM.0000000000002205. PMID 27941370. S2CID 19064475.
185. ^ Lewis, SR; Evans, DJ; Butler, AR; Schofield-Robinson, OJ; Alderson, P (September 21, 2017). "Hypothermia for traumatic brain injury". The Cochrane Database of Systematic Reviews. 9: CD001048. doi:10.1002/14651858.CD001048.pub5. PMC 6483736. PMID 28933514.
186. ^ Martín-Saborido, Carlos; López-Alcalde, Jesús; Ciapponi, Agustín; Sánchez Martín, Carlos Enrique; Garcia Garcia, Elena; Escobar Aguilar, Gema; Palermo, Maria Carolina; Baccaro, Fernando G. (2019). "Indomethacin for intracranial hypertension secondary to severe traumatic brain injury in adults". The Cochrane Database of Systematic Reviews. 2019 (11). doi:10.1002/14651858.CD011725.pub2. ISSN 1469-493X. PMC 6872435. PMID 31752052.
187. ^ Wakai, Abel; Aileen McCabe; Ian Roberts; Gillian Schierhout (2013). "Mannitol for acute traumatic brain injury". The Cochrane Database of Systematic Reviews. 8 (8): 001049. doi:10.1002/14651858.CD001049.pub5. ISSN 1469-493X. PMC 7050611. PMID 23918314.
188. ^ Thal, Serge C.; Eva-Verena Schaible; Winfried Neuhaus; David Scheffer; Moritz Brandstetter; Kristin Engelhard; Christian Wunder; Carola Y. Förster (2013). "Inhibition of proteasomal glucocorticoid receptor degradation restores dexamethasone-mediated stabilization of the blood-brain barrier after traumatic brain injury". Critical Care Medicine. 41 (5): 1305–15. doi:10.1097/CCM.0b013e31827ca494. ISSN 1530-0293. PMID 23474678. S2CID 23399305.
189. ^ Wright, D. W; A. L Kellermann; V. S Hertzberg; et al. (2007). "ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury". Annals of Emergency Medicine. 49 (4): 391–402. doi:10.1016/j.annemergmed.2006.07.932. ISSN 0196-0644. PMID 17011666.
190. ^ Harris, Katie; Scott P. Armstrong; Rita Campos-Pires; Louise Kiru; Nicholas P. Franks; Robert Dickinson (2013). "Neuroprotection against traumatic brain injury by xenon, but not argon, is mediated by inhibition at the N-methyl-D-aspartate receptor glycine site". Anesthesiology. 119 (5): 1137–48. doi:10.1097/ALN.0b013e3182a2a265. ISSN 1528-1175. PMID 23867231. S2CID 9756580.
191. ^ Roberts, Ian; Emma Sydenham (2012). "Barbiturates for acute traumatic brain injury" (PDF). The Cochrane Database of Systematic Reviews. 12: 000033. doi:10.1002/14651858.CD000033.pub2. ISSN 1469-493X. PMC 7061245. PMID 23235573.
192. ^ Sen, Ananda P; Anil Gulati (2010). "Use of magnesium in traumatic brain injury". Neurotherapeutics. 7 (1): 91–99. doi:10.1016/j.nurt.2009.10.014. ISSN 1878-7479. PMC 5084116. PMID 20129501.
193. ^ Arango, Miguel F.; Bainbridge, Daniel (October 8, 2008). "Magnesium for acute traumatic brain injury". The Cochrane Database of Systematic Reviews (4): CD005400. doi:10.1002/14651858.CD005400.pub3. ISSN 1469-493X. PMID 18843689.
194. ^ Langham, J; C Goldfrad; G Teasdale; D Shaw; K Rowan (2003). "Calcium channel blockers for acute traumatic brain injury" (PDF). Cochrane Database of Systematic Reviews (4): 000565. doi:10.1002/14651858.CD000565. ISSN 1469-493X. PMID 14583925.
195. ^ Yi, Jae-Hyuk; Seung-Won Park; Nathaniel Brooks; Bradley T. Lang; Raghu Vemuganti (2008). "PPARγ agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms". Brain Research. 1244: 164–72. doi:10.1016/j.brainres.2008.09.074. ISSN 0006-8993. PMC 2603294. PMID 18948087.
196. ^ Luo, Yumin; Wei Yin; Armando P. Signore; Feng Zhang; Zhen Hong; Suping Wang; Steven H. Graham; Jun Chen (2006). "Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone". Journal of Neurochemistry. 97 (2): 435–48. doi:10.1111/j.1471-4159.2006.03758.x. ISSN 0022-3042. PMID 16539667. S2CID 37759164.
197. ^ Liu, Yuanbin; Richard Dargusch; Pamela Maher; David Schubert (2008). "A broadly neuroprotective derivative of curcumin". Journal of Neurochemistry. 105 (4): 1336–45. doi:10.1111/j.1471-4159.2008.05236.x. ISSN 1471-4159. PMID 18208543. S2CID 13345179.
198. ^ Kelly, D. F; S. M Lee; P. A Pinanong; D. A Hovda (1997). "Paradoxical effects of acute ethanolism in experimental brain injury". Journal of Neurosurgery. 86 (5): 876–82. doi:10.3171/jns.1997.86.5.0876. ISSN 0022-3085. PMID 9126906.
199. ^ Li, W.; S. Dai; J. An; P. Li; X. Chen; R. Xiong; P. Liu; H. Wang; Y. Zhao; M. Zhu; X. Liu; P. Zhu; J.-F. Chen; Y. Zhou (2008). "Chronic but not acute treatment with caffeine attenuates traumatic brain injury in the mouse cortical impact model". Neuroscience. 151 (4): 1198–1207. doi:10.1016/j.neuroscience.2007.11.020. ISSN 0306-4522. PMID 18207647. S2CID 29276898.
200. ^ Nilsson, P; L Hillered; U Pontén; U Ungerstedt (1990). "Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats". Journal of Cerebral Blood Flow and Metabolism. 10 (5): 631–37. doi:10.1038/jcbfm.1990.115. ISSN 0271-678X. PMID 2384536.
201. ^ Vespa, Paul; Marvin Bergsneider; Nayoa Hattori; Hsiao-Ming Wu; Sung-Cheng Huang; Neil A Martin; Thomas C Glenn; David L McArthur; David A Hovda (2005). "Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study". J Cereb Blood Flow Metab. 25 (6): 763–74. doi:10.1038/sj.jcbfm.9600073. ISSN 0271-678X. PMC 4347944. PMID 15716852.
202. ^ Dengler, Julius; Christin Frenzel; Peter Vajkoczy; Stefan Wolf; Peter Horn (2011). "Cerebral tissue oxygenation measured by two different probes: challenges and interpretation". Intensive Care Medicine. 37 (11): 1809–15. doi:10.1007/s00134-011-2316-z. ISSN 1432-1238. PMID 21809108. S2CID 23154956.
203. ^ Rosenthal, Guy; Alex Furmanov; Eyal Itshayek; Yigal Shoshan; Vineeta Singh (2014). "Assessment of a noninvasive cerebral oxygenation monitor in patients with severe traumatic brain injury". Journal of Neurosurgery. 120 (4): 901–07. doi:10.3171/2013.12.JNS131089. ISSN 1933-0693. PMID 24484228.
204. ^ Yates D, Aktar R, Hill J (2007). "Assessment, investigation, and early management of head injury: Summary of NICE guidance". British Medical Journal. 335 (7622): 719–20. doi:10.1136/bmj.39331.702951.47. PMC 2001047. PMID 17916856.
205. ^ a b c Bennett, Michael H.; Trytko, Barbara; Jonker, Benjamin (December 12, 2012). "Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury". The Cochrane Database of Systematic Reviews. 12: CD004609. doi:10.1002/14651858.CD004609.pub3. ISSN 1469-493X. PMID 23235612.
206. ^ Rockswold SB, Rockswold GL, Defillo A (March 2007). "Hyperbaric oxygen in traumatic brain injury". Neurological Research. 29 (2): 162–72. doi:10.1179/016164107X181798. PMID 17439701. S2CID 35914918.
207. ^ Gertler, Paul; Tate, Robyn L.; Cameron, Ian D. (2015). "Non-pharmacological interventions for depression in adults and children with traumatic brain injury". The Cochrane Database of Systematic Reviews (12): CD009871. doi:10.1002/14651858.CD009871.pub2. ISSN 1469-493X. PMID 26663136.
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209. ^ Copplestone, S; Welbourne, J (February 2018). "A narrative review of the clinical application of pressure reactiviy indices in the neurocritical care unit". British Journal of Neurosurgery. 32 (1): 4–12. doi:10.1080/02688697.2017.1416063. PMID 29298527. S2CID 26020481.
## Cited texts
* Boake C, Diller L (2005). "History of rehabilitation for traumatic brain injury". In High WM, Sander AM, Struchen MA, Hart KA (eds.). Rehabilitation for Traumatic Brain Injury. Oxford [Oxfordshire]: Oxford University Press. ISBN 978-0-19-517355-0.
* Granacher RA (2007). Traumatic Brain Injury: Methods for Clinical & Forensic Neuropsychiatric Assessment, Second Edition. Boca Raton: CRC. ISBN 978-0-8493-8138-6.
* LaPlaca MC, Simon CM, Prado GR, Cullen DR (2007). "CNS injury biomechanics and experimental models". In Weber JT (ed.). Neurotrauma: New Insights Into Pathology and Treatment. Amsterdam: Academic Press. ISBN 978-0-444-53017-2.
* Marion DW (1999). "Introduction". In Marion DW (ed.). Traumatic Brain Injury. Stuttgart: Thieme. ISBN 978-0-86577-727-9.
The original version of this article contained text from the NINDS public domain pages on TBI
## External links
Classification
D
* ICD-10: S06
* ICD-9-CM: 800.0-801.9, 803.0-804.9, 850.0-854.1
* MeSH: D001930
* DiseasesDB: 5671
External resources
* MedlinePlus: 000028
* eMedicine: med/2820 neuro/153 ped/929
Wikimedia Commons has media related to Traumatic brain injuries.
* Brain injury at Curlie
* The Brain Injury Hub – information and practical advice to parents and family members of children with acquired brain injury
* Defense and Veterans Brain Injury Center – U.S. Department of Defense Military Health System center for traumatic brain injury
* v
* t
* e
Nonmusculoskeletal injuries of head (head injury) and neck
Intracranial
* see neurotrauma
Extracranial/
facial trauma
eye:
* Black eye
* Eye injury
* Corneal abrasion
ear:
* Perforated eardrum
Either/both
* Penetrating head injury
* v
* t
* e
Neurotrauma
Traumatic brain injury
* Intracranial hemorrhage
* Intra-axial
* Intraparenchymal hemorrhage
* Intraventricular hemorrhage
* Extra-axial
* Subdural hematoma
* Epidural hematoma
* Subarachnoid hemorrhage
* Brain herniation
* Cerebral contusion
* Cerebral laceration
* Concussion
* Post-concussion syndrome
* Second-impact syndrome
* Dementia pugilistica
* Chronic traumatic encephalopathy
* Diffuse axonal injury
* Abusive head trauma
* Penetrating head injury
Spinal cord injury
* Anterior spinal artery syndrome
* Brown-Séquard syndrome
* Cauda equina syndrome
* Central cord syndrome
* Paraplegia
* Posterior cord syndrome
* Spinal cord injury without radiographic abnormality
* Tetraplegia (Quadriplegia)
Peripheral nerves
* Nerve injury
* Peripheral nerve injury
* classification
* Wallerian degeneration
* Injury of accessory nerve
* Brachial plexus injury
* Traumatic neuroma
* v
* t
* e
Trauma
Principles
* Polytrauma
* Major trauma
* Traumatology
* Triage
* Resuscitation
* Trauma triad of death
Assessment
Clinical prediction rules
* Revised Trauma Score
* Injury Severity Score
* Abbreviated Injury Scale
* NACA score
Investigations
* Diagnostic peritoneal lavage
* Focused assessment with sonography for trauma
Management
Principles
* Advanced trauma life support
* Trauma surgery
* Trauma center
* Trauma team
* Damage control surgery
* Early appropriate care
Procedures
* Resuscitative thoracotomy
Pathophysiology
Injury
* MSK
* Bone fracture
* Joint dislocation
* Degloving
* Soft tissue injury
* Resp
* Flail chest
* Pneumothorax
* Hemothorax
* Diaphragmatic rupture
* Pulmonary contusion
* Cardio
* Internal bleeding
* Thoracic aorta injury
* Cardiac tamponade
* GI
* Blunt kidney trauma
* Ruptured spleen
* Neuro
* Penetrating head injury
* Traumatic brain injury
* Intracranial hemorrhage
Mechanism
* Blast injury
* Blunt trauma
* Burn
* Penetrating trauma
* Crush injury
* Stab wound
* Ballistic trauma
* Electrocution
Region
* Abdominal trauma
* Chest trauma
* Facial trauma
* Head injury
* Spinal cord injury
Demographic
* Geriatric trauma
* Pediatric trauma
Complications
* Posttraumatic stress disorder
* Wound healing
* Acute lung injury
* Crush syndrome
* Rhabdomyolysis
* Compartment syndrome
* Contracture
* Volkmann's contracture
* Embolism
* air
* fat
* Chronic traumatic encephalopathy
* Subcutaneous emphysema
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Traumatic brain injury | c0876926 | 2,400 | wikipedia | https://en.wikipedia.org/wiki/Traumatic_brain_injury | 2021-01-18T18:37:11 | {"mesh": ["D000070642"], "icd-9": ["854.1", "800.0", "801.9", "803.0", "850.0", "804.9"], "icd-10": ["S06"], "wikidata": ["Q1995526"]} |
A rare, genetic, isolated, focal palmoplantar keratoderma disease characterized by focal thickening of the skin of the soles, and often of the palms, associated with minimal or no nail involvement. Patients frequently present non-epidermolytic painful plantar blistering and, occasionally, subtle oral leukokeratosis or plantar hyperhidrosis.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Autosomal dominant focal non-epidermolytic palmoplantar keratoderma with plantar blistering | c3810394 | 2,401 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=402003 | 2021-01-23T17:05:57 | {"omim": ["615735"], "icd-10": ["Q82.8"]} |
Chylous ascites is a rare form of ascites caused by accumulation of lymph in the peritoneal cavity, usually due to intra-abdominal malignancy, liver cirrhosis or abdominal surgery complications, and present with painless but progressive abdominal distension, dyspnea and weight gain.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Chylous ascites | c0008732 | 2,402 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1160 | 2021-01-23T17:43:50 | {"gard": ["1359"], "mesh": ["D002915"], "omim": ["208300"], "umls": ["C0008732"], "icd-10": ["I89.8"]} |
Field et al. (1996) used the symbol IDDM11 for a susceptibility locus for insulin-dependent diabetes mellitus located on 14q24.3-q31. The locus was identified by demonstration of significant linkage to microsatellite D14S67, using both maximum likelihood methods and affected sib pair methods. They claimed that this represented the strongest reported evidence for linkage to any IDDM locus outside the HLA region. The subset of families in which affected children did not show increased sharing of HLA genes provided most of the support for D14S67 linkage. There was significant linkage heterogeneity between the HLA-defined subsets of families, suggesting to Field et al. (1996) that IDDM11 may be an important susceptibility locus in families lacking strong HLA region predisposition.
Corder et al. (2001) used 'grade-of-membership' (GoM) in sib pair linkage analysis to map the IDDM11 locus to 14q24.3.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| DIABETES MELLITUS, INSULIN-DEPENDENT, 11 | c1832605 | 2,403 | omim | https://www.omim.org/entry/601208 | 2019-09-22T16:15:14 | {"mesh": ["C563371"], "omim": ["601208"], "synonyms": ["Alternative titles", "INSULIN-DEPENDENT DIABETES MELLITUS 11"]} |
Foville's syndrome
Pons
SpecialtyNeurology
Foville's syndrome is caused by the blockage of the perforating branches of the basilar artery in the region of the brainstem known as the pons.[1] Most frequently caused by vascular disease or tumors involving the dorsal pons.
Structures affected by the infarct are the PPRF, nuclei of cranial nerves VI and VII, corticospinal tract, medial lemniscus, and the medial longitudinal fasciculus. There's involvement of the fifth to eighth cranial nerves, central sympathetic fibres (Horner syndrome) and horizontal gaze palsy.
## Contents
* 1 Presentation
* 2 Diagnosis
* 3 Treatment
* 4 History
* 5 References
* 6 External links
## Presentation[edit]
This produces ipsilateral horizontal gaze palsy and facial nerve palsy and contralateral hemiparesis, hemisensory loss, and internuclear ophthalmoplegia.[citation needed]
## 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)
## History[edit]
Foville's syndrome was initially described by Achille-Louis Foville, a French physician, in 1859.[2]
## References[edit]
1. ^ "Foville syndrome". GPnotebook.
2. ^ Foville, ALF (1859). "Note sur une paralysie peu connue de certains muscles de l'oeil, et sa liaison avec quelques points de l'anatomie de la physiologie de la protubérance annulaire". Gazette Hebdomadaire de Médecine et de Chirurgie. 6: 146.
## External links[edit]
Classification
D
* ICD-10: G46.3
* ICD-9-CM: 344.89
* MeSH: D020526
* DiseasesDB: 32782
* v
* t
* e
Cerebrovascular diseases including stroke
Ischaemic stroke
Brain
* Anterior cerebral artery syndrome
* Middle cerebral artery syndrome
* Posterior cerebral artery syndrome
* Amaurosis fugax
* Moyamoya disease
* Dejerine–Roussy syndrome
* Watershed stroke
* Lacunar stroke
Brain stem
* Brainstem stroke syndrome
* Medulla
* Medial medullary syndrome
* Lateral medullary syndrome
* Pons
* Medial pontine syndrome / Foville's
* Lateral pontine syndrome / Millard-Gubler
* Midbrain
* Weber's syndrome
* Benedikt syndrome
* Claude's syndrome
Cerebellum
* Cerebellar stroke syndrome
Extracranial arteries
* Carotid artery stenosis
* precerebral
* Anterior spinal artery syndrome
* Vertebrobasilar insufficiency
* Subclavian steal syndrome
Classification
* Brain ischemia
* Cerebral infarction
* Classification
* Transient ischemic attack
* Total anterior circulation infarct
* Partial anterior circulation infarct
Other
* CADASIL
* Binswanger's disease
* Transient global amnesia
Haemorrhagic stroke
Extra-axial
* Epidural
* Subdural
* Subarachnoid
Cerebral/Intra-axial
* Intraventricular
Brainstem
* Duret haemorrhages
General
* Intracranial hemorrhage
Aneurysm
* Intracranial aneurysm
* Charcot–Bouchard aneurysm
Other
* Cerebral vasculitis
* Cerebral venous sinus thrombosis
* v
* t
* e
Symptoms, signs and syndromes associated with lesions of the brain and brainstem
Brainstem
Medulla (CN 8, 9, 10, 12)
* Lateral medullary syndrome/Wallenberg
* PICA
* Medial medullary syndrome/Dejerine
* ASA
Pons (CN 5, 6, 7, 8)
* Upper dorsal pontine syndrome/Raymond-Céstan syndrome
* Lateral pontine syndrome (AICA) (lateral)
* Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar)
* Locked-in syndrome
* Internuclear ophthalmoplegia
* One and a half syndrome
Midbrain (CN 3, 4)
* Weber's syndrome
* ventral peduncle, PCA
* Benedikt syndrome
* ventral tegmentum, PCA
* Parinaud's syndrome
* dorsal, tumor
* Claude's syndrome
Other
* Alternating hemiplegia
Cerebellum
* Latearl
* Dysmetria
* Dysdiadochokinesia
* Intention tremor)
* Medial
* Cerebellar ataxia
Basal ganglia
* Chorea
* Dystonia
* Parkinson's disease
Cortex
* ACA syndrome
* MCA syndrome
* PCA syndrome
* Frontal lobe
* Expressive aphasia
* Abulia
* Parietal lobe
* Receptive aphasia
* Hemispatial neglect
* Gerstmann syndrome
* Astereognosis
* Occipital lobe
* Bálint's syndrome
* Cortical blindness
* Pure alexia
* Temporal lobe
* Cortical deafness
* Prosopagnosia
Thalamus
* Thalamic syndrome
Other
* Upper motor neuron lesion
* Aphasia
This article about a medical condition affecting the nervous system is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Foville's syndrome | None | 2,404 | wikipedia | https://en.wikipedia.org/wiki/Foville%27s_syndrome | 2021-01-18T18:33:33 | {"icd-9": ["344.89"], "icd-10": ["G46.3"], "wikidata": ["Q5476358"]} |
## Description
Although nails appear normal at birth, dystrophic changes develop within the first decade of life, resulting in onycholysis of fingernails and anonychia of toenails (summary by Rafiq et al., 2004). This disorder is referred to here as nonsyndromic congenital nail disorder-9 (NDNC9).
For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (161050).
Clinical Features
Rafiq et al. (2004) reported a 6-generation consanguineous Pakistani family with autosomal recessive transmission of a form of hereditary nail dysplasia. Affected individuals had normal nails at birth, but onychodystrophy began at age 7 or 8 and resulted in anonychia of the toenails (complete absence of nails) and onycholysis of the fingernails (wide separation of nail from nail bed and dystrophy of free margins). Associated abnormalities of ectodermal appendages were not observed in any of the affected individuals.
Mapping
In a 6-generation consanguineous Pakistani family segregating autosomal recessive nail dysplasia, Rafiq et al. (2004) performed multipoint linkage analysis and obtained a maximum lod score of 4.85 at marker D17S1301. The authors stated that the gene for this form of nail dysplasia is probably contained within a 5.0-cM region of homozygosity flanked by markers D17S1807 and D17S937, corresponding to 17q25.1-25.3.
INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Nails \- Onycholysis of fingernails \- Dystrophy of free margin of fingernails \- Anonychia of toenails MISCELLANEOUS \- Nails appear normal at birth, with dystrophic changes developing within the first decade of life ▲ Close
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| NAIL DISORDER, NONSYNDROMIC CONGENITAL, 9 | c0265998 | 2,405 | omim | https://www.omim.org/entry/614149 | 2019-09-22T15:56:26 | {"doid": ["0080087"], "mesh": ["C536377"], "omim": ["614149"], "orphanet": ["79143", "90390"], "synonyms": ["Alternative titles", "ANONYCHIA-ONYCHOLYSIS, ISOLATED", "ONYCHODYSTROPHY", "NAIL DYSPLASIA"]} |
A number sign (#) is used with this entry because Cockayne syndrome B (CSB) is caused by mutation in the gene encoding the group 6 excision repair cross-complementing protein (ERCC6; 609413).
Cockayne syndrome A (CSA; 216400) is caused by mutation in the ERCC8 gene (609412) on chromosome 5q11. Among patients with Cockayne syndrome, approximately 80% have mutations in the ERCC6 gene (Licht et al., 2003).
For a phenotypic description and a discussion of genetic heterogeneity of Cockayne syndrome, see 216400.
Clinical Features
Falik-Zaccai et al. (2008) reported a large, highly consanguineous Druze kindred from northern Israel in which 6 members had Cockayne syndrome B. All 6 presented with the congenital severe phenotype that included severe failure to thrive, severe mental retardation, congenital cataracts, loss of adipose tissue, joint contractures, distinctive face with small, deep-set eyes and prominent nasal bridge, kyphosis, and cachectic dwarfism. They had sensorineural hearing loss, no language skills, could not sit or walk independently, and died by the age of 5 years. Cellular studies of the fibroblasts from 3 patients studied in detail showed that transcription-coupled DNA repair was about 18% of normal controls; this defect was corrected by a plasmid containing the cDNA of the ERCC6 gene. Patient cells also showed significantly increased sensitivity to radiation compared to control cells. Prenatal diagnosis of subsequent pregnancies using amniotic cell culture and chorionic villi sampling identified 1 affected infant.
Wilson et al. (2016) reviewed the features and made recommendations regarding the evaluation of 102 patients, 44 females and 58 males, with Cockayne syndrome A or B. The mean age of recruited individuals was 11.5 years, with a range of 3 months to 39 years. All patients were microcephalic and had growth failure leading to proportionate short stature. At the time of the analysis, 28 individuals had died, with a mean age of death of 8.4 years with a range of 17 months to 30 years. The most prevalent features were cold extremities and abnormal brain imaging present in over 80% of individuals, followed by weakness, hearing loss, clinical photosensitivity, tremor, joint contractures, abnormal liver function tests, and abnormal bowel movements, present in over 60% but less than 80%. Cataracts were present in about 50% and were likely to be seen by age 4 years. The majority of patients with abnormal brain imaging had calcifications and white matter changes, with a minority having cerebellar corpus callosum or ventriculomegaly abnormalities. Lower extremity joint contractures were more common than upper extremity ones. Cataracts were more likely to be bilateral. Most patients had low-normal birth growth parameters but rapidly fell off the growth charts postnatally. The authors noted that early development may appear to be normal and suggested that developmental delay may be a poor discriminating factor for early diagnosis. The authors suggested that Cockayne syndrome should be suspected in any child with postnatal growth failure, microcephaly, and any 2 of the following: persistently cold hands and feet, bilateral hearing loss, dermal photosensitivity, intention tremor, joint contractures, progressive loss of body fat, cataracts, or typical facial features. Using these criteria increased clinical recognition of Cockayne syndrome in their cohort of 102 patients to around 90%. The authors cautioned that metronidazole causes acute hepatic failure in Cockayne syndrome, which may be fatal and should be avoided in anyone with a suspected diagnosis of Cockayne syndrome. The authors noted that the phenotypic discordance between sibs is not unusual. The only identified association with younger age at death in Cockayne syndrome was with early onset of cataracts (less than 3 years of age). This association was statistically significant (p = 1.36 x 10(-6)); at 5 years, survival is about 60% for those patients with early cataracts and 95% for those without. Wilson et al. (2016) also found a significant association between early cataracts and the time to development of hearing loss and of contractures, but not of tremor or loss of subcutaneous fat. Degree of photosensitivity was not associated with survival or time until the onset of tremor.
Heterogeneity
### Clinical Heterogeneity
Miyauchi et al. (1994) described 2 brothers with biochemical evidence of Cockayne syndrome B who survived to ages 42 and 55 years. Clinical features appeared in childhood and included growth retardation, mild mental retardation, slowly progressive gait disturbance, and tremor. The proband had characteristic facial features, such as aged appearance, beak-like nose, mandibular prognathia, cataracts, and mild hearing loss. Brain CT scan showed brain atrophy and calcifications. His brother was less severely affected. Their cultured skin fibroblasts showed extreme UV sensitivity but almost normal UV-induced unscheduled DNA synthesis. The patients were classified as genetic complementation group B after study of the recovery of RNA synthesis after UV irradiation of fused cells. Clinical phototesting revealed a reduced threshold for UVB erythema.
Cytogenetics
Fryns et al. (1991) reported a 24-year-old man with clinical and neurologic manifestations suggestive of late-onset Cockayne syndrome. Prometaphase chromosome studies demonstrated an interstitial 10q21.1 deletion in all cells, suggesting that the responsible gene is located in this region.
Molecular Genetics
In 16 patients with Cockayne syndrome B, Mallery et al. (1998) identified 18 inactivating mutations in the ERCC6 gene (see, e.g., 609413.0001-609413.0003). Neither the site nor the nature of the mutation correlated with the severity of the clinical features; severe truncations were found in different patients with either classic or early-onset forms of the disease.
Colella et al. (1999) reported a cellular and molecular analysis of 3 Italian CS patients who were of particular interest because none of them was sun-sensitive, despite showing most of the features of the severe form of CS, including the characteristic cellular sensitivity to UV irradiation. Two related patients were homozygous for a nonsense mutation in the ERCC6 gene (609413.0004). A third patient was a compound heterozygote for 2 mutations.
In 3 affected members of a large Druze kindred with severe Cockayne syndrome B, Falik-Zaccai et al. (2008) identified a homozygous mutation in the ERCC6 gene (609413.0011). The mutation was identified in 7 of 106 healthy Druze individuals from the same village, indicating a high carrier frequency of 1:15.
INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation \- Low birth weight \- Marked failure to thrive \- Postnatal growth retardation \- Cachectic dwarfism HEAD & NECK Head \- Microcephaly \- Mandible prognathism Face \- Loss of facial adipose tissue \- Wizened face Ears \- Malformed ears \- Sensorineural hearing loss Eyes \- Pigmentary retinopathy \- Optic atrophy \- Strabismus \- Hyperopia \- Corneal opacity \- Decreased lacrimation \- Nystagmus \- Cataracts \- Microphthalmos \- Iris hypoplasia \- Microcornea Nose \- Slender nose Teeth \- Dental caries \- Delayed eruption of deciduous teeth \- Malocclusion \- Absent/hypoplastic teeth CARDIOVASCULAR Heart \- Cardiac arrhythmias Vascular \- Hypertension ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly GENITOURINARY External Genitalia (Male) \- Micropenis Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Proteinuria \- Renal failure SKELETAL \- Osteoporosis Skull \- Thickened calvarium Spine \- Kyphosis \- Vertebral body abnormalities \- Intervertebral calcifications Pelvis \- Small, squared off pelvis \- Hypoplastic iliac wings Limbs \- Mild to moderate joint limitation Hands \- Sclerotic ivory phalangeal epiphyses SKIN, NAILS, & HAIR \- Precociously senile appearance Skin \- Photosensitivity \- Scarring \- Pigmentation \- Atrophy \- Anhidrosis \- Dry skin \- Decreased subcutaneous adipose tissue Hair \- Thin, dry hair MUSCLE, SOFT TISSUES \- Decreased subcutaneous adipose tissue NEUROLOGIC Central Nervous System \- Mental retardation \- Normal pressure hydrocephalus \- Poor-absent neurologic development \- Basal ganglia calcifications \- Subcortical white matter calcifications \- Cerebellar calcifications \- Patchy demyelination of subcortical white matter \- Cerebral atrophy \- Seizures Peripheral Nervous System \- Dysmyelination \- Ataxia \- Tremor \- Weakness \- Peripheral neuropathy \- Slowed nerve conduction velocities LABORATORY ABNORMALITIES \- Abnormal myelination in sural nerve biopsies \- Disturbed visual and brainstem auditory evoked responses indicative of CNS demyelination \- Increased cellular sensitivity to UV light MISCELLANEOUS \- Two types, type I or type A (classical Cockayne syndrome, 216400 ) and type II or type B (severe Cockayne syndrome, 133540 ) \- Characteristic face and body by age 2 years \- Death by age 6-7 years \- Death from pneumonia MOLECULAR BASIS \- Caused by mutation in the excision-repair cross-complementing group 6 gene (ERCC6, 609413.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| COCKAYNE SYNDROME B | c0751038 | 2,406 | omim | https://www.omim.org/entry/133540 | 2019-09-22T16:41:29 | {"doid": ["2962"], "mesh": ["D003057"], "omim": ["133540"], "orphanet": ["90322", "191", "90321", "90324"], "genereviews": ["NBK1342"]} |
Inherited epidermolysis bullosa (EB) encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues.
## Epidemiology
All types and subtypes of EB are rare; the overall incidence and prevalence of the disease in the United States are approximately 1/53,000 live births and 1/125,000, respectively, and similar estimates have been obtained in some European countries. EB affects individuals from all ethnic origins and there is no gender predilection.
## Clinical description
Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Four major types of inherited EB have been defined: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), each with numerous subtypes, and Kindler syndrome (see these terms). These forms differ not only phenotypically and genotypically but more importantly by the site of ultrastructural disruption or cleavage.
## Etiology
Each EB subtype is known to arise from mutations within the genes coding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis.
## Diagnostic methods
EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis.
## Differential diagnosis
Extensive differential diagnosis is not usually required in EB.
## Antenatal diagnosis
Molecular prenatal diagnosis may be available if the disease-causing mutation in the family has been identified.
## Genetic counseling
EB is inherited in either an autosomal dominant or autosomal recessive manner, depending on the EB type and subtype. Genetic counseling should be offered to affected families.
## Management and treatment
Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct the extracutaneous complications, whenever possible.
## Prognosis
Prognosis varies considerably and is based on both EB subtype and the overall health of the patient.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Inherited epidermolysis bullosa | c1274224 | 2,407 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79361 | 2021-01-23T18:44:29 | {"umls": ["C1274224"], "icd-10": ["Q81.0", "Q81.1", "Q81.2", "Q81.8", "Q81.9"], "synonyms": ["Epidermolysis bullosa hereditaria", "Hereditary epidermolysis bullosa"]} |
Shwachman-Diamond syndrome is an inherited condition that affects many parts of the body, particularly the bone marrow, pancreas, and bones.
The major function of bone marrow is to produce new blood cells. These include red blood cells, which carry oxygen to the body's tissues; white blood cells, which fight infection; and platelets, which are blood cells that are necessary for normal blood clotting. In Shwachman-Diamond syndrome, the bone marrow malfunctions and does not make some or all types of white blood cells. A shortage of neutrophils, the most common type of white blood cell, causes a condition called neutropenia. Most people with Shwachman-Diamond syndrome have at least occasional episodes of neutropenia, which makes them more vulnerable to infections, often involving the lungs (pneumonia), ears (otitis media), or skin. Less commonly, bone marrow abnormalities lead to a shortage of red blood cells (anemia), which causes fatigue and weakness, or a reduction in the amount of platelets (thrombocytopenia), which can result in easy bruising and abnormal bleeding.
People with Shwachman-Diamond syndrome have an increased risk of several serious complications related to their malfunctioning bone marrow. Specifically, they have a higher-than-average chance of developing myelodysplastic syndrome (MDS) and aplastic anemia, which are disorders caused by abnormal blood stem cells, and a cancer of blood-forming tissue known as acute myeloid leukemia (AML).
Shwachman-Diamond syndrome also affects the pancreas, which is an organ that plays an essential role in digestion. One of this organ's main functions is to produce enzymes that help break down and use nutrients from food. In most infants with Shwachman-Diamond syndrome, the pancreas does not produce enough of these enzymes. This condition is known as pancreatic insufficiency. Infants with pancreatic insufficiency have trouble digesting food and absorbing nutrients and vitamins that are needed for growth. As a result, they often have fatty, foul-smelling stools (steatorrhea); are slow to grow and gain weight (failure to thrive); and experience malnutrition. Pancreatic insufficiency often improves with age in people with Shwachman-Diamond syndrome.
Skeletal abnormalities are another common feature of Shwachman-Diamond syndrome. Many affected individuals have problems with bone formation and growth, most often affecting the hips and knees. Low bone density is also frequently associated with this condition. Some affected infants are born with a narrow rib cage and short ribs, which can cause life-threatening problems with breathing. The combination of skeletal abnormalities and slow growth results in short stature in most people with this disorder.
The complications of Shwachman-Diamond syndrome can affect several other parts of the body, including the liver, heart, endocrine system (which produces hormones), eyes, teeth, and skin. Additionally, studies suggest that Shwachman-Diamond syndrome may be associated with delayed speech and the delayed development of motor skills such as sitting, standing, and walking.
## Frequency
Shwachman-Diamond syndrome is a rare condition that is thought to occur in approximately 1 in 80,000 newborns. Because the signs and symptoms are variable and can be mild in some affected individuals, doctors suspect the condition is underdiagnosed.
## Causes
Mutations in the SBDS gene have been identified in about 90 percent of people with the characteristic features of Shwachman-Diamond syndrome. This gene provides instructions for making a protein that is critical in building ribosomes. Ribosomes are cellular structures that process the cell's genetic instructions to create proteins. SBDS gene mutations reduce the amount or impair the function of the SBDS protein. It is unclear how these changes lead to the major signs and symptoms of Shwachman-Diamond syndrome. Researchers suspect that a shortage of functional SBDS impairs ribosome formation, which may reduce the production of other proteins and alter developmental processes.
Other genes involved in Shwachman-Diamond syndrome appear to play roles in the assembly or function of ribosomes. Mutations in each of these genes account for a very small percentage of cases of the condition. In some cases, no mutations in any of the genes associated with the condition are found, and the cause of the disorder is unknown.
### Learn more about the gene associated with Shwachman-Diamond syndrome
* SBDS
Additional Information from NCBI Gene:
* DNAJC21
* EFL1
* SRP54
## Inheritance Pattern
Most cases of Shwachman-Diamond syndrome, including those caused by mutations in the SBDS gene, are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Typically, the parents of the affected individual each carry one copy of the mutated gene, but they do not show signs and symptoms of the condition. In some cases, one parent does not carry a copy of the mutated gene. Instead a new (de novo) mutation occurs in the gene during the formation of reproductive cells (eggs or sperm) in the parent or during early embryonic development.
Rarely, the 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. These cases usually result from de novo mutations in the gene and occur in people with no history of the disorder in their family.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Shwachman-Diamond syndrome | c0272170 | 2,408 | medlineplus | https://medlineplus.gov/genetics/condition/shwachman-diamond-syndrome/ | 2021-01-27T08:24:43 | {"gard": ["4863"], "mesh": ["C537330"], "omim": ["260400"], "synonyms": []} |
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Lymphomatoid papulosis
SpecialtyDermatology
Lymphomatoid papulosis (LyP) is a rare skin disorder. The overall prevalence rate of lymphomatoid papulosis is estimated at 1.2 to 1.9 cases per 1,000,000 population. This rare condition has only been studied in depth since 1968.[1]
## Contents
* 1 Presentation
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 Prognosis
* 6 See also
* 7 References
* 8 External links
## Presentation[edit]
It can appear very similar to anaplastic large cell lymphoma.[2] Type "A" is CD30 positive, while type "B" is CD30 negative.[3]
It has been described as "clinically benign but histologically malignant."[4]
## Cause[edit]
This section is empty. You can help by adding to it. (June 2017)
## Diagnosis[edit]
This section is empty. You can help by adding to it. (June 2017)
## Treatment[edit]
It may respond to methotrexate or PUVA.[5]
## Prognosis[edit]
It can evolve into lymphoma.[6]
## See also[edit]
* Cutaneous T-cell lymphoma
* Parapsoriasis
* Secondary cutaneous CD30+ large cell lymphoma
* List of cutaneous conditions
## References[edit]
1. ^ Macaulay WL (January 1968). "Lymphomatoid papulosis. A continuing self-healing eruption, clinically benign--histologically malignant". Arch Dermatol. 97 (1): 23–30. doi:10.1001/archderm.97.1.23. PMID 5634442.
2. ^ El Shabrawi-Caelen L, Kerl H, Cerroni L (April 2004). "Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C". Arch Dermatol. 140 (4): 441–7. doi:10.1001/archderm.140.4.441. PMID 15096372. Archived from the original on 2011-05-24.
3. ^ Neal S. Young; Stanton L. Gerson; Katherine A. High (2006). Clinical hematology. Elsevier Health Sciences. pp. 555–. ISBN 978-0-323-01908-8. Retrieved 14 May 2011.
4. ^ Maria Proytcheva (14 March 2011). Diagnostic Pediatric Hematopathology. Cambridge University Press. pp. 544–. ISBN 978-0-521-88160-9. Retrieved 15 May 2011.
5. ^ Magro CM, Crowson AN, Morrison C, Merati K, Porcu P, Wright ED (April 2006). "CD8+ lymphomatoid papulosis and its differential diagnosis". Am. J. Clin. Pathol. 125 (4): 490–501. doi:10.1309/NNV4-L5G5-A0KF-1T06. PMID 16627259.
6. ^ Dalle S, Balme B, Thomas L (2006). "Lymphomatoid papulosis localized to the face". Dermatol. Online J. 12 (3): 9. PMID 16638423.
## External links[edit]
Classification
D
* ICD-10: L41.2
* ICD-O: 9718/1
* MeSH: D017731
* DiseasesDB: 33778
* SNOMED CT: 31047003
External resources
* eMedicine: derm/254
* Orphanet: 98842
* v
* t
* e
Leukaemias, lymphomas and related disease
B cell
(lymphoma,
leukemia)
(most CD19
* CD20)
By
development/
marker
TdT+
* ALL (Precursor B acute lymphoblastic leukemia/lymphoma)
CD5+
* naive B cell (CLL/SLL)
* mantle zone (Mantle cell)
CD22+
* Prolymphocytic
* CD11c+ (Hairy cell leukemia)
CD79a+
* germinal center/follicular B cell (Follicular
* Burkitt's
* GCB DLBCL
* Primary cutaneous follicle center lymphoma)
* marginal zone/marginal zone B-cell (Splenic marginal zone
* MALT
* Nodal marginal zone
* Primary cutaneous marginal zone lymphoma)
RS (CD15+, CD30+)
* Classic Hodgkin lymphoma (Nodular sclerosis)
* CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma)
PCDs/PP
(CD38+/CD138+)
* see immunoproliferative immunoglobulin disorders
By infection
* KSHV (Primary effusion)
* EBV
* Lymphomatoid granulomatosis
* Post-transplant lymphoproliferative disorder
* Classic Hodgkin lymphoma
* Burkitt's lymphoma
* HCV
* Splenic marginal zone lymphoma
* HIV (AIDS-related lymphoma)
* Helicobacter pylori (MALT lymphoma)
Cutaneous
* Diffuse large B-cell lymphoma
* Intravascular large B-cell lymphoma
* Primary cutaneous marginal zone lymphoma
* Primary cutaneous immunocytoma
* Plasmacytoma
* Plasmacytosis
* Primary cutaneous follicle center lymphoma
T/NK
T cell
(lymphoma,
leukemia)
(most CD3
* CD4
* CD8)
By
development/
marker
* TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma)
* prolymphocyte (Prolymphocytic)
* CD30+ (Anaplastic large-cell lymphoma
* Lymphomatoid papulosis type A)
Cutaneous
MF+variants
* indolent: Mycosis fungoides
* Pagetoid reticulosis
* Granulomatous slack skin
aggressive: Sézary disease
* Adult T-cell leukemia/lymphoma
Non-MF
* CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma
* Pleomorphic T-cell lymphoma
* Lymphomatoid papulosis type B
* CD30+: CD30+ cutaneous T-cell lymphoma
* Secondary cutaneous CD30+ large-cell lymphoma
* Lymphomatoid papulosis type A
Other
peripheral
* Hepatosplenic
* Angioimmunoblastic
* Enteropathy-associated T-cell lymphoma
* Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma)
* Subcutaneous T-cell lymphoma
By infection
* HTLV-1 (Adult T-cell leukemia/lymphoma)
NK cell/
(most CD56)
* Aggressive NK-cell leukemia
* Blastic NK cell lymphoma
T or NK
* EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma)
* Large granular lymphocytic leukemia
Lymphoid+
myeloid
* Acute biphenotypic leukaemia
Lymphocytosis
* Lymphoproliferative disorders (X-linked lymphoproliferative disease
* Autoimmune lymphoproliferative syndrome)
* Leukemoid reaction
* Diffuse infiltrative lymphocytosis syndrome
Cutaneous lymphoid hyperplasia
* Cutaneous lymphoid hyperplasia
* with bandlike and perivascular patterns
* with nodular pattern
* Jessner lymphocytic infiltrate of the skin
General
* Hematological malignancy
* leukemia
* Lymphoproliferative disorders
* Lymphoid leukemias
* v
* t
* e
Papulosquamous disorders
Psoriasis
Pustular
* Generalized pustular psoriasis (Impetigo herpetiformis)
* Acropustulosis/Pustulosis palmaris et plantaris (Pustular bacterid)
* Annular pustular psoriasis
* Localized pustular psoriasis
Other
* Guttate psoriasis
* Psoriatic arthritis
* Psoriatic erythroderma
* Drug-induced psoriasis
* Inverse psoriasis
* Napkin psoriasis
* Seborrheic-like psoriasis
Parapsoriasis
* Pityriasis lichenoides (Pityriasis lichenoides et varioliformis acuta, Pityriasis lichenoides chronica)
* Lymphomatoid papulosis
* Small plaque parapsoriasis (Digitate dermatosis, Xanthoerythrodermia perstans)
* Large plaque parapsoriasis (Retiform parapsoriasis)
Other pityriasis
* Pityriasis rosea
* Pityriasis rubra pilaris
* Pityriasis rotunda
* Pityriasis amiantacea
Other lichenoid
Lichen planus
* configuration
* Annular
* Linear
* morphology
* Hypertrophic
* Atrophic
* Bullous
* Ulcerative
* Actinic
* Pigmented
* site
* Mucosal
* Nails
* Peno-ginival
* Vulvovaginal
* overlap synromes
* with lichen sclerosus
* with lupus erythematosis
* other:
* Hepatitis-associated lichen planus
* Lichen planus pemphigoides
Other
* Lichen nitidus
* Lichen striatus
* Lichen ruber moniliformis
* Gianotti–Crosti syndrome
* Erythema dyschromicum perstans
* Idiopathic eruptive macular pigmentation
* Keratosis lichenoides chronica
* Kraurosis vulvae
* Lichen sclerosus
* Lichenoid dermatitis
* Lichenoid reaction of graft-versus-host disease
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Lymphomatoid papulosis | c0206182 | 2,409 | wikipedia | https://en.wikipedia.org/wiki/Lymphomatoid_papulosis | 2021-01-18T18:53:56 | {"gard": ["6944"], "mesh": ["D017731"], "umls": ["C0206182"], "icd-10": ["C86.6", "L41.2"], "orphanet": ["98842"], "wikidata": ["Q1878745"]} |
A number sign (#) is used with this entry because of evidence that myopia-23 (MYP23) is caused by homozygous mutation in the LRPAP1 gene (104225) on chromosome 4p16.
Description
Myopia, or nearsightedness, is a refractive error of the eye. Light rays from a distant object are focused in front of the retina and those from a near object are focused in the retina; therefore distant objects are blurry and near objects are clear (summary by Kaiser et al., 2004).
For a discussion of genetic heterogeneity of myopia, see 160700.
Molecular Genetics
In 3 consanguineous Saudi Arabian families in which multiple sibs, aged 2 to 16 years, had nonsyndromic extreme myopia with spherical equivalents of -17 diopters or greater and subnormal best-corrected visual acuity, Aldahmesh et al. (2013) performed autozygome analysis and identified only 1 interval exclusively shared among all 8 affected individuals. Linkage analysis confirmed the autozygous interval, and exome sequencing revealed 2 homozygous truncating mutations in the LRPAP1 gene: a 1-bp deletion in 1 family (104225.0001) and a 2-bp deletion in the other 2 families (104225.0002). The mutations, which segregated fully with myopia in each family, were not found in 210 Saudi exome files or in the SNP databases of the 1000 Genomes Project or Exome Variant Server. Analysis of the LRPAP1 gene in 100 individuals with myopia of -6 diopters or greater did not reveal any evidence of an increased load of rare variants compared to 100 similarly screened controls.
In a 5-year-old Chinese boy (HM759), born to consanguineous parents, with bilateral high myopia, Jiang et al. (2015) identified homozygosity for a frameshift mutation in the LRPAP1 gene (104225.0003). The parents were unaffected, but their DNA was not available for testing. Functional studies were not performed.
INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Myopia, extreme \- Increased axial length of globe \- Decreased visual acuity MOLECULAR BASIS \- Caused by mutation in the low density lipoprotein receptor-related protein associated protein 1 gene (LRPAP1, 104225.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| MYOPIA 23, AUTOSOMAL RECESSIVE | c0027092 | 2,410 | omim | https://www.omim.org/entry/615431 | 2019-09-22T15:52:09 | {"doid": ["11830"], "mesh": ["D009216"], "omim": ["615431"], "orphanet": ["98619"]} |
## Cloning and Expression
Guanylyl cyclases, catalyzing the production of cGMP from GTP, are classified as soluble and membrane forms (Garbers and Lowe, 1994). The membrane guanylyl cyclases, often termed guanylyl cyclases A through F, form a family of cell-surface receptors with a similar topographic structure: an extracellular ligand-binding domain, a single membrane-spanning domain, and an intracellular region that contains a protein kinase-like domain and a cyclase catalytic domain. GC-A and GC-B function as receptors for natriuretic peptides; they are also referred to as atrial natriuretic peptide receptor A (NPR1; 108960) and type B (NPR2; 108961). NPR3 (108962) encodes a protein with only the ligand-binding transmembrane, and 37-amino acid cytoplasmic domains. Fulle et al. (1995) cloned an additional membrane guanylyl cyclase (GC-D or Gucy2d) from a rat olfactory cDNA library. Gucy2d is specifically expressed in a subpopulation of olfactory sensory neurons. The rat and mouse Gucy2d genes are homologs of human GUCY2E. In the human, GUCY2E is a transcribed pseudogene (Scott, 2009).
Mapping
By interspecific backcross analysis, Yang et al. (1996) determined that the mouse Gucy2d gene maps to chromosome 7. Close proximity of the mouse Gucy2d gene to Omp (olfactory marker protein; 164340) and Hbb (beta-globin; 141900) suggested that the human homolog maps either to 11p15.4 or 11q13.4-q14.1. Yang et al. (1996) identified identical exon/intron boundaries within the extracellular and cytoplasmic domains of mouse Gucy2d, Gucy2e (see 600179), and Gucy2f (300041) genomic clones.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| GUANYLATE CYCLASE 2E, PSEUDOGENE | c3887944 | 2,411 | omim | https://www.omim.org/entry/601138 | 2019-09-22T16:15:28 | {"omim": ["601138"], "synonyms": ["Alternative titles", "GUCY2E", "GUANYLYL CYCLASE, MEMBRANE, TYPE E", "GC-E", "GUCY2D, MOUSE, HOMOLOG OF"]} |
A number sign (#) is used with this entry because Noonan syndrome-4 (NS4) is caused by heterozygous mutation in the SOS1 gene (182530) on chromosome 2p22.
For a phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Clinical Features
Roberts et al. (2007) and Tartaglia et al. (2007) delineated a Noonan syndrome phenotype caused by mutation in the SOS1 gene that lies within the Noonan syndrome spectrum but is distinctive. Roberts et al. (2007) noted 2 significant differences: pulmonic stenosis was more frequent in patients with SOS1 mutations than in those without SOS1 or PTPN11 mutations, and atrial septal defect was relatively rare in affected individuals with SOS1 mutations compared to those with PTPN11 mutations. Tartaglia et al. (2007) noted ectodermal features including keratosis pilaris and curly hair that were significantly more prevalent among individuals with an SOS1 mutation compared with the general Noonan population. They observed height below the third percentile in only 2 of 15 individuals with an SOS1 mutation, whereas the prevalence is approximately 70% among patients with Noonan syndrome in general and among those with a PTPN11 mutation. In contrast, macrocephaly was overrepresented among those with SOS1 mutations. Only one individual with an SOS1 mutation had mental retardation, potentially attributable to critical illness as a newborn. In comparison, 30% of all children with Noonan syndrome require special education.
Zenker et al. (2007) reported that Noonan syndrome patients with SOS1 mutations commonly had ectodermal manifestations including keratosis pilaris of the face, sparse eyebrows, curly hair, and, in 1 patient, ichthyosiform skin changes. By comparing clinical features of a cohort of 42 patients with PTPN11 mutations derived from a previous study with those of their current study of 28 patients with SOS1 mutations, Zenker et al. (2007) confirmed a significantly higher prevalence of keratosis pilaris/hyperkeratotic skin and curly hair in patients with SOS1 mutations compared with those with PTP11 alterations (58% vs 6% and 78% vs 34%, respectively). Moreover, ocular ptosis was observed more frequently in patients with NS with SOS1 mutations than in patients with a PTPN11 mutation (80% vs 54%).
Ferrero et al. (2008) reported a newborn with Noonan syndrome due to SOS1 mutation (T266K; 182530.0002). He presented with facial dysmorphisms and prenatal anomalies, not associated with other congenital defects. The pregnancy was characterized by polyhydramnios and increased fetal nuchal translucency. Dysmorphic facial features included hypertelorism, epicanthal folds, flat nasal bridge, low-set posteriorly rotated ears, and short neck. Other features included moderated pulmonic stenosis and bilateral cryptorchidism. Developmental milestones were normal at 24 months of age. There were no coagulation abnormalities.
Other Features
Mascheroni et al. (2008) reported a girl with NS4 who presented at age 13 years with swelling and severe pain in her right foot and ankle, which was found to result from pigmented villonodular synovitis (PVNS). Histologically, the synovia was hyperplastic, with villi covered by reactive-appearing synovial cells in multiple layers and histio-fibroblastic and capillary proliferation. History revealed that she had congenital pulmonary valve stenosis and ventricular septal defect, and a coagulopathy with partial factor VIII and XI deficiencies. Physical examination showed short stature, curly hair, sparse eyebrows, hypertelorism, flat nasal bridge, epicanthal folds, prominent pale blue eyes, bilateral ptosis, thick lips, low-set retroverted ears with thickened helices, facial keratosis pilaris, wide-spaced nipples, pectus excavatum, and scoliosis. Psychomotor and cognitive development was normal. Mascheroni et al. (2008) suggested that PVNS is a proliferative lesion that can be part of the phenotypic spectrum of Noonan syndrome.
Hanna et al. (2009) reported 2 brothers, born of consanguineous parents, with Noonan syndrome-like disorder with multiple giant cell lesions. One boy presented at age 4.5 years with a 2-year history of bilateral progressive swelling of the mandible. A preliminary diagnosis of cherubism (118400) was considered. Radiographic studies showed multilocular lesions of the mandibular rami, consistent with giant cell lesions. The boy's 6.5-year-old brother presented with severe pulmonary valvular stenosis and was found to have similar multilocular lesions of the mandible as his brother. Both boys had characteristic facial features of Noonan syndrome, including high anterior hairline with frontal bossing, follicular hyperkeratosis of the forehead (keratosis pilaris), depressed nasal bridge, hypertelorism, downslanting palpebral fissures, and low-set and posteriorly angulated ears with thick helices. Other features included short neck and widely spaced nipples. Both showed normal development and normal stature. The father showed milder features of the disorder, with long face, downslanting palpebral fissures, low-set ears, and widely spaced nipples. Molecular studies identified a heterozygous mutation in the SOS1 gene (W432R; 182530.0006) in all 3 individuals.
Molecular Genetics
Roberts et al. (2007) and Tartaglia et al. (2007) found mutation in the SOS1 gene (182530) in Noonan syndrome patients without mutation in PTPN11 (176876) or KRAS2 (190070). Gain-of-function mutations in PTPN11, which encodes the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases, and less than 5% of cases are caused by mutations in KRAS2. SHP2 is required for RAS-ERK MAP kinase (MAPK; see 176948) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. The phenotypically related cardiofaciocutaneous syndrome (CFCS; 115150) is caused by gain-of-function mutations in 1 of 4 different genes: KRAS, BRAF (164757), MEK1 (176872), or MEK2 (601263). The common features of these disorders probably result from increased ERK activation (Roberts et al., 2007). Discovery of these disease genes have established Noonan syndrome and related traits as disorders of dysregulated RAS-MAPK signaling (Tartaglia et al., 2007). Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. They represent a major cause of Noonan syndrome and the first example of activating mutations in a RAS guanine nucleotide exchange factor (GEF) associated with human disease.
Zenker et al. (2007) investigated SOS1 in a large cohort of patients with disorders of the NS-CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1, and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with Noonan syndrome, thus confirming SOS1 as the second major gene for that disorder.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Head \- Macrocephaly Ears \- Low-set posteriorly rotated ears Eyes \- Sparse eyebrows \- Ptosis \- Hypertelorism \- Downslanting palpebral fissures \- Epicanthal folds \- Blue eyes Nose \- Flat nasal bridge Mouth \- Thick lips Teeth \- Dental malocclusion Neck \- Webbed neck \- Short neck CARDIOVASCULAR Heart \- Congenital heart defect \- Hypertrophic cardiomyopathy \- Ventricular septal defects \- Pulmonic stenosis CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum inferiorly Breasts \- Widely spaced nipples GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL Spine \- Scoliosis Limbs \- Cubitus valgus \- Blunt fingertips \- Polyarticular villonodular synovitis in knees, ankles, wrists, and/or elbows (in some patients) SKIN, NAILS, & HAIR Skin \- Ectodermal symptoms \- Keratosis pilaris Hair \- High anterior hairline \- Curly hair \- Sparse eyebrows NEUROLOGIC Central Nervous System \- Mild cognitive impairment (less common) HEMATOLOGY \- Prolonged bleeding time (less common) NEOPLASIA \- Multiple giant cell granulomas (bones, joints, soft tissues) LABORATORY ABNORMALITIES \- Partial deficiency of factor XI (less common) \- Partial deficiency of factor XIII (less common) MOLECULAR BASIS \- Caused by mutation in the SOS Ras/Rac guanine nucleotide exchange factor 1 gene (SOS1, 182530.0002 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| NOONAN SYNDROME 4 | c0028326 | 2,412 | omim | https://www.omim.org/entry/610733 | 2019-09-22T16:04:11 | {"doid": ["0060582"], "mesh": ["D009634"], "omim": ["610733"], "orphanet": ["648"], "genereviews": ["NBK1124"]} |
Erythema elevatum diutinum (EED) is a disorder of the skin associated with small blood vessel inflammation (vasculitis). Symptoms include red, purple, brown or yellow bumps of different sizes that grow on or just below the skin. These growths are located mainly on the elbows, knees, ankles, hands, and fingers. People with EED may also have joint pain, but few other symptoms. EED symptoms begin in adulthood and can last for many years. Many cases get better on their own, but this may take many years. The cause of EED is unknown. Diagnosis is made based on the symptoms and a skin biopsy to look at the skin growths. Treatment includes antibiotics and other medications.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Erythema elevatum diutinum | c0263398 | 2,413 | gard | https://rarediseases.info.nih.gov/diseases/8653/erythema-elevatum-diutinum | 2021-01-18T18:00:39 | {"mesh": ["C535509"], "umls": ["C0263398"], "orphanet": ["90000"], "synonyms": []} |
3C syndrome
Other namesCCC dysplasia, Craniocerebellocardiac dysplasia[1] or Ritscher–Schinzel syndrome,[2]
SpecialtyMedical genetics
3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.
## Contents
* 1 Signs and symptoms
* 2 Genetics
* 3 Diagnosis
* 3.1 Differential diagnosis
* 4 Management
* 5 Prognosis
* 6 Epidemiology
* 7 History
* 8 Other animals
* 9 References
* 10 External links
## Signs and symptoms[edit]
The classical triad of symptoms that defines 3C syndrome includes certain heart defects, hypoplasia (underdevelopment) of the cerebellum, and cranial dysmorphisms, which can take various forms. The heart defects and cranial dysmorphisms are heterogeneous in individuals who are all classed as having Ritscher-Schinzel syndrome.[2]
Heart defects commonly seen with Ritscher-Schinzel syndrome are associated with the endocardial cushion and are the most important factor in determining a diagnosis. The mitral valve and tricuspid valve of the heart can be malformed, the atrioventricular canal can be complete instead of developing into the interatrial septum and interventricular septum, and conotruncal heart defects, which include tetralogy of Fallot, double outlet right ventricle, transposition of the great vessels,[2] and hypoplastic left heart syndrome. Aortic stenosis and pulmonary stenosis have also been associated with 3C syndrome.[3]
The cranial dysmorphisms associated with 3C syndrome are heterogeneous and include a degree of macrocephaly, a large anterior fontanel, a particularly prominent occiput and forehead, ocular hypertelorism (wide-set eyes), slanted palpebral fissures, cleft palate, a depressed nasal bridge, cleft palate with associated bifid uvula,[2] low-set ears, micrognathia (an abnormally small jaw),[4] brachycephaly (flattened head), and ocular coloboma.[3] Low-set ears are the most common cranial dysmorphism seen in 3C syndrome, and ocular coloboma is the least common of the non-concurrent symptoms (cleft lip co-occurring with cleft palate is the least common).[5]
Cranial dysplasias associated with 3C syndrome are also reflected in the brain. Besides the cerebellar hypoplasia, cysts are commonly found in the posterior cranial fossa, the ventricles and the cisterna magna are dilated/enlarged, and Dandy-Walker malformation is present. These are reflected in the developmental delays typical of the disease.[4][5] 75% of children with 3C syndrome have Dandy-Walker malformation and hydrocephalus.[6]
Signs and symptoms in other body systems are also associated with 3C syndrome. In the skeletal system, ribs may be absent, and hemivertebrae, syndactyly (fusion of fingers together), and clinodactyly (curvature of the fifth finger) may be present.[3][6] In the GI and genitourinary systems, anal atresia, hypospadia (misplaced urethra), and hydronephrosis may exist. Adrenal hypoplasia and growth hormone deficiency are associated endocrine consequences of Ritscher-Schinzel syndrome.[3] Some immunodeficiency has also been reported in connection with 3C syndrome.[6]
Many children with the disorder die as infants due to severe congenital heart disease.[4] The proband of Ritscher and Schinzel's original study was still alive at the age of 21.[7]
A fetus with 3C syndrome may have an umbilical cord with one umbilical artery instead of two.[3][7]
## Genetics[edit]
3C syndrome has an autosomal recessive pattern of inheritance. This means that two parents with one copy of the gene each will not have the disease themselves, but can pass on the gene to their children. Statistically, one in four of these children will inherit both copies of the recessive gene and develop the disease.
3C syndrome is an autosomal recessive disease, caused by a mutation on the long arm of chromosome 8 at 8q24.13, the locus for KIAA0196,[4] the gene for the protein strumpellin. Strumpellin is highly expressed in skeletal muscle cells and mutations in it are also associated with spastic paraplegia. Strumpellin is involved in endosomal transport and cell death processes.[8] The mutation occurs at a splice site and causes a substantial decrease in the amount of strumpellin produced by the cell. The phenotype is similar to 6pter-p24 deletion syndrome and 6p25 deletion syndrome but has a different etiology.[4][7]
The only way to test for this condition before birth is through ultrasound.
* First-trimester ultrasounds can detected nuchal abnormalities
* Second-trimester ultrasounds can pick up characteristic major structural abnormalities.[9]
Because 3C syndrome is an autosomal recessive disorder, parents with one child with the disorder have a 25% chance of having another child with the disorder.[4]
## Diagnosis[edit]
### Differential diagnosis[edit]
There is an overlap in symptoms between 3C syndrome and Joubert syndrome. Joubert syndrome often manifests with similar cerebellar hypoplasia and its sequelae, including hyperpnea, ataxia, changes in eye movement, and cleft lip and palate. Occasionally, Joubert syndrome will include heart malformations. Brachmann-de Lange syndrome must also be differentiated from 3C syndrome. It presents with similar craniofacial and heart abnormalities and can include Dandy-Walker phenotype, making it difficult to distinguish. Dandy-Walker malformation is also occasionally seen in Ellis-van Creveld syndrome, which is characterized by heart defects and malformed alveolar ridge.[5] Many disorders include the Dandy-Walker phenotype and thus it is not pathognomonic for 3C syndrome.[10]
CHARGE syndrome can also be misdiagnosed. This is because both CHARGE syndrome and 3C syndrome share symptoms of ocular colobomas, cardiac defects, growth retardation, and minor facial abnormalities.[2]
Coffin-Siris syndrome presents with fifth-finger deformities and congenital heart defects. It is distinguished from 3C syndrome by differences in facial dysmorphisms.[6]
## Management[edit]
The outcome of this disease is dependent on the severity of the cardiac defects. Approximately 1 in 3 children with this diagnosis require shunting for the hydrocephaly that is often a consequence. Some children require extra assistance or therapy for delayed psychomotor and speech development, including hypotonia.[2]
## Prognosis[edit]
Prognoses for 3C syndrome vary widely based on the specific constellation of symptoms seen in an individual. Typically, the gravity of the prognosis correlates with the severity of the cardiac abnormalities. For children with less severe cardiac abnormalities, the developmental prognosis depends on the cerebellar abnormalities that are present. Severe cerebellar hypoplasia is associated with growth and speech delays, as well as hypotonia and general growth deficiencies.[5]
## Epidemiology[edit]
3C syndrome is very rare, occurring in less than 1 birth per million.[2] Because of consanguinity due to a founder effect, it is much more common in a remote First Nations village in Manitoba, where 1 in 9 people carries the recessive gene.[4]
## History[edit]
The syndrome was first reported in 1987 in two sisters who had similar craniofacial abnormalities, Dandy-Walker phenotype, and congenital heart abnormalities. Neither of the parents was affected, indicating that the disorder was transmitted in an autosomal recessive pattern.[4][11] The syndrome's symptoms were further refined in 1989 when the third case of the syndrome was reported, with similar craniofacial abnormalities to the first two cases, ventricular septal defect, and enlargement of the cisterna magna and fourth ventricle of the brain.[5]
## Other animals[edit]
Animal models of 3C syndrome have not been created; however, strumpellin is a highly conserved protein, with 12 known homologs and 83 known orthologs.[8]
## References[edit]
1. ^ Disease ID 5666 at NIH's Office of Rare Diseases
2. ^ a b c d e f g "3C syndrome". Orphanet. Retrieved 11 April 2014.
3. ^ a b c d e Kniffin, Cassandra L.; Jackson, John F. (6 January 2014). "Ritscher-Schinzel Syndrome - Clinical Synopsis". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 12 April 2014.
4. ^ a b c d e f g h Kniffin, Cassandra L.; McCusick, Victor A. (6 January 2014). "Ritscher-Schinzel Syndrome". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 11 April 2014.
5. ^ a b c d e Leonardi, Michael L.; Pai, G. Shashidhar; Wilkes, Beth; Lebel, Robert Roger (15 August 2001). "Ritscher-Schinzel cranio-cerebello-cardiac (3C) syndrome: Report of four new cases and review". American Journal of Medical Genetics. 102 (3): 237–242. doi:10.1002/ajmg.1449. PMID 11484200.
6. ^ a b c d Gorlin, Robert J.; Cohen Jr., Michael; Hennekam, Raoul C.M. (2001). Syndromes of the Head and Neck (4 ed.). Oxford University Press. ISBN 9780199747726.
7. ^ a b c Jones, Kenneth Lyons; Jones, Marilyn Crandall; del Campo, Miguel (2013). Smith's Recognizable Patterns of Human Malformation (7th ed.). Elsevier Health Sciences. ISBN 9780323186681.
8. ^ a b "KIAA0196". NIH. Retrieved 12 April 2014.
9. ^ Rusnak, A. J., Hadfield, M. I., Chudley, A. E., Marles, S. L., Reid, G. J., & Chodirker, B. N. (2008). Increased Nuchal Translucency Thickness: A Potential Indicator for Ritscher-Schinzel Syndrome. Fetal Diagnosis & Therapy, 24(4), 395-399. doi:10.1159/000165697
10. ^ Albright, A. Leland; Pollack, Ian F. (2011). Principles and Practice of Pediatric Neurosurgery. Thieme. ISBN 9781604064605.
11. ^ Ritscher, D.; Schinzel, A.; Boltshauser, E.; Briner, J.; Arbenz, U.; Sigg, P. (February 1987). "Dandy-Walker(like) malformation, atrio-ventricular septal defect and a similar pattern of minor anomalies in 2 sisters: a new syndrome?". American Journal of Medical Genetics. 26 (2): 481–491. doi:10.1002/ajmg.1320260227. PMID 3812597.
## External links[edit]
Classification
D
* ICD-10: Q87.0
* OMIM: 220210
* MeSH: C535313
External resources
* Orphanet: 7
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| 3C syndrome | c0796137 | 2,414 | wikipedia | https://en.wikipedia.org/wiki/3C_syndrome | 2021-01-18T18:41:17 | {"mesh": ["C535313"], "umls": ["C0796137"], "orphanet": ["7"], "wikidata": ["Q2155008"]} |
Micrograph showing cortical pseudolaminar necrosis. H&E-LFB stain.
Cortical pseudolaminar necrosis, also known as cortical laminar necrosis and simply laminar necrosis, is the (uncontrolled) death of cells in the (cerebral) cortex of the brain in a band-like pattern,[1] with a relative preservation of cells immediately adjacent to the meninges.
It is seen in the context of cerebral hypoxic-ischemic insults, e.g. status epilepticus, strokes.[2]
Histologically, grey matter is more vulnerable than white matter to necrosis due to lack of oxygen. The third layer of the grey matter is the most vulnerable. Damage is greater in the sulci when compared to gyri of the brain.[2]
When seen on CT scan, it shows hyperdensity in the surface of the cortex. Cortical enhancement is seen after two weeks, with maximum intensity at one to two months, and resolved after six months.[2]
On MRI scan, early changes show low T1 intensity due to ischemic changes. There is high T1 intensity due to accumulation of neuronal damage, reactive tissue changes, and deposition of fat-laden macrophages.[2]
## See also[edit]
* Cardiovascular disease
* Reactive astrocyte
* status epilepticus
* Stroke
## References[edit]
1. ^ Hypoxic and Ischemic Encephalopathy. neuropathology.neoucom.edu. Accessed on: 29 December 2010.
2. ^ a b c d Samain, J.; Haven, F.; Gille, M.; Mathys, P. (2011-06-18). "Typical CT and MRI features of cortical laminar necrosis". Journal of the Belgian Society of Radiology. 94 (6): 357. doi:10.5334/jbr-btr.713. ISSN 2514-8281.
## External links[edit]
* Hypoxic-ischemic encephalopathy - principles (neuropathology-web.org)
* Laminar necrosis on MRI (rochester.edu)
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Cortical pseudolaminar necrosis | c0948229 | 2,415 | wikipedia | https://en.wikipedia.org/wiki/Cortical_pseudolaminar_necrosis | 2021-01-18T18:45:10 | {"umls": ["C0948229"], "wikidata": ["Q5173270"]} |
Spasmodic torticollis
Muscles of the neck
SpecialtyNeurology
Spasmodic torticollis is an extremely painful chronic neurological movement disorder causing the neck to involuntarily turn to the left, right, upwards, and/or downwards. The condition is also referred to as "cervical dystonia". Both agonist and antagonist muscles contract simultaneously during dystonic movement.[1] Causes of the disorder are predominantly idiopathic. A small number of patients develop the disorder as a result of another disorder or disease. Most patients first experience symptoms midlife. The most common treatment for spasmodic torticollis is the use of botulinum toxin type A.
## Contents
* 1 Signs and symptoms
* 2 Pathophysiology
* 3 Diagnosis
* 3.1 Classification
* 3.1.1 Primary
* 3.1.2 Secondary
* 3.1.3 Head positions
* 4 Treatment
* 4.1 Oral medications
* 4.2 Botulinum toxin
* 4.3 Deep brain stimulation
* 4.4 Physical Interventions
* 5 Epidemiology
* 6 References
* 7 External links
## Signs and symptoms[edit]
Initial symptoms of spasmodic torticollis are usually mild. Some feel an invisible tremor of their head for a few months at onset. Then the head may turn, pull or tilt in jerky movements, or sustain a prolonged position involuntarily. Over time, the involuntary spasm of the neck muscles will increase in frequency and strength until it reaches a plateau. Symptoms can also worsen while the patient is walking or during periods of increased stress. Other symptoms include muscle hypertrophy, neck pain, dysarthria and tremor.[2] Studies have shown that over 75% of patients report neck pain,[1] and 33% to 40% experience tremor of the head.[3]
## Pathophysiology[edit]
Coronal sections of human brain labeling the basal ganglia.
The pathophysiology of spasmodic torticollis is still relatively unknown. Spasmodic torticollis is considered neurochemical in nature, and does not result in structural neurodegenerative changes. Although no lesions are present in the basal ganglia in primary spasmodic torticollis, fMRI and PET studies have shown abnormalities of the basal ganglia and hyper activation of the cortical areas.[4] Studies have suggested that there is a functional imbalance in the striatal control of the globus pallidus, specifically the substantia nigra pars reticulata. The studies hypothesize the hyper activation of the cortical areas is due to reduced pallidal inhibition of the thalamus, leading to over activity of the medial and prefrontal cortical areas and under activity of the primary motor cortex during movement.[5] It has also been suggested that the functional imbalance is due to an imbalance of neurotransmitters such as dopamine, acetylcholine, and gamma-aminobutyric acid. These neurotransmitters are secreted from the basal ganglia, traveling to muscle groups in the neck. An increase in neurotransmitters causes spasms to occur in the neck, resulting in spasmodic torticollis.[6] Studies of local field potentials have also shown an increase of 4–10 Hz oscillatory activity in the globus pallidus internus during myoclonic episodes and an increase of 5–7 Hz activity in dystonic muscles when compared to other primary dystonias. This indicates that oscillatory activity in these frequency bands may be involved in the pathophysiology of spasmodic torticollis.[7]
## Diagnosis[edit]
The most commonly used scale to rate the severity of spasmodic torticollis is the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). It has been shown that this rating system has widespread acceptance for use in clinical trials, and has been shown to have “good interobserver reliability.”[8] There are three scales in the TWSTRS: torticollis severity scale, disability scale, and pain scale. These scales are used to represent the severity, the pain, and the general lifestyle of spasmodic torticollis.
### Classification[edit]
Spasmodic torticollis is a form of focal dystonia, a neuromuscular disorder that consists of sustained muscle contractions causing repetitive and twisting movements and abnormal postures in a single body region.[9] There are two main ways to categorize spasmodic torticollis: age of onset, and cause. The disorder is categorized as early onset if the patient is diagnosed before the age of 27, and late onset thereafter. The causes are categorized as either primary (idiopathic) or secondary (symptomatic). Spasmodic torticollis can be further categorized by the direction and rotation of head movement.
#### Primary[edit]
Primary spasmodic torticollis is defined as having no other abnormality other than dystonic movement and occasional tremor in the neck.[1] This type of spasmodic torticollis is usually inherited. Studies have shown that the DYT7 locus on chromosome 18p in a German family and the DYT13 locus on chromosome 1p36 in an Italian family is associated with spasmodic torticollis. The inheritance for both loci is autosomal dominant. These loci are all autosomal dominantly inherited with reduced penetrance. Although these loci have been found, it is still not clear the extent of influence the loci have on spasmodic torticollis.[6]
#### Secondary[edit]
When other conditions lead to spasmodic torticollis, it is said that the spasmodic torticollis is secondary. A variety of conditions can cause brain injury, from external factors to diseases. These conditions are listed below:[1]
* Perinatal (during birth) cerebral injury
* Kernicterus
* Cerebrovascular diseases
* Drug induced
* Central nervous system tumor
* Peripheral or central trauma
* Infectious or post infectious encephalopathies
* Toxins
* Metabolic
* Paraneoplastic syndromes
* Central pontine myelinolysis
Secondary spasmodic torticollis is diagnosed when any of the following are present: history of exogenous insult or exposure, neurological abnormalities other than dystonia, abnormalities on brain imaging, particularly in the basal ganglia.[1]
#### Head positions[edit]
To further classify spasmodic torticollis, one can note the position of the head.
* Torticollis is the horizontal turning (rotational collis) of the head, and uses the ipsilateral splenius, and contralateral sternocleidomastoid muscles. This is the "chin-to-shoulder" version.
* Laterocollis is the tilting of the head from side to side. This is the "ear-to-shoulder" version. This involves many more muscles: ipsilateral sternocleidomastoid, ipsilateral splenius, ipsilateral scalene complex, ipsilateral levator scapulae, and ipsilateral posterior paravertebrals.
* The flexion of the neck (head tilts forwards) is anterocollis. This is the "chin-to-chest" version and is the most difficult version to address. This movement utilizes the bilateral sternocleidomastoid, bilateral scalene complex, bilateral submental complex.
* Retrocollis is the extension of the neck (head tilts back) and uses the following muscles for movement: bilateral splenius, bilateral upper trapezius, bilateral deep posterior paravertebrals. This is the "chin-in-the-air" version.
A combination of these head positions is common; many patients experience turning and tilting actions of the head.[10]
## Treatment[edit]
There are several treatments for spasmodic torticollis, the most commonly used being botulinum toxin injections in the dystonic muscle of the neck. Other treatments include sensory trick for a mild occasional twinge, oral medications, and deep brain stimulation. Combinations of these treatments have been used to control spasmodic torticollis.[7] In addition, selective surgical denervation of nerves triggering muscle contractions may offer relief from spasms and pain, and limit damage to the spine as a result of torqued posture. Spinal fibrosis (i.e., locking of spinal facets due to muscular contortion resulting in fused vertebrae) may occur rapidly. Therefore, it is important to seriously evaluate the option of surgical denervation as early as possible.
This suggests that the desynchronization of the frequency range is movement related.[5] Obtaining relief via a "sensory trick", also known as a geste antagoniste, is a common characteristic present in focal dystonias, most prevalently in cervical dystonia; however, it has also been seen in patients with blepharospasm.[11] Sensory tricks offer only temporary and often partial relief of spasmodic torticollis. 74% of patients report only partial relief of spasmodic torticollis compared to 26% reporting complete relief. The sensory trick must also be applied by the patient themselves. When the sensory trick is applied by an examiner, only 32% of patients report relief comparable to relief during self-application.[7] Since the root of the problem is neurological, doctors have explored sensorimotor retraining activities to enable the brain to "rewire" itself and eliminate dystonic movements.[12][13][14][15]
### Oral medications[edit]
In the past, dopamine blocking agents have been used in the treatment of spasmodic torticollis. Treatment was based on the theory that there is an imbalance of the neurotransmitter dopamine in the basal ganglia. These drugs have fallen out of fashion due to various serious side effects: sedation, parkinsonism, and tardive dyskinesia.[16] Other oral medications can be used in low doses to treat early stages of spasmodic torticollis. Relief from spasmodic torticollis is higher in those patients who take anticholinergic agents when compared to other oral medications. Many have reported complete management with gabapentin alone or in combination with another drug such as clonazepam[citation needed]. 50% of patients who use anticholinergic agents report relief, 21% of patients report relief from clonazepam, 11% of patients report relief from baclofen, and 13% from other benzodiazepines.[17]
Higher doses of these medications can be used for later stages of spasmodic torticollis; however, the frequency and severity of side effects associated with the medications are usually not tolerated. Side effects include dry mouth, cognitive disturbance, drowsiness, diplopia, glaucoma and urinary retention.[18]
### Botulinum toxin[edit]
Target molecules of botulinum (BoNT) and tetanus (TeNT) toxins inside the axon terminal.[1]
The most commonly used treatment for spasmodic torticollis is the use of botulinum toxin injection in the dystonic musculature. Botulinum toxin type A is most often used; it prevents the release of acetylcholine from the presynaptic axon of the motor end plate, paralyzing the dystonic muscle.[16] By disabling the movement of the antagonist muscle, the agonist muscle is allowed to move freely. With botulinum toxin injections, patients experience relief from spasmodic torticollis for approximately 12 to 16 weeks.[19] There are several type A preparations available worldwide; however Botox and Dysport are the only preparations approved by the U.S. Food and Drug Administration (FDA) for clinical use in the United States.
Some patients experience or develop immunoresistance to botulinum toxin type A and must use botulinum toxin type B. Approximately 4% to 17% of patients develop botulinum toxin type A antibodies. The only botulinum toxin type B accessible in the United States is Myobloc. Treatment using botulinum toxin type B is comparable to type A, with an increased frequency of the side effect dry mouth.[10][20]
Common side effects include pain at the injection site (up to 28%), dysphagia due to the spread to adjacent muscles (11% to 40%), dry mouth (up to 33%), fatigue (up to 17%), and weakness of the injected or adjacent muscle (up to 56%).[16] A Cochrane review published in 2016 reported moderate-quality evidence that a single Botulinum toxin-B treatment session could improve cervical dystonia symptoms by 10% to 20%, although with an increased risk of dry mouth and swallowing difficulties.[21] Another Cochrane review published in 2020 for Botulinum toxin-A found similar results.[22]
### Deep brain stimulation[edit]
Insertion of electrode during surgery
Deep brain stimulation to the basal ganglia and thalamus has recently been used as a successful treatment for tremors of patients with Parkinson's disease. This technique is currently, as of 2007, being trialed in patients with spasmodic torticollis. Patients are subjected to stimulation of the globus pallidus internus, or the subthalamic nucleus. The device is analogous to a pacemaker: an external battery is placed subcutaneously, with wires under the skin which enter the skull and a region of the brain. To stimulate the globus pallidus internus, microelectrodes are placed into the globus pallidus internus bilaterally. After the surgery is performed, multiple visits are required to program the settings for the stimulator. The stimulation of the globus pallidus internus disrupts the abnormal discharge pattern in the globus pallidus internus, resulting in inhibition of hyperactive cortical activity. Globus pallidus internus deep brain stimulation is the preferred surgical procedure, due to the lower frequency of side effects.[16] Advantages of deep brain stimulation include the reversibility of the procedure, and the ability to adjust the settings of the stimulation.[17]
In one study, patients who had developed immunoresistance to botulinum toxin underwent globus pallidus internus deep brain stimulation, showing improvement by 54.4% after three to six months.
There is a low rate of side effects for those who undergo deep brain stimulation. The most common side effect is headache, occurring in 15% of patients, followed by infection (4.4%) and cognitive dysfunction (4%). Serious side effects are seizure (1.2%), intracerebral hemorrhage (0.6%), intraventricular hemorrhage (0.6%), and large subdural hematoma (0.3%).[16]
### Physical Interventions[edit]
Physical treatment options for cervical dystonia include biofeedback, mechanical braces as well as patients self-performing a geste antagoniste. Physical therapy also has an important role in managing spasmodic torticollis by providing stretching and strengthening exercises to aid the patient in keeping their head in proper alignment with their body.[19] Patients with cervical dystonia ranked physical therapy intervention second to botulinum toxin injections in overall effectiveness in reducing symptoms[23] and patients receiving physiotherapy in conjunction with botulinum toxin injections reported enhanced effects of treatment compared to the injections alone.[24] One study examined patients with cervical dystonia who were treated with a physiotherapy program that included muscle stretching and relaxation, balance and coordination training, and exercises for muscle strengthening and endurance. A significant reduction in pain and severity of dystonia as well as increased postural awareness and quality of life was found.[25]
## Epidemiology[edit]
Spasmodic torticollis is one of the most common forms of dystonia seen in neurology clinics, occurring in approximately 0.390% of the United States population in 2007 (390 per 100,000).[3] Worldwide, it has been reported that the incidence rate of spasmodic torticollis is at least 1.2 per 100,000 person years,[26] and a prevalence rate of 57 per 1 million.[27] The exact prevalence of the disorder is not known; several family and population studies show that as many as 25% of cervical dystonia patients have relatives that are undiagnosed.[28][29] Studies have shown that spasmodic torticollis is not diagnosed immediately; many patients are diagnosed well after a year of seeking medical attention.[1] A survey of 59 patients diagnosed with spasmodic torticollis show that 43% of the patients visited at least four physicians before the diagnosis was made.[30]
There is a higher prevalence of spasmodic torticollis in females; females are 1.5 times more likely to develop spasmodic torticollis than males. The prevalence rate of spasmodic torticollis also increases with age, most patients show symptoms from ages 50–69. The average onset age of spasmodic torticollis is 41.[1]
## References[edit]
1. ^ a b c d e f g Geyer HL; Bressman SB. (2006). "The diagnosis of dystonia". The Lancet Neurology. 5 (9): 780–790. doi:10.1016/S1474-4422(06)70547-6. PMID 16914406. S2CID 28374695.
2. ^ "Spasmodic Torticollis – Signs and Symptoms". NSTA. National Spasmodic Torticollis Association. Retrieved December 29, 2018.
3. ^ a b Jankovic J; Tsui J; Bergeron C. (2007). "Prevalence of Cervical Dystonia and Spasmodic Torticollis in the United States general population". Parkinsonism and Related Disorders. 13 (7): 411–6. doi:10.1016/j.parkreldis.2007.02.005. PMID 17442609.
4. ^ Vacherot F, Vaugoyeau M, Mallau S, Soulayrol S, Assaiante C, Azulay JP (May 2007). "Postural control and sensory integration in cervical dystonia". Clin Neurophysiol. 118 (5): 1019–27. doi:10.1016/j.clinph.2007.01.013. PMID 17383228. S2CID 45602523.
5. ^ a b Uc EY; Rodnitzky RL. (2003). "Childhood Dystonia". Seminars in Pediatric Neurology. 10 (1): 52–61. doi:10.1016/S1071-9091(02)00010-4. PMID 12785748.
6. ^ a b de Carvalho Aguiar PM, Ozelius LJ (September 2002). "Classification and genetics of dystonia". Lancet Neurol. 1 (5): 316–25. doi:10.1016/S1474-4422(02)00137-0. PMID 12849429. S2CID 29200547.
7. ^ a b c Tang JK, et al. (2007). "Changes in cortical and pallidal oscillatory activity during the execution of a sensory trick in patients with cervical dystonia". Experimental Neurology. 204 (2): 845–8. doi:10.1016/j.expneurol.2007.01.010. hdl:1807/17904. PMID 17307166. S2CID 3255050.
8. ^ Salvia P, Champagne O, Feipel V, Rooze M, de Beyl DZ (May 2006). "Clinical and goniometric evaluation of patients with spasmodic torticollis". Clin Biomech (Bristol, Avon). 21 (4): 323–9. doi:10.1016/j.clinbiomech.2005.11.011. PMID 16427167.
9. ^ Richter A, Löscher W (April 1998). "Pathology of idiopathic dystonia: findings from genetic animal models". Prog. Neurobiol. 54 (6): 633–77. doi:10.1016/S0301-0082(97)00089-0. PMID 9560845. S2CID 53173608.
10. ^ a b Brashear A. (2004). "Treatment of cervical dystonia with botulinum toxin". Operative Techniques in Otolaryngology–Head and Neck Surgery. 15 (2): 122–7. doi:10.1016/j.otot.2004.03.004.
11. ^ Poisson, A.; Krack P.; Thobois S.; Loiraud C.; Serra G.; Vial C.; Broussolle E. (2012). "History of the "geste antagoniste" sign in cervical dystonia". Journal of Neurology. 259 (8): 1580–1584. doi:10.1007/s00415-011-6380-7. PMID 22234840. S2CID 27142003.
12. ^ TEDx Talk. Federico Bitti. Cervical Dystonia. Rewiring the brain through dance. https://www.youtube.com/watch?v=DwkHK3rfKO0
13. ^ TEDx Talk . Joaquin Farias. Dystonia. Your movement can heal your brain. https://www.youtube.com/watch?v=czW-xBvDtHY
14. ^ Farias J. Limitless. How your movements can heal your brain. An essay on the neurodynamics of dystonia. Galene editions 2016
15. ^ Farias J. Intertwined. How to induce neuroplasticity. A new approach to rehabilitate dystonias. Galene editions 2012.
16. ^ a b c d e Adam OR, Jankovic J (2007). "Treatment of dystonia". Parkinsonism Relat. Disord. 13 (Suppl 3): S362–8. doi:10.1016/S1353-8020(08)70031-2. PMID 18267265.
17. ^ a b Crowner BE. (2007). "dystonia: disease profile and clinical management". Physical Therapy. 87 (11): 1511–26. doi:10.2522/ptj.20060272. PMID 17878433.
18. ^ Ochudlo S; Drzyzga K; Drzyzga LR; Opala G. (2007). "Various patterns of gestes antagonists in cervical dystonia". Parkinsonism and Related Disorders. 13 (7): 417–420. doi:10.1016/j.parkreldis.2007.01.004. PMID 17355914.
19. ^ a b Velickovic M, Benabou R, Brin MF (2001). "Cervical dystonia pathophysiology and treatment options". Drugs. 61 (13): 1921–43. doi:10.2165/00003495-200161130-00004. PMID 11708764. S2CID 46954613.
20. ^ Walker, Thomas J.; Dayan, Steven H. (2014-02-01). "Comparison and Overview of Currently Available Neurotoxins". The Journal of Clinical and Aesthetic Dermatology. 7 (2): 31–39. ISSN 1941-2789. PMC 3935649. PMID 24587850.
21. ^ Marques, RE; Duarte, GS; Rodrigues, FB; Castelão, M; Ferreira, J; Sampaio, C; Moore, AP; Costa, J (13 May 2016). "Botulinum toxin type B for cervical dystonia". The Cochrane Database of Systematic Reviews. 5 (5): CD004315. doi:10.1002/14651858.CD004315.pub3. PMID 27176573.
22. ^ Rodrigues, Filipe B.; Duarte, Gonçalo S.; Marques, Raquel E.; Castelão, Mafalda; Ferreira, Joaquim; Sampaio, Cristina; Moore, Austen P.; Costa, João (November 12, 2020). "Botulinum toxin type A therapy for cervical dystonia". The Cochrane Database of Systematic Reviews. 11: CD003633. doi:10.1002/14651858.CD003633.pub4. ISSN 1469-493X. PMID 33180963.
23. ^ Silfors, Anders; Göran Solders (2002). "Living with dystonia. A questionnaire among members of the Swedish Dystonia Patient Association". Läkartidningen. 99 (8): 786–789.
24. ^ Tassorelli C, Mancini F, Balloni L, Pacchetti C, Sandrini G, Nappi G, Martignoni E (December 2006). "Botulinum toxin and neuromotor rehabilitation: An integrated approach to idiopathic cervical dystonia". Mov. Disord. 21 (12): 2240–3. doi:10.1002/mds.21145. PMID 17029278. S2CID 16366190.
25. ^ Zetterberg L, Halvorsen K, Färnstrand C, Aquilonius SM, Lindmark B (2008). "Physiotherapy in cervical dystonia: six experimental single-case studies". Physiother Theory Pract. 24 (4): 275–90. doi:10.1080/09593980701884816. PMID 18574753. S2CID 20722262.
26. ^ Claypool DW, Duane DD, Ilstrup DM, Melton LJ (September 1995). "Epidemiology and outcome of cervical dystonia (spasmodic torticollis) in Rochester, Minnesota". Mov. Disord. 10 (5): 608–14. doi:10.1002/mds.870100513. PMID 8552113. S2CID 25177370.
27. ^ The Epidemiological Study of Dystonia in Europe (ESDE) Collaborative (2000). "A prevalence study of primary dystonia in eight European countries". Journal of Neurology. 247 (10): 787–92. doi:10.1007/s004150070094. PMID 11127535. S2CID 26041305.
28. ^ Waddy HM, Fletcher NA, Harding AE, Marsden CD (March 1991). "A genetic study of idiopathic focal dystonias". Ann. Neurol. 29 (3): 320–4. doi:10.1002/ana.410290315. PMID 2042948. S2CID 37961232.
29. ^ Duffey PO, Butler AG, Hawthorne MR, Barnes MP (1998). "The epidemiology of the primary dystonias in the north of England". Adv Neurol. 78: 121–5. PMID 9750909.
30. ^ van Herwaarden GM, Anten HW, Hoogduin CA, et al. (August 1994). "Idiopathic spasmodic torticollis: a survey of the clinical syndromes and patients' experiences". Clin Neurol Neurosurg. 96 (3): 222–5. doi:10.1016/0303-8467(94)90072-8. PMID 7988090. S2CID 27554275.
* Dystonia Medical Research Foundation: Cervical Dystonia
## External links[edit]
Classification
D
* ICD-10: G24.3
* ICD-9-CM: 333.83
* MeSH: D014103
* DiseasesDB: 13180
* SNOMED CT: 74333002
External resources
* eMedicine: emerg/597 orthoped/452
* 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
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Spasmodic torticollis | c0949445 | 2,416 | wikipedia | https://en.wikipedia.org/wiki/Spasmodic_torticollis | 2021-01-18T19:02:19 | {"gard": ["10668"], "mesh": ["D014103"], "umls": ["C0949445", "C0152116"], "icd-9": ["333.83"], "icd-10": ["G24.3"], "wikidata": ["Q6152510"]} |
For a phenotypic description and a discussion of genetic heterogeneity of essential hypertension, see 145500.
Mapping
Using rural Chinese sib pairs with extreme blood pressure, Xu et al. (1999) identified suggestive linkage for regions on chromosomes 15 and 16. By refining the trait definition and genotyping additional markers, Xu et al. (1999) detected significant linkage (maximum lod score = 3.77) near D15S203 at the telomeric end of 15q in lower extreme diastolic blood pressure sib pairs. Using a second independent data set from the same geographic area, they marginally replicated (P = 0.05) this result, suggesting that this locus is very likely to be involved in the regulation of diastolic blood pressure.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| HYPERTENSION, ESSENTIAL, SUSCEPTIBILITY TO, 2 | c1858497 | 2,417 | omim | https://www.omim.org/entry/604329 | 2019-09-22T16:12:11 | {"omim": ["604329"], "synonyms": ["Alternative titles", "HYT2"]} |
A subtype of autosomal recessive limb girdle muscular dystrophy characterized by childhood onset of severe, progressive, proximal skeletal muscle weakness and atrophy of the upper and lower limbs with later involvement of distal muscles and development of severe quadraparesis, calf hypertrophy, triangular tongue, and dilated cardiomyopathy. Skeletal muscles undergo diffuse, bilateral, symmetric and severe atrophy with fat infiltration.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| LIMS2-related limb-girdle muscular dystrophy | c4225192 | 2,418 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=466801 | 2021-01-23T17:53:13 | {"omim": ["616827"], "synonyms": ["Autosomal recessive limb-girdle muscular dystrophy type 2W", "LGMD type 2W", "LGMD2W", "LIMS2-related LGM", "Limb-girdle muscular dystrophy type 2W"]} |
A number sign (#) is used with this entry because Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia is caused by heterozygous mutation in the CBL gene (165360).
For a general phenotypic description and a discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).
Description
Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; 163950) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by Martinelli et al., 2010). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as also seen in patients with Noonan syndrome (summary by Niemeyer et al., 2010).
Clinical Features
Martinelli et al. (2010) reported 4 unrelated probands, including 1 who met the diagnostic criteria for NS and 3 who had a phenotype reminiscent of Noonan syndrome, but without fulfilling the complete diagnostic criteria. Clinical features were highly variable, but generally included dysmorphic facial features, short neck, developmental delay, hyperextensible joints, and thorax abnormalities with widely spaced nipples. The facial features consisted of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Three had cardiac defects, such as enlarged left atrium with dysrhythmias, bicuspid aortic valve with stenosis, and mitral valve insufficiency. None of the patients developed a hematologic malignancy.
Perez et al. (2010) reported 3 unrelated female patients who developed juvenile myelomonocytic leukemia (JMML) at ages 26 months, 13 months, and 12 months, respectively. Each also had additional features suggestive of an underlying developmental disorder reminiscent of Noonan syndrome. One female child had failure to thrive with poor sucking and postnatal growth retardation and delayed psychomotor development. Dysmorphic facial features included broad forehead, hypertelorism, epicanthic folds, deeply grooved philtrum, thick lips, mild retrognathism, thick, posteriorly rotated ears with overfolded helices, short neck, thin hair and low posterior hairline. She had a single cafe-au-lait spot on the abdomen. She was hyperactive, with short attention span and poor verbal skills. The second child was Tunisian and showed postnatal failure to thrive. She also had microcephaly, triangular facies, high cranial vault, bilateral epicanthic folds, thick lips, prominent philtrum, posteriorly rotated helices, and somewhat sparse hair. Brain imaging showed nonspecific hyperintense signals in the periventricular white matter, but psychomotor development was normal. The third child had a broad forehead, arched eyebrows, hypertelorism, palpebral ptosis, short upturned nose, flat malar areas, deeply grooved philtrum, posteriorly rotated ears with thick helices and large lobules. Other features included pectus excavatum, hypermobile finger joints, redundant skinfolds, and 3 cafe-au-lait spots. She had mildly delayed development but was in the first grade. All 3 received successful cord blood allograft treatment for JMML.
Niemeyer et al. (2010) reported 21 children with JMML who had homozygous CBL mutations in leukemic cells. Sixteen of 21 patients had been previously reported by Loh et al. (2009). Normal tissue from 17 of 21 children was found to harbor a heterozygous germline mutation (see, e.g., 165360.0005-165360.0009), and normal tissue from 4 children was not available for analysis. A large percentage of these children showed dysmorphic facial features, developmental delay, cryptorchidism, and impaired growth, consistent with a Noonan syndrome-like disorder. The leukemia improved spontaneously in 5 of 6 children who did not undergo transplantation, even though the homozygous CBL mutation persisted in peripheral blood. In addition, 4 of these patients developed clinical signs consistent with vascular pathology, including optic atrophy, hypertension and an acquired cardiomyopathy; 1 had Takayasu arteritis. Niemeyer et al. (2010) postulated that the CBL mutation contributed to dysregulated lymphocyte signaling and vasculitis.
Bulow et al. (2015) reported 3 unrelated patients with genetically confirmed NSLL who presented with symptoms prenatally. One patient showed fetal pleural effusions at 21 weeks' gestation, necessitating thoracocentesis at gestational week 27. After birth at 31+5 weeks, the patient was diagnosed with chylothorax, which resolved at age 9 months. On fetal ultrasound, the second child showed hydrothorax, ascites (fetal hydrops), and hepatosplenomegaly, and the third child showed fetal hydrops and pleural effusions; both of these pregnancies were complicated by polyhydramnios. All patients had additional classic features of the disorder, including dysmorphic facial features, cardiac malformations, and delayed development. Only 1 of the patients developed JMML. Bulow et al. (2015) noted that the abnormalities of the lymphatic system observed in these patients was consistent with alteration of the RAS (see, e.g., 190020) signaling pathway.
Molecular Genetics
Martinelli et al. (2010) identified 4 different heterozygous mutations in the CBL gene (165360.0001-165360.0004) in 4 unrelated probands with a Noonan syndrome-like disorder. Two of the mutations were de novo, and 2 were inherited from an affected father. In vitro functional expression studies showed that the mutations all caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS (190020).
In 3 unrelated patients with a Noonan syndrome-like disorder with juvenile myelomonocytic leukemia, Perez et al. (2010) identified a heterozygous germline mutation in the CBL gene (Y371H; 165360.0005). The mutation occurred de novo in 2 patients and was inherited from an unaffected father in 1 patient. Leukemia cells of all patients showed somatic loss of heterozygosity at chromosome 11q23, including the CBL gene. The findings indicated that heterozygous mutation in the CBL gene is associated with predisposition for the development of JMML. Perez et al. (2010) suggested the moniker 'CBL syndrome.'
Pathogenesis
Loh et al. (2009) reported 3 patients who presented with JMML who had a heterozygous germline CBL mutation, whereas their tumor cells had homozygous mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high levels of STAT5 (601511) in response to GM-CSF. These findings indicated that reduplication of an inherited CBL mutation in a pluripotent hematopoietic stem cell confers a selective advantage for the homozygous state. They did not find CBL mutations in JMML patients with known PTPN11 (176876)/RAS mutation, indicating that CBL and PTPN11/RAS mutations are mutually exclusive. The finding that heterozygous germline mutations may predispose to development of JMML suggested that CBL acts as a tumor suppressor gene.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (in some patients) HEAD & NECK Face \- Frontal bossing \- Triangular face \- Long philtrum Ears \- Large ears \- Low-set ears Eyes \- Hypertelorism \- Ptosis \- Downslanting palpebral fissures Nose \- Depressed nasal bridge Mouth \- Thick lips Neck \- Short neck \- Webbed neck CARDIOVASCULAR Heart \- Congenital heart defects \- Aortic stenosis \- Mitral insufficiency Vascular \- Chylothorax (in some patients) RESPIRATORY Lung \- Pleural effusions due to chylothorax (in some patients) CHEST External Features \- Pectus excavatum Breasts \- Widely spaced nipples GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Joint laxity Limbs \- Cubitus valgus SKIN, NAILS, & HAIR Skin \- Cafe-au-lait spots \- Lymphedema (in some patients) Hair \- Thin hair MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development, mild \- Language delay NEOPLASIA \- Increased susceptibility to juvenile myelomonocytic leukemia PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios (in some patients) \- Fetal hydrops (in some patients) MISCELLANEOUS \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the Cas-Br-M murine ecotropic retroviral transforming sequence homolog gene (CBL, 165360.0001 ) ▲ 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
| NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA | c3150803 | 2,419 | omim | https://www.omim.org/entry/613563 | 2019-09-22T15:58:17 | {"omim": ["613563"], "orphanet": ["363972"], "synonyms": ["Noonan syndrome-like disorder with JMML", "CBL syndrome", "Alternative titles", "CBL MUTATION-ASSOCIATED SYNDROME", "CBL SYNDROME"]} |
Skin condition
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Find sources: "Acne mechanica" – news · newspapers · books · scholar · JSTOR (December 2019)
Acne mechanica
SpecialtyDermatology
Acne mechanica is an acneiform eruption that has been observed after repetitive physical trauma to the skin such as rubbing, occurring from clothing (belts and straps) or sports equipment (football helmets and shoulder pads).[1][2]:499 In addition to those mechanisms, the skin not getting enough exposure to air also contributes to the formation of acne mechanica. It is often mistaken as a rash that forms on sweaty skin that is constantly being rubbed, but in reality, it is a breakout of acne mechanica. The term "acne" itself describes the occurrence in which hair follicles (also known as pores) in the skin get clogged by oil, dead skin cells, dirt and bacteria, or cosmetic products and create a pimple. Pimples can vary in type, size, and shape, but the sole basis of them occurring is the same - the oil gland in the pore becomes clogged and sometimes infected, which creates pus in order to fight the infection and subsequently causes the development of swollen, red lesions on the skin.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Mechanism
* 4 Diagnosis
* 5 Treatment
* 6 Prognosis
* 7 Epidemiology
* 8 Research Directions
* 9 See also
* 10 References
## Signs and symptoms[edit]
The signs and symptoms at an early stage are harder to be seen. At first look, acne mechanica seems very similar to any other type of acne. However, it differs in how it is caused. A lot of acne has to do with hormones, the amount of oil production in the skin, and genetic predispositions. Acne mechanica specifically refers to the skin irritation that is formed by excess pressure, heat, and rubbing against the skin.
When the skin is constantly rubbed, it initially becomes rough and then starts to develop acne-like bumps with continuing irritation like sweating or more friction. If the skin continues to be irritated for a longer period of time, a more serious acne lesion develops that grows in size and redness. They appear as small, red tender bumps called papules. There may be a combination of whiteheads and blackheads that also appear around the area affected, the difference being that whiteheads are closed and clogged pores whereas blackheads are also clogged but open pores. The symptoms may vary also depending on a person's skin type; overly oily or dry skin can cause a number of symptoms that heighten the possibility for acne mechanica to develop.[3][4]
## Cause[edit]
Repetitive rubbing of the skin, in instances such as backpack strings rubbing on your shoulders or helmet straps rubbing on your chin are actions that can irritate the skin and cause acne mechanica.
Acne mechanica is a specific type of acne that is caused by friction, heat, and/or pressure on the skin. Especially occurs when the skin is not exposed to air. It is commonly found in athletes because sweaty, constantly rubbed skin by a tight uniform, for example, can result in a rash. What may look like a rash is actually acne mechanica. Another common area for acne mechanica to show up is on the sides of your face where you hold your cell phone, especially with the added bacteria it carries on it.
There are some people who are more prone to develop acne mechanica. The biggest group of people affected by this type of acne are teenagers and young adults in their twenties who already experience issues with acne on their back, shoulders, and buttocks.
Other people who have a type of acne commonly described as "sandpaper acne," which is characterized as small but rough acne lesions that are not very visible but feel like sandpaper to the touch, also are more prone to developing acne mechanica.[4][5]
## Mechanism[edit]
Acne mechanica specifically is triggered by both mechanical and heat stress on the skin working together to cause this irritation. The skin that is exposed to these stressors initially develops a harder surface to protect itself, but if the skin is continually dealing with this pressure, it gets irritated and forms a rash. At this point, it gets qualified as acne mechanica.
When you are in a hot climate or are working out and your body temperature rises, the heat causes the pores in your skin to open up. The dilation of the pores makes it easier for bacteria, oil, and dead skin cells to collect in the pores and clog them. Every pore in your body has a tiny hair follicle, and the blockage causes the hair follicle to become irritated and inflamed, which ends up forming pimples; specifically acne mechanica. White blood cells flood the area of inflammation, and once they die, they accumulate on the surface of the pore, causing what is known as a “whitehead”. When people pop pimples, pus comes out, which has the dead white blood cells in it that originally came to diffuse the inflammation.
Depending on the continuation of the stressors, the inflammatory pimples (also known as papules and pustules) can develop into nodules and cysts, which are more severe forms of acne that are rooted deeper within the skin.[3][6]
## Diagnosis[edit]
Acne mechanica can be diagnosed by a dermatologist via a physical examination. In more extreme cases, a skin biopsy is performed to examine the pathology.
Family and medical history are also looked at to see if the patient has a hereditary tendency to certain conditions that cause different types of acne, which may play a role in acne mechanica development. For example, if a patient's parents had acne, there is a very strong probability they will also have similar issues. The issues can range from things like overproducing dead skin cells or the pores having a higher tendency to clog.[7]
## Treatment[edit]
Acne mechanica has no direct cure, however, there are preventive measures that can be taken to minimize its breakouts. The most obvious solution to prevent extra rubbing or heat entrapment on the surface of the skin is to wear either loose-fitting clothes or wearing clothes made out of more breathable fabrics, especially during exercising, playing sports, or when performing physical activities such as hiking. Loose clothes will not rub as much and create the mechanical stress on the skin. Instead of wearing clothes made out of polyester and rayon, choosing cotton materials will help relieve the heat stress on the skin and not trap sweat in the pores. Taking showers immediately after any form of physical exercise will also help keep the skin as clean as possible. Keeping up with a skin care regimen so the skin is moisturized helps as well. Using skin care products specifically with salicylic acid or benzoyl peroxide help exfoliate the skin in a gentle manner and get rid of bacteria. Both of these chemicals in a facial cleanser may create a tingling sensation on people with extremely sensitive skin. Other topical ointments can be used once consulted with a dermatologist.[3][8][9]
## Prognosis[edit]
Long term effects of acne mechanica include potential scarring and skin discoloration at the area of the acne lesion if rubbing of the skin continues. It is not a lethal condition and the acne will clear up on its own once the heat and pressure stressors are avoided and if the skin is kept clean so the pores do not continue to become clogged.[10]
## Epidemiology[edit]
Acne mechanica is most prevalent among athletes, soldiers in warm climates, teenagers and young adults. The athletes and soldiers can get rashes from their equipment and uniforms constantly rubbing their skin while sweating, which turn into acne mechanica lesions. Men tend to be more prone to develop acne mechanica because they produce more oil (also known as sebum) in their glands, even though their glands are actually smaller than women's. This is also a reason why men's acne tends to remain a problem for longer once its developed. Acne in general is hereditary from parents to child, so genetics play a factor as well. People who already have acne and have a problematic skin type that tends to create clogged pores are more likely to develop acne mechanica as well.[11]
## Research Directions[edit]
Although not exactly having to do with acne mechanica and the heat or pressure stressors that cause it, there is still not a lot of research relating to different organ's health relating to acne appearing on different areas of the body and face. A correlation between the two could be explored in future studies.[12]
## See also[edit]
* List of cutaneous conditions
## References[edit]
1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). Page 685. McGraw-Hill. ISBN 0-07-138076-0.
2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
3. ^ a b c "Acne - Symptoms and causes". Mayo Clinic. Retrieved 2020-06-18.
4. ^ a b "What Is Acne Mechanica? - Acne Center - Everyday Health". EverydayHealth.com. Retrieved 2020-06-18.
5. ^ "Acne: sandpaper acne". www.pcds.org.uk. Retrieved 2020-06-18.
6. ^ Praderio, Caroline. "Here's what actually hides inside your pimples". Insider. Retrieved 2020-06-18.
7. ^ "Skin biopsy - Mayo Clinic". www.mayoclinic.org. Retrieved 2020-06-18.
8. ^ "6 Ways To Prevent Body Acne". www.dermalogica.com. Retrieved 2020-06-18.
9. ^ "Which Is Better for Acne, Salicylic Acid or Benzoyl Peroxide?". Healthline. Retrieved 2020-06-18.
10. ^ "Skin Experts". asds.net. Retrieved 2020-06-18.
11. ^ Darcey, Melissa (23 March 2018). "Is Acne Genetic?". Pathway Genomics Laboratory.
12. ^ "Acne face map: Causes of breakouts". www.medicalnewstoday.com. Retrieved 2020-06-18.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Acne mechanica | c0263460 | 2,420 | wikipedia | https://en.wikipedia.org/wiki/Acne_mechanica | 2021-01-18T18:37:57 | {"umls": ["C0263460", "C0856047"], "wikidata": ["Q4674428"]} |
Macrosomia-microphthalmia-cleft palate syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by early macrosomia, bilateral severe microphthalmia and a protuberant abdomen with hepatomegaly. Additional reported features include brachycephaly, large fontanelles, prominent forehead, upturned nose and median cleft palate. Cyanotic apneic spells and overwhelming infection lead to death within the first 6 months of life. There have been no further descriptions in the literature since 1989.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Macrosomia-microphthalmia-cleft palate syndrome | c1855467 | 2,421 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2432 | 2021-01-23T18:28:25 | {"gard": ["177"], "mesh": ["C537830"], "omim": ["248110"], "umls": ["C1855467"], "icd-10": ["Q87.0"], "synonyms": ["Teebi-Al Saleh-Hassoon syndrome"]} |
## Summary
### Clinical characteristics.
Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized skull, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence.
### Diagnosis/testing.
The diagnosis of DTD rests on a combination of clinical, radiologic, and histopathologic features. The diagnosis is confirmed by molecular genetic testing of SLC26A2, the only gene in which pathogenic variants are known to cause DTD. Biochemical studies of fibroblasts and/or chondrocytes may be used in the rare instances in which molecular genetic testing fails to identify SLC26A2 pathogenic variants.
### Management.
Treatment of manifestations: In children, physiotherapy and casting to maintain joint positioning and mobility as much as possible; surgical correction of clubfoot when ambulation becomes impossible; cervical spine surgery restricted to individuals with clinical or neurophysiologic evidence of spinal cord impingement; surgical correction of scoliosis in those at risk for rapid increase in curvature; total arthroplasty of hips and knees in relatively young adults to decrease pain and increase mobility; treatment of cystic ear swelling is conservative.
Prevention of Primary Manifestations: Physical therapy may prevent early joint contractures.
Surveillance: Annual monitoring of spinal curvature and joint contractures.
Agents/circumstances to avoid: Obesity, which places an excessive load on the large, weight-bearing joints.
Other: Undertake orthopedic surgery with caution as deformities tend to recur.
### Genetic counseling.
DTD is inherited in an autosomal recessive manner. At conception, each sib of a proband with DTD 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. The unaffected sibs of a proband have a 2/3 chance of being heterozygotes. Prenatal diagnosis for pregnancies at increased risk is possible if both disease-causing alleles of an affected family member have been identified. Ultrasound examination early in pregnancy is a reasonable complement or alternative to prenatal diagnosis by molecular genetic testing.
## Diagnosis
### Clinical Diagnosis
Diastrophic dysplasia (DTD) encompasses a range of disease that varies from severe (atelosteogenesis type 2) to mild (formerly called "diastrophic variant," recessive multiple epiphyseal dysplasia [rMED, EDM4]).
Clinical features [Superti-Furga 2001, Superti-Furga 2002]
* Limb shortening
* Normal-sized skull
* Slight trunk shortening
* Hitchhiker thumbs (Figure 1)
* Small chest
* Protuberant abdomen
* Contractures of large joints
* Dislocation of the radius
* Cleft palate (in ~1/3 of individuals)
* Cystic ear swelling in the neonatal period (in ~2/3 of infants with classic findings)
* Other usual findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead
#### Figure 1.
Hand of a newborn with diastrophic dysplasia, showing brachydactyly (short fingers), absence of flexion creases of the fingers, and proximally placed, abducted "hitchhiker thumb." The thumb deformity results in difficulty with thumb opposition, affecting (more...)
Radiographic findings
* The skull appears of normal size with disproportionate short skeleton.
* Cervical kyphosis is seen in most newborns and children with DTD.
* Ossification of the upper thoracic vertebrae may be incomplete with broadening of cervical spinal canal ("cobra-like" appearance).
* Coronal clefts may be present in the lumbar and lower thoracic vertebrae.
* Narrowing of the interpedicular distance from L1 to L5 is a constant finding.
* The more cephalad ribs are short and the chest can be bell shaped.
* The sternum may present duplication of the ossification centers.
* The ilia are hypoplastic with flat acetabula.
* The long bones appear moderately shortened with some metaphyseal flaring.
* The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic.
* The femur is distally rounded.
* The patella may appear fragmented or multilayered.
* Radius and tibia may be bowed.
* Proximal radial dislocation may be present at birth.
* Hands may exhibit typical features (Figure 2):
* Hitchhiker thumb with ulnar deviation of the fingers
* Shortness of the first metacarpal
* Delta-shaped proximal and middle phalanges
* In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age
#### Figure 2.
Radiograph of the hand of a three-year-old child with diastrophic dysplasia. The phalanges are short; some show a "delta"-shape deformity. Ossification of the carpal bones is advanced for age, a phenomenon known as "pseudo-acceleration" of the bone age, (more...)
### Testing
Histologic and biochemical testing provide important information.
Histopathology testing. The histopathology of cartilage is similar to that seen in atelosteogenesis type 2 (AO2) and achondrogenesis type 1B (ACG1B), as it reflects the paucity of sulfated proteoglycans in cartilage matrix. It shows an abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity. Some chondrocytes appear surrounded by lamellar material forming concentric rings; in some cases, these are indistinguishable from the collagen rings typical of ACG1B. The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous bone shows no ossification abnormalities [Superti-Furga 2001, Superti-Furga 2002].
Biochemical testing. The incorporation of sulfate into macromolecules can be studied in cultured chondrocytes and/or skin fibroblasts through double labeling with 3H-glycine and 35S-sodium sulfate. After incubation with these compounds and purification, the electrophoretic analysis of medium proteoglycans reveals a lack of sulfate incorporation, which can be observed even in total macromolecules.
Note: (1) The determination of sulfate uptake is cumbersome and not used for diagnostic purposes. (2) The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is recommended only in the rare instance in which the diagnosis of DTD is strongly suspected but molecular genetic testing fails to detect SLC26A2 pathogenic variants [Rossi et al 1996, Superti-Furga et al 1996a, Rossi et al 1997, Rossi et al 1998, Rossi et al 2003].
#### Molecular Genetic Testing
Gene. SLC26A2 is the only gene in which pathogenic variants are known to cause diastrophic dysplasia (DTD) [Hästbacka et al 1994, Superti-Furga et al 1996a, Rossi & Superti-Furga 2001, Superti-Furga 2001, Superti-Furga 2002].
### Table 1.
Molecular Genetic Testing Used in Diastrophic Dysplasia
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Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
SLC26A2Targeted analysis for pathogenic variants analysisPanel of selected variants 4See footnote 5
Sequence analysis 6Sequence variants>90% 7
Deletion/duplication analysis 8(Multi)exon and whole-gene deletion/duplicationUnknown, none reported
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants.
3\.
Percent of disease alleles detected in individuals with typical clinical, radiologic, and histologic features of DTD
4\.
Variant panel may vary by laboratory.
5\.
Dependent on variant panel and population tested. The four most common SLC26A2 pathogenic variants (p.Arg279Trp, c.-26+2T>C (IVS1+2T>C), p.Arg178Ter, and p.Cys653Ser) account for approximately 65% of disease alleles in diastrophic dysplasia (70% of disease alleles in all SLC26A2-related dysplasias).
6\.
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.
7\.
90% of alleles in individuals with radiologic and histologic features compatible with the diagnosis of DTD [Rossi & Superti-Furga 2001]
8\.
Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
### Testing Strategy
To confirm/establish the diagnosis in a proband
* Clinical and radiologic features can strongly suggest the diagnosis of DTD.
* Molecular genetic testing, the diagnostic test of choice in probands with clinical and radiologic findings compatible with DTD, allows for precise diagnosis in the great majority of cases.
* Single gene testing of SLC26A2:
* Targeted analysis for the four most common pathogenic variants is likely to identify one or both alleles in a significant proportion of probands (one allele in >1/2 of cases and both alleles in 1/3 of cases).
* Sequence analysis of the entire coding region may be performed initially, or when only one or neither allele has been identified by targeted analysis for pathogenic variants.
* Histologic and biochemical tests provide confirmatory information but are usually not required to establish the clinical diagnosis. Note: These tests are particularly helpful in aborted fetuses, when the radiographic material is of poor quality.
* The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is possible in the rare cases in which the diagnosis of DTD is strongly suspected but variant analysis fails to detect SLC26A2 pathogenic variants.
## Clinical Characteristics
### Clinical Description
Neonates with diastrophic dysplasia (DTD) may experience respiratory insufficiency because of the small rib cage and tracheal instability and collapsibility. Mechanical ventilation is required in a significant proportion of infants. Mortality in the first months of life is increased, mainly because of respiratory complications such as pneumonia, sometimes aspiration pneumonia.
From the newborn period throughout life, the disorder appears to involve the skeleton as well as the tendons, ligaments, and joint capsules, which are tighter and shorter than normal, causing restricted joint mobility. Growth of the tendons and joint capsules may be impaired; Peltonen et al [2003] reported a high prevalence of congenital aplasia of menisci and cruciate ligaments within the knee joints. Pretibial dimples may be present, possibly a consequence of reduced intrauterine movement.
Joint contractures and spine deformity tend to worsen with age. Painful degenerative arthrosis of the hip is common in young adults. Anterior tilting of the pelvis may occur as a consequence and contribute to exaggerate the lumbar lordosis. The spine frequently develops excessive lumbar lordosis, thoracolumbar kyphosis, and scoliosis. In anteroposterior radiographs of the lumbar spine, a decrease of the vertebral interpedicular distance is almost invariably observed; however, related neurologic symptoms are only rarely observed [Remes et al 2004].
The knee may be unstable in childhood, but flexion contractures develop with progressive valgus deformity and lateral positioning of the patella. The development and position of the patella may determine whether contraction of the quadriceps muscle results in extension of the knee or paradoxical flexion of the knee. If paradoxical flexion occurs, severe difficulty with walking results [Remes et al 2004].
Because of foot deformities and shortened tendons, many adults with DTD are unable to place their heels on the ground. Thus, they stand solely on their metatarsals and toes. Typically, the adult with classic DTD stands on his toes because of severe clubfoot and has marked lumbar lordosis and thoracic kyphoscoliosis; this appearance originally prompted use of the term "diastrophic" (twisted).
Brachydactyly, ulnar deviation, phalangeal synostosis, and ankylosis of the fingers with significant disability may be observed. Phalangeal synostosis, usually between proximal and middle phalanges, develops in those fingers that have an abnormal phalangeal patterning at birth, including so-called delta-shaped phalanges that usually lack a proper joint space. Often, newborns with DTD lack phalangeal flexion creases (Figure 1), a sign of marked reduction of joint motion already present at early developmental stages. The thumb may be placed more proximally than usual and may also be hypotonic and thus weak (probably because of ligamentous dysplasia). As a consequence, some individuals may have difficulty opposing the thumb and the index finger to accomplish a pincer grasp. In older children and adults, ulnar deviation of the second finger frequently occurs together with radial deviation of the fifth finger (clinodactyly), giving a characteristic "brackets" appearance.
The facial appearance of children and young adults with DTD is remarkably different from the "standard" chondrodysplasia face with a depressed nasal bridge and anteverted nares. The forehead is broad with a high anterior hairline; the palpebral fissures may be downslanting; the nose is not shortened or stubby as in other chondrodysplasias but rather long and thin because of hypoplastic alae nasi; the nares are not anteverted; the facial tissues are tight; the mouth is small, and the mandible normally developed. Cystic ear swelling is frequent in individuals with DTD, a feature not reported in individuals with milder findings consistent with the recessive multiple epiphyseal dysplasia (rMED) phenotype. Ear swelling can be associated with inflammation and pain [Cushing et al 2011].
Adult stature ranged between 100 and 140 cm in an early review of Americans and Europeans with DTD. A 1982 study reported a mean adult height of 118 cm [Horton et al 1982], while a study of Finnish individuals with DTD (who are genetically homogeneous at the SLC26A2 locus) revealed a mean adult height of 136 cm for males and 129 cm for females [Mäkitie & Kaitila 1997]. The discrepancy in mean height between the older studies and the later Finnish study may be the result of variant heterogeneity or may reflect bias of ascertainment of more severely affected individuals in the older studies. It must be noted that the usefulness of such growth curves in predicting adult height is limited by the occurrence of many different allelic combinations [Superti-Furga 2001, Superti-Furga 2002]
In addition to the skeletal abnormalities, a mild degree of muscular hypoplasia of the thighs and legs is common.
Neurologic complications may occur, particularly in the cervical region. Cervical kyphosis is seen in lateral radiographs in most newborns; in most cases, it lessens over the first three to five years of life but in some cases, severe cervical kyphosis may lead to spinal cord compression, either spontaneously or during the procedure of endotracheal intubation, which requires hyperextension of the neck. A newborn with DTD and severe cervical kyphosis died immediately after birth of respiratory insufficiency; autopsy revealed neuronal degeneration and gliosis of the cervical spinal cord that had developed before birth.
Newer MRI findings have confirmed that in DTD, the foramen magnum is of normal size but the cervical spinal canal is narrowed. Individual cervical vertebral bodies (usually C3 to C5) may be hypoplastic, but the frequently observed kyphosis is not explained by changes of the vertebral bodies and may thus be the consequence of abnormal intervertebral disks. The rate of spontaneous correction of cervical kyphosis is rather high.
Cervical spina bifida occulta has been frequently reported in individuals with DTD.
Hearing loss is unusual in individuals with DTD, although it may be overestimated if studies are based on small cohorts [Tunkel et al 2012]. Vision defects are seldom observed, although a tendency towards myopia has been reported.
Mental development and intelligence are usually normal; numerous individuals affected by DTD attain high academic and social recognition or success in the arts.
MRI studies have shown a peculiar signal anomaly of intervertebral disks, suggesting reduced water content. This anomaly may be the consequence of reduced proteoglycan sulfation.
### Genotype-Phenotype Correlations
Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders that extends from lethal achondrogenesis type 1B (ACG1B) to mild recessive multiple epiphyseal dysplasia (EDM4/rMED). Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural pathogenic variants in transmembrane domains of the sulfate transporter are associated with ACG1B, while pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996b, Karniski 2001, Maeda et al 2006].
The pathogenic variant p.Arg279Trp is the most common SLC26A2 variant found outside of Finland (45% of alleles); it results in the mild EDM4 phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) and atelosteogenesis type 2 (AO2) phenotypes when found in the compound heterozygous state [Barbosa et al 2011].
Pathogenic variant p.Arg178Ter is the second most common variant (9% of alleles) and is associated with a more severe DTD phenotype or even the perinatal-lethal AO2 phenotype, particularly when combined in trans with the p.Arg279Trp variant.
Pathogenic variants p.Cys653Ser and c.-26+2T>C are the third most common variants (8% of alleles).
Pathogenic variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when present in trans with other pathogenic variants [Czarny-Ratajczak et al 2010].
Pathogenic variant c.-26+2T>C is sometimes referred to as the "Finnish" variant, because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous. It is the only variant that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Dwyer et al 2010].
The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (AO2 and DTD) if the second allele is a relatively mild variant. Indeed, missense variants located outside of the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of a null allele [Rossi & Superti-Furga 2001].
### Penetrance
For pathogenic variants in SLC26A2, penetrance is complete.
### Nomenclature
Diastrophic dysplasia (DTD) was recognized as a distinct entity by Lamy & Maroteaux [1960]. At that time, they described a disorder that "resembled achondroplasia in the newborn period but had a quite distinct evolution." The name was chosen to indicate the "twisted" appearance of the spine and limbs in severely affected individuals. The clinical and radiographic features of diastrophic dysplasia are so characteristic that no other name has been associated with the condition.
The existence of clinical variability was recognized early; instances of "severe" or "lethal" DTD are now classified as atelosteogenesis type 2 (AO2), while milder cases, once termed "diastrophic variant," are now classified as recessive multiple epiphyseal dysplasia (rMED, EDM4).
DTD is classified in the "sulfation disorder" group of the current Nosology and Classification of Genetic Skeletal Disorders [Superti-Furga & Unger 2007].
### Prevalence
No reliable data exist regarding the prevalence of DTD. In the experience of several genetic and metabolic centers that can compare its incidence with that of other genetic diseases, DTD disorders are generally believed to be in the range of approximately 1:100,000.
## Differential Diagnosis
Diastrophic dysplasia (DTD) is part of a disease spectrum. At the severe end, it borders a condition defined as atelosteogenesis type 2 that is commonly lethal in the perinatal period. Affected individuals present around birth or before. At the mild end, DTD can present as what was formerly called "diastrophic variant" and borders recessive multiple epiphyseal dysplasia; this differential diagnosis is usually considered in toddlers or school-age children.
Premature carpal ossification and digital malformations can be seen in newborns and infants with otopalatodigital syndrome (caused by mutation of FLNA; see Otopalatodigital Spectrum Disorders), in the Larsen syndrome/atelosteogenesis 1 spectrum (caused by mutation of FLNB), in Desbuquois dysplasia [Miyake et al 2008, Panzer et al 2008], and in chondrodysplasia and abnormal joint development (IMPAD1) [Vissers et al 2011].
Contractures and mesomelic limb shortening reminiscent of diastrophic dysplasia can be seen in omodysplasia. Congenital contractures with mild skeletal anomalies can be seen in various forms of congenital arthrogryposis.
Differential diagnosis in the prenatal period must include skeletal dysplasias as well as other conditions with reduced length and/or contractures. Even the demonstration of a hitchhiker thumb deformity is not pathognomonic.
## Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with diastrophic dysplasia (DTD), the following evaluations are recommended:
* Cervical films (antero-posterior, lateral, and in flexion-extension)
* Complete skeletal survey
* Orthopedic referral
* Physical therapy consultation
* Clinical genetics consultation
### Treatment of Manifestations
In children, the principle is to maintain joint positioning and mobility as much as possible by physical means (physiotherapy and casting, e.g., for clubfeet); however, tightness of joint capsules and ligaments in diastrophic dysplasia makes correction by casting or other physical means difficult.
Surgical correction of clubfoot is indicated when the foot deformity makes ambulation impossible; however, surgery needs to be undertaken with caution as deformities tend to recur. Simple tenotomy does not suffice, and more extensive plasty of tarsal bones may be needed [Weiner et al 2008].
The rate of spontaneous correction of cervical kyphosis is rather high, and cervical spine surgery in infancy may be restricted to individuals with clinical or neurophysiologic evidence of spinal cord impingement.
Indications for surgical correction of scoliosis have not been established nor have criteria to define a successful surgical outcome [Matsuyama et al 1999, Remes et al 2001]. It should be noted that surgical series are inevitably biased toward more severely affected individuals. Although surgery before puberty may be helpful for those who have developed severe spinal deformity with respiratory compromise or neurologic signs, surgical correction of scoliosis is best postponed until after puberty in the majority of individuals with diastrophic dysplasia [Jalanko et al 2009]. The key issue seems to be the early identification of those individuals at risk for rapid increase in scoliotic curvature.
Total arthroplasty of hips and knees decreased pain and increased mobility in a group of adult Finnish individuals with premature degenerative arthrosis [Helenius et al 2003a, Helenius et al 2003b]. The authors concluded that arthroplasty is indicated in "relatively young adults" with DTD.
A conservative approach to the treatment of cystic ear swelling is recommended [Cushing et al 2011].
### Prevention of Primary Manifestations
Physical therapy may prevent early joint contractures.
### Surveillance
Annual monitoring of spinal curvature to prevent neurologic complications and joint contractures is appropriate.
### Agents/Circumstances to Avoid
Obesity places an excessive load on the large weight-bearing joints and thus should be avoided.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Pregnancy Management
Although not specific to DTD, women with severe kyphoscoliosis may experience complications related to thoracic compression in later stages of pregnancy and need to be monitored closely. Kyphoscoliosis can also complicate the use of spinal anaesthetics and consultation with an anaesthesiologist prior to delivery would be advisable.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Diastrophic Dysplasia | c0220726 | 2,422 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1350/ | 2021-01-18T21:30:53 | {"mesh": ["C536170"], "synonyms": ["Diastrophic Dwarfism"]} |
Cataract-aberrant oral frenula-growth delay syndrome is characterized by cataracts and short stature associated with variable anomalies, including aberrant oral frenula, a characteristic facial appearance (posteriorly angulated ears, upslanting palpebral fissures, small nose, ptosis and epicanthal folds) cavernous hemangiomas and hernias. It has been described in a mother and her two children. It is transmitted as an autosomal dominant trait.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Cataract-aberrant oral frenula-growth delay syndrome | c1861835 | 2,423 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1373 | 2021-01-23T18:46:08 | {"gard": ["5554"], "mesh": ["C536691"], "omim": ["115645"], "umls": ["C1861835"], "icd-10": ["Q87.8"], "synonyms": ["Wellesley-Carman-French syndrome"]} |
Trehalase deficiency is a metabolic condition in which the body lacks an enzyme called trehalase and is not able to convert trehalose, a disaccharide (sugar composed of two monosaccharides) into glucose (sugar composed of one monosaccharide). Trehalose is found naturally in mushrooms, algae and insects. Trehalose may additionally be found in manufactured food products, medications, and cosmetics. For trehalose to be digested and absorbed by the digestive system, it must be broken down into glucose. Individuals with this deficiency are therefore unable to breakdown and absorb trehalose. This may lead to vomiting, abdominal discomfort and diarrhea after eating foods containing trehalose. Trehalase deficiency is caused by mutations in the TREH gene. Both autosomal recessive and autosomal dominant inheritance patterns have been described in the medical literature. Treatment involves avoidance or restriction of products that contain trehalose.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Trehalase deficiency | c0268187 | 2,424 | gard | https://rarediseases.info.nih.gov/diseases/10372/trehalase-deficiency | 2021-01-18T17:57:19 | {"mesh": ["C562603"], "omim": ["612119"], "umls": ["C0268187"], "synonyms": ["Trehalose intolerance"]} |
A number sign (#) is used with this entry because familial candidiasis-4 (CANDF4) is caused by homozygous mutation in the DEC1 (CLEC7A) gene (606264) on chromosome 12p13.
For a general description and a discussion of genetic heterogeneity of familial chronic candidiasis, see CANDF1 (114580).
Clinical Features
Ferwerda et al. (2009) studied a nonconsanguineous Caucasian family of Dutch ancestry in which 2 sisters had recurrent vulvovaginal candidiasis and onychomycosis. Another sister and their mother had chronic onychomycosis, whereas their father had only transient onychomycosis, with a relatively late age at onset and complete recovery. Microbiologic assessment of the nails of the 3 sisters revealed growth of Trichophyton rubrum. The proband had cells that were hyporesponsive to Candida albicans stimulation, with cytokine production that was 15% or less than that of controls. The lack of cytokine production was pinpointed to an impaired response to beta-glycan, indicating a potential defect in dectin-1 (CLEC7A; 606264) recognition. The patients had no known predisposing factors, such as diabetes (see 125853) or infection with human immunodeficiency virus.
Molecular Genetics
In 3 sisters with recurrent vulvovaginal candidiasis and/or onychomycosis, Ferwerda et al. (2009) identified homozygosity for a nonsense mutation (Y238X; 606264.0001) in the CLEC7A gene. The parents, who had only chronic or intermittent onychomycosis, respectively, were each heterozygous for the mutation.
INHERITANCE \- Autosomal recessive GENITOURINARY External Genitalia (Female) \- Vulvar candidiasis Internal Genitalia (Female) \- Vaginal candidiasis SKIN, NAILS, & HAIR Nails \- Onychomycosis, chronic IMMUNOLOGY \- Recurrent fungal infections MOLECULAR BASIS \- Caused by mutation in the C-type lectin domain family 7, member A gene (CLEC7A, 606264.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| CANDIDIASIS, FAMILIAL, 4 | c0006845 | 2,425 | omim | https://www.omim.org/entry/613108 | 2019-09-22T15:59:37 | {"doid": ["2058"], "mesh": ["D002178"], "omim": ["613108"], "orphanet": ["1334"], "synonyms": ["Alternative titles", "CANDIDIASIS, FAMILIAL CHRONIC MUCOCUTANEOUS"]} |
Loose anagen syndrome is a rare benign hair disorder affecting predominantly blond females in childhood and characterized by the presence of hair that can be easily and painlessly pulled out. Most of the hair is in the anagen phase and lacks an external epithelial sheath. Hair grows back quickly and the condition improves spontaneously with aging. Loose anagen hair can be associated with other anomalies, such as coloboma.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Loose anagen syndrome | c0406468 | 2,426 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=168 | 2021-01-23T17:33:34 | {"gard": ["3287"], "mesh": ["D058247"], "omim": ["600628"], "umls": ["C0406468"], "icd-10": ["L65.1"]} |
The notion of an X-linked form of manic-depressive illness dates back to at least the 1930s when an excess of affected females and a deficiency of male-to-male transmission made this an attractive possibility. The paper by Reich et al. (1969), reporting linkage to colorblindness (see 303800) in 2 kindreds, was a landmark among reports of genetic studies of mental illness. Winokur and Tanna (1969) suggested X-linked dominant inheritance. Without reference to specific genetic hypothesis, Mendlewicz et al. (1972) reported that bipolar (manic-depressive) patients with a family history of similar illness responded better to lithium than those without affected relatives. Mendlewicz and Rainer (1974) concluded further that their data were consistent with X-linked dominant inheritance of manic-depressive illness, with linkage to colorblindness and to Xg loci. Since the latter two loci are far apart, indeed on different arms of the X chromosome, that conclusion on linkage is suspect. Bipolar and unipolar illnesses are distinct. In the bipolar condition, mania occurs sometime during the course of the affective illness. In the unipolar condition, only depressive episodes occur. The evidence for distinctness consists of (a) clinical data which show differences in length and number of episodes and age of onset, and (b) familial data which show high rate of psychosis, especially mania, in bipolar families. It is the bipolar families in which X-linked dominant inheritance has been suggested. Cadoret and Winokur (1975) reviewed the evidence. Mendlewicz et al. (1980) studied a large family of Persian Sephardic Jewish origin in which both manic-depressive psychosis and G6PD deficiency (300908) were segregating. A lod score of 4.32 was obtained for a recombination fraction slightly less than 0.05. (Autosomally transmitted genetic susceptibility has also been demonstrated; see 125480.) Risch et al. (1986) reanalyzed 2 bodies of data, one from a family study of bipolar affective illness in New York (Mendlewicz and Rainer, 1974) and the other from a similar study in Bethesda (Gershon et al., 1982). They concluded that X-linkage exists, but that only a subgroup, possibly one-third, of 'bipolars' carry the X-linked gene. The X-linked subgroup may be associated with early onset (before 30 years of age). As they indicated, linkage studies with X-chromosome RFLP markers will be of great interest and possible usefulness. Baron et al. (1987) studied a new series of pedigrees and again found linkage of bipolar affective illness with colorblindness and G6PD (305900). The maximum lod score ranged from 7.52 (assuming homogeneity) to 9.17 (assuming heterogeneity). The probands originated from the patient population of the Jerusalem Mental Health Center. One pedigree was Polish-Ashkenazi and 4 were non-Ashkenazi originating from Iraq, Yemen, Turkey, and Iran. The Ashkenazi pedigree gave negative lod scores.
Mendlewicz et al. (1987) found a maximum lod score of 3.10 at a recombination fraction of 0.11 for linkage between a manic-depressive locus and the factor IX locus at Xq27 as defined with a TaqI polymorphism. In studies of 7 informative kindreds segregating for manic-depressive illness in a pattern consistent with X-linked inheritance (no instance of father-to-son transmission), Gejman et al. (1990) found lod scores consistently less than -2 in a segment extending from about 10 cM centromeric to F9 to the region of the colorblindness genes.
Hebebrand (1992) pointed out that formal genetic evidence for X-linked dominant inheritance is lacking. There appeared to be two main reasons for this: (1) segregation ratios among the offspring of affected males could not be evaluated adequately because most males had either not reproduced or their offspring were not considered informative by the investigators; and (2) the assumed hemizygous males had not been shown to be more severely affected than the heterozygous females. Hebebrand and Hennighausen (1992) quantitatively evaluated specific segregation patterns and clinical data in 8 positive X-linkage studies including those of Mendlewicz et al. (1972, 1980, 1987) and Baron et al. (1987). They suspected that the pedigree structures observed resulted from ascertaining kindreds with autosomal or multifactorial inheritance, with exclusion of kindreds encompassing male-to-male transmission.
Baron et al. (1993) extended and reevaluated pedigree data, including new individuals, diagnostic follow-up, and analysis with DNA markers, in 3 multigeneration Israeli kindreds. The results showed greatly diminished support for linkage to Xq28. The peak lod scores in 2 of the pedigrees had dropped several lod units to values clearly negative at the RCP--F8--G6PD gene cluster. On the other hand, positive lod scores (maximum = 2.09) at the same map location were sustained in another pedigree. None of the pedigrees showed linkage to more proximal markers, including the Xq28 locus DXS98. Pauls (1993) commented on the problems of linkage analysis in behavioral disorders and outlined methodologic strategies that probably will be necessary for success of molecular genetic studies. Both Baron et al. (1994) and Gershon and Goldin (1994) emphasized that despite the suggestion by Bocchetta et al. (1994) of linkage of bipolar disorder to Xq28, there is no consistent statistical evidence of linkage.
Thomson et al. (2005) investigated the GPR50 gene (300207) as a candidate for mutation in bipolar affective disorder. They compared the allele frequencies of 3 GPR50 polymorphisms in case-control studies of 264 individuals with BPAD, 226 with major depressive disorder (MDD; see 608516), 263 with schizophrenia (see 181500), and 562 ethnically matched controls. A significant association was found between an insertion/deletion polymorphism (del502-505) in exon 2 and an increased risk of both BPAD (p = 0.0070) and MDD (p = 0.011). Analysis restricted to females showed an increase in the association with BPAD and MDD (p = 0.00023 and p = 0.0064, respectively). One SNP (rs13440581) showed weak association with MDD in females (p = 0.0096), and another (rs2072621) showed significant association with schizophrenia in females (p = 0.0014). Thomson et al. (2005) suggested that the deletion variant, or a variant in linkage disequilibrium with this polymorphism, is a sex-specific risk factor for susceptibility to BPAD and that other variants in the gene may be sex-specific risk factors in the development of schizophrenia.
Neuro \- Bipolar affective disorder Misc \- Early onset (before 30 years of age) Inheritance \- ? X-linked dominant vs. multifactorial ▲ 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
| MAJOR AFFECTIVE DISORDER 2 | c1839839 | 2,427 | omim | https://www.omim.org/entry/309200 | 2019-09-22T16:17:53 | {"mesh": ["C564108"], "omim": ["309200"], "synonyms": ["Alternative titles", "MANIC-DEPRESSIVE ILLNESS", "MANIC-DEPRESSIVE PSYCHOSIS, X-LINKED", "BIPOLAR AFFECTIVE DISORDER"]} |
A number sign (#) is used with this entry because of evidence that pulmonary venoocclusive disease-1 (PVOD1) is caused by heterozygous mutation in the BMPR2 gene (600799) on chromosome 2q33.
Description
Pulmonary venoocclusive disease primarily affects the postcapillary venous pulmonary vessels and may involve significant pulmonary capillary dilation and/or proliferation. PVOD is an uncommon cause of pulmonary artery hypertension (PPH; see 178600), a severe condition characterized by elevated pulmonary artery pressure leading to right heart failure and death. PVOD accounts for 5 to 10% of 'idiopathic' PPH and has an estimated incidence of 0.1 to 0.2 cases per million. The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins by fibrous tissue, with intimal thickening present in venules and small veins in lobular septa and, rarely, larger veins. Definitive diagnosis of PVOD requires histologic analysis of a lung sample, although surgical lung biopsy is often too invasive for these frail patients. Patients with PVOD respond poorly to available therapy, therefore it is crucial to distinguish PVOD from other forms of PPH. Radiologic characteristics suggestive of PVOD on high-resolution CT of the chest include nodular ground-glass opacities, septal lines, and lymph node enlargement. In addition, because PVOD mainly affects postcapillary vasculature, it causes chronic elevation of pulmonary capillary pressure and thus promotes occult alveolar hemorrhage, which may be a characteristic feature of PVOD (summary by Montani et al., 2008).
### Genetic Heterogeneity of Pulmonary Venoocclusive Disease
See also PVOD2 (234810), caused by mutation in the EIF2AK4 gene (609280) on chromosome 15q15.
Clinical Features
Voordes et al. (1977) reported pulmonary venoocclusive disease in a male infant who died at the age of 3 months. Both intra- and extrapulmonary veins were involved. A brother had died at the age of 8 weeks of the same disease, limited to the intrapulmonary veins. They suggested that this may have occurred in 2 sibs reported by Rosenthal et al. (1973). They further suggested that the disease may be viral (not genetic), with the mother serving as carrier, and that some instances of isolated extraparenchymal pulmonary vein atresia or obstruction may be this disorder.
Runo et al. (2003) studied a family in which the proband had PVOD and her mother had severe primary pulmonary hypertension (see PPH1; 178600). The proband presented at 36 years of age with dyspnea, prominent pulmonary arteries on chest x-ray, and an elevated mean pulmonary artery pressure of 53 mm Hg. Her disease was initially thought to be PPH, but open lung biopsy revealed findings consistent with PVOD. The patient's mother had died of complications of right heart failure; she had a mean pulmonary artery pressure of 92 mm Hg on right heart catheterization, absence of thromboembolic disease by pulmonary angiography, and no evidence of secondary etiologies. Because lung biopsy and autopsy were not performed, it was unknown whether the mother's pulmonary hypertension was from PPH or PVOD.
Montani et al. (2008) retrospectively reviewed 48 cases of pulmonary artery hypertension, including 24 patients with biopsy-proven PVOD and 24 patients with no evidence of PVOD after meticulous evaluation of lung pathology. Compared to PPH, PVOD was characterized by a higher male-to-female ratio and higher tobacco exposure. Clinical presentation was similar except for a lower body mass index in PVOD patients. In addition, at baseline PVOD patients had significantly lower partial pressure of arterial oxygen, diffusing lung capacity of carbon monoxide per alveolar volume, and oxygen saturation nadir during a 6-minute walk test. Hemodynamic parameters showed a lower mean systemic arterial pressure and right atrial pressure, but no difference in pulmonary capillary wedge pressure. CT of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared to patients with PPH (p less than 0.05 for all). Seven (44%) of 16 PVOD patients who received PPH-specific therapy developed pulmonary edema, and clinical outcomes were worse for PVOD than PPH patients.
Molecular Genetics
In a family in which the proband had PVOD and her mother had pulmonary hypertension, Runo et al. (2003) analyzed the BMPR2 gene and identified heterozygosity for a 1-bp deletion (600799.0021) in the proband and her unaffected sister. DNA was not available from their mother, who died of right heart failure, or from the maternal grandparents.
In a patient with pulmonary arterial hypertension and PVOD, Machado et al. (2006) identified heterozygosity for a nonsense mutation (600799.0022) in the BMPR2 gene.
In a patient with primary pulmonary hypertension and histologic features of PVOD, Aldred et al. (2006) identified heterozygosity for a deletion of exon 2 of the BMPR2 gene (600799.0023). The patient had 3 affected relatives, all of whom were deceased. The same deletion was identified in an unrelated family with primary pulmonary hypertension and no known evidence of PVOD.
In a cohort of 48 patients with PPH, 24 of whom had histologic evidence of PVOD, Montani et al. (2008) identified mutations in the BMPR2 gene in 2 patients with PVOD (600799.0027 and 600799.0028) and in 4 patients with no evidence of PVOD.
INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Prominent second heart sound Vascular \- Elevated jugular venous pressure \- Pulmonary arterial hypertension RESPIRATORY Lung \- Pulmonary veno-occlusive disease seen on biopsy \- Centrilobular ground glass opacities seen on CT \- Thickened interlobular septae seen on CT \- Occult alveolar hemorrhage MISCELLANEOUS \- Variable clinical presentation MOLECULAR BASIS \- Caused by mutation in the bone morphogenetic receptor, type II gene (BMPR2, 600799.0001 ) ▲ 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
| PULMONARY VENOOCCLUSIVE DISEASE 1, AUTOSOMAL DOMINANT | c0034091 | 2,428 | omim | https://www.omim.org/entry/265450 | 2019-09-22T16:23:00 | {"doid": ["5453"], "mesh": ["D011668"], "omim": ["265450"], "orphanet": ["31837"], "synonyms": ["Alternative titles", "PVOD"]} |
Parasitic disease caused by a family of nematode worms
Filariasis
Life cycle of Wuchereria bancrofti, a parasite that causes filariasis
SpecialtyInfectious disease
Filariasis is a parasitic disease caused by an infection with roundworms of the Filarioidea type.[1] These are spread by blood-feeding insects such as black flies and mosquitoes. They belong to the group of diseases called helminthiases.
Eight known filarial worms have humans as a definitive host. These are divided into three groups according to the part of the body they affect:
* Lymphatic filariasis is caused by the worms Wuchereria bancrofti, Brugia malayi, and Brugia timori. These worms occupy the lymphatic system, including the lymph nodes; in chronic cases, these worms lead to the syndrome of elephantiasis.
* Subcutaneous filariasis is caused by Loa loa (the eye worm), Mansonella streptocerca, and Onchocerca volvulus. These worms occupy the layer just under the skin. L. loa causes Loa loa filariasis, while O. volvulus causes river blindness.
* Serous cavity filariasis is caused by the worms Mansonella perstans and Mansonella ozzardi, which occupy the serous cavity of the abdomen. Dirofilaria immitis, the dog heartworm, rarely infects humans.
The adult worms, which usually stay in one tissue, release early larval forms known as microfilariae into the person's blood. These circulating microfilariae can be taken up during a blood meal by an insect vector; in the vector, they develop into infective larvae that can be spread to another person.
Individuals infected by filarial worms may be described as either "microfilaraemic" or "amicrofilaraemic", depending on whether microfilariae can be found in their peripheral blood. Filariasis is diagnosed in microfilaraemic cases primarily through direct observation of microfilariae in the peripheral blood. Occult filariasis is diagnosed in amicrofilaraemic cases based on clinical observations and, in some cases, by finding a circulating antigen in the blood.
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 3.1 Concentration methods
* 4 Treatment
* 5 Society and culture
* 5.1 Research teams
* 5.2 Prospects for elimination
* 6 Other animals
* 6.1 Cattle
* 6.2 Horses
* 6.3 Dogs
* 7 See also
* 8 References
* 9 Further reading
* 10 External links
## Signs and symptoms[edit]
The most spectacular symptom of lymphatic filariasis is elephantiasis – edema with thickening of the skin and underlying tissues—which was the first disease discovered to be transmitted by mosquito bites.[2] Elephantiasis results when the parasites lodge in the lymphatic system.
Elephantiasis affects mainly the lower extremities, while the ears, mucous membranes, and amputation stumps are affected less frequently. However, different species of filarial worms tend to affect different parts of the body; Wuchereria bancrofti can affect the legs, arms, vulva, breasts, and scrotum (causing hydrocele formation), while Brugia timori rarely affects the genitals.[citation needed] Those who develop the chronic stages of elephantiasis are usually free from microfilariae (amicrofilaraemic), and often have adverse immunological reactions to the microfilariae, as well as the adult worms.[2]
The subcutaneous worms present with rashes, urticarial papules, and arthritis, as well as hyper- and hypopigmentation macules. Onchocerca volvulus manifests itself in the eyes, causing "river blindness" (onchocerciasis), one of the leading causes of blindness in the world.[citation needed] Serous cavity filariasis presents with symptoms similar to subcutaneous filariasis, in addition to abdominal pain, because these worms are also deep-tissue dwellers.
## Cause[edit]
Human filarial nematode worms have complicated life cycles, which primarily consists of five stages. After the male and female worms mate, the female gives birth to live microfilariae by the thousands. The microfilariae are taken up by the vector insect (intermediate host) during a blood meal. In the intermediate host, the microfilariae molt and develop into third-stage (infective) larvae. Upon taking another blood meal, the vector insect, such as Culex pipiens, injects the infectious larvae into the dermis layer of the skin. After about one year, the larvae molt through two more stages, maturing into the adult worms.[citation needed]
## Diagnosis[edit]
Microfilaria of Dirofilaria immitis (Heartworms) in a lymph node of a dog with lymphoma. This baby nematode is in a pillow of intermediate-to-large, immature lymphocytes, exhibiting multiple criteria of cancer.[3]
Filariasis is usually diagnosed by identifying microfilariae on Giemsa stained, thin and thick blood film smears, using the "gold standard" known as the finger prick test. The finger prick test draws blood from the capillaries of the finger tip; larger veins can be used for blood extraction, but strict windows of the time of day must be observed. Blood must be drawn at appropriate times, which reflect the feeding activities of the vector insects. Examples are W. bancrofti, whose vector is a mosquito; night is the preferred time for blood collection. Loa loa's vector is the deer fly; daytime collection is preferred. This method of diagnosis is only relevant to microfilariae that use the blood as transport from the lungs to the skin. Some filarial worms, such as M. streptocerca and O. volvulus, produce microfilarae that do not use the blood; they reside in the skin only. For these worms, diagnosis relies upon skin snips and can be carried out at any time.[citation needed]
### Concentration methods[edit]
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Various concentration methods are applied: membrane filter, Knott's concentration method, and sedimentation technique.
Polymerase chain reaction (PCR) and antigenic assays, which detect circulating filarial antigens, are also available for making the diagnosis. The latter are particularly useful in amicrofilaraemic cases. Spot tests for antigen[4] are far more sensitive, and allow the test to be done anytime, rather in the late hours.
Lymph node aspirate and chylous fluid may also yield microfilariae. Medical imaging, such as CT or MRI, may reveal "filarial dance sign" in the chylous fluid; X-ray tests can show calcified adult worms in lymphatics. The DEC provocation test is performed to obtain satisfying numbers of parasites in daytime samples. Xenodiagnosis is now obsolete, and eosinophilia is a nonspecific primary sign.
## Treatment[edit]
The recommended treatment for people outside the United States is albendazole combined with ivermectin.[5][6] A combination of diethylcarbamazine and albendazole is also effective.[5][7] Side effects of the drugs include nausea, vomiting, and headaches.[8] All of these treatments are microfilaricides; they have no effect on the adult worms. While the drugs are critical for treatment of the individual, proper hygiene is also required.[9] There is good evidence that albendazole alone; or addition of albendazole to diethylcarbamazine or ivermectin, makes minimal difference in clearing microfilaria or adult worms from blood circulation.[10] Diethylcarbamazine-medicated salt is effective in controlling lymphatic filariasis while maintaining its coverage at 90% in the community for six months.[11]
Different trials were made to use the known drug at its maximum capacity in absence of new drugs. In a study from India, it was shown that a formulation of albendazole had better anti-filarial efficacy than albendazole itself.[12][non-primary source needed]
In 2003, the common antibiotic doxycycline was suggested for treating elephantiasis.[13] Filarial parasites have symbiotic bacteria in the genus Wolbachia, which live inside the worm and seem to play a major role in both its reproduction and the development of the disease. This drug has shown signs of inhibiting the reproduction of the bacteria, further inducing sterility.[7] Clinical trials in June 2005 by the Liverpool School of Tropical Medicine reported an eight-week course almost completely eliminated microfilaraemia.[14][non-primary source needed] [15]
## Society and culture[edit]
### Research teams[edit]
In 2015 William C. Campbell and Satoshi Ōmura were co-awarded half of that year's Nobel prize in Physiology or Medicine for the discovery of the drug avermectin, which, in the further developed form ivermectin, has decreased the occurrence of lymphatic filariasis.[15]
### Prospects for elimination[edit]
Filarial diseases in humans offer prospects for elimination by means of vermicidal treatment. If the human link in the chain of infection can be broken, then notionally the disease could be wiped out in a season. In practice it is not quite so simple, and there are complications in that multiple species overlap in certain regions and double infections are common. This creates difficulties for routine mass treatment because people with onchocerciasis in particular react badly to treatment for lymphatic filariasis.[16]
## Other animals[edit]
Filariasis can also affect domesticated animals, such as cattle, sheep, and dogs.
### Cattle[edit]
* Verminous hemorrhagic dermatitis is a clinical disease in cattle due to Parafilaria bovicola.
* Intradermal onchocerciasis of cattle results in losses in leather due to Onchocerca dermata, O. ochengi, and O. dukei. O. ochengi is closely related to human O. volvulus (river blindness), sharing the same vector, and could be useful in human medicine research.
* Stenofilaria assamensis and others cause different diseases in Asia, in cattle and zebu.
### Horses[edit]
* "Summer bleeding" is hemorrhagic subcutaneous nodules in the head and upper forelimbs, caused by Parafilaria multipapillosa (North Africa, Southern and Eastern Europe, Asia and South America).[17]
### Dogs[edit]
* Heart filariasis is caused by Dirofilaria immitis.
## See also[edit]
* Ascariasis
* Eradication of infectious diseases
* Helminthiasis
* List of parasites (human)
* Neglected tropical diseases
## References[edit]
1. ^ Center for Disease Control and Prevention. "Lymphatic Filariasis". Retrieved 18 July 2010.
2. ^ a b "Lymphatic filariasis". Health Topics A to Z. Source: The World Health Organization. Retrieved 24 March 2013.
3. ^ Wheeler L. "Microfilaria of Dirofilaria immitis (Heartworms) Surrounded by Neoplastic Lymphocytes". Flickr. Retrieved 2 December 2017.
4. ^ "Seva Fila" (PDF). JB Tropical Disease Research Centre & Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences.
5. ^ a b The Carter Center, Lymphatic Filariasis Elimination Program, retrieved 17 July 2008
6. ^ U.S. Centers for Disease Control, Lymphatic Filariasis Treatment, retrieved 17 July 2008
7. ^ a b Taylor MJ, Hoerauf A, Bockarie M (October 2010). "Lymphatic filariasis and onchocerciasis". Lancet. 376 (9747): 1175–85. doi:10.1016/s0140-6736(10)60586-7. PMID 20739055. S2CID 29589578.
8. ^ Turkington CA. "Filariasis". The Gale Encyclopedia of Public Health. 1: 351–353.
9. ^ Hewitt K, Whitworth JA (1 August 2005). "Filariasis". Medicine. 33 (8): 61–64. doi:10.1383/medc.2005.33.8.61.
10. ^ Macfarlane CL, Budhathoki SS, Johnson S, Richardson M, Garner P (January 2019). "Albendazole alone or in combination with microfilaricidal drugs for lymphatic filariasis". The Cochrane Database of Systematic Reviews. 1 (1): CD003753. doi:10.1002/14651858.CD003753.pub4. PMC 6354574. PMID 30620051.
11. ^ Adinarayanan S, Critchley J, Das PK, Gelband H, et al. (Cochrane Infectious Diseases Group) (January 2007). "Diethylcarbamazine (DEC)-medicated salt for community-based control of lymphatic filariasis". The Cochrane Database of Systematic Reviews (1): CD003758. doi:10.1002/14651858.CD003758.pub2. PMC 6532694. PMID 17253495.
12. ^ Gaur RL, Dixit S, Sahoo MK, Khanna M, Singh S, Murthy PK (April 2007). "Anti-filarial activity of novel formulations of albendazole against experimental brugian filariasis". Parasitology. 134 (Pt 4): 537–44. doi:10.1017/S0031182006001612. PMID 17078904.
13. ^ Hoerauf A, Mand S, Fischer K, Kruppa T, Marfo-Debrekyei Y, Debrah AY, Pfarr KM, Adjei O, Buttner DW (2003), "Doxycycline as a novel strategy against bancroftian filariasis-depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production", Med Microbiol Immunol (Berl), 192 (4): 211–6, doi:10.1007/s00430-002-0174-6, PMID 12684759, S2CID 23349595
14. ^ Taylor MJ, Makunde WH, McGarry HF, Turner JD, Mand S, Hoerauf A (2005), "Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomised placebo-controlled trial", Lancet, 365 (9477): 2116–21, doi:10.1016/S0140-6736(05)66591-9, PMID 15964448, S2CID 21382828
15. ^ a b Andersson J, Forssberg H, Zierath JR (5 October 2015), "Avermectin and Artemisinin - Revolutionary Therapies against Parasitic Diseases" (PDF), The Nobel Assembly at Karolinska Institutet, retrieved 5 October 2015
16. ^ Ndeffo-Mbah ML, Galvani AP (April 2017). "Global elimination of lymphatic filariasis". The Lancet. Infectious Diseases. 17 (4): 358–359. doi:10.1016/S1473-3099(16)30544-8. PMID 28012944.
17. ^ Pringle H (3 March 2011), The Emperor and the Parasite, retrieved 9 March 2011
## Further reading[edit]
* "Special issue", Indian Journal of Urology, 21 (1), January–June 2005
* "Filariasis". Therapeutics in Dermatology. June 2012. Retrieved 24 July 2012.
## External links[edit]
Classification
D
* ICD-10: B74
* ICD-9-CM: 125.0-125.9
* MeSH: D005368
External resources
* Patient UK: Filariasis
Wikimedia Commons has media related to Filariases.
* Page from the "Merck Veterinary Manual" on "Parafilaria multipapillosa" in horses
* v
* t
* e
Parasitic disease caused by helminthiases
Flatworm/
platyhelminth
infection
Fluke/trematode
(Trematode infection)
Blood fluke
* Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum
* Schistosomiasis
* Trichobilharzia regenti
* Swimmer's itch
Liver fluke
* Clonorchis sinensis
* Clonorchiasis
* Dicrocoelium dendriticum / D. hospes
* Dicrocoeliasis
* Fasciola hepatica / F. gigantica
* Fasciolosis
* Opisthorchis viverrini / O. felineus
* Opisthorchiasis
Lung fluke
* Paragonimus westermani / P. kellicotti
* Paragonimiasis
Intestinal fluke
* Fasciolopsis buski
* Fasciolopsiasis
* Metagonimus yokogawai
* Metagonimiasis
* Heterophyes heterophyes
* Heterophyiasis
Cestoda
(Tapeworm infection)
Cyclophyllidea
* Echinococcus granulosus / E. multilocularis
* Echinococcosis
* Taenia saginata / T. asiatica / T. solium (pork)
* Taeniasis / Cysticercosis
* Hymenolepis nana / H. diminuta
* Hymenolepiasis
Pseudophyllidea
* Diphyllobothrium latum
* Diphyllobothriasis
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*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
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| Filariasis | c0016085 | 2,429 | wikipedia | https://en.wikipedia.org/wiki/Filariasis | 2021-01-18T18:57:02 | {"mesh": ["D005368"], "orphanet": ["2034"], "wikidata": ["Q815753"]} |
Group of brain diseases induced by prions
Transmissible spongiform encephalopathy
Other namesPrion disease
SpecialtyInfectious disease
SymptomsDementia, seizures, tremors, insomnia, psychosis, delirium, confusion
Usual onsetMonths to decades
TypesBovine spongiform encephalopathy, Fatal familial insomnia, Creutzfeldt-Jakob disease, kuru, scrapie, chronic wasting disease, Gerstmann-Sträussler-Scheinker syndrome, feline spongiform encephalopathy, transmissible mink encephalopathy, exotic ungulate encephalopathy
CausesPrion
Risk factorsContact with infected fluids, ingestion of infected flesh, having one or two parents that have the disease (in case of fatal familial insomnia)
Diagnostic methodCurrently there is no way to reliably detect prions except at post-mortem
PreventionVaries
Treatmentpalliative care
PrognosisInvariably fatal
FrequencyRare
Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal, conditions that are associated with prions and affect the brain (encephalopathies) and nervous system of many animals, including humans, cattle, and sheep. According to the most widespread hypothesis, they are transmitted by prions, though some other data suggest an involvement of a Spiroplasma infection.[1] Mental and physical abilities deteriorate and many tiny holes appear in the cortex causing it to appear like a sponge when brain tissue obtained at autopsy is examined under a microscope. The disorders cause impairment of brain function, including memory changes, personality changes and problems with movement that worsen chronically.
TSEs of humans include Creutzfeldt–Jakob disease—which has four main forms, the sporadic (sCJD), the hereditary/familial (fCJD), the iatrogenic (iCJD) and the variant form (vCJD)—Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, and the recently discovered variably protease-sensitive prionopathy and familial spongiform encephalopathy. These conditions form a spectrum of diseases with overlapping signs and symptoms. TSEs in non-human mammals include scrapie in sheep, bovine spongiform encephalopathy (BSE)—popularly known as "mad cow's disease"—in cattle and chronic wasting disease (CWD)—also known as 'zombie deer disease'—in deer and elk. The variant form of Creutzfeldt–Jakob disease is caused by exposure to bovine spongiform encephalopathy prions.[2][3][4]
Unlike other kinds of infectious disease, which are spread by agents with a DNA or RNA genome (such as virus or bacteria), the infectious agent in TSEs is believed to be a prion, thus being composed solely of protein material. Misshapen prion proteins carry the disease between individuals and cause deterioration of the brain. TSEs are unique diseases in that their aetiology may be genetic, sporadic, or infectious via ingestion of infected foodstuffs and via iatrogenic means (e.g., blood transfusion).[5] Most TSEs are sporadic and occur in an animal with no prion protein mutation. Inherited TSE occurs in animals carrying a rare mutant prion allele, which expresses prion proteins that contort by themselves into the disease-causing conformation. Transmission occurs when healthy animals consume tainted tissues from others with the disease. In the 1980s and 1990s, bovine spongiform encephalopathy spread in cattle in an epidemic fashion. This occurred because cattle were fed the processed remains of other cattle, a practice now banned in many countries. In turn, consumption (by humans) of bovine-derived foodstuff which contained prion-contaminated tissues resulted in an outbreak of the variant form of Creutzfeldt–Jakob disease in the 1990s and 2000s.[6]
Prions cannot be transmitted through the air or through touching or most other forms of casual contact. However, they may be transmitted through contact with infected tissue, body fluids, or contaminated medical instruments. Normal sterilization procedures such as boiling or irradiating materials fail to render prions non-infective. However, treatment with strong almost undiluted bleach &/or sodium hydroxide, or heating to a minimum of 134ºC, does destroy prions.[7]
## Contents
* 1 Classification
* 2 Features
* 3 Cause
* 3.1 Genetics
* 3.2 Protein-only hypothesis
* 3.3 Multi-component hypothesis
* 3.4 Spiroplasma hypothesis
* 3.5 Viral hypothesis
* 4 Diagnosis
* 5 Epidemiology
* 6 History
* 7 References
* 8 External links
## Classification
Known spongiform encephalopathies ICTVdb Code Disease name Natural host Prion name PrP isoform Ruminant
Non-human mammals
90.001.0.01.001. Scrapie Sheep and goats Scrapie prion PrPSc Yes
90.001.0.01.002. Transmissible mink encephalopathy (TME) Mink TME prion PrPTME No
90.001.0.01.003. Chronic wasting disease (CWD) Elk, White-tailed deer, Mule Deer and Red Deer CWD prion PrPCWD Yes
90.001.0.01.004. Bovine spongiform encephalopathy (BSE)
commonly known as "Mad Cow Disease" Cattle BSE prion PrPBSE Yes
90.001.0.01.005. Feline spongiform encephalopathy (FSE) Cats FSE prion PrPFSE No
90.001.0.01.006. Exotic ungulate encephalopathy (EUE) Nyala and greater kudu EUE prion PrPEUE Yes
Camel spongiform encephalopathy (CSE)[8] Camel PrPCSE Yes
Human diseases
90.001.0.01.007. Kuru Humans Kuru prion PrPKuru No
90.001.0.01.008. Creutzfeldt–Jakob disease (CJD) CJD prion PrPsCJD No
Variant Creutzfeldt–Jakob disease (vCJD, nvCJD) vCJD prion[9] PrPvCJD
90.001.0.01.009. Gerstmann-Sträussler-Scheinker syndrome (GSS) GSS prion PrPGSS No
90.001.0.01.010. Fatal familial insomnia (FFI) FFI prion PrPFFI No
Familial spongiform encephalopathy[10]
## Features
The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change, neuronal loss, astrocytosis, and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system in individual cases.[11]
The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait (ataxia). Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia) and lose the ability to move or speak.[12]
Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.
Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt–Jakob disease has been transmitted to patients taking injections of growth hormone harvested from human pituitary glands, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). It is also believed[by whom?] that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism or similar practices allow the proteins to accumulate over more than one generation. An example is kuru, which reached epidemic proportions in the mid-20th century in the Fore people of Papua New Guinea, who used to consume their dead as a funerary ritual.[13] Laws in developed countries now ban the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.
There exists evidence that prion diseases may be transmissible by the airborne route.[14]
Note that not all encephalopathies are caused by prions, as in the cases of PML (caused by the JC virus), CADASIL (caused by abnormal NOTCH3 protein activity), and Krabbe disease (caused by a deficiency of the enzyme galactosylceramidase). Progressive Spongiform Leukoencephalopathy (PSL)—which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant that causes it among heroin smokers has not yet been identified.[15][16][17][18] This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.
## Cause
### Genetics
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Mutations in the PRNP gene cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. In rare circumstances, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.
The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Under normal circumstances, this protein may be involved in transporting copper into cells. It may also be involved in protecting brain cells and helping them communicate. 24[citation needed] Point-Mutations in this gene cause cells to produce an abnormal form of the prion protein, known as PrPSc. This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.
Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.
In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.
### Protein-only hypothesis
Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrPC into PrPSc. Evidence for this hypothesis:
* Infectivity titre correlates with PrPSc levels. However, this is disputed.[19]
* PrPSc is an isomer of PrPC
* Denaturing PrP removes infectivity[20]
* PrP-null mice cannot be infected[21]
* PrPC depletion in the neural system of mice with established neuroinvasive prion infection reverses early spongeosis and behavioural deficits, halts further disease progression and increases life-span[22]
### Multi-component hypothesis
See also: Protein misfolding cyclic amplification
While not containing a nucleic acid genome, prions may be composed of more than just a protein. Purified PrPC appears unable to convert to the infectious PrPSc form, unless other components are added, such as RNA and lipids.[23] These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.
### Spiroplasma hypothesis
There is some disputed evidence for the role of bacteria of the Spiroplasma genus in the etiology of TSEs, primarily due to the work of Frank Bastian. The fact that PrPSc cannot be detected in about 10% of cases of CWD, while Bastian claims to have successfully cultured Spiroplasma spp. from the brains of 100% of deer with CWD and sheep with scrapie, which were able to spread the disease to other ruminants in the absence of PrPSc,[24] has led him and others to suspect that Spiroplasma infection may be the genuine cause of TSEs. Under this hypothesis PrPSc would merely be an imperfect marker of infection (with both sensitivity and NPV <1) either induced by Spiroplasma directly or by a defence mechanism of the host.
Other researchers have found no evidence for the Spiroplasma hypothesis of TSE causation.[25][26] Bastian however attributes the inability to find Spiroplasma in 100% of cases to genetic variability.[27] Bastian also stated that the authors of the hamster study used different primers for their PCR than he did, which could result in a false negative.
### Viral hypothesis
This hypothesis postulates that an as of yet undiscovered infectious viral agent is the cause of the disease. Evidence for this hypothesis is as follows:
* Incubation time is comparable to a lentivirus
* Strain variation of different isolates of PrPSc[28]
* An increasing titre of PrPSc as the disease progresses suggests a replicating agent.
## Diagnosis
There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrPSc form has started. At present, there is virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrPSc, but there are still no fully accepted methods for use in materials such as blood.
In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a hundred billion (10−11) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrPSc. After amplifying and then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared.[29][30]
## Epidemiology
Transmissible spongiform encephalopathies (TSE) are very rare but can reach epidemic proportions.[clarification needed] It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that, if animals at one farm begin to show the disease after an outbreak on a nearby farm, it is very difficult to determine whether it is the same strain affecting both herds—suggesting transmission—or if the second outbreak came from a completely different source.
Classic Creutzfeldt-Jakob disease (CJD) was discovered in 1920. It occurs sporadically over the world but is very rare. It affects about one person per million each year. Typically, the cause is unknown for these cases. It has been found to be passed on genetically in some cases. 250 patients contracted the disease through iatrogenic transmission (from use of contaminated surgical equipment).[31] This was before equipment sterilization was required in 1976, and there have been no other iatrogenic cases since then. In order to prevent the spread of infection, the World Health Organization created a guide to tell health care workers what to do when CJD appears and how to dispose of contaminated equipment.[32] The Centers for Disease Control and Prevention (CDC) have been keeping surveillance on CJD cases, particularly by looking at death certificate information.[33]
Chronic wasting disease (CWD) is a prion disease found in North America in deer and elk. The first case was identified as a fatal wasting syndrome in the 1960s. It was then recognized as a transmissible spongiform encephalopathy in 1978. Surveillance studies showed the endemic of CWD in free-ranging deer and elk spread in northeastern Colorado, southeastern Wyoming and western Nebraska. It was also discovered that CWD may have been present in a proportion of free-ranging animals decades before the initial recognition. In the United States, the discovery of CWD raised concerns about the transmission of this prion disease to humans. Many apparent cases of CJD were suspected transmission of CWD, however the evidence was lacking and not convincing.[34]
In the 1980s and 1990s, bovine spongiform encephalopathy (BSE or "mad cow disease") spread in cattle at an epidemic rate. The total estimated number of cattle infected was approximately 750,000 between 1980 and 1996. This occurred because the cattle were fed processed remains of other cattle. Then human consumption of these infected cattle caused an outbreak of the human form CJD. There was a dramatic decline in BSE when feeding bans were put in place. On May 20, 2003, the first case of BSE was confirmed in North America. The source could not be clearly identified, but researchers suspect it came from imported BSE-infected cow meat. In the United States, the USDA created safeguards to minimize the risk of BSE exposure to humans.[35]
Variant Creutzfeldt-Jakob disease (vCJD) was discovered in 1996 in England. There is strong evidence to suggest that vCJD was caused by the same prion as bovine spongiform encephalopathy.[36] A total of 231 cases of vCJD have been reported since it was first discovered. These cases have been found in a total of 12 countries with 178 in the United Kingdom, 27 in France, five in Spain, four in Ireland, four in the United States, three in the Netherlands, three in Italy, two in Portugal, two in Canada, and one each in Japan, Saudi Arabia, and Taiwan.[37]
## History
In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in man.[38] Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD.[39] In 1755, an outbreak of scrapie was discussed in the British House of Commons and may have been present in Britain for some time before that.[40] Although there were unsupported claims in 1759 that the disease was contagious, in general it was thought to be due to inbreeding and countermeasures appeared to be successful. Early-20th-century experiments failed to show transmission of scrapie between animals, until extraordinary measures were taken such as the intra-ocular injection of infected nervous tissue. No direct link between scrapie and disease in man was suspected then or has been found since. TSE was first described in man by Alfons Maria Jakob in the 1921.[41] Daniel Carleton Gajdusek's discovery that Kuru was transmitted by cannibalism accompanied by the finding of scrapie-like lesions in the brains of Kuru victims strongly suggested an infectious basis to TSE.[42] A paradigm shift to a non-nucleic infectious entity was required when the results were validated with an explanation of how a prion protein might transmit spongiform encephalopathy.[43] Not until 1988 was the neuropathology of spongiform encephalopathy properly described in cows.[44] The alarming amplification of BSE in the British cattle herd heightened fear of transmission to humans and reinforced the belief in the infectious nature of TSE. This was confirmed with the identification of a Kuru-like disease, called new variant Creutzfeldt–Jakob disease, in humans exposed to BSE.[45] Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission,[46] the search for a viral agent is being continued in some laboratories.[47][48]
## References
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25. ^ Leach R. H., Mathews W. B., Will R. (1983). "Creutzfeldt-Jakob disease". Journal of the Neurological Sciences. 59 (3): 349–353. doi:10.1016/0022-510x(83)90020-5. PMID 6348215.CS1 maint: multiple names: authors list (link)
26. ^ Alexeeva I., Elliott E. J., Rollins S., Gasparich G. E., Lazar J., Rohwer R. G. (2006). "Absence of Spiroplasma or Other Bacterial 16S rRNA Genes in Brain Tissue of Hamsters with Scrapie". Journal of Clinical Microbiology. 44 (1): 91–97. doi:10.1128/JCM.44.1.91-97.2006. PMC 1351941. PMID 16390954.CS1 maint: multiple names: authors list (link)
27. ^ Bastian, Frank O.; Foster, John W. (2001). "Spiroplasma sp.16S rDNA in Creutzfeldt-Jakob Disease and Scrapie as Shown by PCR and DNA Sequence Analysis". Journal of Neuropathology & Experimental Neurology. 60 (6): 613–620. doi:10.1093/jnen/60.6.613. PMID 11398837.
28. ^ Bruce ME (2003). "TSE strain variation". British Medical Bulletin. 66: 99–108. doi:10.1093/bmb/66.1.99. PMID 14522852.
29. ^ "Detecting Prions in Blood" (PDF). Microbiology Today.: 195. August 2010. Retrieved 2011-08-21.
30. ^ "SOFIA: An Assay Platform for Ultrasensitive Detection of PrPSc in Brain and Blood" (PDF). SUNY Downstate Medical Center. Retrieved 2011-08-19.
31. ^ "Transmissible Spongiform Encephalopathies (TSEs), also known as prion diseases | Anses - Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail". www.anses.fr. Retrieved 2017-11-09.
32. ^ "Infection Control | Creutzfeldt-Jakob Disease, Classic (CJD) | Prion Disease | CDC". www.cdc.gov. Retrieved 2017-11-09.
33. ^ "Surveillance for vCJD | Variant Creutzfeldt-Jakob Disease, Classic (CJD) | Prion Disease | CDC". www.cdc.gov. Retrieved 2017-11-09.
34. ^ Belay and Schonberger (2005). "The Public Health Impact of Prion Diseases" (PDF). Annual Review of Public Health. 26: 206–207. doi:10.1146/annurev.publhealth.26.021304.144536. PMID 15760286.
35. ^ Belay and Schonberger (2005). "The Public Health Impact of Prion Diseases" (PDF). Annual Review of Public Health. 26: 198–201. doi:10.1146/annurev.publhealth.26.021304.144536. PMID 15760286.
36. ^ "Variant Creutzfeldt-Jakob disease". World Health Organization. Retrieved 2017-11-09.
37. ^ "Risk for Travelers | Variant Creutzfeldt-Jakob Disease, Classic (CJD) | Prion Disease". www.cdc.gov. Retrieved 2017-11-09.
38. ^ McAlister, V (June 2005). "Sacred disease of our times: failure of the infectious disease model of spongiform encephalopathy". Clin Invest Med. 28 (3): 101–4. PMID 16021982. Retrieved 2011-06-20.
39. ^ Digesta Artis Mulomedicinae, Publius Flavius Vegetius Renatus
40. ^ Brown P, Bradley R; Bradley (December 1998). "1755 and all that: a historical primer of transmissible spongiform encephalopathy". BMJ. 317 (7174): 1688–92. doi:10.1136/bmj.317.7174.1688. PMC 1114482. PMID 9857129.
41. ^ Katscher F. (May 1998). "It's Jakob's disease, not Creutzfeldt's". Nature. 393 (6680): 11. Bibcode:1998Natur.393Q..11K. doi:10.1038/29862. PMID 9590681. S2CID 205000018.
42. ^ Gajdusek DC (Sep 1977). "Unconventional viruses and the origin and disappearance of kuru". Science. 197 (4307): 943–60. Bibcode:1977Sci...197..943C. doi:10.1126/science.142303. PMID 142303.
43. ^ Collins SJ, Lawson VA, Masters CL.; Lawson; Masters (Jan 2004). "Transmissible spongiform encephalopathies". Lancet. 363 (9204): 51–61. doi:10.1016/S0140-6736(03)15171-9. PMID 14723996. S2CID 23212525.CS1 maint: multiple names: authors list (link)
44. ^ Hope J, Reekie LJ, Hunter N, Multhaup G, Beyreuther K, White H, Scott AC, Stack MJ, Dawson M, Wells GA.; Reekie; Hunter; Multhaup; Beyreuther; White; Scott; Stack; Dawson; et al. (Nov 1988). "Fibrils from brains of cows with new cattle disease contain scrapie-associated protein". Nature. 336 (6197): 390–2. Bibcode:1988Natur.336..390H. doi:10.1038/336390a0. PMID 2904126. S2CID 4351199.CS1 maint: multiple names: authors list (link)
45. ^ Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG.; Ironside; Zeidler; Cousens; Estibeiro; Alperovitch; Poser; Pocchiari; Hofman; Smith (April 1996). "A new variant of Creutzfeldt–Jakob disease in the UK". Lancet. 347 (9006): 921–5. doi:10.1016/S0140-6736(96)91412-9. PMID 8598754. S2CID 14230097.CS1 maint: multiple names: authors list (link)
46. ^ McAlister, V (June 2005). "Sacred disease of our times: failure of the infectious disease model of spongiform encephalopathy". Clin Invest Med. 28 (3): 101–4. PMID 16021982. Retrieved 2011-06-20.
47. ^ Manuelidis L, Yu ZX, Barquero N, Banquero N, Mullins B; Yu; Banquero; Mullins (February 2007). "Cells infected with scrapie and Creutzfeldt–Jakob disease agents produce intracellular 25-nm virus-like particles". Proceedings of the National Academy of Sciences of the United States of America. 104 (6): 1965–70. Bibcode:2007PNAS..104.1965M. doi:10.1073/pnas.0610999104. PMC 1794316. PMID 17267596.CS1 maint: multiple names: authors list (link)
48. ^ "Infectious Particles". Manuelidis Lab.
* This entry incorporates public domain text originally from the National Institute of Neurological Disorders and Stroke, National Institutes of Health [1] and the U.S. National Library of Medicine [2]
## External links
Wikimedia Commons has media related to Transmissible spongiform encephalopathies.
* Transmissible spongiform encephalopathy at Curlie
Classification
D
* ICD-10: A81
* ICD-9-CM: 046
* MeSH: D017096
* DiseasesDB: 25165
External resources
* eMedicine: neuro/662
* v
* t
* e
Prion diseases and transmissible spongiform encephalopathy
Prion diseases
in humans
inherited/PRNP:
* fCJD
* Gerstmann–Sträussler–Scheinker syndrome
* Fatal familial insomnia
sporadic:
* sCJD
* Sporadic fatal insomnia
* Variably protease-sensitive prionopathy
acquired/
transmissible:
* iCJD
* vCJD
* Kuru
Prion diseases
in other animals
* Bovine spongiform encephalopathy
* Camel spongiform encephalopathy
* Scrapie
* Chronic wasting disease
* Transmissible mink encephalopathy
* Feline spongiform encephalopathy
* Exotic ungulate encephalopathy
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Transmissible spongiform encephalopathy | c0162534 | 2,430 | wikipedia | https://en.wikipedia.org/wiki/Transmissible_spongiform_encephalopathy | 2021-01-18T18:44:20 | {"mesh": ["D017096"], "umls": ["C0162534"], "icd-9": ["046"], "icd-10": ["A81"], "orphanet": ["56970"], "wikidata": ["Q703961"]} |
Not to be confused with polyurea or Frequent urination.
Polyuria
Other namesUrination - excessive amount[1]
Regulation of urine production by ADH and aldosterone
SpecialtyEndocrinology, nephrology
CausesPolydipsia, Psychogenic polydipsia[2][3]
Diagnostic methodUrine test and blood test[4]
TreatmentDepends on cause[5](See cause)
Polyuria (/ˌpɒliˈjʊəriə/) is excessive or an abnormally large production or passage of urine (greater than 2.5 L[1] or 3 L[6] over 24 hours in adults). Increased production and passage of urine may also be termed diuresis.[7][8] Polyuria often appears in conjunction with polydipsia (increased thirst), though it is possible to have one without the other, and the latter may be a cause or an effect. Primary polydipsia may lead to polyuria.[9] Polyuria is usually viewed as a symptom or sign of another disorder (not a disease by itself), but it can be classed as a disorder, at least when its underlying causes are not clear.[citation needed]
## Contents
* 1 Causes
* 1.1 List of causes
* 2 Mechanism
* 3 Diagnosis
* 4 Treatment
* 5 See also
* 6 References
* 7 Further reading
* 8 External links
## Causes[edit]
The most common cause of polyuria in both adults and children is uncontrolled diabetes mellitus,[6] which causes osmotic diuresis, when glucose levels are so high that glucose is excreted in the urine. Water follows the glucose concentration passively, leading to abnormally high urine output. In the absence of diabetes mellitus, the most common causes are decreased secretion of aldosterone due to adrenal cortical tumor, primary polydipsia (excessive fluid drinking), central diabetes insipidus and nephrogenic diabetes insipidus.[6] Polyuria may also be due to various chemical substances, such as diuretics, caffeine, and ethanol. It may also occur after supraventricular tachycardias, during an onset of atrial fibrillation, childbirth, and the removal of an obstruction within the urinary tract. Diuresis is controlled by antidiuretics such as vasopressin, angiotensin II and aldosterone. Cold diuresis is the occurrence of increased urine production on exposure to cold, which also partially explains immersion diuresis. High-altitude diuresis occurs at altitudes above 10,000 feet (3,000 m) and is a desirable indicator of adaptation to high altitudes. Mountaineers who are adapting well to high altitudes experience this type of diuresis. Persons who produce less urine even in the presence of adequate fluid intake are probably not adapting well to altitude.[medical citation needed]
Urinary tract infection (bacteria are black and bean-shaped)
### List of causes[edit]
Emphysematous cystitis
Lithium-carbonate
General
* polydipsia[3]
* psychogenic polydipsia[2]
* diuretic drugs, osmotic diuresis[10]
Urinary system
* interstitial cystitis[11]
* urinary tract infection [12]
* renal tubular acidosis[13]
* Fanconi syndrome[14]
* nephronophthisis (genetic)[15]
Hormonal
* hypokalemia[16]
* diabetes mellitus[17]
* corticosteroid use[18]
* pheochromocytoma[19]
* hyperparathyroidism[20]
* diabetes insipidus[21]
* hypercalcaemia[22]
* hyperthyroidism[23]
* hypopituitarism[24]
* Conn's disease[25]
* hyperglycaemia[26]
Circulation
* congestive heart failure[27]
* cardiorespiratory disease[28]
* postural orthostatic tachycardia syndrome (POTS)[29]
Neurologic
* cerebral salt-wasting syndrome[30]
* neurologic damage[31]
* migraine[32]
Other
* high doses of riboflavin (vitamin B2)[33]
* high doses of vitamin D[34]
* altitude diuresis[35]
* side effect of lithium[36]
* hemochromatosis[37]
* ochratoxicosis[38]
## Mechanism[edit]
Polyuria in osmotic cases, increases flow amount in the distal nephron where flow rates and velocity are low. The significant pressure increase occurring in the distal nephron takes place particularly in the cortical-collecting ducts. One study from 2008 lays out a hypothesis that hyperglycaemic and osmotic polyuria play roles ultimately in diabetic nephropathy.[39]
## Diagnosis[edit]
Among the possible tests to diagnose polyuria are:[4]
* Urine test
* FBC
* Blood test
* Pituitary function test
## Treatment[edit]
Depending on the cause of the polyuria, the adequate treatment should be afforded. According to NICE, desmopressin can be considered for nocturnal polyuria, which can be caused by diabetes mellitus,[5] if other medical treatments have failed. The recommendation had no studies that met the criteria for consideration.[40]
## See also[edit]
* Oliguria
## References[edit]
1. ^ a b "Urination – excessive amount". Medline Plus. United States National Library of Medicine. 27 December 2013. Retrieved 30 December 2014.
2. ^ a b Rudolf, Mary (2006). Paediatrics and Child Health (2nd ed.). Wiley. p. 142. ISBN 9781444320664. Retrieved 5 August 2015.
3. ^ a b Rippe, editors, Richard S. Irwin, James M. (2008). Irwin and Rippe's intensive care medicine (6th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 909. ISBN 978-0-7817-9153-3. Retrieved 5 August 2015.CS1 maint: extra text: authors list (link)
4. ^ a b "Polyuria. Medical Professional reference for Polyuria. | Patient". Patient. Retrieved 2015-11-08.
5. ^ a b Merseburger, Axel S.; Kuczyk, Markus A.; Moul, Judd W. (2014-10-21). Urology at a Glance. Springer. ISBN 9783642548598.
6. ^ a b c "Polyuria". Merck Manuals. November 2013. Retrieved 30 December 2014.
7. ^ "Definition of Diuresis". MedTerms. 30 October 2013. Retrieved 30 December 2014.
8. ^ "Diuresis". The Free Dictionary. Retrieved 30 December 2014.
9. ^ Parthasarathy, A. (2014-04-30). Case Scenarios in Pediatric and Adolescent Practice. JP Medical Ltd. ISBN 9789351520931.
10. ^ Ronco, Claudio (2009). Critical Care Nephrology (2nd ed.). Saunders. p. 475. ISBN 978-1416042525. Retrieved 5 August 2015.
11. ^ Paulman, Paul (2012). Signs and Symptoms in Family Medicine: A Literature-Based Approach. Elsevier. p. 432. ISBN 978-0323081320. Retrieved 5 August 2015.
12. ^ Drake, edited by Michael Glynn, William M. (2012). Hutchison's clinical methods : an integrated approach to clinical practice (23rd ed.). Edinburgh: Elsevier. p. 378. ISBN 978-0-7020-4091-7. Retrieved 5 August 2015.CS1 maint: extra text: authors list (link)
13. ^ Lee, [edited by] Mary (2013). Basic skills in interpreting laboratory data (5th ed.). Bethesda, Md.: American Society of Health-System Pharmacists. p. 132. ISBN 978-1-58528-343-9. Retrieved 5 August 2015.CS1 maint: extra text: authors list (link)
14. ^ Weissman, [edited by] Barbara N. (2009). Imaging of arthritis and metabolic bone disease. Philadelphia, PA: Mosby/Elsevier. p. 679. ISBN 978-0-323-04177-5. Retrieved 5 August 2015.CS1 maint: extra text: authors list (link)
15. ^ Radiology illustrated : pediatric radiology (1., 2013 ed.). [S.l.]: Springer. 2013. p. 761. ISBN 978-3-642-35572-1. Retrieved 6 August 2015.
16. ^ Chihan, Nina (2007). Nursing Interpreting Signs and Symptoms. Lippincott Williams & Wilkins. p. 481. ISBN 9781582556680. Retrieved 5 August 2015.
17. ^ Brickell, [edited by] Wendy Arneson, Jean (2007). Clinical chemistry : a laboratory perspective. Philadelphia: F.A. Davis Co. p. 411. ISBN 978-0-8036-1498-7. Retrieved 5 August 2015.CS1 maint: extra text: authors list (link)
18. ^ Soni, Andrew Bersten, Neil (2013). Oh's Intensive Care Manual (7. ed.). London: Elsevier Health Sciences. p. 643. ISBN 978-0-7020-4762-6. Retrieved 6 August 2015.
19. ^ "Pediatric Pheochromocytoma Clinical Presentation". Medscape.com. eMedicine. Retrieved 6 August 2015.
20. ^ Ghosh, Srinanda (2007). MCQ's in medical surgical nursing : (with explanatory answers) (1st ed.). New Delhi, India: Jaypee Bros. Medical Publishers (P) Ltd. p. 150. ISBN 978-81-8448-104-4. Retrieved 6 August 2015.
21. ^ Loscalzo, edited by Ajay K. Singh, Joseph (2014). The Brigham intensive review of internal medicine (Second ed.). p. 551. ISBN 978-0-19-935828-1. Retrieved 6 August 2015.CS1 maint: extra text: authors list (link)
22. ^ Acute medicine 201415. [S.l.]: Scion. 2014. p. 312. ISBN 978-1-907904-25-7. Retrieved 6 August 2015.
23. ^ Mariani, Laura (2007). "The Renal Manifestations of Thyroid Disease". Journal of the American Society of Nephrology. 23 (1): 22–26. doi:10.1681/ASN.2010070766. PMID 22021708. Retrieved 6 August 2015.
24. ^ "Panhypopituitarism Clinical Presentation". Medscape.com. eMedicine. Retrieved 6 August 2015.
25. ^ Kost, Michael (2004). Moderate sedation/analgesia : core competencies for practice (2nd ed.). St. Louis, Missouri.: Saunders. p. 43. ISBN 978-0-7216-0324-7. Retrieved 6 August 2015.
26. ^ Schwartz, M. William Schwartz; et al., eds. (2012). The 5-minute pediatric consult (6th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 270. ISBN 978-1-4511-1656-4. Retrieved 6 August 2015.
27. ^ Abrams, Paul (2006). Urodynamics (3. ed.). London: Springer. p. 120. ISBN 978-1-85233-924-1. Retrieved 6 August 2015.
28. ^ Leslie, Shern L. Chew, David (2006). Clinical endocrinology and diabetes. Edinburgh: Churchill Livingstone/Elsevier. p. 21. ISBN 978-0443073038.
29. ^ Pavord, Sherif Gonem; foreword by Ian (2010). Diagnosis in acute medicine. Oxford: Radcliffe Pub. p. 44. ISBN 978-184619-433-7. Retrieved 6 August 2015.
30. ^ Shanley, edited by Derek S. Wheeler, Hector R. Wong, Thomas P. (2014). A Systems Approach (2nd ed.). Springer Verlag. p. 635. ISBN 978-1-4471-6355-8. Retrieved 6 August 2015.CS1 maint: extra text: authors list (link)
31. ^ Parker, Rolland S. (2012). Concussive brain trauma neurobehavioral impairment and maladaptation (Second ed.). Boca Raton, FL: CRC Press. p. 322. ISBN 978-1-4200-0798-5. Retrieved 6 August 2015.
32. ^ "Migraine Headache Clinical Presentation". Medscape.com. eMedicine. Retrieved 6 August 2015.
33. ^ McKee, Mitchell Bebel Stargrove, Jonathan Treasure, Dwight L. (2008). Herb, nutrient, and drug interactions : clinical implications and therapeutic strategies. St. Louis, Mo.: Mosby/Elsevier. p. 267. ISBN 978-0-323-02964-3. Retrieved 6 August 2015.
34. ^ Watkins, edited by W. Allan Walker, John B. (1997). Nutrition in pediatrics : basic science and clinical application (2nd ed.). Hamilton, Ont.: B.C. Decker. p. 205. ISBN 978-1-55009-026-0. Retrieved 6 August 2015.CS1 maint: extra text: authors list (link)
35. ^ Swienton, editors, Richard B. Schwartz, John G. McManus Jr., Raymond E. (2008). Tactical emergency medicine. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 75. ISBN 978-0-7817-7332-4. Retrieved 6 August 2015.CS1 maint: extra text: authors list (link)
36. ^ Vyas, JN (2008). Textbook of Postgraduate Psychiatry (2 Vols.). Jaypee Brothers Publishing. p. 761. ISBN 978-81-7179-648-9. Retrieved 6 August 2015.
37. ^ "Hemochromatosis Clinical Presentation". Medscape.com. eMedicine. Retrieved 6 August 2015.
38. ^ J. W. Bennett; M. Klich (2003). "Mycotoxins". Clin Microbiol Rev. 16 (3): 497–516. doi:10.1128/CMR.16.3.497-516.2003. PMC 164220. PMID 12857779.
39. ^ Wang, Shinong; Mitu, Grace M.; Hirschberg, Raimund (2008-07-01). "Osmotic polyuria: an overlooked mechanism in diabetic nephropathy". Nephrology Dialysis Transplantation. 23 (7): 2167–2172. doi:10.1093/ndt/gfn115. ISSN 0931-0509. PMID 18456680.
40. ^ "Nocturia and nocturnal polyuria in men with lower urinary tract symptoms: oral desmopressin | key-points-from-the-evidence | Advice | NICE". www.nice.org.uk. Retrieved 2015-08-03.
## Further reading[edit]
* Movig, K. L. L.; Baumgarten, R.; Leufkens, H. G. M.; Laarhoven, J. H. M. Van; Egberts, A. C. G. (2003-04-01). "Risk factors for the development of lithium-induced polyuria". The British Journal of Psychiatry. 182 (4): 319–323. doi:10.1192/bjp.182.4.319. ISSN 0007-1250. PMID 12668407.
* Kreder, Karl; Dmochowski, Roger (2007-07-10). The Overactive Bladder: Evaluation and Management. CRC Press. ISBN 9780203931622.
## External links[edit]
Classification
D
* ICD-10: R35
* ICD-9-CM: 788.42
* MeSH: D011141
External resources
* MedlinePlus: 003146
* Patient UK: Polyuria
Scholia has a topic profile for Polyuria.
* v
* t
* e
Symptoms and signs relating to the urinary system
Pain
* Dysuria
* Renal colic
* Costovertebral angle tenderness
* Vesical tenesmus
Control
* Urinary incontinence
* Enuresis
* Diurnal enuresis
* Giggling
* Nocturnal enuresis
* Post-void dribbling
* Stress
* Urge
* Overflow
* Urinary retention
Volume
* Oliguria
* Anuria
* Polyuria
Other
* Lower urinary tract symptoms
* Nocturia
* urgency
* frequency
* Extravasation of urine
* Uremia
Eponymous
* Addis count
* Brewer infarcts
* Lloyd's sign
* Mathe's sign
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Polyuria | c0032617 | 2,431 | wikipedia | https://en.wikipedia.org/wiki/Polyuria | 2021-01-18T18:33:06 | {"mesh": ["D011141"], "umls": ["C0032617"], "icd-9": ["788.42"], "icd-10": ["R35"], "wikidata": ["Q1124286"]} |
HIV superinfection (also called HIV reinfection or SuperAIDS) is a condition in which a person with an established human immunodeficiency virus infection acquires a second strain of HIV, often of a different subtype.[1] These can form a recombinant strain that co-exists with the strain from the initial infection, as well from reinfection with a new virus strain, and may cause more rapid disease progression or carry multiple resistances to certain HIV medications.
HIV superinfection may be interclade, where the second infecting virus is phylogenetically distinct from the initial virus, or intraclade, where the two strains are monophyletic.[2]
People with HIV risk superinfection by the same actions that would place a non-infected person at risk of acquiring HIV. These include sharing needles and forgoing condoms with HIV-positive sexual partners.[3] Cases have been reported globally and studies have shown the incidence rate to be 0–7.7% per year.[3] Research from Uganda published in 2012 indicates that HIV superinfection among HIV-infected individuals within a general population remains unknown.[2] Further research from The Journal of Infectious Diseases indicates that there have been 16 documented cases of superinfection since 2002.[2]
"If a person is infected with a second virus before seroconversion to the first virus has taken place, it is termed a dual infection. Infection with a second strain after seroconversion is known as superinfection."[4]
## Contents
* 1 Immunology
* 2 Causes
* 3 Mechanism
* 3.1 Loss of immune control
* 3.2 Recombination
* 3.2.1 Circulating recombinant forms
* 3.2.2 Unique recombinant forms
* 4 Diagnosis
* 5 Prognosis
* 6 Epidemiology
* 7 History
* 8 Implications for treatment and care
* 8.1 Drug resistance
* 8.2 Impact on vaccine development
* 8.3 Impact on clinical care
* 9 References
## Immunology[edit]
A study conducted in Kenya in 2007 shows that superinfection tends to occur during the course of the initial infection, that is during acute infection, or 1–5 years after initial infection, but not during the latency period.[5] Thus, superinfection occurs after an immune response to the initial infection has already been established.[5]
It is unknown what aspects of the natural immune response to HIV may protect someone from superinfection, but it has been shown that cytotoxic lymphocyte responses do not seem to be protective.[6] Immune responses to initial infection with a particular strain of HIV do not provide protection against superinfection with a different strain.[5] The effect of neutralizing antibodies (NAb) is also unknown, but it has been shown that individuals with HIV tend not to have a NAb response prior to superinfection.[1]
In addition, it has been demonstrated that superinfection can occur in individuals that demonstrate a robust anti-HIV antibody response. The anti-HIV antibody response broadens and strengthens in individuals post-superinfection.[7] The finding that superinfection occurs within and between HIV subtypes suggests that an immune response to initial HIV infection provide limited protection against infection by a new viral strain.[3] This means that HIV-vaccine strategies made to replicate the host's immune response to HIV infection may not prevent new infections.[citation needed]
Studies indicate that superinfection causes a spike in HIV viral load and a decrease in CD4+ cell count similar to those reported during primary HIV infection.[3][8] Early studies of HIV superinfection analysed these spikes to diagnose cases of superinfection.[3] It is unclear whether superinfection causes a sustained increase in viral load.[3] The effect of superinfection on the progression of HIV infection is unclear because of its ambiguous effects on surrogate markers for the disease, such as an increase in viral load or a decrease in CD4 cell count.[1] The potential of superinfection to cause rapid disease progression depends on viral and host factors.[3]
Cases of superinfection are yet to be identified in sufficient numbers to conduct detailed studies on the effect of superinfection on the host immune response.[3]
## Causes[edit]
HIV superinfection is distinct from HIV dual infection, where an individual is simultaneously infected with multiple distinct viral strains. HIV superinfection involves an individual with HIV being infected by a new, phylogenetically distinct HIV strain.[3] Early reports of HIV superinfection were observed in cases of co-infection with HIV-1 and HIV-2.[3]
Studies have shown that a lack of neutralizing antibodies against HIV-1 infection predisposes patients to superinfection.[3] Additionally, the tendency of HIV-1 virions to recombine when two subtypes infect a single cell increases its susceptibility to HIV superinfection.[3] Further evidence of superinfection stems from the fact that nearly 10% of HIV-1 infections are associated with a transmittable recombinant strain.[3] HIV-1 virions are divided into nine subtypes, all of which are characterized by different rates of disease progression, viral load and sensitivity to assays used in detection.[3] When a single cell is infected by two HIV-1 subtypes, they recombine, forming a new, transmittable recombinant strain.[3]
## Mechanism[edit]
### Loss of immune control[edit]
Following initial acute HIV infection, CD8+ T-cells control viral replication and maintain it at a viral set point.[9] Following superinfection, CD8+ T-cells lose control over replication and it deviates from the set point.[9] The mechanism responsible for this is unknown.[9] A weakened T-cell response against the initial virus enables the superinfecting strain to resist immune control, resulting in an increased replication rate and subsequent viremia.[9][10] Increased viral load and a declining T-cell response enables the superinfecting strain to recombine rapidly, further decreasing immune control.[10]
### Recombination[edit]
HIV virions each contain a double-stranded RNA genome.[8] When superinfection occurs, cells contain 2 different HIV strains.[8] These can exchange genetic material such that an RNA strand from each strain is contained in a single virion.[8] As this progeny virion infects new cells, the RNA template transcribed by viral reverse transcriptase changes, resulting in a reverse transcript with genetic material from both parental viruses.[8] Recombination results in a rapid increase in HIV viral diversity, causing quicker adaptations to host immune response and resistance to ART.[8] Recombination tends to produce two distinct recombinant forms, the presence of which are used as evidence of dual infection.[8] The high prevalence of interclade recombinants increases the likelihood of superinfection being more widespread than reported.[11]
#### Circulating recombinant forms[edit]
Circulating recombinant forms (CRFs) are mosaic viruses - recombinants with randomly assorted genetic material from phylogenetically distinct parental viruses.[8] They spread geographically through human propagation, for example CRF02_AG, which is found in west and central Africa, as well as South America.[8] CRF's account for 10% of HIV infections worldwide.[8] There are 15 known CRFs, reported on 4 continents.[8] More recombinants are likely to arise in regions with a growing HIV epidemic and where viral clades intersect, including Africa, Southeast Asia and South America.[8]
#### Unique recombinant forms[edit]
Unique recombinant forms (URFs) are mosaic viruses that have not spread geographically.[8] They are also reported in areas where multiple viral clades intersect.[8]
In 2004, a study by AIDS on sex workers in Nairobi, Kenya reported URF generation in a woman initially infected with clade A, and then 9 years later acquired clade C, which recombined with the initial infecting virus to form a recombinant of clades A and C that fully replaced the parental clade A virions.[12]
## Diagnosis[edit]
Initial reports solely documented interclade superinfection, where patients are infected by a virus of a different clade from the initial virus.[1] This is because the viruses in initial cases were all subtypes of HIV-1, with at least a 30% difference in nucleotides in their envelope proteins that makes such superinfections easier to detect.[1]
Superinfection is identified by the detection of viral recombinants for phylogenetically distinct parent strains.[2]
Multiregion hybridisation assays are used to identify interclade superinfection by detecting genetic differences between parental and progeny strains.[3] Heteroduplex mobility assays can be used to sequence viral genetic material, allowing the detection of samples with a genetic difference exceeding 1.5%.[3]
Bulk sequencing is used to amplify viral RNA to enable the identification of new phylogenetic species in a patient over time.[3] However, this method is poor at detecting genetic differences at levels of 20% of lower.[3]
A third method, next-generation-sequencing assays, was developed in 2005.[13] It enables the rapid sequencing and screening of genomes, detecting genetic differences of 1% or less.[3]
There are no known methods to estimate the timing of superinfection.[3]
## Prognosis[edit]
Studies on individuals with superinfection with 2 strains of HIV showed a poorer prognosis.[14] Superinfection is correlated with a faster progression of the HIV infection.[14] Patients in studies have displayed a shorter lag between seroconversion and experiencing an AIDS-defining clinical condition or death.[14] However, it is unclear whether this rapid conversion is a direct effect of superinfection, or a result of a weaker immune response to the virus caused by superinfection.[14]
## Epidemiology[edit]
It is difficult to gain accurate estimations of the frequency of HIV superinfection because most studies are performed on patients infected with the HIV-1 B subtype, and recombinant strains are difficult to distinguish from the original strain for this subtype.[15]
HIV superinfection has been reported in the US, Canada, Europe, Australia, Asia, and Africa.[3] Data on the prevalence of superinfection has been gathered from case reports and observational studies, suggesting that it is underreported.[3]
Initial care reports and observational studies of superinfection were in men who have sex with men, intravenous drug users and female sex workers.[3] Incidence in heterosexual populations was first reported in rural Africa.[3]
Incidence rates have been reported as 0% to 7.7% annually, although this varies across populations and depends on the frequency of antiretroviral drug use, the length of the follow-up period, and the method used to detect superinfection.[3] However, a study in Uganda conducted using next-generation deep sequencing assays found that the rate of superinfection was large enough to be comparable to the primary HIV infection rate.[2]
Risk factors for superinfection are not clearly understood because of the small number of cases documented.[3] However, the risk factors for primary infection are considered to apply to superinfection, including:
* high number of sexual partners[3]
* limited condom use[3]
* no anti-retroviral use[3]
* detectable plasma viral load[16]
* absence of male circumcision[3]
* non-marital relationships[3]
The results of studies modeling the effect of HIV superinfection on viral recombination have suggested that superinfection has been instrumental in spurring community recombination rates.[17] However, these studies were based on several epidemiological assumptions that are yet to be verified.[17] These include assumptions about the pattern of HIV-1 transmission and that superinfection causes transmission to uninfected sexual partners.[3]
## History[edit]
1987 - First evidence of superinfection reported in studies of chimpanzees.[18]
1991 - HIV-1 found to superinfect HIV-2-infected cells in a study through inducing infection in cells cultured from HIV patient samples.[19]
1999 - In pig tailed macaques, a "window of susceptibility" demonstrated by showing that superinfection with a new viral strain was only possible after initial infection in macaques.[20]
2002 - First definitive study on superinfection after cases reported in IV drug users in Bangkok, Thailand.[21] The initial cases were all interclade superinfections.[21]
2003 - Intraclade infection by an immune response to one strain of HIV-1 cannot prevent superinfection with a second virus from the same clade.[22]
2005 - The ability of HIV superinfection to cause ART resistance.[11]
## Implications for treatment and care[edit]
### Drug resistance[edit]
Because of viral recombination, superinfection patients infected with at least one drug-resistant strain are likely to develop a mosaic recombinant strain with multi-drug resistance.[11] This lowers the potential success of ART.[11] Additionally, the existence of multiple strains of the virus in a host enhances interclade and intraclade recombination, accelerating global virus diversification for HIV.[16]
### Impact on vaccine development[edit]
Research on the development of an HIV-1 vaccine has sought to replicate virus-specific CD8+ T-cell responses, which play a role in the control of HIV-1 replication.[10] Superinfection case reports have shown that superinfecting strains generally had different viral epitopes from the initial infecting cell.[10] An immune response to the initial infection would, therefore, be ineffective against the super-infecting strain, leading to the proliferation of the superinfecting strain.[10]
An HIV-1 vaccine designed to recognize specific viral epitopes would be ineffective as it would not provide protection against HIV-1 viruses that do not share the same epitope.[10] Such an ineffective vaccine could also lead to faster disease progression than in unvaccinated individuals.[8] A successful vaccine would, therefore, have to incorporate viral epitopes derived from several viral subtypes.[21]
### Impact on clinical care[edit]
Increasing rates of antiretroviral therapy (ART) use have led to concerns about the development of drug-resistant strains which could be transmitted through superinfection.[3] Individuals with drug-resistant strains are vulnerable to superinfection with a susceptible strain of the virus, reversing the effect of ART's the clinical aspects of HIV infection.[3] Individuals with HIV were found to have a sudden increase in viral load, or a decrease in CD4 count should be tested for a resistant viral strain to identify the resistance profile of the secondary strain.[3]
Sexual practices, such as serosorting, place individuals with HIV infection at a higher risk of superinfection and other sexually transmitted diseases (STDs).[14] HIV positive individuals engaging in unprotected sex with seroconcordant partners require counseling on the risks of superinfection and STDs, both of which are expressed more virulently because of immunosuppression in HIV patients.[14] Counselling for HIV patients on the risk of HIV superinfection, and encouraging safe sexual and injection practices have shown an improvement in safer sexual practices, reducing the risk of superinfection.[3]
## References[edit]
1. ^ a b c d e Smith DM, Strain MC, Frost SD, Pillai SK, Wong JK, Wrin T, Liu Y, Petropolous CJ, Daar ES, Little SJ, Richman DD (November 2006). "Lack of neutralizing antibody response to HIV-1 predisposes to superinfection". Virology. 355 (1): 1–5. doi:10.1016/j.virol.2006.08.009. PMID 16962152.
2. ^ a b c d e Redd AD, Mullis CE, Serwadda D, Kong X, Martens C, Ricklefs SM, Tobian AA, Xiao C, Grabowski MK, Nalugoda F, Kigozi G, Laeyendecker O, Kagaayi J, Sewankambo N, Gray RH, Porcella SF, Wawer MJ, Quinn TC (July 2012). "The rates of HIV superinfection and primary HIV incidence in a general population in Rakai, Uganda". The Journal of Infectious Diseases. 206 (2): 267–74. doi:10.1093/infdis/jis325. PMC 3415936. PMID 22675216.
3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak Redd AD, Quinn TC, Tobian AA (July 2013). "Frequency and implications of HIV superinfection". The Lancet. Infectious Diseases. 13 (7): 622–8. doi:10.1016/s1473-3099(13)70066-5. PMC 3752600. PMID 23726798.
4. ^ Foley B.T. (2017). HIV and SIV Evolution. In: Shapshak P. et al. (eds) Global Virology II - HIV and NeuroAIDS. doi:10.1007/978-1-4939-7290-6_5.
5. ^ a b c Piantadosi A, Chohan B, Chohan V, McClelland RS, Overbaugh J (November 2007). "Chronic HIV-1 infection frequently fails to protect against superinfection". PLOS Pathogens. 3 (11): e177. doi:10.1371/journal.ppat.0030177. PMC 2077901. PMID 18020705.
6. ^ Blish CA, Dogan OC, Jaoko W, McClelland RS, Mandaliya K, Odem-Davis KS, Richardsonb BA, Overbaugh J (March 2012). "Cellular immune responses and susceptibility to HIV-1 superinfection: a case-control study". AIDS. 26 (5): 643–6. doi:10.1097/QAD.0b013e3283509a0b. PMC 3511787. PMID 22210637.
7. ^ Cortez V, Odem-Davis K, McClelland RS, Jaoko W, Overbaugh J (2012). "HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response". PLOS Pathogens. 8 (3): e1002611. doi:10.1371/journal.ppat.1002611. PMC 3315492. PMID 22479183.
8. ^ a b c d e f g h i j k l m n o Smith DM, Richman DD, Little SJ (August 2005). "HIV superinfection". The Journal of Infectious Diseases. 192 (3): 438–44. doi:10.1086/431682. PMID 15995957.
9. ^ a b c d Streeck H, Li B, Poon AF, Schneidewind A, Gladden AD, Power KA, Daskalakis D, Bazner S, Zuniga R, Brander C, Rosenberg ES, Frost SD, Altfeld M, Allen TM (August 2008). "Immune-driven recombination and loss of control after HIV superinfection". The Journal of Experimental Medicine. 205 (8): 1789–96. doi:10.1084/jem.20080281. PMC 2525594. PMID 18625749.
10. ^ a b c d e f Altfeld M, Allen TM, Yu XG, Johnston MN, Agrawal D, Korber BT, Montefiori DC, O'Connor DH, Davis BT, Lee PK, Maier EL, Harlow J, Goulder PJ, Brander C, Rosenberg ES, Walker BD (November 2002). "HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus". Nature. 420 (6914): 434–9. Bibcode:2002Natur.420..434A. doi:10.1038/nature01200. PMID 12459786. S2CID 52859094.
11. ^ a b c d Smith DM, Wong JK, Hightower GK, Ignacio CC, Koelsch KK, Petropoulos CJ, Richman DD, Little SJ (August 2005). "HIV drug resistance acquired through superinfection". AIDS. 19 (12): 1251–6. doi:10.1097/01.aids.0000180095.12276.ac. PMID 16052079. S2CID 1267726.
12. ^ Fang G, Weiser B, Kuiken C, Philpott SM, Rowland-Jones S, Plummer F, Kimani J, Shi B, Kaul R, Bwayo J, Anzala O, Burger H (January 2004). "Recombination following superinfection by HIV-1". AIDS. 18 (2): 153–9. doi:10.1097/00002030-200401230-00003. PMID 15075531. S2CID 24770809.
13. ^ "Method of the Year". Nature Methods. 5 (1): 1. January 2008. doi:10.1038/nmeth1153. PMID 18175409.
14. ^ a b c d e f Marcus J, McConnel JJ, Grant RM (2005). "HIV Superinfection vs Dual Initial Infection: What Clinicians and Patients Should Know". Medscape HIV/AIDS. 11 (1): 33.
15. ^ Yerly S, Jost S, Monnat M, Telenti A, Cavassini M, Chave JP, Kaiser L, Burgisser P, Perrin L (July 2004). "HIV-1 co/super-infection in intravenous drug users". AIDS. 18 (10): 1413–21. doi:10.1097/01.aids.0000131330.28762.0c. PMID 15199317. S2CID 24853737.
16. ^ a b Campbell MS, Gottlieb GS, Hawes SE, Nickle DC, Wong KG, Deng W, Lampinen TM, Kiviat NB, Mullins JI (May 2009). "HIV-1 superinfection in the antiretroviral therapy era: are seroconcordant sexual partners at risk?". PLOS ONE. 4 (5): e5690. Bibcode:2009PLoSO...4.5690C. doi:10.1371/journal.pone.0005690. PMC 2684644. PMID 19479055.
17. ^ a b Taylor JE, Korber BT (January 2005). "HIV-1 intra-subtype superinfection rates: estimates using a structured coalescent with recombination". Infection, Genetics and Evolution. 5 (1): 85–95. doi:10.1016/j.meegid.2004.07.001. PMID 15567142.
18. ^ Fultz PN, Srinivasan A, Greene CR, Butler D, Swenson RB, McClure HM (December 1987). "Superinfection of a chimpanzee with a second strain of human immunodeficiency virus". Journal of Virology. 61 (12): 4026–9. doi:10.1128/JVI.61.12.4026-4029.1987. PMC 256026. PMID 2446009.
19. ^ Le Guern M, Levy JA (January 1992). "Human immunodeficiency virus (HIV) type 1 can superinfect HIV-2-infected cells: pseudotype virions produced with expanded cellular host range". Proceedings of the National Academy of Sciences of the United States of America. 89 (1): 363–7. Bibcode:1992PNAS...89..363L. doi:10.1073/pnas.89.1.363. JSTOR 2358537. PMC 48237. PMID 1346069.
20. ^ Otten RA, Ellenberger DL, Adams DR, Fridlund CA, Jackson E, Pieniazek D, Rayfield MA (September 1999). "Identification of a window period for susceptibility to dual infection with two distinct human immunodeficiency virus type 2 isolates in a Macaca nemestrina (pig-tailed macaque) model". The Journal of Infectious Diseases. 180 (3): 673–84. doi:10.1086/314968. PMID 10438354.
21. ^ a b c Ramos A, Hu DJ, Nguyen L, Phan KO, Vanichseni S, Promadej N, Choopanya K, Callahan M, Young NL, McNicholl J, Mastro TD, Folks TM, Subbarao S (August 2002). "Intersubtype human immunodeficiency virus type 1 superinfection following seroconversion to primary infection in two injection drug users". Journal of Virology. 76 (15): 7444–52. doi:10.1128/JVI.76.15.7444-7452.2002. PMC 136380. PMID 12097556.
22. ^ Koelsch KK, Smith DM, Little SJ, Ignacio CC, Macaranas TR, Brown AJ, Petropoulos CJ, Richman DD, Wong JK (May 2003). "Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus". AIDS. 17 (7): F11-6. doi:10.1097/00002030-200305020-00001. PMID 12700477. S2CID 30023240.
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*[c.]: circa
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*[nM]: nanomolars
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*[NET]: Norepinephrine transporter
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| HIV superinfection | None | 2,432 | wikipedia | https://en.wikipedia.org/wiki/HIV_superinfection | 2021-01-18T18:52:10 | {"wikidata": ["Q4817339"]} |
Keratosis punctata of the palmar creases
Other namesHyperkeratosis penetrans, Hyperkeratosis punctata, Keratodermia punctata, Keratosis punctata, Keratotic pits of the palmar creases, Lenticular atrophia of the palmar creases, and Punctate keratosis of the palmar creases
SpecialtyDermatology
Keratosis punctata of the palmar creases is a common skin disorder that occurs most often in black patients, with skin lesions that are 1 to 5mm depressions filled with a comedo-like keratinous plug.[1]:212
Treatment with etretinate has been described.[2]
## See also[edit]
* Skin lesion
## References[edit]
1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
2. ^ Just M, Ribera M, Bielsa I, Calatrava A, Ferrándiz C (September 1999). "Keratotsis punctata of the palmar creases: report of two cases associated with ichthyosis vulgaris". Br. J. Dermatol. 141 (3): 551–3. doi:10.1046/j.1365-2133.1999.03058.x. PMID 10583067.
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
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A number sign (#) is used with this entry because DiGeorge syndrome is caused by a 1.5- to 3.0-Mb heterozygous deletion of chromosome 22q11.2. Haploinsufficiency of the TBX1 gene (602054) in particular is responsible for most of the physical malformations. There is evidence that point mutations in the TBX1 gene can also cause the disorder.
Description
DiGeorge syndrome (DGS) comprises hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and outflow tract defects of the heart. Disturbance of cervical neural crest migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype. Most cases result from a deletion of chromosome 22q11.2 (the DiGeorge syndrome chromosome region, or DGCR). Several genes are lost including the putative transcription factor TUPLE1 which is expressed in the appropriate distribution. This deletion may present with a variety of phenotypes: Shprintzen, or velocardiofacial, syndrome (VCFS; 192430); conotruncal anomaly face (or Takao syndrome); and isolated outflow tract defects of the heart including tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch. A collective acronym CATCH22 has been proposed for these differing presentations. A small number of cases of DGS have defects in other chromosomes, notably 10p13 (see 601362). In the mouse, a transgenic Hox A3 (Hox 1.5) knockout produces a phenotype similar to DGS as do the teratogens retinoic acid and alcohol.
Nomenclature
DiGeorge syndrome overlaps clinically with the disorder described by the Japanese as 'conotruncal anomaly face syndrome' (Kinouchi et al., 1976; Takao et al., 1980; Shimizu et al., 1984), where the cardiovascular presentation is the focus of attention. The term conotruncal anomaly face syndrome is cumbersome and has the disadvantage of using embryologic assumptions as a title. It would be appropriate to use Takao syndrome for those cases with a preponderant cardiac presentation in contrast to the low T cell and hypocalcemic presentation in infancy of DiGeorge syndrome and the craniofacial and palatal abnormalities typical of Shprintzen syndrome. These 3 phenotypes may be seen in the same family and most cases of all 3 categories have been shown to have a 22q11 deletion. This led Wilson et al. (1993) to propose the acronym CATCH22 (Cardiac Abnormality/abnormal facies, T cell deficit due to thymic hypoplasia, Cleft palate, Hypocalcemia due to hypoparathyroidism resulting from 22q11 deletion) as a collective acronym for those with the common genetic etiology. Shprintzen (1994) objected to 'lumping' velocardiofacial syndrome with the DiGeorge anomaly, arguing that there is 'no valid evidence to suggest that velocardiofacial syndrome is etiologically heterogeneous...[whereas] the DiGeorge anomaly is known to be so.' Hall (1993) cited data of Driscoll et al. (1993) indicating that velocardiofacial syndrome is etiologically heterogeneous. She stated that '...68% of Shprintzen syndrome patients...have been recognised to have deletions of 22q11.' Shprintzen (1994) refuted her statement, maintaining that it could accurately be stated that deletion was found in 68% of patients sent to the Driscoll laboratory with a diagnosis of velocardiofacial syndrome made by other clinicians. Shprintzen (1994) said that in his sample, 100% had deletion.
Burn (1999), one of the original proposers of the acronym CATCH22, reviewed the discussion of nomenclature. He recognized that the term CATCH22 had a number of negative connotations and that in practice different terms were in use for this phenotype and would continue to be so. Burn (1999) proposed that the term DiGeorge syndrome be reserved for those with neonatal presentation, particularly with thymic hypoplasia and hypocalcemia, and that the designation VCFS be used for children with a presentation dominated by nasal speech due to palatal insufficiency. He also suggested that 'conotruncal anomaly face' be replaced by 'Takao syndrome' and pointed out that the term '22q11 deletion syndrome' was reasonable. Finally, Burn (1999) proposed that 'CATCH phenotype' be used rather than CATCH22 and that the acronym be taken to represent cardiac abnormality, T cell deficit, clefting, and hypocalcemia.
Clinical Features
DiGeorge syndrome is characterized by neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells. The immune deficit is caused by hypoplasia or aplasia of the thymus gland. A variety of cardiac malformations are seen in particular affecting the outflow tract. These include tetralogy of Fallot, type B interrupted aortic arch, truncus arteriosus, right aortic arch and aberrant right subclavian artery. In infancy, micrognathia may be present. The ears are typically low set and deficient in the vertical diameter with abnormal folding of the pinna. Telecanthus with short palpebral fissures is seen. Both upward and downward slanting eyes have been described. The philtrum is short and the mouth relatively small. In the older child the features overlap Shprintzen syndrome (velocardiofacial syndrome) with a rather bulbous nose and square nasal tip and hypernasal speech associated with submucous or overt palatal clefting. Cases presenting later tend to have a milder spectrum of cardiac defect with ventricular septal defect being common.
Short stature and variable mild to moderate learning difficulties are common. A variety of psychiatric disorders have been described in a small proportion of adult cases of velocardiofacial syndrome. These have included paranoid schizophrenia and major depressive illness. Clinical features seen more rarely include hypothyroidism, cleft lip, and deafness.
Goodship et al. (1995) described monozygotic twin brothers with precisely the same 22q11.2 deletion but somewhat discordant clinical phenotype. Both twins had a small mouth, square nasal tip, short palpebral fissures, and small ears with deficient upper helices. Twin 1 had bilateral hair whorls and twin 2 had a right-sided hair whorl. Toes 4 and 5 were curled under bilaterally in both boys, this being more marked in twin 1. The twins were said to have had a single placenta although the findings of a detailed examination were not recorded. Twin 1 weighed 2,200 g and twin 2 weighed 2,800 g. Twin 1 had tetralogy of Fallot, which was repaired at 1 year of age. Twin 2 had a normal cardiovascular system. Twin 1 started taking steps at 24 months of age, while his brother stood at 13 months and walked steadily at 18 months. These observations indicated to Goodship et al. (1995) that differences in deletion size and modifying genetic loci are not responsible for all the phenotypic differences observed in CATCH22.
Vincent et al. (1999) reported the case of female monozygotic twins with 22q11 deletions. The twins shared facial characteristics of DGS/VCFS and immunologic defect. However, only one, who died on day 5, had a cardiac defect, comprised of an interrupted aortic arch with a ventricular septal defect, a truncus arteriosus, and a large arterial duct. The authors stated that this was the fourth report of a discrepant cardiac status between monozygotic twins harboring 22q11 deletions.
Wilson et al. (1992) looked for deletions in 9 families with 2 or more cases of outflow tract heart defects. In 5 of the families, chromosome 22 deletions were detected in all living affected persons studied and also in the clinically normal father of 3 affected children. The deletion was transmitted from parents to offspring and was associated with an increase in the severity of cardiac defects. No deletions were found in 4 families in which the parents were normal and affected sibs had anatomically identical defects, presumably an autosomal recessive form of congenital heart defect.
Fokstuen et al. (1998) analyzed 110 patients with nonselective syndromic or isolated nonfamilial congenital heart malformations by fluorescence in situ hybridization using the D22S75 DGS region probe. A 22q11.2 microdeletion was detected in 9 of 51 (17.6%) syndromic patients. Five were of maternal origin and 4 of paternal origin. None of the 59 patients with isolated congenital cardiac defect had the 22q11.2 deletion. In a study of 157 consecutively catheterized patients with isolated, nonsyndromic cardiac defects, and 25 patients with cardiac malformation and additional abnormalities (10 of whom had been clinically diagnosed as DiGeorge syndrome or velocardiofacial syndrome), Borgmann et al. (1999) found the 22q11.2 microdeletion only in the latter group.
Jawad et al. (2001) studied 195 patients with chromosome 22q11 deletion syndrome and found that diminished T-cell counts in the peripheral blood are common. The pattern of changes seen with aging in normal control patients was also seen in patients with the chromosome 22q11.2 deletion syndrome, although the decline in T cells was blunted. Autoimmune disease was seen in most age groups, although the types of disorders varied according to age. Infections were also common in older patients, although they were seldom life-threatening. Juvenile rheumatoid arthritis with onset between 1.5 and 6 years of age was seen in 4 of the 195 patients; idiopathic thrombocytopenia purpura with onset at 1 to 8 years of age was seen in 8 of 195 patients; autoimmune hemolytic anemia, psoriasis, vitiligo, inflammatory bowel disease, adult rheumatoid arthritis, and rheumatic fever with chorea were each seen in 1 patient of the 195 patients sampled.
Kawame et al. (2001) reported 5 patients with chromosome 22q11.2 deletion that manifested Graves disease between the ages of 27 months and 16 years, and suggested that Graves disease may be part of the clinical spectrum of this disorder.
Bassett et al. (2005) described the phenotypic features of 78 adults with 22q11 deletion syndrome and identified 43 distinct features present in more than 5% of patients. Common characteristic features included intellectual disabilities (92.3%), hypocalcemia (64%), palatal anomalies (42%), and cardiovascular anomalies (25.8%). Other less commonly appreciated features included obesity (35%), hypothyroidism (20.5%), hearing deficits (28%), cholelithiasis (19%), scoliosis (47%), and dermatologic abnormalities (severe acne, 23%; seborrhea, 35%). Significantly, schizophrenia was present in 22.6% of patients.
Maalouf et al. (2004) reported an African American male diagnosed at age 32 years with dysgenesis of the parathyroid glands due to a chromosome 22 microdeletion. Symptomatic hypocalcemia did not develop until age 14 years, a few weeks after initiation of anticonvulsant therapy for generalized tonic-clonic seizures. Because of the timing for onset of symptomatic hypocalcemia, it was presumed that the patient had anticonvulsant-induced hypocalcemia, and he carried that diagnosis for 18 years. Chromosome 22q11 deletion syndrome was first suspected at age 32 years. The diagnosis was confirmed by fluorescence in situ hybridization analysis. This case underscores the variable clinical presentation of this congenital form of hypoparathyroidism.
Kousseff (1984) described 3 sibs with a syndrome of sacral meningocele, conotruncal cardiac defects, unilateral renal agenesis (in 1 sib), low-set and posteriorly angulated ears, retrognathia, and short neck with low posterior hairline. Kousseff (1984) suggested autosomal recessive inheritance. Toriello et al. (1985) reported a similar, isolated case and designated the disorder Kousseff syndrome. Forrester et al. (2002) restudied the family reported by Kousseff (1984) and identified a 22q11-q13 deletion in the proband, his deceased brother, and his father. The proband had spina bifida, shunted hydrocephalus, cleft palate, short stature, cognitive impairment, and the typical craniofacial features of velocardiofacial syndrome, including low-set and dysplastic ears, broad base of the nose, narrow alae nasi, and retrognathia. His brother had died at 2 weeks of age with myelomeningocele, hydrocephalus, transposition of the great vessels, and unilateral renal agenesis, and his sister had died at 22 days of age with myelomeningocele, truncus arteriosus, hypocalcemia, and autopsy findings of absent thymus and parathyroid glands, consistent with DiGeorge anomaly.
Maclean et al. (2004) reported 2 unrelated patients with Kousseff syndrome, 1 with a 22q11.2 deletion and the other without. The first was a 4-year-old girl with a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum, and moderate developmental delay, who had a normal chromosome 22q11.2 FISH test and did not exhibit the facial phenotype of VCFS. The second patient, a male infant who died at 10 days of age, had a large sacral myelomeningocele, hydrocephalus, Arnold-Chiari malformation, atrial septal defect, conoventricular ventricular septal defect, type B interrupted aortic arch, hypocalcemia, and suspected duodenal stenosis; FISH testing revealed a 22q11.2 microdeletion. Maclean et al. (2004) concluded that Kousseff syndrome is a distinct clinical entity that is genetically heterogeneous.
Kujat et al. (2006) reported that 5 (83%) of 6 patients with a 22q11.2 microdeletion had renal anomalies, including renal dysplasia, hydronephrosis, and unilateral renal agenesis.
Robin et al. (2006) reviewed clinical data including brain imaging on 21 patients with polymicrogyria associated with deletion 22q11.2 and another 11 patients from the literature. The authors found that the cortical malformation consisted of perisylvian polymicrogyria of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (p = 0.008).
Forbes et al. (2007) reported the ocular features of 90 consecutive patients with confirmed 22q11.2 deletion syndrome. Posterior embryotoxon was found in 49%, tortuous retinal vessels in 34%, eyelid hooding in 20%, strabismus in 18%, ptosis in 4%, amblyopia in 4%, and tilted optic nerves in 1%.
Sundaram et al. (2007) described 2 patients with 22q11.2 deletion who had absent uterus and unilateral renal agenesis. One patient also had mild developmental delay, hypoparathyroidism, and psychiatric symptoms; the other patient also had high-arched palate, bulbous nasal tip, bicuspid aortic valve, short stature, and primary amenorrhea. Sundaram et al. (2007) suggested that mullerian or uterine/vaginal agenesis be included as part of the clinical spectrum of 22q11.2 deletion syndrome. Scheuerle (2008) reported a 14-year-old Latin American girl with 22q11.2 deletion syndrome who was found to have unilateral renal agenesis, uterine didelphys with duplication of the cervix, and imperforate vaginal hymen with hematometrocolpos.
Binenbaum et al. (2008) reported 4 boys and 3 girls with 22q11.2 deletion syndrome, including 5 who had bilateral sclerocornea. Other eye findings included descemetocele in 5 eyes, microphthalmia in 1 eye, severe anterior segment dysgenesis in 1 eye, and bilateral iridocorneal adhesions in 1 patient. Binenbaum et al. (2008) suggested that a genetic locus at chromosome 22q11.2 may be involved in anterior segment embryogenesis, and that sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome.
Cheung et al. (2014) used a logistic regression model to investigate potential predictors of intellectual disability severity, including neonatal hypocalcemia, neonatal seizures, and complex congenital heart disease in 149 adults with 22q11.2 deletion syndrome, 10 of whom had moderate to severe intellectual disability. The model was highly significant (p less than 0.0001), showing neonatal seizures (p = 0.0018) and neonatal hypocalcemia (p = 0.047) to be significant predictors of a more severe level of intellectual disability. Neonatal seizures were significantly associated with hypocalcemia in the entire sample, regardless of intellectual level.
Biochemical Features
Hypocalcemia secondary to hypoparathyroidism is the key biochemical feature and may be sufficiently severe to be symptomatic. Resolution in early childhood is typical, although the deficient function of the parathyroids may be exposed in adulthood by infusion of disodium edetate (EDTA) (Gidding et al., 1988).
The patient of Gidding et al. (1988) had isolated conotruncal cardiac defect and, despite normal baseline ionized calcium and midmolecule parathyroid hormone levels, she failed to increase the secretion of midmolecular parathyroid hormone appropriately in response to a hypocalcemic challenge. They speculated that this combination of latent-hypoparathyroidism (LHP) and conotruncal cardiac defects should be included in the clinical spectrum of DiGeorge anomaly. Indeed, this woman's fourth child died with DiGeorge anomaly. Seven years after the report by Gidding et al. (1988), Cuneo et al. (1997) restudied the index patient with LHP and evaluated 3 generations of her family for parathyroid dysfunction, cardiac anomalies, and del22q11. Deletions were found in 6 relatives, 3 with conotruncal cardiac defects and 3 with a structurally normal heart. They found significant transgenerational noncardiac phenotypic variability, including learning difficulties, dysmorphic facial appearance, and psychiatric illness. A spectrum of parathyroid gland dysfunction associated with the del22(q11) was seen, ranging from hypocalcemic hypoparathyroidism to normocalcemia with abnormally low basal intact parathyroid hormone levels. In addition, LPH found in the index patient 7 years previously had evolved to frank hypocalcemic hypoparathyroidism.
Other Features
The deficit in thymic function results in a lack of T cells which may be demonstrated by measuring the proportion of CD4 cells (Wilson et al., 1993). Immunohistochemical analysis of the parathyroids reveals a deficit of thyrocalcitonin immunoreactive cells (C cells) (Palacios et al., 1993).
Levy et al. (1997) stated that 10 to 25% of parents of patients with DGS exhibit the 22q11 deletion but are nearly asymptomatic. The authors described 2 female patients carrying a 22q11 microdeletion who presented with idiopathic thrombocytopenic purpura. Both had children with typical manifestations of DGS. The possibility that defective thymic function predisposes patients with DGS to autoimmune diseases was raised.
Evers et al. (2006) reported a 52-year-old man with 22q11.2 deletion. As a child he showed learning disabilities and behavioral problems. As a young adult, he exhibited aggressive outbursts, apathy, echolalia, perseverations, and psychotic features, including delusional thoughts and hallucinations, necessitating long-term care in a psychiatric facility. Since then, he has demonstrated aggressive behavior, periods of withdrawal, and progressive cognitive decline consistent with dementia, particularly since the age of 36 years. An affected autistic sister also had the deletion.
Inheritance
DiGeorge syndrome is usually sporadic and results from de novo deletion within chromosome 22. A long series of reports has recognized the variable features resulting from this deletion in multiple family members with the variable phenotype behaving as an autosomal dominant trait (Steele et al., 1972; Raatikka et al., 1981; Atkin et al., 1982; Rohn et al., 1984; Keppen et al., 1988; Stevens et al., 1990). Stevens et al. (1990) suggested that such familial cases should be regarded as being velocardiofacial syndrome. The variable phenotype was described by Strong (1968) prior to the recognition of DGS. The mother in that family developed a psychotic illness. The first dominant pedigree in which marked clinical variability was associated with dominant transmission of a 22q11 deletion was reported by Wilson et al. (1991); the mother had the typical dysmorphic features. Of the 3 affected offspring, one had coarctation of the aorta, one a ventricular septal defect, and one DGS. Wilson et al. (1991) found 5 of 9 families ascertained on the basis of familial outflow tract defects to have 22q11 deletion. Subtle dysmorphic features typical of those seen in DGS were apparent in several of these affected family members.
Carelle-Calmels et al. (2009) noted that deletion of 22q11.2, resulting in DGS or VCFS, is usually sporadic but has been reported to be inherited in 6 to 28% of patients with these syndromes. They performed cytogenetic studies of the parents of a girl with DGS (or VCFS) who had a deletion of 22q11.2 and found an unexpected rearrangement of both 22q11.2 regions in the unaffected father. He carried a 22q11.2 deletion on one copy of chromosome 22 and a reciprocal 22q11.2 duplication (see 608363) on the other copy of chromosome 22. Genetic compensation, which is consistent with the normal phenotype of the father, was shown through quantitative-expression analyses of genes located within the genetic region associated with the 22q11 deletion syndrome. Carelle-Calmels et al. (2009) noted that this finding has implications for genetic counseling.
Delio et al. (2013) genotyped a total of 389 DNA samples from 22q11 deletion syndrome-affected families. A total of 219 (56%) individuals with 22q11 deletion had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, similar to data for the general population in 11 countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6 to 1.7 times greater than that for males, suggesting that for this region in the genome enhanced meiotic recombination rates, as well as other 22q11.2-specific features, could be responsible for the observed excess in maternal origin.
Cytogenetics
De la Chapelle et al. (1981) suggested that DiGeorge syndrome may be due to a deletion within chromosome 22 or partial duplication of 20p, based on finding the syndrome in members of a family with a 20;22 translocation. Specifically, they observed DGS in 4 members of 1 family and demonstrated monosomy of 22pter-q11 and 20p duplication. Their interpretation that DGS might result from monosomy for 22q11 was confirmed by Kelley et al. (1982) in 3 patients with translocation of 22q11-qter to other chromosomes.
Greenberg et al. (1984) observed partial monosomy due to an unbalanced 4;22 translocation in a 2-month-old male with type 1 truncus arteriosus and features of DGS. The asymptomatic mother showed partial T-cell deficiency and the same unbalanced translocation with deletion of proximal 22q11.
Augusseau et al. (1986) observed telecanthus, microretrognathia, severe aortic coarctation with hypoplastic left aortic arch, decreased E rosettes, and mild neonatal hypocalcemia. The same translocation was present in the clinically normal mother and maternal aunt. The latter had had her fourth pregnancy aborted because of cardiac and other malformations detected on ultrasound. This translocation has proved important in analysis of the expressed sequences in the deleted segment.
The recognition of the importance of 22q11 deletion grew with improving techniques. Greenberg et al. (1988) found chromosome abnormalities in 5 of 27 cases of DGS, 3 with 22q11 deletion though only one of these was an interstitial deletion.
Wilson et al. (1992) reported high resolution banding (more than 850 bands per haploid set) in 30 of 36 cases of DGS and demonstrated 9 cases of interstitial deletion. All other cases were apparently normal. Use of molecular dosage analysis and fluorescence in situ hybridization with probes isolated from within the deleted area revealed deletion in 21 of the 22 cases with normal karyotypes (Carey et al., 1992) giving pooled results of 33 deleted among the consecutive series of 35 cases. Driscoll et al. (1992) also found deletions at the molecular level in all 14 cases studied.
Whereas 90% of cases of DGS may now be attributed to a 22q11 deletion, other chromosome defects have been identified. In the report of Greenberg et al. (1988), there was 1 case of DGS with del10p13 and one with an 18q21.33 deletion. Fukushima et al. (1992) found a female infant with a deletion of 4q21.3-q25 associated with interrupted aortic arch, VSD, ASD, and PDA; T cell deficit and a small thymus at surgery; absent corpus callosum; and dysmorphic features. The possibility of an unrecognized submicroscopic deletion of 22q11 should be considered in such cases, although it is clear that the disturbance of neural crest migration presumed to underlie DGS may be caused by several distinct defects at the molecular level.
Pinto-Escalante et al. (1998) described a premature male infant with mosaic monosomy of chromosome 22. His facial appearance was similar to that in DiGeorge syndrome; hypertonicity, limitation of extension of major joints, and flexion contracture of all fingers were also present. They found previous reports of monosomy 22 in 6 cases, 3 of which were nonmosaic and 3 mosaic. There was great variability in anomalies in these patients; however, the most common anomalies were in the face and joints.
Gottlieb et al. (1998) determined the location and extent of the deletion on chromosome 10 in 5 DiGeorge syndrome patients by means of a combination of heterozygosity tests and fluorescence in situ hybridization analysis. The results did not support the existence of a single, commonly deleted region on 10p in these 5 patients. Rather, they suggested that deletion of more than 1 region on 10p could be associated with the DGS phenotype. Furthermore, there was no obvious correlation between the phenotypic traits of the patients and the extent of the deletion. The patient with the largest deletion exhibited one of the less severe phenotypes. The authors commented that the lack of a correlation between the size of a deletion and the phenotype is observed also with deletions on chromosome 22 and may be a characteristic of haploinsufficiency disorders.
Mapping
A large series of polymorphic markers and some expressed sequences have now been identified in the critical region (Fibison and Emanuel, 1987; Fibison et al., 1990; Scambler et al., 1990). The deletion lies proximal to the breakpoint critical region (151410). Details of the mapping of DGS to 22q11 are located in the Molecular Genetics and Cytogenetics sections of this entry.
Galili et al. (1997) documented homology of synteny between a 150-kb region on mouse chromosome 16 and the portion of 22q11.2 most commonly deleted in DiGeorge syndrome and VCFS. They identified 7 genes, all of which are transcribed in the early mouse embryo.
In 2 children with a DiGeorge syndrome phenotype from a consanguineous family, in whom deletion analysis at 22q11.2 and 10p14-p13 did not reveal any abnormality, Henwood et al. (2001) carried out microsatellite analysis. The affected children were homozygous at 3 markers within the 22q11.2 region, the markers being those at NLJH1, D22S941, and D22S944. The unaffected sib and the unaffected parents were heterozygous at these markers. A subsequent child who appeared to be unaffected was also found to be homozygous for the markers at these loci. Henwood et al. (2001), however, pointed out that nonpenetrance might be possible.
Molecular Genetics
Several expressed sequences have been identified in the region commonly deleted. Aubry et al. (1993) have identified a zinc finger gene ZNF74, and Halford et al. (1993) reported the expressed sequence T10. The gene TUPLE1 (TUP-like enhancer of split gene-1; 600237) reported by Halford et al. (1993) was an attractive candidate for the central features of the syndrome. This putative transcription factor shows homology to the yeast transcription factor TUP, and to Drosophila enhancer of split. It contains 4 WD40 domains and shows evidence of expression at the critical period of development in the outflow tract of the heart and the neural crest derived aspects of the face and upper thorax. The gene localizes to the critical DiGeorge region but was not disrupted by the translocation breakpoint described by Augusseau et al. (1986).
Augusseau et al. (1986) described a patient (ADU) with 'partial' DGS. She had telecanthus, microretrognathia, severe aortic coarctation with hypoplastic left aortic arch, decreased E rosettes, and mild neonatal hypocalcemia. The apparently balanced translocation involved chromosomes 2 and 22: t(2;22)(q14;q11). The same translocation was present in her mother (VDU). The original paper reported that VDU had no features of DGS. However, Budarf et al. (1995) observed that subsequent publications cited VDU as being mildly affected with hypernasal speech, micrognathia, and inverted T4/T8 ratio, which are all features seen in VCFS and DGS. The DGS phenotype in ADU, the VCFS phenotype in VDU, and a balanced translocation of chromosome 22 in both led Budarf et al. (1995) to clone the translocation, sequence the region containing the breakpoint, and analyze the DNA sequence for transcript identification. A gene disrupted by the rearrangement was identified. Their analysis suggested that there are at least 2 transcripts on opposite strands in the region of the t(2;22) breakpoint. The breakpoint disrupted a predicted ORF of one of these genes, deleting 11 nucleotides at the translocation junction. Additional fluorescence in situ hybridization studies and Southern blot analysis demonstrated that the deletions in chromosome 22 deletion-positive patients with DGS/VCFS include both of the transcripts at the t(2;22) breakpoint. Support that either of these putative genes is of significance in the etiology of DGS might come from determining whether all deleted patients are hemizygous for these loci and whether mutations in these genes are detectable in nondeletion patients with features of DGS. Lacking such evidence, the possibility remains that the translocation separates a locus control region from its target gene or produces a position effect. This has been suggested for the role of translocations seen in association with autosomal sex reversal and campomelic dysplasia (CMPD; 114290), where several disease-causing translocation breakpoints map 50 kb or more 5-prime of the SOX9 gene (608160).
Bartsch et al. (2003) used cytogenetic and analyses to study a series of 295 patients with suspected DiGeorge/velocardiofacial syndrome. They identified 58 subjects with a 22q11 deletion, and none with a 10p deletion. The common deletion was present in 52 subjects, the proximal deletion in 5, and an atypical proximal deletion due to a 1;22 translocation in 1. Bartsch et al. (2003) suggested that intellectual and/or behavioral outcome may be better with the proximal versus the common 22q11 deletion.
Demczuk et al. (1995) pointed to the existence of a strong tendency for 22q11.2 deletions in DGS, VCFS, and isolated conotruncal cardiac disease to be of maternal origin. With their experience of 22 cases in which parental origin could be determined, combined with recent results from the literature, 24 cases were found to be of maternal origin and 8 of paternal origin, yielding a probability of less than 0.01.
Demczuk et al. (1995) reported the isolation and cloning of a gene encoding a potential adhesion receptor protein (600594) in the DGCR. They designated the gene DGCR2 and suggested DGCR1 as a symbol for the TUPLE1 gene.
Pizzuti et al. (1996) described the cloning and tissue expression of a human homolog of the Drosophila 'dishevelled' gene (601225), a gene required for the establishment of fly embryonic segments. The 3-prime untranslated region of the gene was positioned within the DGS critical region and was found to be deleted in DGS patients. The authors stated that the gene may be involved in the pathogenesis of DGS.
Demczuk et al. (1996) described the cloning of a gene, which they referred to as DGCR6 (601279), from the DGS critical region. The putative protein encoded by this gene shows homology with Drosophila melanogaster gonadal protein (gdl) and with the gamma-1 chain of human laminin (150290), which maps to chromosome 1q31.
Edelmann et al. (1999) developed hamster-human somatic hybrid cell lines from VCFS/DGS patients and showed by use of haplotype analysis with a set of 16 ordered genetic markers on 22q11 that the breakpoints occurred within similar low copy repeats, designated LCR22s. Models were presented to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders.
Shaikh et al. (2000) completed sequencing of the 3-Mb typically deleted region (TDR) and identified 4 LCRs within it. Although the LCRs differed in content and organization of shared modules, those modules that were common between them shared 97 to 98% sequence identity with one another. Sequence analysis of rearranged junction fragments from variant deletions in 3 DGS/VCFS patients implicated the LCRs directly in the formation of 22q11.2 deletions. FISH analysis of nonhuman primates suggested that the duplication events which generated the nest of LCRs may have occurred at least 20 to 25 million years ago.
Stalmans et al. (2003) reported that absence of the 164-amino acid isoform of Vegf (Vegf164; see 192240), the only one that binds neuropilin-1 (602069), causes birth defects in mice reminiscent of those found in patients with deletion of 22q11. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down Vegf levels enhanced the pharyngeal arch artery defects induced by Tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a Vegf promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. Stalmans et al. (2003) concluded that genetic data in mouse, fish, and human indicated that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome.
Baldini (2002) reviewed the molecular basis of DiGeorge syndrome, with special emphasis on mouse models and the role of TBX1 in development of the pharyngeal arches.
Yagi et al. (2003) screened for mutations in the coding sequence of TBX1 in 13 patients from 10 families who had the 22q11.2 syndrome phenotype but no detectable deletion in 22q11.2. They identified 3 mutations in TBX1 in 2 unrelated patients: 1 mutation was found in a case of sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and a second in a sporadic case of DiGeorge syndrome (602054.0002). A third mutation was found in 3 patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome. The findings of Yagi et al. (2003) indicated that TBX1 mutations are responsible for 5 major phenotypes of the 22q11.2 syndrome, namely, abnormal facies (conotruncal anomaly face), cardiac defects, thymic hypoplasia, velopharyngeal insufficiency of the cleft palate, and parathyroid dysfunction with hypocalcemia; these mutations did not appear to be responsible for typical mental retardation that is commonly seen in patients with the deletion form of 22q11.2 syndrome.
Saitta et al. (2004) traced the grandparental origin of regions flanking de novo 3-Mb deletions in 20 informative 3-generation families with DiGeorge or velocardiofacial syndromes. Haplotype reconstruction of the flanking regions showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19 of 20 families, whereas the normal chromosome 22 in these probands showed interchromosomal exchanges in 2 of 15 informative meioses, a rate consistent with the genetic distance. Immunostaining with MLH1 antibody showed meiotic exchanges localized to the distal region of chromosome 22q in 75% of human spermatocytes tested, also reflecting the genetic map. There was no effect of proband gender or parental age on crossover frequency, and parental origin studies in 65 de novo 3-Mb deletions demonstrated no bias. Unlike Williams syndrome (194050), FISH analysis showed no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11-deleted patients or in 8 nondeleted patients with a DGS/VCFS phenotype. Saitta et al. (2004) concluded that significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 are the likely etiology for these deletions. Since this type of exchange occurs more often for 22q11 deletions than for deletions of 7q11, 15q11, 17p11, and 17q11, they suggested that there is a difference in the meiotic behavior of chromosome 22.
Fernandez et al. (2005) found that 7 (13%) of 55 index patients with 22q11.2 deletion syndrome diagnosed by FISH analysis had inherited the deletion; 2 of the index patients were related as half sibs and had received the deletion from their shared mother. Using molecular techniques to characterize the size of the deletion, The authors found that 3 of 5 families had the smaller 1.5- to 2-Mb deletion and 2 families had the larger 3-Mb deletion; the size of the deletion in 1 family could not be determined. The findings suggested that small deletions may be more common in familial inheritance than larger deletions. Although the clinical severity did not differ between the 2 groups of patients, Fernandez et al. (2005) postulated that the smaller deletion may be associated with higher fecundity than the larger deletion.
Paylor et al. (2006) identified a heterozygous 23-bp deletion in the TBX1 gene (602054.0004) in a mother and 2 sons with VCFS. The mother also had major depression (608516) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., 608638 and 209850). Paylor et al. (2006) suggested that the TBX1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome.
Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 22q11.2 deletion was identified in 93 cases and no controls for a p value of 9.15 x 10(-21) and a frequency in cases of 1 of 169.
Genotype/Phenotype Correlations
Patients with DiGeorge syndrome are hemizygous for the COMT gene (116790). In a study of 21 nonpsychotic DiGeorge syndrome patients aged 7 to 16 years, Shashi et al. (2006) found that those carrying the met allele of the COMT V158M polymorphism (116790.0001), which results in increased dopamine in the prefrontal cortex, performed better on tests of general cognitive ability and on a specific test of prefrontal cognition compared to those with the val allele. Glaser et al. (2006) tested measures of executive function, IQ, and memory in 34 children and young adults with the 22q11.2 deletion syndrome (14 hemizygous for val158 and 30 for met158). No significant differences were detected between met- and val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. Glaser et al. (2006) suggested that either the COMT polymorphism has a small effect on executive function in 22q11.2 deletion syndrome or no effect exists at all.
Lopez-Rivera et al. (2017) conducted a genomewide search for structural variants in 2 cohorts: 2,080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. Exome and targeted resequencing was performed in samples obtained from 586 additional patients with congenital kidney anomalies. Functional studies were also performed in zebrafish and mice. Lopez-Rivera et al. (2017) identified heterozygous deletion of chromosome 22q11.2 in 1% of patients with congenital kidney anomalies and in 0.01% of population controls (OR = 81.5, p = 4.5 x 10(-14)). The main driver of renal disease in DiGeorge syndrome was a 370-kb region containing 9 genes. In zebrafish embryos, an induced loss of function in snap29 (604202), aifm3 (617298), and crkl (602007) resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Lopez-Rivera et al. (2017) concluded that a recurrent 370-kb deletion in the 22q11.2 locus is the driver of kidney defects in DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the 9 genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver.
Heterogeneity
The association of the DiGeorge syndrome with at least 2 and possibly more chromosomal locations suggests strongly that several genes are involved in control of migration of neural crest cells and their subsequent fixation and differentiation at different sites. In the mouse, Chisaka and Capecchi (1991) described a knockout of Hox A3(1.5) which produced a recessive phenocopy of DGS. This gene maps to human chromosome 7, an area not yet implicated in the cause of the human syndrome.
One explanation for the wide variation in phenotype would be the need for more than 1 gene defect to produce the severe version. Thus, for example, impaired signal and receptor may be needed to produce the full phenotype. Environmental factors could also play an additive role. Features of DGS have been described in children with clinical evidence of fetal alcohol syndrome. Ammann et al. (1982) found 4 children among a referral population with immunodeficiency who had hypocalcemia with decreased levels of parathormone, and T cell rosette formation of between 9 and 50% (normal over 65%). All 4 had cardiovascular lesions compatible with DGS; VSD with right aortic arch, truncus arteriosus and pulmonary stenosis, aberrant subclavian artery and pulmonary valve stenosis respectively. Two of the children had absent thymus at direct examination. The alcohol may have directly disrupted neural crest migration or have exposed a genetic predisposition. Among a series of pregnancies exposed to the teratogen isotretinoin (vitamin A) reported by Lammer et al. (1985) 21 malformed infants were investigated; 8 had conotruncal defects or aortic arch anomalies, 6 had micrognathia, 3 had cleft palate and 7 had thymic defects. Several of these children would satisfy the diagnostic criteria of DGS. Again, it is likely that this environmental challenge is exposing the same susceptible pathways of development as are impaired by the 22q11 deletion though the possibility of an interaction between the insult and genotype remains open.
Diagnosis
The dysmorphic facial appearance in an individual with a major outflow tract defect of the heart or a history of recurrent infection should raise suspicion. In infancy, hypocalcemia is a characteristic feature although this may be intermittent and has a tendency to resolve during the first year. Immunological assessment relies on chest radiography to detect a thymic shadow, a notoriously unreliable investigation, particularly in the stressed infant, and measurement of the CD4-positive subset of white cells. With the rapid progress in molecular cytogenetics, the investigation of choice is now a standard karyotype to exclude major rearrangements and fluorescence in situ hybridization using probes from within the deletion segment, preferably those close to the translocation breakpoint site. Where cell suspension or fresh blood cannot be obtained for karyotype, allele loss may be sought with a series of the hypervariable probes in the region. Parents should be screened for carrier status.
Clinical Management
Calcium supplements and 1,25-cholecalciferol may be needed to treat hypocalcemia. Thymic transplantation has been employed though this is difficult to assess since children tend to improve with age. Any affected child undergoing major surgery should have a supply of irradiated blood to avoid graft-versus-host disease (GVHD; see 614395) until immunocompetence has been demonstrated. Clefts may be submucous and should be sought. Speech therapy and additional educational assistance may be needed. Cardiac defects are the usual focus of clinical management. Early echocardiography is essential in any child where other features suggest the diagnosis.
Markert et al. (1999) treated 5 infants with the complete DiGeorge syndrome by transplantation of allogeneic, postnatal thymus tissue. All of them had severely reduced T-cell function. Their peripheral blood mononuclear cells did not respond to mitogens. After transplantation of thymus tissue, T-cell proliferative responses to mitogens developed in 4 patients. No graft-vs-host disease or graft rejection was detected, even in a case with full haplotype mismatch. Two of the patients survived with restoration of immune function, 11 months and 5.5 years after transplantation, respectively; 3 patients died from infection or abnormalities unrelated to transplantation. The authors concluded that early thymus transplantation (before the development of infectious complications) may promote successful immune reconstitution in the complete DiGeorge syndrome.
Pathogenesis
By analyzing head profile radiographs, Molsted et al. (2010) found an increased frequency of abnormalities in the morphology of the sella turcica in 33 patients with chromosome 22q11.2 deletion syndrome, including 30 with either velopharyngeal insufficiency or palatal abnormalities, compared controls. Patients showed deviations mostly in the posterior part of the dorsum sellae, and patients had increased cranial base angles compared to controls. Molsted et al. (2010) noted that abnormal morphology of the cranial base and the sella turcica should be considered a cranial malformation. Taking into account that the main features of the disorder are palatal abnormalities, thymic hypoplasia, hypothyroidism, and cardiac defects, the findings of Molsted et al. (2010) suggested a defect in the neural crest developmental field that includes the thyroid, thymus, and conotruncal septum of the heart.
Population Genetics
A preliminary population study in the Northern region of England, which has a birth population of 40,000 per annum, revealed 9 cases born in 1993 with 22q11 deletions who presented with neonatal features. One of these was familial with an asymptomatic carrier father. The overall birth prevalence appeared to be at least 1 in 4,000 (Burn et al., 1995). Goodship et al. (1998) presented prospective prevalence data derived from the same health region. Since approximately 75% of patients with 22q11 deletion have a cardiac abnormality, all infants with significant congenital heart disease born in 1994 and 1995 who were referred to the Northern (United Kingdom) Genetics Service were screened for 22q11 deletion. Significant congenital heart disease was defined as major structural malformation or disease requiring early invasive investigation or intervention. Additional cases born during this period without apparent heart malformation in whom a diagnosis of 22q11 deletion was made by a clinical geneticist were included. Among 69,129 live births there were 207 babies with significant congenital heart disease; fluorescence in situ hybridization analyses were performed in 170 of these. Five of these had 22q11 deletions. One baby with type B interruption of the aortic arch, ventricular septal defect, and 22q11 deletion was diagnosed at autopsy following sudden death at 11 days. Three further infants were diagnosed on the basis of a laryngeal web and hypocalcemia, dysmorphism, and dysmorphism with nasal voice, respectively. The minimum birth prevalence from these data was 13 per 100,000 live births, making 22q11 deletion the second most common cause of congenital heart disease after Down syndrome.
Botto et al. (2003) identified 43 children with laboratory-confirmed 22q11.2 deletion among infants born in Atlanta, Georgia from 1994 to 1999. The overall prevalence was 1 in 5,950 births, with a prevalence of 1 in 6,000 to 1 in 6,5000 among whites, blacks, and Asians, and 1 in 3,800 among Hispanics. Most affected children (81%) had a heart defect, most commonly a conotruncal defect. Other common features included absent thymus (28%), central nervous system anomalies (12%), and renal anomalies (12%). Botto et al. (2003) estimated that at least 700 infants with 22q11.2 deletion syndrome are born annually in the United States.
Animal Model
Lindsay et al. (1999) created an animal model for the DiGeorge syndrome using Cre-loxP chromosome engineering to delete a portion of mouse chromosome 16B that is homologous to human chromosome 22q11. At birth, heterozygous deleted mice were recovered at the predicted mendelian ratio, but no homozygous deleted mice were recovered. Deleted mice that survived on the first day of life were viable and fertile and grew normally. Forty-two deleted embryos were examined at 18.5 days postcoitum; 26% of them had cardiovascular abnormalities. The most common abnormality (found in 6 embryos) was retroesophageal right subclavian artery, which originated from the descending aorta, dorsal to the emergence of the left subclavian artery. In examining 56 adult deleted mice, they found that 18% had cardiovascular abnormalities. Lindsay et al. (1999) traced the embryologic origin of these abnormalities to defective development of the fourth pharyngeal arch arteries. Unlike patients with DiGeorge syndrome, deleted mice had normal levels of calcium, phosphorus, and parathyroid hormone, and normal percentages of B and T cells. The thymus was normal in size. In addition, no deleted mice had cleft palate or gross palatal abnormalities. Lindsay et al. (1999) genetically complemented the deletion using a chromosome carrying a duplication of the deleted region. Genetic complementation corrected the heart defects, indicating that they are caused by reduced dosage of genes located within the deleted region.
Puech et al. (2000) used Cre-mediated recombination of LoxP sites in embryonic stem cells and mice to generate a 550-kb deletion encompassing 16 of the 27 genes that had been found in a 1.5-Mb region of 22q11 in the corresponding region of mouse chromosome 16. Mice heterozygous for this deletion were normal and exhibited no cardiovascular abnormalities.
Lindsay et al. (2001) used a combination of chromosome engineering and P1 artificial chromosome transgenesis to localize the gene in mouse chromosome 16 haploinsufficiency for which causes the cardiovascular phenotype described by Lindsay et al. (1999). Lindsay et al. (2001) showed that Tbx1 (602054), a member of the T-box transcription factor family, is required for normal development of the pharyngeal arch arteries in a gene dosage-dependent manner. Deletion of 1 copy of Tbx1 affects the development of the fourth pharyngeal arch arteries, whereas homozygous mutation severely disrupts the entire pharyngeal arch artery system. Lindsay et al. (2001) concluded that haploinsufficiency of Tbx1 is sufficient to generate at least 1 important component of the DiGeorge syndrome phenotype in mice. Their data demonstrated the suitability of the mouse for the genetic dissection of microdeletion syndromes.
Jerome and Papaioannou (2001) investigated the potential role of the Tbx1 gene in the causation of the DiGeorge syndrome phenotype. This gene, which encodes a transcription factor of the T-box family, maps to 22q11. They produced a null mutation of the Tbx1 gene in mice and found that mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome. Moreover, Tbx1 -/- mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of the thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae, and cleft palate. On the basis of this phenotype in mice, Jerome and Papaioannou (2001) proposed that TBX1 in humans is an etiology of DGS/VCFS.
To investigate the etiology of VCFS/DGS, Merscher et al. (2001) used a Cre-loxP strategy to generate mice that were hemizygous for a 1.5-Mb deletion corresponding to that on 22q11 in VCFS/DGS patients. These mice exhibited significant perinatal lethality and had conotruncal and parathyroid defects. The conotruncal defects could be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 developed conotruncal defects. These results together with the expression patterns of TBX1 suggested a major role for the TBX1 gene in the molecular etiology of VCFS/DGS.
Funke et al. (2001) reported that mice overexpressing 4 transgenes (PNUTL1, 602724; GP1BB, 138720; TBX1, 602054; and WDR14, 610778) had chronic otitis media, a hyperactive circling behavior, and sensorineural hearing loss. This was associated with middle and inner ear malformations analogous to human Mondini dysplasia, reported to occur in VCFS/DGS patients. Based upon its pattern of expression in the ear and functional studies of the gene, the authors hypothesized that Tbx1 likely plays a central role in the etiology of ear defects in these mice, and that haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.
The CRKL gene (602007) encodes an SH2-SH3-SH3 adaptor protein closely related to the Crk (164762) gene products. CRKL maps within the common deletion region for DGS/VCFS. Guris et al. (2001) reported that mice homozygous for a targeted null mutation at the Crkl locus exhibited defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac outflow tract, thymus, parathyroid glands, and craniofacial structures. They showed that the migration and early expansion of the neural crest cells is unaffected in Crkl -/- embryos. Guris et al. (2001) concluded that the similarity between the Crkl -/- phenotype and the clinical manifestations of DGS/VCFS implicate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.
Schinke and Izumo (2001) reviewed the genetic structure of the 22q11 region associated with DGS and the syntenic region of mouse chromosome 16. The gene order is inverted between human and mouse in a segment of this region. A table accompanying the figure summarized the phenotypes of mice homozygous or heterozygous mutant for chromosomal deletions or gene mutations of specific regions.
Lindsay and Baldini (2001) showed that in their mouse deletion model Df1, the aortic arch patterning defects that occur in heterozygous deletion mice (Df1/+) are associated with a differentiation impairment of vascular smooth muscle in the 4th pharyngeal arch arteries (PAAs) during early embryogenesis. As in humans, not all deletion mice presented with cardiovascular defects at birth. However, all Df1/+ embryos have abnormally small 4th PAAs during early embryogenesis, but many embryos later overcome this early defect, coincident with the appearance of vascular smooth muscle differentiation. The authors speculated that embryos born with aortic arch patterning defects probably represent a more severely affected group that fails to attain sufficient 4th PAA growth for normal remodeling of the PAA system.
Paylor et al. (2001) showed that Df1/+ mice have deficits in learning, memory, and sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. The finding of sensorimotor gating deficits is particularly significant because DGS patients with schizophrenia and schizotypal personality disorder show similar deficits. By detailed mapping of Df1/+ mice, Paylor et al. (2006) found that the PPI deficit was due to haploinsufficiency of 2 adjacent genes, Tbx1 and Gnb1l. Mutation in either gene was sufficient to cause reduced PPI. Paylor et al. (2006) suggested that the Tbx1 gene may be a candidate for psychiatric disease in patients with DGS.
Vermot et al. (2003) generated mice bearing a hypomorphic allele of the gene encoding the retinoic acid-synthesizing enzyme RALDH2 (603687). The resulting mutant mice, which died perinatally, exhibited features of DiGeorge syndrome with heart outflow tract septation defects and anomalies of the aortic arch-derived head and neck arteries, laryngeal-tracheal cartilage defects, and thyroid/parathyroid aplasia or hypoplasia. Analysis of the Raldh2 hypomorph embryos showed selective defects of the posterior (third to sixth) branchial arches, including absence or hypoplasia of the corresponding aortic arches and pharyngeal pouches, and local downregulation of retinoic acid-target genes. Thus, a decreased level of embryonic retinoic acid (through genetic and/or nutritional causes) could represent a major modifier of the expressivity of human 22q11del-associated DiGeorge/velocardiofacial syndromes and, if severe enough, could on its own lead to the clinical features of the DiGeorge syndrome.
Liao et al. (2004) reported that mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures. Neither pattern of malformation precisely modeled VCFS or DGS. Furthermore, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and 3 other transgenes had similar malformations to VCFS/DGS patients. By employing genetic complementation studies, the authors demonstrated that altered TBX1 dosage, rather than overexpression of the other transgenes, was responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a TBX1 dose-dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome.
Long et al. (2006) found that mice hemizygous for a 1.5-Mb deletion on chromosome 16 (Lgdel/+) genes showed impairments in grip strength and nociception compared to wildtype mice. Lgdel/+ mice also showed impairment in prepulse inhibition (PPI) on sensorimotor gating testing, suggestive of neuropsychiatric impairment. Mice heterozygous for a mutation in the Tbx1 gene showed mildly impaired grip strength and decreased movement initiation. Mice with complete loss of the Gscl gene (601845) showed no behavioral changes on any of the tests.
Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. Stark et al. (2008) engineered a mouse strain carrying a hemizygous 1.3-Mb chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. The hemizygous microdeletion, called Df(16)A(+/-), encompassed 27 genes and represented most of the functional genes in the human segment. Behaviorally, Df(16)A(+/-) mice were hyperactive compared to wildtype littermates and showed deficits in the PPI task. Males, but not females, appeared fearful of exploring their environment. Stark et al. (2008) found that Df(16)A(+/-) mice had abnormal brain microarchitecture, although no gross brain abnormalities were present. In the hippocampus, Df(16)A(+/-) mice had reduced number and size of dendritic spines and decreased dendritic complexity of CA1 pyramidal neurons. Analysis of heterozygous Dgcr8 (609030)-deficient mice revealed that altered miRNA biogenesis, dendritic complexity, and PPI performance in Df(16)A(+/-) mice was due to Dgcr8 haploinsufficiency. Stark et al. (2008) concluded that abnormal miRNA processing contributes to the behavioral and neuronal deficits associated with the human 22q11.2 deletion.
Choi and Klingensmith (2009) demonstrated that chordin (CHRD; 603475) is a modifier of the craniofacial anomalies observed in Tbx1 mutations in mice. The Chrd-null mouse phenotype includes dysmorphic ears, absence of the thymus, persistent truncus arteriosus, and cleft palate, which is similar to the phenotype of Tbx1-null mice. However, penetrance of the Chrd phenotype is highly dependent on genetic background. In an inbred Chrd-null mouse strain with full penetrance, the authors found that a splice site mutation in the Tbx1 gene was a modifier influencing phenotypic expression. Chrd-null mice without the Tbx1 mutation had a low penetrance of mandibular hypoplasia, but no cardiac or thoracic organ malformations. The hypomorphic Tbx1 allele resulted in defects resembling 22q11 deletion syndrome, but with a low penetrance of craniofacial malformations, unless Chrd was also mutant. Expression studies suggested that Chrd has a role in promoting Tbx1 expression. The findings suggested that chordin is a modifier of the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11 deletion syndrome.
In a mouse model of chromosome 22q11 deletion syndrome, Meechan et al. (2009) demonstrated that decreased dosage of genes in this region was associated with compromised neurogenesis and differentiation in the cerebral cortex. There was a specific disruption of proliferation of basal progenitor cells in the subventricular zone and medial cortical regions. Apical progenitors and radial migration were not affected. Microarray analysis showed decreased expression of genes involved in cell-cycle function in the 22q11 region, including Ranbp1 (601180) and Cdc45l (603465), as well as those outside of the 22q11 region (e.g., cyclin D1, 168461; E2f2, 600426; and Sesn2, 607767). There was a decrease in number of projection neurons in cortical layer 2-4, but not layer 5/6, and this change was associated with aberrant distribution of interneurons in upper and lower cortical layers. Deletion of the Tbx1 (602054) or Prodh (606810) genes did not disrupt basal progenitors. The findings provided evidence that diminished dosage of certain genes within the chromosome 22q11 region disrupts cortical neurogenesis and interneuron migration, which likely changes cortical circuitry, leading to cognitive deficits.
Sigurdsson et al. (2010) studied Df(16)A(+/-) mice, which model a microdeletion on human chromosome 22q11.2 that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, Sigurdsson et al. (2010) measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wildtype mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A(+/-) mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A(+/-) mice to learn the task and increased more slowly during task acquisition. Sigurdsson et al. (2010) concluded that their data suggested how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level, and further suggested that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.
History
The original description of the syndrome was derived from a published discussion at an immunology meeting (Cooper et al., 1965). DiGeorge (1968) published a formal report 3 years later. The report by Strong (1968) predated this formal report and probably represents the same variable disorder. Kimura (1977) reported velopharyngeal deficiency in a series of patients without cleft palate. The Japanese language report by Kinouchi et al. (1976) and the English reports, by Takao et al. (1980)and Shimizu et al. (1984), delineated the syndrome in the Japanese population. The acronym CATCH22 derives from the phrase Catch 22, which was used by Joseph Heller as the title of his book (Heller, 1962).
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (20% of adults) Weight \- Obesity (35% of adults) HEAD & NECK Face \- Micrognathia Ears \- Low-set ears \- Abnormal folded pinna \- Middle ear abnormalities \- Hearing deficits (28% of adults) Eyes \- Posterior embryotoxon \- Tortuous retinal vasculature \- Hypertelorism \- Short palpebral fissures \- Eyelid hooding \- Amblyopia \- Strabismus (15% of adults) \- Exotropia \- Esophoria \- Sclerocornea \- Accommodative esotropia \- Complicated strabismus Nose \- Blunted nose \- Short philtrum Mouth \- High arched palate \- Cleft palate \- Bifid uvula CARDIOVASCULAR Heart \- Cardiovascular malformations (26% of adults) \- Tetralogy of Fallot \- Truncus arteriosus \- Interrupted aortic arch \- Right aortic arch \- Ventricular septal defect Vascular \- Patent ductus arteriosus ABDOMEN External Features \- Umbilical hernia \- Femoral hernia Biliary Tract \- Cholelithiasis (19% of adults) GENITOURINARY External Genitalia (Male) \- Inguinal hernia SKELETAL Spine \- Scoliosis (47% of adults) SKIN, NAILS, & HAIR Skin \- Severe acne (23% of adults) \- Seborrhea (35% of adults) NEUROLOGIC Central Nervous System \- Mild to moderate learning difficulties \- Delayed psychomotor development \- Late-onset speech development \- Tetany \- Seizures (40%) Behavioral Psychiatric Manifestations \- Attention deficit disorder \- Schizophrenia (22% of adults) \- Bipolar disorder VOICE \- Hypernasal speech ENDOCRINE FEATURES \- Parathyroid hypoplasia \- Parathyroid absence \- Thymic hypoplasia \- Thymic aplasia \- Accessory thyroid tissue \- Hypothyroidism (20% of adults) IMMUNOLOGY \- Immune defect due to a T cell deficit \- Susceptibility to infection LABORATORY ABNORMALITIES \- Neonatal hypocalcemia \- Hypocalcemia (64% of adults) \- T-cell deficit \- 85-90% DGS patients have deletion of 22q11.2 \- Other cytogenic abnormalities have been associated with DGS phenotype including monosomy 10p13, 11p13, and 4q21 MISCELLANEOUS \- Incidence is estimated to be between 1 in 2,000 and 1 in 7,000 live births \- Hernia occurs in 22% of adults \- Usually sporadic disorder resulting from de novo 22q11.2 deletion \- 22q11.2 deletion can present with a variety of phenotypes including velocardiofacial syndrome ( 192430 ) MOLECULAR BASIS \- A contiguous gene syndrome involving deletion of the DiGeorge syndrome chromosome region (DGCR) involving mutations in TUP-like enhancer of split 1 (TUPLE1, 600237 ) and DiGeorge critical region gene 2 (DGCR2, 600594 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| DIGEORGE SYNDROME | c0012236 | 2,434 | omim | https://www.omim.org/entry/188400 | 2019-09-22T16:32:34 | {"doid": ["11198"], "mesh": ["D004062"], "omim": ["188400"], "icd-9": ["279.11"], "icd-10": ["D82.1"], "orphanet": ["567"], "synonyms": ["Alternative titles", "CHROMOSOME 22q11.2 DELETION SYNDROME", "HYPOPLASIA OF THYMUS AND PARATHYROIDS", "THIRD AND FOURTH PHARYNGEAL POUCH SYNDROME"], "genereviews": ["NBK1523"]} |
Guttmacher syndrome is an extremely rare syndrome characterized by hypoplastic thumbs and halluces, 5th finger clinobrachydactyly, postaxial polydactyly of the hands, short or uniphalangeal 2nd toes with absent nails and hypospadias.
## Epidemiology
It has been described in a father and his son and daughter.
## Clinical description
The affected patients have normal mental development. Except for postaxial polydactyly of the hands and uniphalangeal 2nd toes with absent nails, features are in common with hand-foot-genital syndrome (HFGS, see this term) caused by mutations in the HOXA13 gene.
## Etiology
In all three affected individuals with Guttmacher syndrome, two different sequence alterations were identified in HOXA13 gene: a de novo missense mutation and a deletion in the promoter region of the gene, inherited from an unaffected parent, which may contribute to the phenotype in the affected individuals.
## Genetic counseling
The condition is inherited in an autosomal dominant manner.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Guttmacher syndrome | c1867801 | 2,435 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2957 | 2021-01-23T17:47:17 | {"gard": ["4470"], "mesh": ["C538278"], "omim": ["176305"], "umls": ["C1867801"], "icd-10": ["Q87.2"], "synonyms": ["Preaxial deficiency-postaxial polydactyly-hypospadias syndrome"]} |
A rare infectious disease characterized by acute onset of high fever associated with debilitating polyarthralgia and usually accompanied by an erythematous skin rash (that may progress to vesiculobullous lesions in children) caused by the mosquitoe-borne Chikungunya virus. Myalgia, severe headache, and lymphadenopathy are frequently associated. Chronically the disease may cause recurrent, long-term polyarthralgia, arthritis, fatigue, and depression.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Chikungunya | c0008055 | 2,436 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324625 | 2021-01-23T18:05:15 | {"gard": ["6038"], "mesh": ["D065632"], "umls": ["C0008055"], "icd-10": ["A92.0"]} |
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Low pressure hydrocephalus
Ventricles position
SpecialtyNeurology
Low-pressure hydrocephalus (LPH) is a condition whereby ventricles are enlarged and the individual experiences severe dementia, inability to walk, and incontinence – despite very low intracranial pressure (ICP). Low pressure hydrocephalus appears to be a more acute form of normal pressure hydrocephalus. If not diagnosed in a timely fashion, the individual runs the risk of remaining in the low pressure hydrocephalic state or LPHS. Shunt revisions, even when they are set to drain at a low ICP, are not always effective. The pressure in the brain does not get high enough to allow the cerebrospinal fluid to drain in a shunt system, therefore the shunt is open, but malfunctioning in LPH. In cases of LPH, chronic infarcts can also develop along the corona radiata in response to the tension in the brain as the ventricles increase in size. Certain causes of LPH include trauma, tumor, bleeding, inflammation of the lining of the brain, whole brain radiation, as well as other brain pathology that affects the compliance of the brain parenchyma. One treatment for the LPHS is an external ventricular drain (EVD) set at negative pressures. According to Pang & Altschuler et al.,[citation needed] a controlled, steady, negative pressure siphoning with EVD, carefully monitored with partial computer tomography scans is a safe and effective way of treating LPH. In their experience, this approach helps restore the brain mantle. They caution against dropping or raising the pressure of the EVD too quickly as it increases risk and also destabilizes the ventricles. Getting the ventricles smaller, is the initial step, stabilising them is the second step before placing a shunt – which is the final step in therapy. Any variation from this formula can lead to an ineffective, yet patent shunt system, despite a low-pressure setting. Care should be taken with EVD therapy, as mismanagement of the EVD can lead to long-term permanent complications and brain injury.
## References[edit]
## Further reading[edit]
* Pang, Dachling; Altschuler, Eric (1994). "Low-Pressure Hydrocephalic State and Viscoelastic Alterations in the Brain". Neurosurgery. 35 (4): 643–55, discussion 655–56. doi:10.1227/00006123-199410000-00010.
* Owler, B.K.; Jacobson, E.E.; Johnston, I.H. (2001). "Low pressure hydrocephalus: Issues of diagnosis and treatment in five cases". British Journal of Neurosurgery. 15 (4): 353–59. doi:10.1080/02688690120072531. PMID 11599454.
* Lesniak, M.S.; Clatterbuck, R.E.; Rigamonti, D.; Williams, M.A. (2002). "Low pressure hydrocephalus and ventriculomegaly: hysteresis, non-linear dynamics, and the benefits of CSF diversion". British Journal of Neurosurgery. 16 (6): 555–61. doi:10.1080/02688690209168360. PMID 12617236.
This article about a medical condition affecting the nervous system is a stub. You can help Wikipedia by expanding it.
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*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Low pressure hydrocephalus | c0020258 | 2,437 | wikipedia | https://en.wikipedia.org/wiki/Low_pressure_hydrocephalus | 2021-01-18T19:03:08 | {"mesh": ["D006850"], "wikidata": ["Q6693036"]} |
Celibacy syndrome (Japanese: セックスしない症候群, sekkusu shinai shōkōgun) is a media hypothesis proposing that a growing number of Japanese adults have lost interest in sexual activity and have also lost interest in romantic love, dating and marriage.[1] Following a report in The Guardian, the theory gained widespread attention in English media outlets in 2013,[2] and was subsequently refuted by several journalists and bloggers.[3][4][5]
## Contents
* 1 Reports and causes
* 2 Criticism
* 3 See also
* 4 References
## Reports and causes[edit]
In addition to celibacy, the theory cites declining numbers of marriages and declining birthrates in Japan.[1] According to surveys conducted by the Japan Association for Sex Education, between 2011 and 2013, the number of female college students reporting to be virgins increased. Additionally, surveys conducted by the Japanese Family Planning Association (JFPA) indicated a high number of Japanese women who reported that they "were not interested in or despised sexual contact".[1] Meanwhile, surveys conducted by the National Institute of Population and Social Security Research in Japan in 2008 and 2013, revealed that the number of Japanese men and women reporting to not be in any kind of romantic relationship grew by 10%.[1][2]
The theory attributes two possible causes for these reports: the past two decades of economic stagnation as well as high gender inequality in Japan.[1]
## Criticism[edit]
Joshua Keating accused The Guardian and other media outlets of using "cherry-picked" data in order to make a sensational claim that appeals to Western notions of a "weird Japan".[3] The Washington Post pointed to contrary statistics that indicate that Japanese youth are having sex more frequently than ever.[5]
## See also[edit]
* Aging of Japan
* Herbivore men
## References[edit]
1. ^ a b c d e Haworth, Abigail (20 October 2013). "Why have young people in Japan stopped having sex?". The Guardian. Retrieved 8 December 2013.
2. ^ a b "Celibacy syndrome hits Japan with more young people avoiding sex". News.com.au. 21 October 2013. Retrieved 8 December 2013.
3. ^ a b Keating, Joshua (23 October 2013). "No, Japanese People Haven't Given Up on Sex". Slate. Retrieved 28 December 2014.
4. ^ Scott, Carl (13 October 2013). ""Yuko and Hiro" Do Not Despise Sex". First Things. Retrieved 28 December 2014.
5. ^ a b Matthews, Dylan (23 October 2013). "Don't worry. The Japanese are having plenty of sex". The Washington Post. Archived from the original on 4 July 2015. Retrieved 28 December 2014.
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*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Celibacy syndrome | None | 2,438 | wikipedia | https://en.wikipedia.org/wiki/Celibacy_syndrome | 2021-01-18T19:00:02 | {"wikidata": ["Q15137364"]} |
FGFR2-related bent bone dysplasia is a rare, genetic, lethal, primary bone dysplasia characterized by dysmorphic craniofacial features (low-set, posteriorly rotated ears, hypertelorism, megalophtalmos, flattened and hypoplastic midface, micrognathia), hypomineralization of the calvarium, craniosynostosis, hypoplastic clavicles and pubis, and bent long bones (particularly involving the femora), caused by germline mutations in the FGFR2 gene. Prematurely erupted fetal teeth, osteopenia, hirsutism, clitoromegaly, gingival hyperplasia, and hepatosplenomegaly with extramedullary hematopoesis may also be associated.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| FGFR2-related bent bone dysplasia | c3281247 | 2,439 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=313855 | 2021-01-23T18:26:01 | {"gard": ["10965"], "omim": ["614592"], "synonyms": ["Perinatal lethal bent bone dysplasia"]} |
A rare childhood-onset epilepsy syndrome associated with infection and characterized by a biphasic clinical course. The initial symptom is a prolonged febrile seizure on day 1 (the first phase). Afterwards, patients have variable levels of consciousness from normal to coma. Irrespective of the consciousness levels, magnetic resonance imaging (MRI) during the first 2 days shows no abnormality. During the second phase (usually days 4 - 6), patients show a cluster of seizures and deterioration of consciousness. Diffusion-weighted images (DWI) on MRI reveal the brain lesions with reduced diffusion predominantly in the subcortical white matter. After the second acute phase, consciousness levels improve with the emerging focal neurological signs. Neurological outcomes of AESD vary from normal to mild or severe sequelae including cerebral atrophy, mental retardation, paralysis and epilepsy.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
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*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
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*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
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*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
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*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Acute encephalopathy with biphasic seizures and late reduced diffusion | c4707658 | 2,440 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363549 | 2021-01-23T18:39:46 | {"icd-10": ["G40.4"], "synonyms": ["AESD", "AIEF", "Acute infantile encephalopathy predominantly affecting the frontal lobes"]} |
This article needs editing for compliance with Wikipedia's Manual of Style. In particular, it has problems with not using MEDMOS. Please help improve it if you can. (February 2018) (Learn how and when to remove this template message)
It has been suggested that this article be split into articles titled Dysfibrinogenemia and Hereditary fibrinogen Aα-Chain amyloidosis. (Discuss) (March 2019)
Dysfibrinogenemia
Other namesDysfibrinogenemia, familial[1]
The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with normal blood clotting and/or lysis of blood clots. The condition therefore may cause pathological bleeding and/or thrombosis.[2][3][4] Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. It is associated primarily with pathological bleeding.[5] Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.[6]
Congenital dysfibrinogenemia is the commonest of these three disorders. Some 100 different genetic mutations occurring in more than 400 families have been found to cause it.[5][7] All of these mutations as well as those causing hereditary fibrinogen Aα-Chain amyloidosis exhibit partial penetrance, i.e. only some family members with one of these mutant genes develop dysfibrinogenemia-related symptoms.[8][6] While both of these congenital disorders as well as acquired dysfibrinogenemia are considered very rare, it is estimated that ~0.8% of individuals with venous thrombosis have either a congenital or acquired dysfibrinogenemia. Hence, the dysfibrinogenemia disorders may be highly under-diagnosed conditions due to isolated thrombotic events that are not appreciated as reflecting an underlying fibrinogen disorder.[3]
Congenital dysfibrinogenemia is distinguished from a similar inherited disorder, congenital hypodysfibrinogenemia. Both disorders involve the circulation of dysfunctional fibrinogen but in congenital hypodysfibrinogenemia plasma fibrinogen levels are low while in congenital dysfibrinogenemia they are normal. Furthermore, the two disorders involve different gene mutations and inheritance patterns as well as somewhat different symptoms.[3][9]
## Contents
* 1 Fibrinogen
* 2 Congenital dysfibrinogenemia
* 2.1 Presentation
* 2.2 Pathophysiology
* 2.3 Diagnosis
* 2.4 Treatment
* 2.4.1 Asymptomatic individuals
* 2.4.2 Symptomatic individuals
* 3 Hereditary fibrinogen Aα-Chain amyloidosis
* 3.1 Presentation
* 3.2 Pathophysiology
* 3.3 Diagnosis
* 3.4 Treatment
* 4 Acquired dysfibrinogenemia
* 4.1 Presentation
* 4.2 Pathophysiology
* 4.3 Diagnosis
* 4.4 Treatment
* 5 References
* 6 External links
## Fibrinogen[edit]
Main article: Fibrinogen
Fibrinogen is a glycoprotein made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, although once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.[9][10] The final secreted, hepatocyte-derived glycoprotein is made of two trimers each of which is composed of three polypeptide chains, Aα (also termed α) encoded by the FGA gene, Bβ (also termed β) encoded by the FGB gene, and γ encoded by the FGG gene. All three genes are located on the long (i.e. "p") arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively) and may contain mutations that are the cause of congenital dysfibrinogenemia. The heximer is assembled as a protein in the endoplasmic reticulum of hepatocytes and then transferred to the Golgi where Polysaccharides (i.e. complex sugars) and sialic acid are added by respective glycosylation and sialylation enzyme pathways thereby converting the heximer to a functional fibrinogen glycoprotein. The final circulating glycoprotein (notated as (AαBβγ)2, (αβγ)2, Aα2Bβ2γ2, or α2β2γ2) is arranged as a long flexible rod with nodules at both ends termed D domains and central nodule termed the E domain.[11][12]
The normal process of blood clot formation involves the coordinated operation of two separate pathways that feed into a final common pathway: 1) primary hemostasis, i.e. the adhesion, activation, and aggregation of circulating blood platelets at sites of vascular injury and 2) secondary hemostasis, i.e. cleavage of the Aα and Bβ chains of fibrinogen by thrombin to form individual fibrin strands plus the respective fibrinopeptides A and B formed from this cleavage. In the final common pathway fibrin is cross-linked by activated clotting factor XIII (termed factor XIIIa) to form mature gel-like fibrin clots. Subsequent fibrinolysis pathways act to limit clot formation and dissolve clots no longer needed. Fibrinogen and its Aα fibrin chain have several functions in this process:[4][10][13][14]
* Blood clotting: fibrinogen concentration is the rate-limiting factor in blood clot formation and along with blood platelets is critical to this formation (see Coagulation).
* Platelet aggregation: fibrinogen promotes platelet aggregation by cross-linking platelet Glycoprotein IIb/IIIa receptors and thereby promotes blood clot formation through the primary hemostasis pathway.
* Blood clot lysis: The Aα fibrin chain formed from fibrinogen binds tissue plasminogen activator, an agent that breaks down blood clots to participate thereby in promoting fibrinolysis.
Based on these fibrinogen functions, a fibrinogen mutation may act either to inhibit or promote blood clot formation and/or lysis to thereby produce in individuals a diathesis to develop pathological bleeding, thrombosis, or both conditions.[4]
## Congenital dysfibrinogenemia[edit]
### Presentation[edit]
Many cases of congenital dysfibrinogenemia are asymptomatic. Since manifestations of the disorder generally occur in early adulthood or middle-age, younger individuals with a gene mutation causing it may not have had time to develop symptoms while previously asymptomatic individuals of advanced age with such a mutation are unlikely to develop symptoms. Bleeding episodes in most cases of this disorder are mild and commonly involve easy bruising and menorrhagia. Less common manifestations of bleeding may be severe or even life-threatening; these include excessive bleeding after tooth extraction, surgery, vaginal birth, and miscarriage. Rarely, these individuals may suffer hemarthrosis or cerebral hemorrhage. In one study of 37 individuals >50 years old afflicted with this disorder, 19% had a history of thrombosis. Thrombotic complications occur in both arteries and veins and include transient ischemic attack, ischemic stroke, myocardial infarction, retinal artery thrombosis, peripheral artery thrombosis, and deep vein thrombosis. In one series of 33 individuals with a history of thrombosis due to congenital dysfibrinogenemia, five developed chronic pulmonary hypertension due to ongoing pulmonary embolism probably stemming form deep vein thrombosis. About 26% of individuals with the disorder suffer both bleeding and thrombosis complications.[5][14]
### Pathophysiology[edit]
Congenital dysfibrinogenemia is most often caused by a single autosomal dominant missense mutation in the Aα, Bβ, or γ gene; rarely, it is caused by a homozygous or compound heterozygous missense mutation, a deletion, frameshift mutation, insert mutation, or splice site mutation in one of these genes. The most frequent sites for these mutations code for the N-terminus of the Aα chain or the C-terminus of the γ chain that lead to defective assembly of fibrin in early clot formation and thereby a bleeding predisposition.[4] Two particular missense mutations represent the majority (74% in one study of 101 individuals) of all mutations associated with dysfibrinogenemia and therefore represent prime sites to examine in the initial testing of individuals having a congenital dysfibrinogenmia bleeding disorder. These mutations alter the codon coded for the amino acid arginine at either the 35th position of FGA (termed Arg35; see fibrinogen Metz1 and fibrinogen Bicetre in the Table below) and or the 301st position of FGG (termed Arg301; see fibrinogen Baltimore IV in the Table below).[11]
The following Table lists examples of mutations causing congenital dysfibrinogenemias. It gives: a) the mutated protein's trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the cloned gene), and the names of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; c) the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using standard abbreviations) found in the normal-mutated circulating fibrinogen; d) the cause of the mutated fibrinogen's misfunction(s); e) the clinical consequence(s) of the mutation; and f) comments. Unless noted as a deletion (del), frame shift (fs), or homozygous mutation, all mutations are heterozygous, missense mutations.[5][15]
Trivial name Gene: site of mutation Protein chain: site mutation Pathophysiology Clinical disorder Comment
fibrinogen Detroit FGA: c.114G>C/T Aα: Arg19Ser abnormal Polymerization bleeding relatively rare; first description of congenital dysfibrinogenmia[16]
fibrinogen Metz1 FGA: c.103C>T Aα: Arg35Cys delayed release of fibrinopeptide A bleeding relatively common
fibrinogen Bicetrel FGA: c.104C>G Aα: Arg35His delayed release of fibrinopeptide A bleeding relatively common
fibrinogen Perth FGA: c.1541delC Aα: Pro495Leufs thin clot, increased clot strength, impaired plasmin generation bleeding and thrombosis relatively rare
fibrinogen Naples FGB: c.292G>A Bβ: Ala68thr defective thrombin binding thrombosis relatively rare; homozygous
fibrinogen BaltimoreIV FGG: c.901C>T λ: Arg301Cys impaired fiber interactions thrombosis relatively common
fibrinogen Vlissingen FGG: c.1033_1038del λ: del Asn319-Asp320 impaired fiber interactions thrombosis relatively rare; nucleotides 1033-1038 and amino acids 319-320 deleted
fibrinogen BarccelonaIV FGG: c.902G>A λ: Arg301His impaired fiber interactions thrombosis relatively common
### Diagnosis[edit]
The diagnosis of congenital dysfibrinogenmia is made by clinical laboratory studies that find normal levels of plasma fibrinogen but significant excess in the amount of immunologically detected compared to functionally detected (i.e. able to be clotted) fibrinogen. The ratio of functionally-detected to immunologically detected fibrinogen masses in these cases is <0.7. Partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests are usually prolonged regardless of history of bleeding or thrombosis.[11] Where available, laboratory analyses of the fibrinogen genes and peptide chains solidify the diagnosis. Initial examination of these genes or protein chains should search specifically for "hot spot" mutations, i.e. the most common mutations (see Pathophysiology section) that comprise the large bulk of mutations in the disorder.[5] In cases of dysfibrinogenemia in which acquired disease is suspected, diagnosis requires a proper diagnosis of the presence of a causable disease.[4]
Congenital dysfibrinogenmia is initially distinguished form congenital hypodysfibrinogenemia by the finding of normal immunologically-detected levels of fibrinogen in congenital dysfibrinogenemia and sub-normal levels of immunologically-detected fibrinogen in congenital hypodysfibrinogenemia. Both disorders exhibit mass ratios of functionally-detected to immunologically-detected fibrinogen that are below <0.7. Genetic and protein analyses can definitively differentiate the two disorders.[9]
### Treatment[edit]
In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses.[9] Due to the rareness of this disorder, treatment of individuals with these presentations are based primarily on case reports, guidelines set by the United Kingdom, and expert opinions rather than controlled clinical studies.[5]
#### Asymptomatic individuals[edit]
Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus the propensity of the particular mutation type to develop these complications.[5] In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving childbirth. Women with the disorder appear to have an increased rate of miscarriages and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for prophylaxis therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery.[5][9]
#### Symptomatic individuals[edit]
Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating hemophilia. They should avoid all medications that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of fresh frozen plasma and/or cryoprecipitate (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter. Tranexamic acid or fibrinogen concentrates are recommended for prophylactic treatment prior to minor surgery while fibrinogen concentrates are recommended prior to major surgery with fibrinogen concentrates usage seeking to maintain fibrinogen activity levels at >1 gram/liter. Women undergoing vaginal or Cesarean child birth should be treated at a hemophilia center with fibrinogen concentrates to maintain fibrinogen activity levels at 1.5 gram/liter. The latter individuals require careful observation for bleeding during their post-partum periods.[5]
Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating hemophilia using antithrombotic agents. They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights. Venous thrombosis should be treated with low molecular weight heparin for a period that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use prophylactic anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended.[5]
## Hereditary fibrinogen Aα-Chain amyloidosis[edit]
### Presentation[edit]
Individuals with hereditary fibrinogen Aα-chain amyloidosis present with evidence ranging from asymptomatic proteinuria to progressive renal impairment and end-stage kidney disease. They do not evidence pathological bleeding or thrombosis and their amyloidosis is non-systemic in that it is restricted to the kidney. In a report on 474 patients with renal amyloidosis, hereditary fibrinogen Aα chain disease represented only 1.3% of all cases whereas aberrant immunoglobulin-induced renal amyloidosis (e.g. AL amyloidosis) represented 86% of the cases).[17] Hereditary fibrinogen Aα-Chain amyloidosis is, however, the most common form of familial renal amyloidosis.[5][6]
### Pathophysiology[edit]
Certain mutations in the fibrinogen Aα-chain gene cause a form of familial renal amyloidosis termed hereditary fibrinogen Aα-Chain amyloidosis.[6] The disorder is due to autosomal dominant inheritance of Aα chain mutations the most common of which is hemoglobin Indianopolis, a heterzyogus missense (c.1718G>T: Arg554Leu) mutation. Other missense mutations causing this disorder are unnamed; they include 1634A>T: Glu526Val; c.1670C>A: Thr538lys; c.1676A.T:Glu540Val; and c1712C>A:Pro552His. A deletion mutation causing a frameshift viz., c.1622delT: Thr525Leu, is also a cause of the disorder. The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney. The mutant fibrinogen does not appear to accumulate in, or injure, extra-renal tissues.[5][6][17]
### Diagnosis[edit]
The diagnosis of this disorder depends on demonstrating: 1) a dysfunctional plasma fibrinogen, i.e. significantly less functionally-detected compared to immunologically-detected fibrinogen; b) presence of signs and/or symptoms of kidney disease; and c) histological evidence of often massive obliteration of renal glomeruli by amyloid as detected by Congo red staining. There also should be no evidence for systemic amyloidosis. Specialized centers use immunological and genetic studies to define the nature of the renal amyloid deposits, the presence of FGA gene mutations, and the occurrence of these mutations in family members. The disorder exhibits a highly variable penetrance among family members.[17][6] Hereditary fibrinogen Aα-Chain amyloidosis shows variable penetrance among family members, a distinctive histological appearance, proteinuria, progressive renal impairment, and markedly better survival rates than other forms of systemic renal amyloidosis.[6]
### Treatment[edit]
Treatment of hereditary fibrinogen Aα-Chain amyloidosis has relied on chronic maintenance hemodialysis and, where possible, kidney transplantation. While recurrence of amyloidosis in the transplanted kidney occurs and is to be expected, transplant survival rates for this form of amyloidosis are significantly better than those for transplants in other forms of systemic renal amyloidosis. Relatively healthy individuals with hereditary fibrinogen Aα-Chain-related renal amyloidosis may be considered for kidney and liver bi-transplantation with the expectation that survival of the transplanted kidney will be prolonged by replacing the fibrinogen Aα-Chain-producing liver with a non-diseased donor liver.[6]
## Acquired dysfibrinogenemia[edit]
### Presentation[edit]
Acquired dysfibrinogenemia commonly present with signs, symptoms, and/or prior diagnoses of the underlying causative disease or drug intake in an individual with an otherwise unexplained bleeding tendency or episode. Bleeding appears to be more prominent in acquired compared to congenital dysfibrinogenemia; pathological thrombosis, while potentially occurring in these individuals as a complication of their underlying disease, is an uncommon feature of the acquired disorder.[4]
### Pathophysiology[edit]
Acquired dysfibrinogenemia occurs as a known or presumed consequence of an underlying disease which directly or indirectly interferes with the clotting function of fibrinogen. Individuals with acquired dysfibrinogenemias have a greater tendency for bleeding complications than those with congenital fibrinogenemia.[4][18][19] The following Table gives some abnormalities, causes, and apparent pathophysiology along with some comments on examples of acquired dysfibrinogenemia.[3][4]
Abnormality Cause Pathophysiology Comment
incorrect post-translational modification of fibrinogen severe liver disease abnormal fibrinogen sialylation most common cause of acquired dysfibrinogenemia
monoclonal antibody plasma cell dyscrasias such as multiple myeloma and MGUS monoclonal antibody interferes with clotting uncommon
polyclonal antibody autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis polyclonal antibody interferes with clotting uncommon
production of abnormal fibrinogen by cancer cervical cancer of epithelium, renal cell carcinoma, others paraneoplastic effect of cancer extremely rare
Drug effect mithramycin, isoniazid, direct thrombin inhibitors (e.g. heparin, dabigatran, bivalirudin, argatroban) unclear extremely rare case reports
### Diagnosis[edit]
Diagnosis of acquired dysfibrinogenemia uses the same laboratory tests that are used for congenital dysfibrinogenemia plus evidence for an underlying causative disease.[4]
### Treatment[edit]
Treatment of acquired dysfibrinogenemia follows the guidelines recommended for congenital dysfibrinogenemia.[4] In addition, treatment of any disease thought to be responsible for the dysfibrinogenemia might be useful. For example, therapeutic plasma exchange and chemotherapy to reduce monoclonal antibody levels has been used successfully to reverse otherwise uncontrollable bleeding in cases of multiple myeloma-associated dysfibrinogenemia.[20][21]
## References[edit]
1. ^ "Dysfibrinogenemia". Genetic and Rare Diseases (GARD). NIH. Retrieved 19 March 2019.
2. ^ Dysfibrinogenemia at eMedicine
3. ^ a b c d Caimi G, Canino B, Lo Presti R, Urso C, Hopps E (2017). "Clinical conditions responsible for hyperviscosity and skin ulcers complications" (PDF). Clinical Hemorheology and Microcirculation. 67 (1): 25–34. doi:10.3233/CH-160218. hdl:10447/238851. PMID 28550239.
4. ^ a b c d e f g h i j Besser MW, MacDonald SG (2016). "Acquired hypofibrinogenemia: current perspectives". Journal of Blood Medicine. 7: 217–225. doi:10.2147/JBM.S90693. PMC 5045218. PMID 27713652.
5. ^ a b c d e f g h i j k l Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P (2015). "Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management". Journal of Thrombosis and Haemostasis. 13 (6): 909–19. doi:10.1111/jth.12916. PMID 25816717. S2CID 10955092.
6. ^ a b c d e f g h Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN (2009). "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis". Journal of the American Society of Nephrology. 20 (2): 444–51. doi:10.1681/ASN.2008060614. PMC 2637055. PMID 19073821.
7. ^ McDonagh, J (2001). "Dysfibrinogenemia and other disorders of fibrinogen structure or function". In Colman R, Hirsh J, Marder V, Clowes A, George J (eds.). Hemostasis and Thrombosis (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 855–92. ISBN 978-0-7817-1455-6.
8. ^ Hayes, T (2002). "Dysfibrinogenemia and thrombosis". Archives of Pathology & Laboratory Medicine. 126 (11): 1387–90. doi:10.1043/0003-9985(2002)126<1387:DAT>2.0.CO;2 (inactive 2021-01-14). PMID 12421146.CS1 maint: DOI inactive as of January 2021 (link)
9. ^ a b c d e Casini A, de Moerloose P, Neerman-Arbez M (2016). "Clinical Features and Management of Congenital Fibrinogen Deficiencies". Seminars in Thrombosis and Hemostasis. 42 (4): 366–74. doi:10.1055/s-0036-1571339. PMID 27019462.
10. ^ a b Repetto O, De Re V (2017). "Coagulation and fibrinolysis in gastric cancer". Annals of the New York Academy of Sciences. 1404 (1): 27–48. Bibcode:2017NYASA1404...27R. doi:10.1111/nyas.13454. PMID 28833193. S2CID 10878584.
11. ^ a b c Neerman-Arbez M, de Moerloose P, Casini A (2016). "Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders". Seminars in Thrombosis and Hemostasis. 42 (4): 356–65. doi:10.1055/s-0036-1571340. PMID 27019463.
12. ^ Duval C, Ariëns RA (2017). "Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II" (PDF). Matrix Biology. 60–61: 8–15. doi:10.1016/j.matbio.2016.09.010. PMID 27784620.
13. ^ Mosesson MW (2005). "Fibrinogen and fibrin structure and functions". Journal of Thrombosis and Haemostasis. 3 (8): 1894–904. doi:10.1111/j.1538-7836.2005.01365.x. PMID 16102057. S2CID 22077267.
14. ^ a b Ruiz-Saez A (2013). "Occurrence of thrombosis in rare bleeding disorders". Seminars in Thrombosis and Hemostasis. 39 (6): 684–92. doi:10.1055/s-0033-1353391. PMID 23929306.
15. ^ Tengborn L, Blombäck M, Berntorp E (2015). "Tranexamic acid--an old drug still going strong and making a revival". Thrombosis Research. 135 (2): 231–42. doi:10.1016/j.thromres.2014.11.012. PMID 25559460.
16. ^ Blombäck M, Blombäck B, Mammen EF, Prasad AS (1968). "Fibrinogen Detroit--a molecular defect in the N-terminal disulphide knot of human fibrinogen?". Nature. 218 (5137): 134–7. Bibcode:1968Natur.218..134B. doi:10.1038/218134a0. PMID 5645286. S2CID 4165737.
17. ^ a b c Said SM, Sethi S, Valeri AM, Leung N, Cornell LD, Fidler ME, Herrera Hernandez L, Vrana JA, Theis JD, Quint PS, Dogan A, Nasr SH (2013). "Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases". Clinical Journal of the American Society of Nephrology. 8 (9): 1515–23. doi:10.2215/CJN.10491012. PMC 3805078. PMID 23704299.
18. ^ Ashby MA, Lazarchick J (1986). "Acquired dysfibrinogenemia secondary to mithramycin toxicity". The American Journal of the Medical Sciences. 292 (1): 53–5. doi:10.1097/00000441-198607000-00011. PMID 2940861.
19. ^ "UpToDate".
20. ^ Kotlín R, Sobotková A, Riedel T, Salaj P, Suttnar J, Reicheltová Z, Májek P, Khaznadar T, Dyr JE (2008). "Acquired dysfibrinogenemia secondary to multiple myeloma". Acta Haematologica. 120 (2): 75–81. doi:10.1159/000160182. PMID 18841003. S2CID 45965368.
21. ^ Post GR, James L, Alapat D, Guillory V, Cottler-Fox M, Nakagawa M (2013). "A case of acquired dysfibrinogenemia in multiple myeloma treated with therapeutic plasma exchange". Transfusion and Apheresis Science. 48 (1): 35–8. doi:10.1016/j.transci.2012.06.021. PMID 22842111.
## External links[edit]
Classification
D
* ICD-10: D68.2
* OMIM: 616004
External resources
* Orphanet: 98881
* v
* t
* e
Disorders of bleeding and clotting
Coagulation · coagulopathy · Bleeding diathesis
Clotting
By cause
* Clotting factors
* Antithrombin III deficiency
* Protein C deficiency
* Activated protein C resistance
* Protein S deficiency
* Factor V Leiden
* Prothrombin G20210A
* Platelets
* Sticky platelet syndrome
* Thrombocytosis
* Essential thrombocythaemia
* DIC
* Purpura fulminans
* Antiphospholipid syndrome
Clots
* Thrombophilia
* Thrombus
* Thrombosis
* Virchow's triad
* Trousseau sign of malignancy
By site
* Deep vein thrombosis
* Bancroft's sign
* Homans sign
* Lisker's sign
* Louvel's sign
* Lowenberg's sign
* Peabody's sign
* Pratt's sign
* Rose's sign
* Pulmonary embolism
* Renal vein thrombosis
Bleeding
By cause
Thrombocytopenia
* Thrombocytopenic purpura: ITP
* Evans syndrome
* TM
* TTP
* Upshaw–Schulman syndrome
* Heparin-induced thrombocytopenia
* May–Hegglin anomaly
Platelet function
* adhesion
* Bernard–Soulier syndrome
* aggregation
* Glanzmann's thrombasthenia
* platelet storage pool deficiency
* Hermansky–Pudlak syndrome
* Gray platelet syndrome
Clotting factor
* Haemophilia
* A/VIII
* B/IX
* C/XI
* von Willebrand disease
* Hypoprothrombinemia/II
* Factor VII deficiency
* Factor X deficiency
* Factor XII deficiency
* Factor XIII deficiency
* Dysfibrinogenemia
* Congenital afibrinogenemia
Signs and symptoms
* Bleeding
* Bruise
* Haematoma
* Petechia
* Purpura
* Nonthrombocytopenic purpura
By site
* head
* Epistaxis
* Haemoptysis
* Intracranial haemorrhage
* Hyphaema
* Subconjunctival haemorrhage
* torso
* Haemothorax
* Haemopericardium
* Pulmonary haematoma
* abdomen
* Gastrointestinal bleeding
* Haemobilia
* Haemoperitoneum
* Haematocele
* Haematosalpinx
* joint
* Haemarthrosis
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Dysfibrinogenemia | c1260903 | 2,441 | wikipedia | https://en.wikipedia.org/wiki/Dysfibrinogenemia | 2021-01-18T18:42:16 | {"gard": ["2004"], "umls": ["C1260903", "C0272350"], "orphanet": ["335", "98881", "248408"], "wikidata": ["Q5319404"]} |
Sutherland et al. (1980) and Scheres and Hustinx (1980) identified a new class of fragile site at 10q25 that requires bromodeoxyuridine in the culture medium for expression. It appears to be inherited in a mendelian dominant manner and is polymorphic in the Australian population where the frequency was found to be about 1 in 60 no. 10 chromosomes (Sutherland et al., 1980). Sutherland (1981) ascertained this polymorphism 49 times. In one couple, both parents and some of the first-degree relatives of each were heterozygous for the heteromorphism. Two of their children were homozygous, yet phenotypically normal. Sutherland (1982) pointed out that 'this fragile site and its non-fragile allelomorph can be considered to constitute the first true chromosomal polymorphism to be described in man.' The 'gene frequency' was 0.013; the population was in Hardy-Weinberg equilibrium and segregation analysis confirmed codominant inheritance.
Hewett et al. (1998) reported that the bromodeoxyuridine-inducible, distamycin A-insensitive fragile site FRA10B is composed of AT-rich expanded repeats of approximately 42 bp. Differences in repeat motif length or composition between different FRA10B families indicate multiple independent expansion events. Some FRA10B alleles comprise a mixture of different expanded repeat motifs. Hewett et al. (1998) observed several allele lengths and grouped them into 4 categories: short normal (approximately 66% of alleles), intermediate normal (approximately 33%), long normal (less than 1%), and FRA10B expanded (approximately 1%). FRA10B fragile site and long normal alleles share flanking polymorphisms. Somatic and intergenerational FRA10B repeat instability analogous to that found in expanded trinucleotide repeats supports dynamic mutation as a common mechanism for repeat expansion.
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| FRAGILE SITE 10q25 | c1850980 | 2,442 | omim | https://www.omim.org/entry/136620 | 2019-09-22T16:40:57 | {"omim": ["136620"], "synonyms": ["Alternative titles", "BrdU-DEPENDENT FRAGILE SITE"]} |
Blau syndrome is a rare condition characterized mainly by skin rash, arthritis and uveitis. It has variable expressivity and usually affects preschool age children younger than four years of age. Characteristic findings include synovial effusions (fluid in the joints due to inflammation) and cysts, anterior uveitis (swelling and irritation of the uvea) and focal posterior synechiae (adhesion of the iris to the cornea). Permanent bending of the fingers and toes (camptodactyly) and other findings have also been reported. It is caused by mutations in the NOD2 gene and is inherited in an autosomal dominant manner. Blau syndrome and early-onset sarcoidosis have the same symptoms and genetic cause, but early-onset sarcoidosis is caused by de novo (new) mutations and occurs sporadically (in individuals with no history of the disorder in the family).
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Blau syndrome | c1861303 | 2,443 | gard | https://rarediseases.info.nih.gov/diseases/304/blau-syndrome | 2021-01-18T18:01:46 | {"mesh": ["C538157"], "omim": ["186580"], "umls": ["C1861303"], "orphanet": ["90340"], "synonyms": ["Arthrocutaneouveal granulomatosis", "ACUG", "Granulomatosis, familial, Blau type", "Granulomatous inflammatory arthritis, dermatitis, and uveitis, familial", "Synovitis granulomatous with uveitis and cranial neuropathies", "Granulomatosis, familial juvenile systemic", "Jabs syndrome", "Early onset sarcoidosis (former)"]} |
For a phenotypic description and a discussion of genetic heterogeneity of attention deficit-hyperactivity disorder, see 143465.
Clinical Features
Rommelse et al. (2008) cited 10 neuropsychologic cognitive and motor measures that had been shown to be candidate ADHD phenotypes: stop task, shifting attentional set, time test, visuo-spatial sequencing, digit span (a measure of working memory), pursuit, tracking, tapping, baseline speed, and motor timing.
Mapping
In genomewide linkage analyses in a Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 unaffected sibs, Rommelse et al. (2008) used 8 neuropsychologic cognitive and motor measures that had been shown to be candidate ADHD phenotypes (those with heritabilities greater than 0.2) as quantitative traits. They also used an overall component score of neuropsychologic functioning. A total of 5,407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. They found a significant genomewide linkage signal for digit span on chromosome 13q12.11, with a lod score of 3.959 at SNP rs1974047.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ATTENTION DEFICIT-HYPERACTIVITY DISORDER, SUSCEPTIBILITY TO, 6 | c2676740 | 2,444 | omim | https://www.omim.org/entry/612312 | 2019-09-22T16:01:50 | {"omim": ["612312"], "synonyms": ["Alternative titles", "ADHD6", "DIGIT SPAN QUANTITATIVE TRAIT LOCUS"]} |
A number sign (#) is used with this entry because the Vel blood group system is determined by the SMIM1 gene (615242), which encodes the Vel antigen, on chromosome 1p36.
Description
The Vel blood group system is defined by the presence of the Vel antigen on red blood cells. Vel is a high frequency antigen that shows variable strength, ranging from strong to weak. The rare Vel-negative blood type is inherited as an autosomal recessive trait and is typically unveiled when Vel-negative individuals develop anti-Vel antibodies after transfusion or pregnancy; Vel alloantibodies are never 'naturally occurring.' Individuals with anti-Vel antibodies may develop severe acute hemolytic transfusion reactions when transfused with Vel-positive blood. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel (summary by Daniels, 2002; Storry et al., 2013; Cvejic et al., 2013; Ballif et al., 2013).
Clinical Features
Sussman and Miller (1952) first described the Vel-negative blood group phenotype in a 66-year-old woman who developed a severe acute intravascular hemolytic episode after a blood transfusion due to antibodies against a newly defined antigen named 'Vel.' She had a history of 3 pregnancies and colon cancer requiring transfusions.
Levine et al. (1961) reported a family in which 7 individuals spanning 3 generations were negative for the Vel red blood cell antigen. The proband was a woman who had been pregnant 6 times and received blood transfusions at least twice. She developed a severe transfusion reaction and was found to carry the Vel antibody in her serum, whereas her red cells lacked the Vel antigen. The other Vel-negative family members did not have serum anti-Vel antibodies.
Subsequent reports of hemolytic reactions after transfusion of Vel-positive RBCs to Vel-negative individuals with antibody to Vel, as well as hemolytic disease of the newborns of Vel-negative mothers, established Vel as a clinically important blood group antigen (summary by Storry et al., 2013).
Mapping
By SNP analysis of 20 Vel-negative individuals primarily of Swedish origin, including 5 individuals from 2 families, Storry et al. (2013) identified a 97-kb haplotype block on chromosome 1p36 that segregated with the phenotype. A homozygous founder mutation was postulated.
Molecular Genetics
By SNP mapping followed by candidate gene sequencing of 20 Vel-negative individuals, Storry et al. (2013) identified a homozygous 17-bp deletion in the SMIM1 gene (615242.0001) in all individuals. The findings were confirmed in 15 additional Vel-negative individuals, predominantly of European descent. Direct genotyping identified 30 heterozygous deletion carriers among 520 Swedish blood donors. The deletion was not found in the 1000 Genomes Project data, but was found in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) database: 57 of 5,763 European Americans and 6 of 3,198 in African Americans, yielding heterozygote frequencies of about 1 in 50 and 1 in 267, respectively.
By exome sequencing of 5 individuals negative for the Vel antigen, Cvejic et al. (2013) found that 4 were homozygous and 1 was heterozygous for a 17-bp frameshift deletion in the SMIM1 gene. Combined with a follow-up study of additional Vel-negative individuals, a total of 63 of 69 Vel-negative individuals were found to be homozygous for the deletion. Five individuals classified as Vel-negative were heterozygous for the deletion and 1 was heterozygous for a missense mutation (M51R) only. Heterozygosity for the null allele in these individuals is most likely explained by misclassification of extremely weak Vel expression as Vel-negative. In addition, 19 of 20 individuals with weak Vel expression were heterozygous for the deletion. One individual with weak expression was heterozygous for a missense mutation (M51K). The 2 missense mutations may lead to inability of the SMIM1 protein to incorporate in the membrane, or may modify the epitope, leading to decreased binding of the antibody. Functional studies were not performed on the M51R or M51K variants. Expression of the Vel antigen on SMIM1-transfected HEK293T cells confirmed that SMIM1 is the gene underlying the Vel blood group. All 24 Vel-negative individuals or those with weak Vel expression who were heterozygous for the deletion were homozygous for the major A allele of SNP rs1175550, which is present in intron 2 of the STIM1 gene and is associated with decreased SMIM1 transcript levels. The findings suggested that this SNP contributes to variable expression of the Vel antigen.
Ballif et al. (2013) simultaneously identified the homozygous 17-bp deletion in the SMIM1 gene as the genetic basis for the Vel-negative blood group. Heterozygosity for the deletion was associated with weak Vel expression, consistent with a dosage effect. A common origin for the deletion was apparent.
Population Genetics
Population studies estimate the prevalence of Vel-negative individuals at 1 in 4,000 in Europe, with a slightly higher prevalence in northern Scandinavia (1 in 1,700) (summary by Storry et al., 2013).
INHERITANCE \- Autosomal recessive HEMATOLOGY \- Acute hemolytic transfusion reaction when transfused with Vel-positive blood MISCELLANEOUS \- Clinical manifestations only occur if Vel-negative individuals have anti-Vel antibodies and are transfused with Vel-positive blood \- Antibodies can develop after pregnancy or transfusion MOLECULAR BASIS \- Caused by mutation in the small integral membrane protein 1 gene (SMIM1, 615242.0001 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| BLOOD GROUP, VEL SYSTEM | c3808966 | 2,445 | omim | https://www.omim.org/entry/615264 | 2019-09-22T15:52:44 | {"omim": ["615264"]} |
This article may require cleanup to meet Wikipedia's quality standards. The specific problem is: There are many sections but detail is lacking and they could be expanded Please help improve this article if you can. (June 2018) (Learn how and when to remove this template message)
Heimler syndrome
Autosomal recessive pattern is the inheritance manner of this condition
CausesMutations in the PEX1 or PEX6 genes
Heimler syndrome is a rare autosomal recessive condition characterized by sensorineural hearing loss, amelogenesis imperfecta, nail abnormalities and occasional or late-onset retinal pigmentation
## Contents
* 1 Signs/symptoms
* 2 Genetics
* 3 Epidemiology
* 4 Diagnosis
* 4.1 Differential diagnosis
* 5 Treatment
* 6 Prognosis
* 7 History
* 8 References
* 9 External links
## Signs/symptoms[edit]
This condition is characterised by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, nail abnormalities and occasional or late-onset retinal pigmentation abnormalities.
## Genetics[edit]
This condition is caused by mutations in peroxisomal biogenesis factor 1 (PEX1) or peroxisomal biogenesis factor 6 (PEX6) genes.[1] These gene are involved in peroxisome biogenesis. PEX 1 is located on long arm of chromosome 7 (7q21).2 PEX 6 is located on the short arm of chromosome 6 (6p21). These genes encode AAA+ ATPases. They form part of the mechanism that shuttles the peroxisome targeting signal receptor protein PEX5 back to the cytosol after release of its protein cargo within the peroxisomal lumen.
## Epidemiology[edit]
This is rare disorder. Precise estimates of its prevelence are not known but it appears be to be < 1/106
## Diagnosis[edit]
The diagnosis is made on clinical grounds and confirmed by gene sequencing.
### Differential diagnosis[edit]
None has been reported to date.
## Treatment[edit]
There is no treatment for this condition known at present.
## Prognosis[edit]
This condition tends to produce only mild abnormalities. Life expectancy is normal.
## History[edit]
This condition was first described in 1991.[2]
## References[edit]
1. ^ Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G (2015) Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am J Hum Genet 97(4):535-545
2. ^ Heimler A, Fox JE, Hershey JE, Crespi P: Sensorineural hearing loss, enamel hypoplasia, and nail abnormalities in sibs. Am J Med Genet 39: 192–195
## External links[edit]
Classification
D
* OMIM: 234580
* MeSH: C535994
The Global Foundation for Peroxisomal Disorders - www.thegfpd.org
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Heimler syndrome | c1856186 | 2,446 | wikipedia | https://en.wikipedia.org/wiki/Heimler_syndrome | 2021-01-18T18:47:59 | {"gard": ["1687"], "mesh": ["C535994"], "orphanet": ["3220"], "wikidata": ["Q55345705"]} |
Tarsal tunnel syndrome is a nerve disorder that is characterized by pain in the ankle, foot, and toes. This condition is caused by compression of the posterior tibial nerve, which runs through a canal near the heel into the sole of the foot. When tissues around this nerve become inflamed, they can press on the nerve and cause the pain associated with tarsal tunnel syndrome.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Tarsal tunnel syndrome | c0039319 | 2,447 | gard | https://rarediseases.info.nih.gov/diseases/7733/tarsal-tunnel-syndrome | 2021-01-18T17:57:24 | {"mesh": ["D013641"], "umls": ["C0039319"], "synonyms": ["Posterior Tibial Nerve Neuralgia", "Neuropathy of the posterior tibial nerve and its branches"]} |
Progressive familial intrahepatic cholestasis type 3 (PFIC3), a type of progressive familial intrahepatic cholestasis (PFIC, see this term), is a late-onset hereditary disorder in bile formation that is hepatocellular in origin. Onset may occur from infancy to young adulthood.
## Epidemiology
Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC3 represents one third of PFIC cases.
## Clinical description
Clinical signs of cholestasis (discolored stools, dark urine) appear within the first year of life in about one third of patients, or later with recurrent episodes of jaundice and mild pruritus. PFIC3 evolves into secondary biliary cirrhosis. Gastrointestinal bleeding due to portal hypertension might be the presenting symptom in adolescents or young adults.
## Etiology
PFIC3 is due to mutations in the ABCB4 gene (7q21), encoding the multi-drug resistant 3 protein (MDR3), resulting in impaired biliary phospholipid (PL) secretion. Detergent effects of hydrophobic bile salts are not countered by biliary PLs and lead to cholangitis. Low biliary PL levels are insufficient to maintain solubility of cholesterol and promote bile lithogenicity.
## Diagnostic methods
PFIC3 should be suspected in children, adolescents, or young adults with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis. Patients present with high serum gamma-GT activity, normal cholesterol levels and moderately elevated bile acid concentrations. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals portal fibrosis and true ductular proliferation with mixed inflammatory infiltrate and, at a later stage, signs of biliary cirrhosis. MDR3 immunostaining is helpful for diagnosis. Cholangiography shows a normal biliary tree making it possible to rule out sclerosing cholangitis. Bile collection allows biliary lipid analysis showing decreased biliary phospholipid levels. Genotyping confirms the diagnosis.
## Differential diagnosis
Differential diagnosis includes biliary tract diseases and causes of intrahepatic cholestasis and of cirrhosis with elevated gamma-GT.
## Antenatal diagnosis
Prenatal diagnosis can be proposed if a mutation has been identified in each parent.
## Genetic counseling
Transmission is autosomal recessive.
## Management and treatment
Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage. Beneficial effects of UDCA are usually observed in patients who harbored at least one missense mutation. In half of the patients, UDCA therapy fails and liver transplantation is required due to liver failure. In patients responding to UDCA, PFIC3 may be complicated by cirrhosis, portal hypertension and hepatocellular carcinoma. Furthermore, patients are at high risk of biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course, especially if UDCA therapy is stopped. Specialized follow-up is mandatory and lifelong.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Progressive familial intrahepatic cholestasis type 3 | c1865643 | 2,448 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79305 | 2021-01-23T17:11:40 | {"gard": ["1289"], "mesh": ["C535935"], "omim": ["602347"], "umls": ["C1865643"], "icd-10": ["K76.8"], "synonyms": ["PFIC3"]} |
Vasoplegic syndrome (VPS) is a postperfusion syndrome characterized by low systemic vascular resistance and a high cardiac output.
## Contents
* 1 Causes
* 2 Diagnosis
* 2.1 Definition
* 3 Treatment
* 4 Epidemiology
* 5 References
## Causes[edit]
VPS occurs more frequently after on pump CABG surgery versus off pump CABG surgery.[1] Hypothermia during surgery may also increase ones risk of developing VPS post operatively.[2]
## Diagnosis[edit]
### Definition[edit]
Vasoplegic syndrome is defined as low systemic vascular resistance (SVR index <1,600 dyn∙sec/cm5/m2) and high cardiac output (cardiac index >2.5 l/min/m2) within the first 4 postoperative hours.[3]
## Treatment[edit]
There is some evidence to support the use of methylene blue in the treatment of this condition.[4][5]
## Epidemiology[edit]
One case series reports a rate of 1 in 120 cases.[6]
## References[edit]
1. ^ Sun X, Zhang L, Hill PC, et al. (October 2008). "Is incidence of postoperative vasoplegic syndrome different between off-pump and on-pump coronary artery bypass grafting surgery?". Eur J Cardiothorac Surg. 34 (4): 820–5. doi:10.1016/j.ejcts.2008.07.012. PMID 18715792.
2. ^ Xu J, Long C, Qi R, Xie L, Shi S, Zhang Y (January 2002). "[Study of mechanism of vasoplegic syndrome for open heart surgery]". Zhonghua Yi Xue Za Zhi (in Chinese). 82 (2): 127–30. PMID 11953144.
3. ^ Iribarren, J.; Jimenez, J.; Brouard, M.; Lorenzo, J.; Perez, R.; Lorente, L.; Nuñez, C.; Lorenzo, L.; Henry, C.; Martinez, R.; Mora, M. (2007-03-22). "Critical Care | Full text | Vasoplegic syndrome after cardiopulmonary bypass surgery – associated factors and clinical outcomes: a nested case-control study". Critical Care. 11 (2): P254. doi:10.1186/cc5414.
4. ^ "BestBets: Is Methylene Blue of benefit in treating adult patients who develop vasoplegic syndrome during Cardiac Surgery".
5. ^ Stawicki SP, Sims C, Sarani B, Grossman MD, Gracias VH (May 2008). "Methylene blue and vasoplegia: who, when, and how?". Mini Rev Med Chem. 8 (5): 472–90. doi:10.2174/138955708784223477. PMID 18473936.
6. ^ Gomes WJ, Carvalho AC, Palma JH, Gonçalves Júnior I, Buffolo E (1994). "[Vasoplegic syndrome: a new dilemma]". Rev Assoc Med Bras. 40 (4): 304. PMID 7633508.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Vasoplegic syndrome | c2717957 | 2,449 | wikipedia | https://en.wikipedia.org/wiki/Vasoplegic_syndrome | 2021-01-18T19:09:37 | {"mesh": ["D056987"], "umls": ["C2717957"], "wikidata": ["Q3554941"]} |
Necrobiotic xanthogranuloma
Other namesNXG[1]
SpecialtyDermatology
Necrobiotic xanthogranuloma (also known as "necrobiotic xanthogranuloma with paraproteinemia"[2]) is a multisystem disease that affects older adults, and is characterized by prominent skin findings.[3]:707
## See also[edit]
* List of cutaneous conditions
## References[edit]
1. ^ "Necrobiotic xanthogranuloma | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 21 April 2019.
2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
3. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6.
## External links[edit]
Classification
D
* ICD-10: D76.3
* MeSH: D058252
External resources
* Orphanet: 158011
* v
* t
* e
Cutaneous keratosis, ulcer, atrophy, and necrobiosis
Epidermal thickening
* keratoderma: Keratoderma climactericum
* Paraneoplastic keratoderma
* Acrokeratosis paraneoplastica of Bazex
* Aquagenic keratoderma
* Drug-induced keratoderma
* psoriasis
* Keratoderma blennorrhagicum
* keratosis: Seborrheic keratosis
* Clonal seborrheic keratosis
* Common seborrheic keratosis
* Irritated seborrheic keratosis
* Seborrheic keratosis with squamous atypia
* Reticulated seborrheic keratosis
* Dermatosis papulosa nigra
* Keratosis punctata of the palmar creases
* other hyperkeratosis: Acanthosis nigricans
* Confluent and reticulated papillomatosis
* Callus
* Ichthyosis acquisita
* Arsenical keratosis
* Chronic scar keratosis
* Hyperkeratosis lenticularis perstans
* Hydrocarbon keratosis
* Hyperkeratosis of the nipple and areola
* Inverted follicular keratosis
* Lichenoid keratosis
* Multiple minute digitate hyperkeratosis
* PUVA keratosis
* Reactional keratosis
* Stucco keratosis
* Thermal keratosis
* Viral keratosis
* Warty dyskeratoma
* Waxy keratosis of childhood
* other hypertrophy: Keloid
* Hypertrophic scar
* Cutis verticis gyrata
Necrobiosis/granuloma
Necrobiotic/palisading
* Granuloma annulare
* Perforating
* Generalized
* Subcutaneous
* Granuloma annulare in HIV disease
* Localized granuloma annulare
* Patch-type granuloma annulare
* Necrobiosis lipoidica
* Annular elastolytic giant-cell granuloma
* Granuloma multiforme
* Necrobiotic xanthogranuloma
* Palisaded neutrophilic and granulomatous dermatitis
* Rheumatoid nodulosis
* Interstitial granulomatous dermatitis/Interstitial granulomatous drug reaction
Foreign body granuloma
* Beryllium granuloma
* Mercury granuloma
* Silica granuloma
* Silicone granuloma
* Zirconium granuloma
* Soot tattoo
* Tattoo
* Carbon stain
Other/ungrouped
* eosinophilic dermatosis
* Granuloma faciale
Dermis/
localized CTD
Cutaneous lupus
erythematosus
* chronic: Discoid
* Panniculitis
* subacute: Neonatal
* ungrouped: Chilblain
* Lupus erythematosus–lichen planus overlap syndrome
* Tumid
* Verrucous
* Rowell's syndrome
Scleroderma/
Morphea
* Localized scleroderma
* Localized morphea
* Morphea–lichen sclerosus et atrophicus overlap
* Generalized morphea
* Atrophoderma of Pasini and Pierini
* Pansclerotic morphea
* Morphea profunda
* Linear scleroderma
Atrophic/
atrophoderma
* Lichen sclerosus
* Anetoderma
* Schweninger–Buzzi anetoderma
* Jadassohn–Pellizzari anetoderma
* Atrophoderma of Pasini and Pierini
* Acrodermatitis chronica atrophicans
* Semicircular lipoatrophy
* Follicular atrophoderma
* Linear atrophoderma of Moulin
Perforating
* Kyrle disease
* Reactive perforating collagenosis
* Elastosis perforans serpiginosa
* Perforating folliculitis
* Acquired perforating dermatosis
Skin ulcer
* Pyoderma gangrenosum
Other
* Calcinosis cutis
* Sclerodactyly
* Poikiloderma vasculare atrophicans
* Ainhum/Pseudo-ainhum
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Necrobiotic xanthogranuloma | c1275339 | 2,450 | wikipedia | https://en.wikipedia.org/wiki/Necrobiotic_xanthogranuloma | 2021-01-18T18:38:01 | {"gard": ["10951"], "mesh": ["D058252"], "umls": ["C1275339"], "orphanet": ["158011"], "wikidata": ["Q4021720"]} |
Elastosis perforans serpiginosa
Other namesEPS[1]
Elastosis perforans serpiginosa: Hyperkeratotic plaque of papules[2]
SpecialtyDermatology
Elastosis perforans serpiginosa is a unique perforating disorder characterized by transepidermal elimination of elastic fibers and distinctive clinical lesions, which are serpiginous in distribution and can be associated with specific diseases.[3][4]
* Histopathology of elastosis perforans serpiginosa: Degenerated elastic fibers and transepidermal perforating canals (arrow points at one of them)[2]
* This condition is inherited in an autosomal dominant manner.
## See also[edit]
* List of cutaneous conditions
* Poikiloderma vasculare atrophicans
## References[edit]
1. ^ "OMIM Entry - 130100 - ELASTOSIS PERFORANS SERPIGINOSA; EPS". omim.org. Retrieved 19 April 2019.
2. ^ a b Hosen, Mohammad J.; Lamoen, Anouck; De Paepe, Anne; Vanakker, Olivier M. (2012). "Histopathology of Pseudoxanthoma Elasticum and Related Disorders: Histological Hallmarks and Diagnostic Clues". Scientifica. 2012: 1–15. doi:10.6064/2012/598262. ISSN 2090-908X.
-Creative Commons Attribution 3.0 Unported license
3. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). Page 1041. McGraw-Hill. ISBN 0-07-138076-0.
4. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
## External links[edit]
Classification
D
* ICD-10: L87.2 (ILDS L87.200)
* OMIM: 130100
* MeSH: C536202
* DiseasesDB: 29813
External resources
* eMedicine: article/1074280
* v
* t
* e
Cutaneous keratosis, ulcer, atrophy, and necrobiosis
Epidermal thickening
* keratoderma: Keratoderma climactericum
* Paraneoplastic keratoderma
* Acrokeratosis paraneoplastica of Bazex
* Aquagenic keratoderma
* Drug-induced keratoderma
* psoriasis
* Keratoderma blennorrhagicum
* keratosis: Seborrheic keratosis
* Clonal seborrheic keratosis
* Common seborrheic keratosis
* Irritated seborrheic keratosis
* Seborrheic keratosis with squamous atypia
* Reticulated seborrheic keratosis
* Dermatosis papulosa nigra
* Keratosis punctata of the palmar creases
* other hyperkeratosis: Acanthosis nigricans
* Confluent and reticulated papillomatosis
* Callus
* Ichthyosis acquisita
* Arsenical keratosis
* Chronic scar keratosis
* Hyperkeratosis lenticularis perstans
* Hydrocarbon keratosis
* Hyperkeratosis of the nipple and areola
* Inverted follicular keratosis
* Lichenoid keratosis
* Multiple minute digitate hyperkeratosis
* PUVA keratosis
* Reactional keratosis
* Stucco keratosis
* Thermal keratosis
* Viral keratosis
* Warty dyskeratoma
* Waxy keratosis of childhood
* other hypertrophy: Keloid
* Hypertrophic scar
* Cutis verticis gyrata
Necrobiosis/granuloma
Necrobiotic/palisading
* Granuloma annulare
* Perforating
* Generalized
* Subcutaneous
* Granuloma annulare in HIV disease
* Localized granuloma annulare
* Patch-type granuloma annulare
* Necrobiosis lipoidica
* Annular elastolytic giant-cell granuloma
* Granuloma multiforme
* Necrobiotic xanthogranuloma
* Palisaded neutrophilic and granulomatous dermatitis
* Rheumatoid nodulosis
* Interstitial granulomatous dermatitis/Interstitial granulomatous drug reaction
Foreign body granuloma
* Beryllium granuloma
* Mercury granuloma
* Silica granuloma
* Silicone granuloma
* Zirconium granuloma
* Soot tattoo
* Tattoo
* Carbon stain
Other/ungrouped
* eosinophilic dermatosis
* Granuloma faciale
Dermis/
localized CTD
Cutaneous lupus
erythematosus
* chronic: Discoid
* Panniculitis
* subacute: Neonatal
* ungrouped: Chilblain
* Lupus erythematosus–lichen planus overlap syndrome
* Tumid
* Verrucous
* Rowell's syndrome
Scleroderma/
Morphea
* Localized scleroderma
* Localized morphea
* Morphea–lichen sclerosus et atrophicus overlap
* Generalized morphea
* Atrophoderma of Pasini and Pierini
* Pansclerotic morphea
* Morphea profunda
* Linear scleroderma
Atrophic/
atrophoderma
* Lichen sclerosus
* Anetoderma
* Schweninger–Buzzi anetoderma
* Jadassohn–Pellizzari anetoderma
* Atrophoderma of Pasini and Pierini
* Acrodermatitis chronica atrophicans
* Semicircular lipoatrophy
* Follicular atrophoderma
* Linear atrophoderma of Moulin
Perforating
* Kyrle disease
* Reactive perforating collagenosis
* Elastosis perforans serpiginosa
* Perforating folliculitis
* Acquired perforating dermatosis
Skin ulcer
* Pyoderma gangrenosum
Other
* Calcinosis cutis
* Sclerodactyly
* Poikiloderma vasculare atrophicans
* Ainhum/Pseudo-ainhum
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Elastosis perforans serpiginosa | c0221271 | 2,451 | wikipedia | https://en.wikipedia.org/wiki/Elastosis_perforans_serpiginosa | 2021-01-18T18:34:18 | {"gard": ["10103"], "mesh": ["C536202"], "umls": ["C0221271"], "icd-10": ["L87.2"], "orphanet": ["79148"], "wikidata": ["Q5353584"]} |
Deletion of the gulonolactone oxidase gene on 8p21 is a genetic disease that affects 100% of humans. Lack of the enzyme causes severe connective tissue disease and makes humans dependent upon dietary supplements of ascorbic acid; see 240400. Gilbert and Zevit (2001) pointed out that another genetic condition, affecting 100% of human males, is congenital lack of a baculum (os priapi; os penis). Whereas most mammals (including common species such as dogs and mice) and most other primates (except spider monkeys) have a penile bone, human males lack this bone and must rely on fluid hydraulics to maintain erections. The size of the rodent baculum is regulated by the posterior members of the HOXD (142987) set of transcription factors (Williams-Ashman and Reddi, 1991; Zakany et al., 1997). Gilbert and Zevit (2001) suggested that it was not a costal rib but rather the penile 'rib' or baculum that God removed from Adam to create Eve (Genesis 2:21-23). Genesis also states that 'the Lord God closed up the flesh.' Gilbert and Zevit (2001) suggested that the raphe on the penis and scrotum was thought to be the surgical scar.
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*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| BACULUM, CONGENITAL ABSENCE OF | c1853565 | 2,452 | omim | https://www.omim.org/entry/606174 | 2019-09-22T16:10:36 | {"omim": ["606174"], "synonyms": ["Alternative titles", "OS PENIS, CONGENITAL ABSENCE OF"]} |
Back strain
SpecialtyFamily medicine
Back strain is the injury occurring to muscles or tendons. Due to back strain, the tendons and muscles supporting the spine are twisted or pulled. Chronic back strain occurs because of the sustained trauma and wearing out of the back muscles[1] Acute back strain can occur following a single instance of over stressing of back muscles, as in lifting a heavy object. Chronic back strain is more common than the acute type.
To avoid back strain it is important to bend the knees whenever you lift a heavy object – see partial squats.[2]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 References
* 6 External links
## Signs and symptoms[edit]
The pain over the back is localized and does not radiate into the leg. It occurs suddenly and may be accompanied by muscle spasms. The pain is dull, aching type and decreases on rest. It may be aggravated with activity.[3]
## Cause[edit]
Back strain occurs more in women than men and is more common after pregnancy. Lean people, those standing for long hours and those doing sedentary work in bad posture are prone to back strain. Back strain is also more common in people with excessive curving of the back, weak muscles (as in muscular dystrophies) and tight thigh muscles. People who play sports involving lifting heavy weights, pushing and pulling are also prone to back strain.
## Diagnosis[edit]
The diagnosis of mild back strain can be made with a medical history and physical examination. In case of more severe strains, an X-ray should be taken to rule out fracture and disc herniation.
## Treatment[edit]
Back strain is treated using analgesics such as ibuprofen, rest and use of ice packs. The patient can resume activities 24-48 hours after pain and swelling is reduced. It is not recommended to have prolonged immobilization or bed rest. If the pain does not subside in two weeks, additional treatment may be required. Prevention of back strain is possible by adopting proper body mechanics while sitting, standing and lifting.[4] Cessation of smoking, maintaining a healthy diet, exercise and normal weight is also good for preventing back strain. Temporary pain relief may be achieved through application of a menthol-based pain relief cream.
## References[edit]
1. ^ Maheswari. Essential Orthopedics. New Delhi: Jeypee Publications. p. 262.
2. ^ "Lifting technique". Back.com. Retrieved 2013-11-24.
3. ^ "Back strains and sprains". Clevland Clinic. Clevland Clinic. Retrieved 1 December 2016.
4. ^ "Lumbar strain". Johns Hopkins Medicine. The Johns Hopkins Hospital. Retrieved 1 December 2016.
## External links[edit]
Classification
D
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Back strain | c0347721 | 2,453 | wikipedia | https://en.wikipedia.org/wiki/Back_strain | 2021-01-18T18:50:16 | {"umls": ["C0347721"], "wikidata": ["Q28136363"]} |
Pleomorphic liposarcoma (PLS), the rarest subtype of liposarcoma (LS; see this term), is an aggressive, fast growing tumor located usually in the deep soft tissues of the lower and upper extremities. It is characterized by a variable number of pleomorphic lipoblasts and, in contrast to dedifferentiated liposarcoma, it lacks any association with well-differentiated liposarcoma (see these terms).
## Epidemiology
The incidence is approximately 1/2,000,000 per year and it accounts for 5-10% of all LS cases.
## Clinical description
PLS usually presents in older individuals with a typical age at diagnosis of 50-70 years. PLS is most commonly a firm, rapidly growing mass in the deep compartments of the lower and upper extremities but can also be located in the abdomen or chest wall in rare cases. PLS has a high (>50%) risk of metastasis, primarily to the lungs. Metastasis is rapid, often leading to death.
## Etiology
The etiology is unknown. PLS is characterized by highly complex chromosome alterations, including polyploidy and various chromosomal duplications, deletions and complex rearrangements.
## Diagnostic methods
When a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally sampled by multiple core biopsies to make the histological diagnosis of PLS. Histologically PLS contains a variable number of pleomorphic lipoblasts, with hemorrhage and necrosis commonly observed.
## Differential diagnosis
PLS can often be mistaken for myxofibrosarcoma or pleomorphic undifferentiated sarcoma (see these terms).
## Management and treatment
Treatment involves the surgical excision of the tumor and surrounding normal tissue. In rare cases amputation of the limb is necessary. Tumors that are large (>5-8 cm) or marginally resectable may be treated with preoperative chemotherapy. Adjuvant radiation is recommended if the surgical margin is narrow or positive for sarcoma. Lifelong follow-up is recommended in order to monitor for recurrence at the initial site as well as distant metastasis.
## Prognosis
PLS has the poorest prognosis of all the LS subtypes. Five-year survival is 59%.
*[v]: View this template
*[t]: Discuss this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Pleomorphic liposarcoma | c0205825 | 2,454 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99969 | 2021-01-23T17:06:48 | {"mesh": ["D008080"], "umls": ["C0205825"], "icd-10": ["C49.9"], "synonyms": ["PLS"]} |
Chilblain lupus erythematosus
Other namesChilblain lupus erythematosus of Hutchinson[1]
SpecialtyDermatology
Chilblain lupus erythematosus is a chronic, unremitting form of lupus erythematosus with the fingertips, rims of ears, calves, and heels affected, especially in women.[2][3][4]
## See also[edit]
* Lupus erythematosus
* List of cutaneous conditions
## References[edit]
1. ^ Franceschini F, Calzavara-Pinton P, Valsecchi L, et al. (1999). "Chilblain lupus erythematosus is associated with antibodies to SSA/Ro". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 455: 167–71. doi:10.1007/978-1-4615-4857-7_24. ISBN 978-1-4613-7203-5. PMID 10599339.
2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Page 159. ISBN 0-7216-2921-0.
3. ^ Aoki T, Ishizawa T, Hozumi Y, Aso K, Kondo S (March 1996). "Chilblain lupus erythematosus of Hutchinson responding to surgical treatment: a report of two patients with anti-Ro/SS-A antibodies". Br. J. Dermatol. 134 (3): 533–7. doi:10.1111/j.1365-2133.1996.tb16244.x. PMID 8731683.
4. ^ Boehm I et al. Chilblain lupus erythematosus Hutchinson: successful treatment with mycophenolate mofetil. Arch Dermatol 2001;137:235–236 url=http://archderm.jamanetwork.com/article.aspx?articleid=478189
## External links[edit]
Classification
D
* ICD-10: L93.2 (ILDS L93.260)
* MeSH: C535924 C535924, C535924
This cutaneous condition article is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Chilblain lupus erythematosus | c0024145 | 2,455 | wikipedia | https://en.wikipedia.org/wiki/Chilblain_lupus_erythematosus | 2021-01-18T19:01:16 | {"mesh": ["C535924"], "umls": ["C0024145"], "orphanet": ["90280"], "wikidata": ["Q5097618"]} |
Oculocutaneous albinism
Other namesOCA
SpecialtyOphthalmology, dermatology
Oculocutaneous albinism is a form of albinism involving the eyes (oculo-), the skin (-cutaneous), and the hair.[1] Overall, an estimated 1 in 20,000 people worldwide are born with oculocutaneous albinism.[1] OCA is caused by mutations in several genes that control the synthesis of melanin within the melanocytes.[2] Seven types of oculocutaneous albinism have been described, all caused by a disruption of melanin synthesis and all autosomal recessive disorders.[3][4][5]:864 Oculocutaneous albinism is also found in non-human animals.
## Contents
* 1 Types
* 2 See also
* 3 References
* 4 External links
## Types[edit]
The following types of oculocutaneous albinism have been identified in humans.
Name OMIM Gene Description
OCA1 203100
606952 TYR OCA1 is caused by mutations of the tyrosinase gene, and can occur in two variations. The first is OCA1a, and means that the organism cannot synthesize melanin whatsoever.[6] The hair is usually white (often translucent) and the skin is very pale. Vision usually ranges from 20/200 to 20/400. The second is OCA1b, which has several subtypes itself.[7] Some individuals with OCA1b can tan and also develop pigment in the hair.[8] One subtype of OCA1b is called OCA1b TS (temperature sensitive), where the tyrosinase can only function below a certain temperature, which causes the body hair in cooler body regions to develop pigment (i.e. get darker). (An equivalent mutation produces the points pattern in Siamese cats.[9]) Another variant of OCA1b, called Albinism, yellow mutant type, is more common among the Amish than in other populations. It results in blonde hair and the eventual development of skin pigmentation during infancy, though at birth is difficult to distinguish from other types.[7][10] About 1 in 40,000 people have some form of OCA1.[11]
OCA2 203200 OCA2 The most common type of albinism is caused by mutation of the P gene. People with OCA2 generally have more pigment and better vision than those with OCA1, but cannot tan like some with OCA1b. A little pigment can develop in freckles or moles.[8] People with OCA2 usually have fair skin, but are often not as pale as OCA1. They have pale blonde to golden, strawberry blonde, or even brown hair, and most commonly blue eyes. Affected people of African descent usually have a different phenotype (appearance): yellow hair, pale skin, and blue, gray or hazel eyes. About 1 in 15,000 people have OCA2.[12][11] The gene MC1R doesn't cause OCA2, but does affect its presentation.[1]
OCA3 203290 TYRP1 Has only been partially researched and documented. It is caused by mutation of the tyrosinase-related protein-1 (Tyrp1) gene. Cases have been reported in Africa and New Guinea. Affected individuals typically have red hair, reddish-brown skin and blue or gray eyes. Variants may include rufous oculocutaneous albinism (ROCA or xanthism). The incidence rate of OCA3 is unknown.[13][11]
OCA4 606574 SLC45A2 Is very rare outside Japan, where OCA4 accounts for 24% of albinism cases. OCA4 can only be distinguished from OCA2 through genetic testing, and is caused by mutation of this membrane-associated transporter protein (MATP) gene.[14][11] Several German patients were identified in 2004.[15]
OCA5 615312 OCA5 was identified in a Pakistani family with "golden-colored hair, white skin, nystagmus, photophobia, foveal hypoplasia, and impaired visual acuity, regardless of their sex and age". Genetic analysis localized the defect to human chromosome region 4q24, but failed to identify a candidate gene.[16][17]
OCA6 113750 SLC24A5 One of the rarest forms of OCA, OCA6 was detected in Chinese individuals but is not thought to be limited to this ethnicity. It is heterogeneous in its effect of hair color, and results from mutations in the SLC24A5 gene, a membrane transporter that plays a role in pigmentation in a range of vertebrate species.[17][18]
OCA7 615179 C10orf11 OCA7 was originally characterized in a family from the Faroe Islands, but was subsequently identified in a Lithuanian patient. It is characterized by lighter pigmentation and significant effects on the eye, including decreased visual acuity and misrouting of neuronal tracks through the optic chiasm. It is due to mutation of a gene of unknown function, C10orf11 (11th uncharacterized open reading frame on chromosome 10, OMIM: 614537).[17][19]
## See also[edit]
* Piebaldism
* List of skin conditions
* List of cutaneous conditions associated with increased risk of nonmelanoma skin cancer
## References[edit]
1. ^ a b c "Oculocutaneous albinism". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 5 August 2020.
2. ^ "Orphanet: Oculocutaneous albinism". Orphanet.
3. ^ "OMIM Entry - #615179 - ALBINISM, OCULOCUTANEOUS, TYPE VII; OCA7". Online Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 16 June 2020.
4. ^ Grønskov K, Ek J, Brondum-Nielsen K (2007). "Oculocutaneous albinism". Orphanet Journal of Rare Diseases. 2. Article 43. doi:10.1186/1750-1172-2-43. PMC 2211462. PMID 17980020.
5. ^ James WD, Berger T, Elston DM (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10 ed.). Saunders. ISBN 0-7216-2921-0.
6. ^ "OMIM Entry - #203100 - ALBINISM, OCULOCUTANEOUS, TYPE IA; OCA1A". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
7. ^ a b "OMIM Entry - #606952 - ALBINISM, OCULOCUTANEOUS, TYPE IB; OCA1B". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
8. ^ a b King RA, Summers G, Haefemeyer JW, LeRoy B (2009). "Facts about Albinism". Archived from the original on 15 February 2009.
9. ^ Giebel LB, Tripathi RK, King RA, Spritz RA (March 1991). "A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse". The Journal of Clinical Investigation. 87 (3): 1119–1122. doi:10.1172/JCI115075. PMC 329910. PMID 1900309.
10. ^ Peracha MO, Eliott D, Garcia-Valenzuela E (13 September 2005). Gordon K 3rd, Talavera F, Rowsey JJ, Brown LL, Roy H Sr (eds.). "Ocular Manifestations of Albinism". eMedicine. WebMD. Archived from the original on 9 June 2007. Retrieved 31 March 2007.
11. ^ a b c d Boissy RE, Nordlund JJ (22 August 2005). Ortonne JP, Vinson RP, Perry V, Gelfand JM, James WD (eds.). "Albinism". eMedicine. WebMD. Archived from the original on 8 June 2007. Retrieved 31 March 2007.
12. ^ "OMIM Entry - #203200 - ALBINISM, OCULOCUTANEOUS, TYPE II; OCA2". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
13. ^ "OMIM Entry - #203290 - ALBINISM, OCULOCUTANEOUS, TYPE III; OCA3". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
14. ^ "OMIM Entry - #606574 - ALBINISM, OCULOCUTANEOUS, TYPE IV; OCA4". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
15. ^ Rundshagen U, Zühlke C, Opitz S, Schwinger E, Käsmann-Kellner B (February 2004). "Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4". Human Mutation. 23 (2): 106–110. doi:10.1002/humu.10311. PMID 14722913.
16. ^ "OMIM Entry - #615312 - ALBINISM, OCULOCUTANEOUS, TYPE V; OCA5". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
17. ^ a b c Montoliu L, Grønskov K, Wei A, Martínez-García M, Fernández A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed Z, Rosenberg T, Li W (January 2014). "Increasing the complexity: new genes and new types of albinism". Pigment Cell & Melanoma Research. 27 (1): 11–18. doi:10.1111/pcmr.12167. PMID 24066960.
18. ^ "OMIM Entry - #113750 - ALBINISM, OCULOCUTANEOUS, TYPE VI; OCA6". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
19. ^ "OMIM Entry - #615179 - ALBINISM, OCULOCUTANEOUS, TYPE VII; OCA7". Mendelian Inheritance in Man. Johns Hopkins University. Retrieved 5 August 2020.
## External links[edit]
Classification
D
* ICD-10: E70.3
* ICD-10-CM: E70.32
* ICD-9-CM: 270.2
* OMIM: 203100 203200 203290 606574
* MeSH: D016115
External resources
* GeneReviews: Oculocutaneous Albinism Type 1
* Orphanet: 55
* Oculocutaneous albinism information at RareDiseases.org
* NCBI Genetic Testing Registry
* v
* t
* e
Inborn error of amino acid metabolism
K→acetyl-CoA
Lysine/straight chain
* Glutaric acidemia type 1
* type 2
* Hyperlysinemia
* Pipecolic acidemia
* Saccharopinuria
Leucine
* 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
* 3-Methylcrotonyl-CoA carboxylase deficiency
* 3-Methylglutaconic aciduria 1
* Isovaleric acidemia
* Maple syrup urine disease
Tryptophan
* Hypertryptophanemia
G
G→pyruvate→citrate
Glycine
* D-Glyceric acidemia
* Glutathione synthetase deficiency
* Sarcosinemia
* Glycine→Creatine: GAMT deficiency
* Glycine encephalopathy
G→glutamate→
α-ketoglutarate
Histidine
* Carnosinemia
* Histidinemia
* Urocanic aciduria
Proline
* Hyperprolinemia
* Prolidase deficiency
Glutamate/glutamine
* SSADHD
G→propionyl-CoA→
succinyl-CoA
Valine
* Hypervalinemia
* Isobutyryl-CoA dehydrogenase deficiency
* Maple syrup urine disease
Isoleucine
* 2-Methylbutyryl-CoA dehydrogenase deficiency
* Beta-ketothiolase deficiency
* Maple syrup urine disease
Methionine
* Cystathioninuria
* Homocystinuria
* Hypermethioninemia
General BC/OA
* Methylmalonic acidemia
* Methylmalonyl-CoA mutase deficiency
* Propionic acidemia
G→fumarate
Phenylalanine/tyrosine
Phenylketonuria
* 6-Pyruvoyltetrahydropterin synthase deficiency
* Tetrahydrobiopterin deficiency
Tyrosinemia
* Alkaptonuria/Ochronosis
* Tyrosinemia type I
* Tyrosinemia type II
* Tyrosinemia type III/Hawkinsinuria
Tyrosine→Melanin
* Albinism: Ocular albinism (1)
* Oculocutaneous albinism (Hermansky–Pudlak syndrome)
* Waardenburg syndrome
Tyrosine→Norepinephrine
* Dopamine beta hydroxylase deficiency
* reverse: Brunner syndrome
G→oxaloacetate
Urea cycle/Hyperammonemia
(arginine
* aspartate)
* Argininemia
* Argininosuccinic aciduria
* Carbamoyl phosphate synthetase I deficiency
* Citrullinemia
* N-Acetylglutamate synthase deficiency
* Ornithine transcarbamylase deficiency/translocase deficiency
Transport/
IE of RTT
* Solute carrier family: Cystinuria
* Hartnup disease
* Iminoglycinuria
* Lysinuric protein intolerance
* Fanconi syndrome: Oculocerebrorenal syndrome
* Cystinosis
Other
* 2-Hydroxyglutaric aciduria
* Aminoacylase 1 deficiency
* Ethylmalonic encephalopathy
* Fumarase deficiency
* Trimethylaminuria
* v
* t
* e
Pigmentation disorders/Dyschromia
Hypo-/
leucism
Loss of
melanocytes
Vitiligo
* Quadrichrome vitiligo
* Vitiligo ponctué
Syndromic
* Alezzandrini syndrome
* Vogt–Koyanagi–Harada syndrome
Melanocyte
development
* Piebaldism
* Waardenburg syndrome
* Tietz syndrome
Loss of melanin/
amelanism
Albinism
* Oculocutaneous albinism
* Ocular albinism
Melanosome
transfer
* Hermansky–Pudlak syndrome
* Chédiak–Higashi syndrome
* Griscelli syndrome
* Elejalde syndrome
* Griscelli syndrome type 2
* Griscelli syndrome type 3
Other
* Cross syndrome
* ABCD syndrome
* Albinism–deafness syndrome
* Idiopathic guttate hypomelanosis
* Phylloid hypomelanosis
* Progressive macular hypomelanosis
Leukoderma w/o
hypomelanosis
* Vasospastic macule
* Woronoff's ring
* Nevus anemicus
Ungrouped
* Nevus depigmentosus
* Postinflammatory hypopigmentation
* Pityriasis alba
* Vagabond's leukomelanoderma
* Yemenite deaf-blind hypopigmentation syndrome
* Wende–Bauckus syndrome
Hyper-
Melanin/
Melanosis/
Melanism
Reticulated
* Dermatopathia pigmentosa reticularis
* Pigmentatio reticularis faciei et colli
* Reticulate acropigmentation of Kitamura
* Reticular pigmented anomaly of the flexures
* Naegeli–Franceschetti–Jadassohn syndrome
* Dyskeratosis congenita
* X-linked reticulate pigmentary disorder
* Galli–Galli disease
* Revesz syndrome
Diffuse/
circumscribed
* Lentigo/Lentiginosis: Lentigo simplex
* Liver spot
* Centrofacial lentiginosis
* Generalized lentiginosis
* Inherited patterned lentiginosis in black persons
* Ink spot lentigo
* Lentigo maligna
* Mucosal lentigines
* Partial unilateral lentiginosis
* PUVA lentigines
* Melasma
* Erythema dyschromicum perstans
* Lichen planus pigmentosus
* Café au lait spot
* Poikiloderma (Poikiloderma of Civatte
* Poikiloderma vasculare atrophicans)
* Riehl melanosis
Linear
* Incontinentia pigmenti
* Scratch dermatitis
* Shiitake mushroom dermatitis
Other/
ungrouped
* Acanthosis nigricans
* Freckle
* Familial progressive hyperpigmentation
* Pallister–Killian syndrome
* Periorbital hyperpigmentation
* Photoleukomelanodermatitis of Kobori
* Postinflammatory hyperpigmentation
* Transient neonatal pustular melanosis
Other
pigments
Iron
* Hemochromatosis
* Iron metallic discoloration
* Pigmented purpuric dermatosis
* Schamberg disease
* Majocchi's disease
* Gougerot–Blum syndrome
* Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis
* Lichen aureus
* Angioma serpiginosum
* Hemosiderin hyperpigmentation
Other
metals
* Argyria
* Chrysiasis
* Arsenic poisoning
* Lead poisoning
* Titanium metallic discoloration
Other
* Carotenosis
* Tar melanosis
Dyschromia
* Dyschromatosis symmetrica hereditaria
* Dyschromatosis universalis hereditaria
See also
* Skin color
* Skin whitening
* Tanning
* Sunless
* Tattoo
* removal
* Depigmentation
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Oculocutaneous albinism | c0078918 | 2,456 | wikipedia | https://en.wikipedia.org/wiki/Oculocutaneous_albinism | 2021-01-18T18:30:53 | {"gard": ["10958"], "mesh": ["D016115"], "umls": ["C0078918"], "icd-9": ["270.2"], "orphanet": ["55"], "wikidata": ["Q2017741"]} |
Vulvovaginal rhabdomyosarcoma is a rare vulvovaginal tumour, a highly malignant soft tissue sarcoma composed of cells with round to oval or spindle-shaped nuclei and eosinophilic cytoplasm that may show differentiation towards striated muscle cells. It usually affects children and presents with a vulvar or vaginal mass that may be polypoid or grape-like (embryonal subtype) and associated with bleeding and ulceration.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Vulvovaginal rhabdomyosarcoma | c4707823 | 2,457 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=206492 | 2021-01-23T19:10:56 | {"icd-10": ["C52"]} |
Distinctively shaped callus of dead skin
For other uses, see Corn (disambiguation).
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Corn (Medicine)
Painful corns
A corn (or clavus, plural clavi or clavuses) is a distinctively shaped callus of dead skin that usually occurs on thin or glabrous (hairless and smooth) skin surfaces, especially on the dorsal surface of toes or fingers. They can sometimes occur on the thicker skin of the palms or bottom of the feet.
Corns form when the pressure point against the skin traces an elliptical or semi-elliptical path during the rubbing motion, the center of which is at the point of pressure, gradually widening.
## Contents
* 1 Signs and symptoms
* 2 Diagnosis
* 3 Treatment
* 4 References
## Signs and symptoms[edit]
The hard part at the center of the corn resembles a barley seed, that is like a funnel with a broad raised top and a pointed bottom. Because of their shape, corns intensify the pressure at the tip and can cause deep tissue damage and ulceration.[1] Hard corns are especially problematic for people with insensitive skin due to damaged nerves (e.g., in people with diabetes mellitus). The scientific name for a corn is heloma (plural helomata). A hard corn is called a heloma durum, while a soft corn is called a heloma molle.
The location of soft corns tends to differ from that of hard corns. Hard corns occur on dry, flat surfaces of skin. Soft corns (frequently found between adjacent toes) stay moist, keeping the surrounding skin soft. The corn's center is not soft, however, but indurated.
## Diagnosis[edit]
To exclude other differential diagnoses, a skin biopsy may be taken.[1] Imaging studies can be used in order to detect any underlying bony abnormalities that cause abnormal pressure on the overlying skin.[1] For this purpose, a plain radiograph usually suffices, but, occasionally, CT scanning is used.[1]
## Treatment[edit]
A corn after treatment
Treatment of corns includes paring of the lesions, which immediately reduces pain.[1] Another popular method is to use a corn plaster, a felt ring with a core of salicylic acid that relieves pressure and erodes the hard skin.[2] However, if an abnormal pressure source remains, the corn generally returns. If the source of any abnormal pressure is detected, this may be avoided, usually through a change to more comfortable footwear or with various types of shoe inserts or footwear with extra toe space. In extreme cases correcting gait abnormalities may be required.[1] If no other treatment is effective, surgery may be performed.[1]
## References[edit]
1. ^ a b c d e f g eMedicine > Clavus By Nanette Silverberg. Updated: Apr 9, 2010
2. ^ Corn on netdoctor.co.uk
Classification
D
External resources
* MedlinePlus: 001232
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Corn (medicine) | None | 2,458 | wikipedia | https://en.wikipedia.org/wiki/Corn_(medicine) | 2021-01-18T18:55:06 | {"icd-10": ["L84"], "wikidata": ["Q154558"]} |
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Infantile free sialic acid storage disease
This condition is inherited via an autosomal recessive manner
Infantile free sialic acid storage disease (ISSD) is a lysosomal storage disease.[1] ISSD occurs when sialic acid is unable to be transported out of the lysosomal membrane and instead accumulates in the tissue, causing free sialic acid to be excreted in the urine. Mutations in the SLC17A5 (solute carrier family 17 (anion/sugar transporter), member 50) gene cause all forms of sialic acid storage disease. The SLC17A5 gene is located on the long (q) arm of chromosome 6 between positions 14 and 15. This gene provides instructions for producing a protein called sialin that is located mainly on the membranes of lysosomes, compartments in the cell that digest and recycle materials.[citation needed]
ISSD is the most severe form of the sialic acid storage diseases. Babies with this condition have severe developmental delay, weak muscle tone (hypotonia), and failure to gain weight and grow at the expected rate (failure to thrive). They may have unusual facial features that are often described as "coarse," seizures, bone malformations, enlarged liver and spleen (hepatosplenomegaly), and an enlarged heart (cardiomegaly).
ISSD is a rare autosomal recessive disorder and affects 1 in 528,000 live births worldwide.
## Contents
* 1 Symptoms and signs
* 2 Cause
* 3 Diagnosis
* 4 Treatment
* 5 References
* 6 External links
## Symptoms and signs[edit]
Symptoms present by eight months of age and are marked by developmental delay followed by neurological complications such as seizures, involuntary eye movements, and ataxia, involuntary muscle movements and failure to gain weight and grow at the expected rate (failure to thrive). Babies with this condition also have and enlarged liver and spleen (hepatosplenomegaly) and enlarged heart (cardiomegaly).
## Cause[edit]
This section is empty. You can help by adding to it. (July 2017)
## Diagnosis[edit]
A diagnosis can be made by measuring cultured tissue samples for increased levels of free sialic acid. Prenatal testing is also available for known carriers of this disorder[citation needed]
## Treatment[edit]
There is no treatment for ISSD. Treatment is limited to controlling the symptoms of this disorder such as administering anti-convulsant medication to control seizure episodes.
## References[edit]
1. ^ "OMIM Entry - # 269920 - INFANTILE SIALIC ACID STORAGE DISEASE; ISSD". omim.org. Retrieved 2017-05-27.
## External links[edit]
* GeneReviews/NCBI/NIH/UW entry on Free Sialic Acid Storage Disorders
Classification
D
* ICD-10: E77.8
* OMIM: 269920
External resources
* Orphanet: 309324
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Infantile free sialic acid storage disease | c1963905 | 2,459 | wikipedia | https://en.wikipedia.org/wiki/Infantile_free_sialic_acid_storage_disease | 2021-01-18T18:52:07 | {"gard": ["175"], "umls": ["C1963905"], "orphanet": ["834", "309324"], "wikidata": ["Q2280692"]} |
Carotid-cavernous fistula
Other namesCCF
Oblique section through the cavernous sinus.
SpecialtyNeurology, cardiology
A carotid-cavernous fistula results from an abnormal communication between the arterial and venous systems within the cavernous sinus in the skull. It is a type of arteriovenous fistula. As arterial blood under high pressure enters the cavernous sinus, the normal venous return to the cavernous sinus is impeded and this causes engorgement of the draining veins, manifesting most dramatically as a sudden engorgement and redness of the eye of the same side.
## Contents
* 1 Presentation
* 2 Causes
* 3 Diagnosis
* 3.1 Classification
* 4 Treatment
* 5 References
* 6 External links
## Presentation[edit]
dilated blood vessels in the eye in CCF [1]
CCF symptoms include bruit (a humming sound within the skull due to high blood flow through the arteriovenous fistula), progressive visual loss, and pulsatile proptosis or progressive bulging of the eye due to dilatation of the veins draining the eye. Pain is the symptom that patients often find the most difficult to tolerate.
Patients usually present with sudden or insidious onset of redness in one eye, associated with progressive proptosis or bulging.
They may have a history of similar episodes in the past.
## Causes[edit]
Carotid cavernous fistulae may form following closed or penetrating head trauma, surgical damage, rupture of an intracavernous aneurysm, or in association with connective tissue disorders, vascular diseases and dural fistulas.
## Diagnosis[edit]
Selective angiography of the external carotid artery showing an indirect type D right carotid cavernous fistula, filling of the cavernous sinus (arrow) and retrograde drainage into the right superior ophthalmic vein (arrowhead) [1]
This is based on MRI scan, magnetic resonance angiography and CT scan. A cerebral digital subtraction angiography (DSA) enhances visualization of the fistula.
* CT scans classically show an enlarged superior ophthalmic vein, cavernous sinus enlargement ipsilateral (same side) as the abnormality and possibly diffuse enlargement of all the extraocular muscles resulting from venous engorgement.
* Selective arteriography is used to evaluate arteriovenous fistulas.
* High resolution digital subtraction angiography may help in classifying CCF into dural and direct type and thus formulate a strategy to treat it either by a balloon or coil or both with or without preservation of parent ipsilateral carotid artery.[citation needed]
### Classification[edit]
Various classifications have been proposed for CCF. They may be divided into low-flow or high-flow, traumatic or spontaneous and direct or indirect. The traumatic CCF typically occurs after a basal skull fracture. The spontaneous dural cavernous fistula which is more common usually results from a degenerative process in older patients with systemic hypertension and atherosclerosis. Direct fistulas occur when the Internal Carotid artery (ICA) itself fistulizes into the Cavernous sinus whereas indirect is when a branch of the ICA or External Carotid artery (ECA) communicates with the cavernous sinus.
A popular classification divides CCF into four varieties depending on the type of arterial supply.
Type Description
A Fistulous supply from the internal carotid artery
B Supply from the dural branches of internal carotid artery
C from meningeal branches of ext carotid artery
D combined ICA+ECA
## Treatment[edit]
The mainstay of treatment for CCF is endovascular therapy. This may be transarterial (mostly in the case of direct CCF) or transvenous (most commonly in indirect CCF). Occasionally, more direct approaches, such as direct transorbital puncture of the cavernous sinus or cannulation of the draining superior orbital vein are used when conventional approaches are not possible. Spontaneous resolution of indirect fistulae has been reported but is uncommon. Staged manual compression of the ipsilateral carotid has been reported to assist with spontaneous closure in selected cases.
Direct CCF may be treated by occlusion of the affected cavernous sinus (coils, balloon, liquid agents), or by reconstruction of the damaged internal carotid artery (stent, coils or liquid agents).
Indirect CCF may be treated by occlusion of the affected cavernous sinus with coils, liquid agents or a combination of both.[2][3][4]
## References[edit]
1. ^ a b Thinda, S; Melson, MR; Kuchtey, RW (Jul 28, 2012). "Worsening angle closure glaucoma and choroidal detachments subsequent to closure of a carotid cavernous fistula". BMC Ophthalmology. 12: 28. doi:10.1186/1471-2415-12-28. PMC 3412712. PMID 22839357.
2. ^ Ong, CK; Wang, LL; Parkinson, RJ; Wenderoth, JD (2009). "Onyx embolisation of cavernous sinus dural arteriovenous fistula via direct percutaneous transorbital puncture". Journal of Medical Imaging and Radiation Oncology. 53 (3): 291–5. doi:10.1111/j.1754-9485.2009.02086.x. PMID 19624295.
3. ^ Bhatia, Kartik D; Wang, Lily; Parkinson, Richard J; Wenderoth, Jason D (2009). "Successful Treatment of Six Cases of Indirect Carotid-Cavernous Fistula with Ethylene Vinyl Alcohol Copolymer (Onyx) Transvenous Embolization". Journal of Neuro-Ophthalmology. 29 (1): 3–8. doi:10.1097/WNO.0b013e318199c85c. PMID 19458567.
4. ^ Nadarajah, M.; Power, M.; Barry, B.; Wenderoth, J. (2011). "Treatment of a traumatic carotid-cavernous fistula by the sole use of a flow diverting stent". Journal of NeuroInterventional Surgery. 4 (3): e1. doi:10.1136/neurintsurg-2011-010000. PMID 21990483.
## External links[edit]
Classification
D
* MeSH: D020216
* DiseasesDB: 2152
External resources
* eMedicine: oph/204 radio/134
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Carotid-cavernous fistula | c0238045 | 2,460 | wikipedia | https://en.wikipedia.org/wiki/Carotid-cavernous_fistula | 2021-01-18T19:07:53 | {"mesh": ["D020216"], "wikidata": ["Q5045537"]} |
A number sign (#) is used with this entry because of evidence that susceptibility to idiopathic generalized epilepsy-14 (EIG14) is conferred by heterozygous mutation in the SLC12A5 gene (606726) on chromosome 20q13.
For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see EIG (600669).
Clinical Features
Kahle et al. (2014) reported 8 patients of French Canadian origin with idiopathic generalized epilepsy with onset between 3 and 21 years of age. Seizure types included generalized tonic-clonic, absence, and myoclonic. EEG results, when available, showed generalized spike-wave discharges or diffuse theta waves. None of the patients had febrile seizures.
Puskarjov et al. (2014) reported an Australian family in which several individuals had febrile seizures. Additional clinical details were not provided.
Inheritance
The transmission pattern of EIG14 in the families reported by Kahle et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.
Molecular Genetics
Kahle et al. (2014) identified 2 different heterozygous missense variants in the SLC12A5 gene (R952H, 606726.0004 and R1049C, 606726.0005) that were enriched among individuals of French Canadian origin with EIG14 compared to controls. The R952H variant was found in 5 of 380 patients with EIG (allele frequency of 0.66%) and in 5 of 1,214 controls (allele frequency of 0.21%), yielding an odds ratio (OR) of 3.21 for development of EIG (p = 0.065). The R1049C variant was found in 3 of 380 patients with EIG (allele frequency of 0.39) and in 1 of 1,214 controls (allele frequency of 4.12 x 10(-4)), yielding an odds ratio (OR) of 9.61 (p = 0.044). In vitro functional expression studies showed that the variants impaired chloride extrusion capacities, resulting in less hyperpolarized glycine equilibrium potentials, and also impaired stimulatory phosphorylation at residue ser940, a key regulatory site of channel function. The overall effect impaired the function of SLC12A5. The authors used a targeted DNA-sequencing approach to screen the cytoplasmic C-terminal region of SLC12A5, which is an important regulatory region of transporter function.
Puskarjov et al. (2014) identified a heterozygous R952H variant in the SLC12A5 gene in 3 affected members of an Australian family with febrile seizures. Segregation of the variant in this kindred was difficult because of uncertain phenotyping, but there was some evidence of incomplete penetrance. In vitro functional expression studies showed markedly decreased surface expression of the mutant protein (61% of wildtype) as well as decreased chloride extrusion compared to wildtype. Thus, the mutant protein was associated with deficits in maintaining the chloride driving force required for hyperpolarizing GABA-mediated responses. Transfection of the variant into rats and into mouse cortical neurons showed that it compromised dendritic spine formation and maturation. Puskarjov et al. (2014) suggested that the decrease in SLC12A5-dependent hyperpolarizing inhibition would promote triggering of seizures, and that decreased dendritic spine formation could lead to desynchronization of overall excitability, which may also contribute to seizures.
INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures \- Generalized tonic-clonic seizures \- Absence seizures \- Myoclonic seizures \- Febrile seizures (1 family) \- Generalized spike-wave discharges seen on EEG MISCELLANEOUS \- Variable age at onset, but most often in the first 2 decades \- Incomplete penetrance MOLECULAR BASIS \- Susceptibility conferred by mutation in the solute carrier family 12 (potassium/chloride transporter), member 5 gene (SLC12A5, 606726.0004 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 14 | c4225245 | 2,461 | omim | https://www.omim.org/entry/616685 | 2019-09-22T15:48:17 | {"omim": ["616685"]} |
Canavan disease is a progressive, fatal, genetic disorder affecting the central nervous system, muscles, and eyes. Early symptoms in infancy may include increased head size, weakness, low muscle tone and loss of head control. Symptoms progress to seizures, blindness, inability to move voluntarily and difficulty eating solids or swallowing liquids. This condition is caused by changes in the ASPA gene and is inherited in an autosomal recessive pattern. Canavan disease is diagnosed based on symptoms, laboratory testing, and genetic testing. There is no specific treatment. Treatment is focused on managing symptoms.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Canavan disease | c0206307 | 2,462 | gard | https://rarediseases.info.nih.gov/diseases/5984/canavan-disease | 2021-01-18T18:01:39 | {"mesh": ["D017825"], "omim": ["271900"], "umls": ["C0206307"], "orphanet": ["141"], "synonyms": ["Canavan-van Bogaert-Bertrand disease", "Spongy degeneration of the central nervous system", "Von Bogaert-Bertrand disease", "Aspartoacylase deficiency", "ASPA deficiency", "ASP deficiency", "ACY2 deficiency", "Aminoacylase 2 deficiency"]} |
For a discussion of the genetic heterogeneity in serum adiponectin levels, see ADIPQTL1 (612556).
Mapping
Jee et al. (2010) measured adiponectin (605441) levels in and genotyped 4,001 Korean volunteers using a genomewide marker panel in a 2-stage design, and analyzed selected markers in another 2,304 individuals in follow-up replication studies. The SNP most strongly associated with mean log adiponectin was rs3865188, located 17.9-kb upstream of the cadherin-13 gene (CDH13; 601364) on chromosome 16q23.3 (p = 1.69 x 10(-15) in the initial sample, p = 6.58 x 10(-39) in the second genomewide sample, and p = 2.12 x 10(-32) in the replication sample). The metaanalysis p value for rs3865188 in all 6,305 individuals was 2.82 x 10(-83), and the association of rs3865188 with high molecular weight adiponectin was even stronger in the third sample (p = 7.36 x 10(-58)). Jee et al. (2010) observed that rs3865188 was in complete linkage disequilibrium with a CDH13 promoter SNP, rs12444338, located 543 bp upstream of the CDH13 transcription start site, and a reporter assay to evaluate the effects of rs12444338 revealed that the major allele increased CDH13 expression 2.2 fold. Jee et al. (2010) concluded that genetic variants in CDH13 influence adiponectin levels in Korean adults.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ADIPONECTIN, SERUM LEVEL OF, QUANTITATIVE TRAIT LOCUS 5 | c3151203 | 2,463 | omim | https://www.omim.org/entry/613836 | 2019-09-22T15:57:17 | {"omim": ["613836"]} |
A number sign (#) is used with this entry because at least some cases of carpal tunnel syndrome are caused by heterozygous mutation in the TTR gene, encoding transthyretin (176300), on chromosome 18q12.
Susceptibility to the development of carpal tunnel syndrome (613353) may also be conferred by heterozygous mutation in the SH3TC2 gene (608206) on chromosome 5q32.
Clinical Features
Danta (1975) reported carpal tunnel syndrome (constrictive median neuropathy) in 4 persons in 3 generations with male-to-male transmission. Symptoms began in the first decade in father and son, and in both the median nerve at operation was found to be constricted under a thickened transverse carpal ligament. Carpal tunnel syndrome has been described in amyloid neuropathy (see 176300) and in mucopolysaccharidoses (e.g., 253200) and mucolipidoses (252600).
Gray et al. (1979) described bilateral carpal tunnel syndrome in 19 of 43 living members of a nonconsanguineous family, with male-to-male transmission. Sixty-three percent of the affected persons also had symptomatic digital flexor tenosynovitis, often polytendinous, which required surgery in 4. Age of onset was most often in the twenties but was at age 10 in 1 patient.
Vallat and Dunoyer (1979) reported carpal tunnel syndrome in father and daughter.
Kishi et al. (1975) and Kishi and Folkers (1976) used the level of erythrocyte glutamic oxaloacetic transaminase (EGOT) as a measure of vitamin B6 deficiency. Ellis et al. (1977) demonstrated severe deficiency of B6 in CTS. Administration of pyridoxine corrected the B6 deficiency and alleviated the neurologic disorder (Ellis et al., 1979). Further documentation of the improvement, which may obviate surgery, was presented by Ellis et al. (1982). They concluded that, since K(m) values of EGOT were identical in patients with and without CTS but with identical specific activities, CTS is a primary deficiency of B6, not a dependency state.
Serratrice et al. (1985) described familial occurrence and onset at an early age (before 12 years) especially in the right hand (see also Lettin, 1965). McDonnell et al. (1987) described 5 definite and 3 possible cases of carpal tunnel syndrome in 3 generations of a family. A remarkable feature was the development of symptoms as early as age 4 years.
Swoboda et al. (1998) described the case of a 7-month-old son of consanguineous Indian parents who presented with the recurrent chewing of his fingers in a median nerve distribution as the primary manifestation of carpal tunnel syndrome, in conjunction with features consistent with congenital insensitivity to pain. Electromyography (EMG) demonstrated severe median nerve entrapment at the wrist bilaterally, but other nerves were normal. In spite of clinical evidence of diffuse pain insensitivity, sural nerve and skin biopsies were normal, and he had no evidence of autonomic dysfunction. Hand findings evolved with scarring and infection of median innervated digits and loss of fine motor skills. Carpal tunnel release resulted in complete clinical resolution and significant EMG improvement. Milder symptoms and EMG evidence of median nerve entrapment were demonstrated in both parents, paternal grandparents, and several of his father's sibs. Swoboda et al. (1998) suggested that the child was homozygous for a mutant allele that in its heterozygous state predisposed to familial autosomal dominant carpal tunnel syndrome. Homozygosity for this or another mutant allele may have been responsible for his congenital insensitivity to pain.
Stoll and Maitrot (1998) studied the family of an otherwise healthy 35-year-old woman with carpal tunnel syndrome and found that 7 other members of the family in 4 generations were affected. Only 2 of the 8 were male. None of the secondary causes of carpal tunnel syndrome, such as amyloidosis, were found in the family.
Gossett and Chance (1998) reviewed reports of families with familial carpal tunnel syndrome and the guidelines used for the diagnosis. They identified 7 new 'potential' familial CTS pedigrees on the basis of their having 4 or more members with symptoms. In all but 2 pedigrees, however, an explanation other than familial CTS was found. Gossett and Chance (1998) concluded that familial isolated CTS is a rare, but genetically distinct disorder.
Mapping
Sparkes et al. (1985) found no linkage between idiopathic carpal tunnel syndrome and 20 informative markers. For 8 of these, linkage was excluded by a lod score less than 2.0.
Cytogenetics
There are conditions that mimic the symptoms of CTS or predispose people to develop it. One such condition is hereditary neuropathy with liability to pressure palsies (HNNP; 162500). This disorder most frequently manifests initially as a peripheral nerve entrapment, including median nerve compression at the carpal canal with delayed nerve conduction velocities. Potocki et al. (1999) described a family with dominantly inherited CTS that was associated with the chromosome deletion in 17p12 that causes HNPP. HNPP is probably underdiagnosed because it typically has episodic and transient clinical manifestations. Stockton et al. (2001) evaluated 50 patients diagnosed with idiopathic CTS and found no instance of the chromosome 17 microdeletion that causes HNPP.
Molecular Genetics
Elstner et al. (2006) reported a large family in which 9 members over 3 generations had bilateral carpal tunnel syndrome. The pedigree was compatible with autosomal dominant inheritance, but there was some evidence for an X-linked dominant transmission that was lethal in the hemizygous male: there was an almost exclusive occurrence of CTS in females, a preponderance of female to male offspring, and several male miscarriages. The affected matriarch had 6 sisters, no brother, 5 daughters, and 2 male miscarriages. The phenotype in this pedigree was consistent with anticipation, since the onset of CTS was approximately 20 years earlier in the third generation than in the second. Elstner et al. (2006) analyzed the peripheral myelin protein-22 (PMP22; 601097) and transthyretin (TTR; 176300) genes but found no alterations in affected family members; and linkage to the connexin-32 (GJB1; 304040) locus was excluded by haplotype analysis.
Murakami et al. (1994) studied 2 sibs from a Japanese family with carpal tunnel syndrome. At the time of surgical carpal tunnel release, Congo-red stained biopsy material was obtained demonstrating the presence of amyloid. There were no other neurologic abnormalities, no orthostatic hypotension, no gastrointestinal problems or sphincter disturbances, and no vitreous opacities. The father, who had had symptoms of carpal tunnel syndrome, died at the age of 76 of pneumonia. In the sibs a tyr114-to-his substitution in transthyretin was detected (176300.0033).
Misc \- Responsive to pyridoxine administration \- Early onset age Limbs \- Thickened transverse carpal ligament \- Digital flexor tenosynovitis Neuro \- Constrictive median neuropathy \- Tunnel sign Lab \- Vitamin B6 deficiency Inheritance \- Autosomal dominant ▲ Close
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| CARPAL TUNNEL SYNDROME | c0007286 | 2,464 | omim | https://www.omim.org/entry/115430 | 2019-09-22T16:43:40 | {"doid": ["12169"], "mesh": ["D002349"], "omim": ["115430"], "icd-9": ["354.0"], "icd-10": ["G56.00", "G56.0"], "synonyms": ["Alternative titles", "CTS", "AMYOTROPHY, THENAR, OF CARPAL ORIGIN"]} |
A number sign (#) is used with this entry because Diamond-Blackfan anemia-7 (DBA7) is caused by heterozygous mutation in the gene encoding ribosomal protein L11 (RPL11; 604175) on chromosome 1p36.
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).
For a discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650).
Clinical Features
Gazda et al. (2008) reviewed medical records of DBA7 patients and found that associated physical malformations, predominantly involving the thumb, were seen in 12 of the 18 patients and included triphalangeal thumbs, small extra thumbs, and flat thenar muscles, as well as ventricular septal defect, tetralogy of Fallot, horseshoe kidney, and vesicoureteral reflux. One patient had uterine cancer.
Gerrard et al. (2013) reported 3 unrelated patients with DBA7. A 7-year-old Caucasian boy was diagnosed at birth and had elevated erythrocyte adenosine deaminase (ADA; 608958). He also had patent ductus arteriosus, hypoplastic thumbs, recurrent chest infections, and vitamin D deficiency. The disorder was steroid-responsive. A 5-year-old Indian girl was diagnosed at age 3 months. She had growth retardation and recurrent infections, and was transfusion-dependent. A 7-year-old Caucasian girl was born by cesarean section due to fetal distress, and was diagnosed with anemia at age 12 months. She had growth retardation, recurrent otitis, mouth ulcers, neutropenia, hypoplastic thumbs, scoliosis, Cathie facies, and Sprengel shoulder deformity. Erythrocyte ADA was elevated.
Molecular Genetics
Gazda et al. (2008) screened 196 probands with Diamond-Blackfan anemia for mutations in 25 genes encoding ribosomal proteins and identified 11 different heterozygous mutations in the RPL11 gene in 13 probands and 5 additional family members (see, e.g., 604175.0001-604175.0004). The mutations segregated with disease in multiplex families and were not found in at least 150 controls; functional studies demonstrated defects in the maturation of ribosomal RNAs associated with mutation in the RPL11 gene.
Gerrard et al. (2013) identified heterozygous truncating mutations in the RPL11 gene (see, e.g., 604175.0005-604175.0006) in 3 of 19 patients with DBA who were screened for mutations in 80 ribosomal protein genes.
INHERITANCE \- Autosomal dominant GROWTH Other \- Intrauterine growth retardation (some patients) \- Growth retardation HEAD & NECK Face \- Cathie facies Ears \- Auditory canal atresia \- Otitis media, recurrent \- Hearing loss Nose \- Choanal atresia Mouth \- Cleft palate CARDIOVASCULAR Heart \- Ostium secundum atrial septal defect \- Patent ductus arteriosus \- Ventricular septal defect CHEST Ribs Sternum Clavicles & Scapulae \- Sprengel deformity ABDOMEN Liver \- Hepatic iron overload, mild to severe Gastrointestinal \- Eosinophilic esophagitis \- Gastrointestinal reflux SKELETAL \- Osteoporosis \- Osteopenia Spine \- Scoliosis Hands \- Hypoplastic thumbs \- Triphalangeal thumbs NEUROLOGIC Central Nervous System \- Delayed linguistic development (rare) HEMATOLOGY \- Anemia \- Neutropenia IMMUNOLOGY \- Recurrent infections (chest, otitis media) PRENATAL MANIFESTATIONS Movement \- Fetal distress Amniotic Fluid \- Polyhydramnios Placenta & Umbilical Cord \- High eADA in cord blood Delivery \- Poor progression in labor LABORATORY ABNORMALITIES \- Vitamin D deficiency \- Elevated erythrocyte adenosine deaminase (eADA) MISCELLANEOUS \- Onset is usually in the first years of life MOLECULAR BASIS \- Caused by mutation in the ribosomal protein L11 gene (RPL11, 604175.0001 ) ▲ Close
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| DIAMOND-BLACKFAN ANEMIA 7 | c1260899 | 2,465 | omim | https://www.omim.org/entry/612562 | 2019-09-22T16:01:15 | {"doid": ["1339"], "mesh": ["D029503"], "omim": ["612562"], "orphanet": ["124"], "genereviews": ["NBK7047"]} |
Hyperferritinemia cataract syndrome is a rare condition that is characterized by elevated levels of ferritin (an iron-storing protein) in the blood and early onset cataracts. Without treatment, these cataracts often become progressively worse leading to dimming and blurriness of vision. The severity of the condition can vary significantly from person to person, even among members of the same family. Hyperferritinemia cataract syndrome is caused by changes (mutations) in the FTL gene and is inherited in an autosomal dominant manner. Treatment is generally focused on improving vision and may include glasses, contact lenses and/or cataract surgery.
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Hyperferritinemia cataract syndrome | c1833213 | 2,466 | gard | https://rarediseases.info.nih.gov/diseases/2806/hyperferritinemia-cataract-syndrome | 2021-01-18T17:59:55 | {"mesh": ["C538137"], "omim": ["600886"], "umls": ["C1833213"], "orphanet": ["163"], "synonyms": ["Hereditary hyperferritinemia cataract syndrome", "Cataract-hyperferritinemia syndrome", "Bonneau-Beaumont syndrome"]} |
A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced (herpes-specific) encephalopathy (IIAE5) is caused by heterozygous mutation in the TRAF3 gene (601896) on chromosome 14q32. One such patient has been reported.
For a phenotypic description of herpes simplex encephalitis (HSE) and a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.
Clinical Features
Perez de Diego et al. (2010) described a 4-year-old French girl from nonconsanguineous parents who presented with persistent high fever before the onset of other symptoms, including diarrhea and convulsions, followed by epilepsy and aphasia. Her cerebrospinal fluid contained herpes simplex virus (HSV)-1, and she responded well to 3 weeks of intravenous acyclovir treatment. At age 18 years, she was healthy and had normal responses to other infectious diseases, including other HSV family members.
Inheritance
In the patient reported by Perez de Diego et al. (2010), susceptibility to HSE was inherited in an autosomal dominant manner.
Molecular Genetics
In a patient with susceptibility to HSE, Perez de Diego et al. (2010) identified a heterozygous C-to-T substitution at position 352 in exon 4 of the TRAF3 gene, resulting in a nonconservative missense change, arg118 to trp (R118W; 601896.0001). The parents and brothers of the patient were homozygous for wildtype TRAF3.
*[v]: View this template
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*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED (HERPES-SPECIFIC), SUSCEPTIBILITY TO, 5 | c0276226 | 2,467 | omim | https://www.omim.org/entry/614849 | 2019-09-22T15:54:02 | {"mesh": ["D020803"], "omim": ["614849"], "orphanet": ["1930"], "synonyms": ["Alternative titles", "HERPES SIMPLEX ENCEPHALITIS, SUSCEPTIBILITY TO, 3"]} |
A syndrome characterized by bone loss
Gorham's disease
Other namesAcro-osteolysis syndrome, Breschet-Gorham-Stout syndrome,[1] Cystic angiomatosis of bone,[1] Disappearing bone disease, Disseminated lymphangiomatosis, Disseminated osseous bone disease, Essential osteolysis, Gorham-Stout syndrome, Gorham's lymphangiomatosis, Hemangiomata with osteolysis,[1] Idiopathic massive osteolysis, Massive osteolysis,[1] Morbus-Gorham-Stout disease, Osteolysis and angiomatous nevi,[1] Skeletal lymphangiomatosis, Skeletal hemangiomatosis, Thoracic lymphangiomatosis.
Gorham's disease involving the left parietal bone: X-ray of the skull lateral view (A) showing a osteolytic area in left parietal region. CT scan bony window (B), MRI T1W Axial (C) and T2W Sagittal (D) revealing skull defect with normal brain parenchyma.
SpecialtyRheumatology
Gorham's disease (pronounced GOR-amz), also known as Gorham vanishing bone disease and phantom bone disease,[1] is a very rare skeletal condition of unknown cause, characterized by the uncontrolled proliferation of distended, thin-walled vascular or lymphatic channels within bone, which leads to resorption and replacement of bone with angiomas and/or fibrosis.[2][3]
## Contents
* 1 Signs and symptoms
* 2 Causes
* 3 Diagnosis
* 4 Management
* 5 Epidemiology
* 6 History
* 7 References
* 8 Further reading
* 9 External links
## Signs and symptoms[edit]
The symptoms of Gorham's disease vary depending on the bones involved. It may affect any part of the skeleton, but the most common sites of disease are the shoulder, skull, pelvic girdle, jaw, ribs, and spine.[4][5][6][7]
In some cases, no symptoms are seen until a fracture occurs either spontaneously or following minor trauma, such as a fall. An acute onset of localized pain and swelling may occur. More commonly, pain of no apparent cause increases in frequency and intensity over time and may eventually be accompanied by weakness and noticeable deformity of the area. The rate of progression is unpredictable, and the prognosis can be difficult. The disease may stabilize after a number of years, go into spontaneous remission, or in cases involving the chest and upper spine, prove fatal. Recurrence of the disease following remission can also occur. Involvement of the spine and skull base may cause a poor outcome from neurological complications. In many cases, the end result of Gorham's disease is severe deformity and functional disability.[4][5][8]
Symptoms such as difficulty breathing and chest pain may be present if the disease is present in the ribs, scapula, or thoracic vertebrae. These may indicate that the disease has spread from the bone into the chest cavity. The breathing problems may be misdiagnosed as asthma, because the damage done to the lungs can cause the same types of changes to lung function testing as seen in asthma.[6] Extension of the lesions into the chest may lead to the development of chylous pleural and pericardial effusions. Chyle is rich in protein and white blood cells that are important in fighting infection. The loss of chyle into the chest can have serious consequences, including infection, malnutrition, and respiratory distress and failure. These complications or their symptoms, such as difficulty breathing, chest pain, poor growth or weight loss, and infection have sometimes been the first indications of the condition.[6][7][8]
## Causes[edit]
The specific cause of Gorham's disease remains unknown. Bone mass and strength are obtained and maintained through a process of bone destruction and replacement that occurs at the cellular level throughout a person's life. Cells called osteoclasts secrete enzymes that dissolve old bone, allowing another type of cells called osteoblasts to form new bone. Except in growing bone, the rate of breakdown equals the rate of building, thereby maintaining bone mass. In Gorham's disease, that process is disrupted.[2][3][4][9][10][11]
Gorham and Stout found that vascular anomalies always occupied space that normally would be filled with new bone and speculated that the presence of angiomatosis may lead to chemical changes in the bone.[2][9] Gorham and others speculated that such a change in the bone chemistry might cause an imbalance in the rate of osteoclast to osteoblast activity such that more bone is dissolved than is replaced.[9] Beginning in the 1990s, elevated levels of a protein called interleukin-6 (IL-6) being detected in people with the disease were reported, leading some to suggest that increased levels of IL-6 and vascular endothelial growth factor (VEGF) may contribute to the chemical changes Gorham and others believed were the cause of this type of osteolysis.[4][12]
In 1999, Möller and colleagues[4] concluded, "The Gorham-Stout syndrome may be, essentially, a monocentric bone disease with a focally increased bone resorption due to an increased number of paracrine – or autocrine – stimulated hyperactive osteoclasts. The resorbed bone is replaced by a markedly vascularized fibrous tissue. The apparent contradiction concerning the presence or absence or the number of osteoclasts, may be explained by the different phases of the syndrome." They further stated that their histopathological study provided good evidence that osteolytic changes seen in Gorham's disease are the result of hyperactive osteoclastic bone. However, others have concluded that lymphangiomatosis and Gorham's disease should be considered as a spectrum of disease rather than separate diseases.[13]
While a consensus exists that Gorham's is caused by deranged osteoclastic activity,[2][4][9][11] no conclusive evidence has been found as to what causes this behavior to begin.
## Diagnosis[edit]
In 1983, Heffez and colleagues[10] published a case report in which they suggested eight criteria for a definitive diagnosis of Gorham's disease:[citation needed]
* Positive biopsy with the presence of angiomatous tissue
* Absence of cellular atypia
* Minimal or no osteoblastic response or dystrophic calcifications
* Evidence of local bone progressive osseous resorption
* Nonexpansile, nonulcerative lesions
* No involvement of viscera
* Osteolytic radiographic pattern
* Negative hereditary, metabolic, neoplastic, immunologic, or infectious etiology
In the early stages of the disease, X-rays reveal changes resembling patchy osteoporosis. As the disease progresses, bone deformity occurs with further loss of bone mass, and in the tubular bones (the long bones of the arms and legs), a concentric shrinkage is often seen which has been described as having a "sucked candy" appearance. Once the cortex (the outer shell) of the bone has been disrupted, and vascular channels may invade adjacent soft tissues and joints. Eventually, complete or near-complete resorption of the bone occurs and may extend to adjacent bones, though spontaneous arrest of bone loss has been reported on occasion. Throughout this process, as the bone is destroyed, it is replaced by angiomatous and/or fibrous tissue.[2][3][4][11][14]
Often, Gorham's disease is not recognized until a fracture occurs, with subsequent improper bone healing. The diagnosis essentially is one of exclusion and must be based on combined clinical, radiological, and histopathological findings.[4] X-rays, CT scans, MRIs, ultrasounds, and nuclear medicine (bone scans) are all important tools in the diagnostic workup and surgical planning, but none has the ability alone to produce a definitive diagnosis. Surgical biopsy with histological identification of the vascular or lymphatic proliferation within a generous section of the affected bone is an essential component in the diagnostic process.[4][5][8]
Recognition of the disease requires a high index of suspicion and an extensive workup. Because of its serious morbidity, Gorham's must always be considered in the differential diagnosis of osteolytic lesions.[3]
## Management[edit]
Treatment of Gorham's disease is for the most part palliative and limited to symptom management.[citation needed]
Sometimes, the bone destruction spontaneously ceases and no treatment is required, but when the disease is progressive, aggressive intervention may be necessary. Duffy and colleagues[6] reported that around 17% of people with Gorham's disease in the ribs, shoulder, or upper spine experience extension of the disease into the chest, leading to chylothorax with its serious consequences, and that the mortality rate in this group can reach as high as 64% without surgical intervention.
A search of the medical literature reveals multiple case reports of interventions with varying rates of success as follows:[citation needed]
Cardiothoracic (heart and lung):
* Pleurodesis
* Ligation of thoracic duct
* Pleurperitoneal shunt
* Radiation therapy
* Pleurectomy
* Surgical resection
* Thalidomide
* Interferon alpha-2b
* TPN (total parenteral nutrition)
* Thoracentesis
* Diet rich in medium-chain triglycerides and protein
* Chemotherapy
* Sclerotherapy
* Transplantation
Skeletal:
* Interferon alpha-2b
* Bisphosphonate (e.g. pamidronate)
* Surgical resection
* Radiation therapy
* Sclerotherapy
* Percutaneous bone cement
* Bone graft
* Prosthesis
* Surgical stabilization
* Amputation
To date, no known interventions are consistently effective for Gorham's, and all reported interventions are considered experimental treatments, though many are routine for other conditions. Some people may require a combination of these approaches. Unfortunately, some people will not respond to any intervention.[citation needed]
## Epidemiology[edit]
Gorham's disease is extremely rare and may occur at any age, though it is most often recognized in children and young adults. It strikes males and females of all races and exhibits no inheritance pattern. The medical literature contains case reports from every continent. Because it is so rare, and commonly misdiagnosed, exactly how many people are affected by this disease is not known. The literature frequently cites that fewer than 200 cases have been reported, though a consensus is building that many more cases occur around the world than have been reported.[citation needed]
## History[edit]
The first known report of the condition came in 1838 in an article titled "A Boneless Arm" in what was then The Boston Medical and Surgical Journal (now The New England Journal of Medicine).[15] It is a brief report chronicling the case of Mr. Brown who had, in 1819 at age 18 years, broken his right upper arm in an accident. The person suffered two subsequent accidents, which fractured the arm twice more "before the curative process had been completed." At the time of the report in 1838, the person was reported as having remarkable use of the arm, in spite of the humerus bone having apparently disappeared – X-rays did not yet exist. Thirty-four years later, a follow-up report was published in the same journal, following Mr. Brown's death from pneumonia at the age of 70 years.[16] The person had requested the arm "be dissected and preserved for the benefit of medical science" and this report contains a detailed pathological description of the arm and shoulder. Abnormalities of the remaining bones of the arm and shoulder are noted and the authors report that the arteries, veins, and nerves appeared normal. No mention was made of lymphatic vessels. Though several reports of similar cases were published in the interim, more than 80 years passed before another significant report of the condition appeared in the medical literature.[citation needed]
Both born in 1885, Lemuel Whittington Gorham, MD, and Arthur Purdy Stout, MD, had long, distinguished careers in medicine and shared a lifelong interest in pathology.[17][18][19] Dr. Gorham practiced and taught medicine and oncology and from the mid-1950s through the early 1960s conducted and reported the classical clinicopathological investigations of pulmonary embolism. During this time, he also authored several case series on osteolysis of bone. Dr. Stout began his career as a surgeon and became a pioneer in tumor pathology, publishing Human Cancer in 1932. This work became the model for the Atlas of Tumor Pathology project, which Stout oversaw as chairman of the National Research Council in the 1950s. In his later years, Dr. Stout embarked on a systematic study of soft tissue tumors in children and was among the first to link cigarette smoking to lung cancer.[citation needed]
In 1954, Gorham and three others published a two case series, with a brief review of 16 similar cases from the medical literature, that advanced the hypothesis that angiomatosis was responsible for this unusual form of massive osteolysis.[9] That same year, Gorham and Stout presented to the American Association of Physicians their paper (in abstract form), "Massive Osteolysis (Acute Spontaneous Absorption of Bone, Phantom Bone, Disappearing Bone): Its Relation to Hemangiomatosis".[2] The paper was published in its entirety in October 1955 in The Journal of Bone and Joint Surgery, concluding that:
1. There now exists the basis for a new syndrome which is supported by a remarkable similarity of clinical and [x-ray] findings in twenty-four cases, and by an equally convincing similarity of the histological picture in eight of these, which we have personally studied.
2. However it is accomplished, the progressive osteolysis is always associated with an angiomatosis of blood and sometimes of lymphatic vessels, which seemingly are responsible for it.
The most typical presentation is that of osteolysis of a single bone or the bones connected by a shared joint, such as the shoulder. Although the disease can attack any bone, the shoulder is one of the most commonly involved areas, along with the skull and pelvic girdle. Spontaneous fractures are common and may be the first sign of the disease.[4] A hallmark of the disease is the lack of bone healing following fracture.[citation needed]
## References[edit]
1. ^ a b c d e f "Gorham vanishing bone disease information". Disease Database. Retrieved 19 April 2012.
2. ^ a b c d e f Gorham LW, Stout AP. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone): its relation to hemangiomatosis. J Bone Joint Surg [Am] 1955;37-A:985-1004.
3. ^ a b c d Ross JL., Schinella R., and Shenkman L. Massive osteolysis: An unusual cause of bone destruction. The American Journal of Medicine 1978; 65(2): 367-372.
4. ^ a b c d e f g h i j MÖLLER, G., Priemel, M., Amling, M. Werner, M., Kuhlmey, A. S., Delling, G. "The Gorham-Stout syndrome (Gorham's massive osteolysis) A REPORT OF SIX CASES WITH HISTOPATHOLOGICAL FINDINGS." Journal of Bone and Joint Surgery (Br) 81B.3 (1999): 501-6. Web. 2 Sep 2011.
5. ^ a b c Yalniz E., Alicioglu B., Benlier E., Yilmaz1 B., Altaner S. Gorham-Stout Disease of the Humerus. JBR–BTR, 2008, 91: 14-17.
6. ^ a b c d Duffy B, Manon R, Patel R, Welsh JS, et al. A case of Gorham's disease with chylothorax treated curatively with radiation therapy. Clin Med Res. 2005;3:83–6.
7. ^ a b Lee WS, Kim SH, Kim I, et al. Chylothorax in Gorham's disease. J Korean Med Sci. 2002;17:826–9.
8. ^ a b c Chattopadhyay P, Bandyopadhyay A, Das S, Kundu A J. Gorham's disease with spontaneous recovery. Singapore Med J 2009; 50(7).
9. ^ a b c d e Gorham, L.W., Wright, A.W., Shultz, H. H., and Maxon, F. C. "Disappearing bones: A rare form of massive osteolysis: Report of two cases, one with autopsy findings." American Journal of Medicine 17.5 (1954): 674-682.
10. ^ a b Heffez L, Doku HC, Carter BL, et al: Perspectives on massive osteolysis. Report of a case and review of the literature. Oral Surg Oral Med Oral Pathol 55:331-343, 1983.
11. ^ a b c Johnson, Philip M. and McClure, James G. Observations on Massive Osteolysis: A Review of the Literature and Report of a Case. Radiology July 1958 71:28-42.
12. ^ Dupond JL, Bermont L, Runge M, de Billy M. Plasma VEGF determination in disseminated lymphangiomatosis-Gorham-Stout syndrome: a marker of activity? A case report with a 5-year follow-up. Bone. 2010 Mar;46(3):873-6.
13. ^ Aviv RI, McHugh K, Hunt J. Angiomatosis of bone and soft tissue: a spectrum of disease from diffuse lymphangiomatosis to vanishing bone disease in young patients. Clin Radiol. 2001 Mar;56(3):184-90.
14. ^ Torg JS, Steel HH. Sequential roentgenographic changes occurring in massive osteolysis. J Bone Joint Surg Am 1969; 51:1649-55.
15. ^ Jackson JBS. A boneless arm. Boston Med Surg J 1838;18:368-9.
16. ^ Jackson JBS. Absorption of the humerus after fracture. Boston Med Surg J 1872;10:245-7.
17. ^ "Arthur Purdy Stout Society". Retrieved 2 September 2011.
18. ^ Azur, HA. "Arthur Purdy Stout (1885–1967), a pioneer of surgical pathology: a survey of his Notes on the Education of an "Oncological" Surgical Pathologist.." Annals of Diagnostic Pathology 2.4 (1998): 271-9. PubMed.gov. Web. 2 Sep 2011.
19. ^ WRIGHT, I.S. "Memorial. L. Whittington Gorham, M.D.." Transactions of the American Clinical and Climatological Association 80. (1969): n. pag. PubMed Central. Web. 2 Sep 2011.
## Further reading[edit]
* Dellinger, M. T., Garg, N, Olsen, B.R., 2014. Viewpoints on vessels and vanishing bones in Gorham-Stout disease. Bone. 63C, 47–52.
* Lala S, Mulliken JB, Alomari AI, Fishman SJ, Kozakewich HP, Chaudry G. Gorham-Stout disease and generalized lymphatic anomaly—clinical, radiologic, and histologic differentiation. Skeletal Radiol. 2013 Jul;42(7):917-24. doi: 10.1007/s00256-012-1565-4. Epub 2013 Jan 31.
* Trenor, C, Chaudry G. Complex lymphatic anomalies, Semin Pediatr Surg. 2014 Aug;23(4):186-90. doi:10.1053/j.sempedsurg.2014.07.006. Epub 2014 Jul 22.
## External links[edit]
Classification
D
* ICD-9-CM: 733.99}
* MeSH: D010015
* DiseasesDB: 31515
* SNOMED CT: 1515008
External resources
* Orphanet: 73
* v
* t
* e
Bone and joint disease
Bone
Inflammation
endocrine:
* Osteitis fibrosa cystica
* Brown tumor
infection:
* Osteomyelitis
* Sequestrum
* Involucrum
* Sesamoiditis
* Brodie abscess
* Periostitis
* Vertebral osteomyelitis
Metabolic
* Bone density
* Osteoporosis
* Juvenile
* Osteopenia
* Osteomalacia
* Paget's disease of bone
* Hypophosphatasia
Bone resorption
* Osteolysis
* Hajdu–Cheney syndrome
* Ainhum
* Gorham's disease
Other
* Ischaemia
* Avascular necrosis
* Osteonecrosis of the jaw
* Complex regional pain syndrome
* Hypertrophic pulmonary osteoarthropathy
* Nonossifying fibroma
* Pseudarthrosis
* Stress fracture
* Fibrous dysplasia
* Monostotic
* Polyostotic
* Skeletal fluorosis
* bone cyst
* Aneurysmal bone cyst
* Hyperostosis
* Infantile cortical hyperostosis
* Osteosclerosis
* Melorheostosis
* Pycnodysostosis
Joint
Chondritis
* Relapsing polychondritis
Other
* Tietze's syndrome
Combined
Osteochondritis
* Osteochondritis dissecans
Child
leg:
* hip
* Legg–Calvé–Perthes syndrome
* tibia
* Osgood–Schlatter disease
* Blount's disease
* foot
* Köhler disease
* Sever's disease
spine
* * Scheuermann's_disease
arm:
* wrist
* Kienböck's disease
* elbow
* Panner disease
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Gorham's disease | c0029436 | 2,468 | wikipedia | https://en.wikipedia.org/wiki/Gorham%27s_disease | 2021-01-18T18:29:32 | {"gard": ["6542"], "mesh": ["D010015"], "umls": ["C0029436"], "icd-9": ["733.99"], "orphanet": ["73"], "wikidata": ["Q1538277"]} |
Resistant ovary syndrome, previously known as Savage syndrome, is a cause of ovarian failure that can lead to secondary amenorrhea. Resistant ovaries result from a functional disturbance of the gonadotropin receptors in the ovarian follicles. It may be a cause of primary or secondary amenorrhea and is resistant to exogenous gonadotropin stimulation.
Diagnosis of this condition requires that the patient has a normal 46,XX karyotype, normal secondary sexual characteristics, elevated plasma follicle-stimulating hormone and luteinizing hormone – in the menopausal range – and that normal, multiple follicles are seen on ovarian biopsy.
Spontaneous reversal of the receptor resistance may occur.[1]
## References[edit]
1. ^ http://www.acfs2000.com/basic_services/premature-ovarian-failure-pof.html
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Gonadotropin-resistant ovary syndrome | c0086367 | 2,469 | wikipedia | https://en.wikipedia.org/wiki/Gonadotropin-resistant_ovary_syndrome | 2021-01-18T18:54:08 | {"mesh": ["D016649"], "umls": ["C0086367"], "wikidata": ["Q5581327"]} |
Facial arteriovenous malformation is a rare vascular anomaly characterized by abnormal communication between arteries and veins, bypassing the capillary bed, located in the facial area. Lesions may be asymptomatic or may manifest with pain, ulceration, pulsation, tinnitus, minor bleeding or potentially life-threatening hemorrhage, blurred vision, impaired hearing, headache, paresthesia, enlargement of facial bones with intraosseous lesions, intraosseous hemangiomas, and speech, breathing and swallowing difficulties, as well as neuropathy.
*[v]: View this template
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Facial arteriovenous malformation | None | 2,470 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=156230 | 2021-01-23T19:07:10 | {"icd-10": ["Q27.3"]} |
A number sign (#) is used with this entry because catecholaminergic polymorphic ventricular tachycardia-2 (CPVT2) is caused by homozygous or compound heterozygous mutation in the gene encoding calsequestrin-2 (CASQ2; 114251) on chromosome 1p13.
For a general phenotypic description and a discussion of genetic heterogeneity of CPVT, see 604772.
Clinical Features
Lahat et al. (2001) studied 41 members of 7 families from a highly inbred Bedouin tribe in northern Israel in which 9 children had unexplained sudden death, 7 during vigorous exercise and 2 during excitement. In addition, 12 other children had onset of recurrent syncope and seizures at around 6 years of age, with 70% of the episodes occurring during vigorous physical activity and 30% following sudden excitement. The parents of affected children were all related and were all asymptomatic. Affected individuals exhibited a relative resting bradycardia and mild prolongation of the QTc segment compared to unaffected sibs; polymorphic ventricular tachycardia (PVT) was inducible by treadmill or isoproterenol infusion in all affected individuals and 1 asymptomatic sib, appearing at a mean sinus rate of 110 bpm. Mean age at onset was 7 years, with penetrance of 100% by age 10 years and a high mortality rate when left untreated.
Di Barletta et al. (2006) reported a 6-year-old boy with a history of effort-induced syncopal episodes from 3 years of age, in whom exercise stress testing demonstrated rapid PVT; Holter monitoring showed several runs of asymptomatic polymorphic and bidirectional sustained VT at rates of 170 to 180 bpm during outdoor play. The authors also described an unrelated 17-year-old girl with onset of syncopal episodes at 4 years of age and PVT of up to 200 bpm on ECG, in whom antiarrhythmic therapy and left cardiac sympathetic denervation were unsuccessful and who ultimately required an implantable cardioverter defibrillator. Family history was negative in both cases.
Mapping
Lahat et al. (2001) performed genomewide linkage analysis in 7 consanguineous Bedouin families segregating catecholamine-induced PVT in an autosomal recessive fashion and mapped the disease locus to a 16-Mb interval on chromosome 1p21-p13, with a maximum lod score of 8.24 obtained at D1S189 (theta = 0).
Molecular Genetics
Lahat et al. (2001) analyzed the CASQ2 gene in members of 7 consanguineous Bedouin families in Israel with CPVT and identified homozygosity for a mutation (N307H; 114251.0001) in all affected individuals.
Di Barletta et al. (2006) analyzed the CASQ2 gene in a 6-year-old boy and an unrelated 17-year-old girl with CPVT and identified homozygosity for a 16-bp deletion (114251.0002) and compound heterozygosity for the 16-bp deletion and a missense mutation (114251.0003), respectively. Parental consanguinity was denied in both families, and nonconsanguinity was confirmed by haplotype analysis. None of 11 heterozygous carriers identified in the 2 families developed ventricular arrhythmias.
INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Polymorphic ventricular tachycardia induced by physical activity, stress, or catecholamine infusion \- Bradycardia, relative resting \- Syncope \- Sudden death NEUROLOGIC Central Nervous System \- Seizures MOLECULAR BASIS \- Caused by mutation in the calsequestrin-2 gene (CASQ2, 114251.0002 ) ▲ Close
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 2 | c1631597 | 2,471 | omim | https://www.omim.org/entry/611938 | 2019-09-22T16:02:37 | {"doid": ["0060676"], "mesh": ["C536334"], "omim": ["611938"], "orphanet": ["3286"], "synonyms": ["Alternative titles", "VENTRICULAR TACHYCARDIA, STRESS-INDUCED POLYMORPHIC"], "genereviews": ["NBK1289"]} |
## Description
The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400).
Clinical Features
HSN1 with cough and gastroesophageal reflux (GER) was described by Spring et al. (2002). The first symptoms of HSN1 with cough and GER were sometimes an unexplained chronic cough, which could progress to cough syncope. Monitoring of esophageal pH for 24 hours showed the cough to be temporally associated with GER and impaired laryngeal sensation. The disorder usually presented in adult life, with either cough or GER symptoms. The cough may occur between the second and the fourth decades. Sensory loss began in the feet and legs between the third and fifth decades. Achilles tendon reflexes were decreased in some individuals, and nerve conduction velocity studies showed an axonal neuropathy with absent or reduced sensory nerve action potentials. Nerve biopsy showed loss of unmyelinated and myelinated axons.
Spring et al. (2005) reported detailed clinical features of the 2 unrelated affected families studied by Kok et al. (2003). Affected individuals had onset in early adulthood of paroxysmal cough and frequent throat clearing associated with gastroesophageal reflux, with later onset of an axonal neuropathy with distal sensory impairment of the upper and lower limb. The cough was triggered by noxious odors or by pressure in the external auditory canal and could be severe. Variable features included bilateral sensorineural hearing loss, lancinating pains, alacrima, and impotence.
Mapping
Kok et al. (2003) identified 2 families with HSN1 with cough and GER. One, a 3-generation Australian family, was large enough for linkage studies. Male-to-male transmission indicated autosomal dominant inheritance. The second unrelated family with 9 at-risk family members was large enough for haplotype studies. Genome screen showed linkage to 3p24-p22, with a lod score of 3.51 at marker D3S2338 and a recombination fraction of 0.0. The 2 families did not share a common disease haplotype.
INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Hearing loss, sensorineural Eyes \- Alacrima RESPIRATORY \- Cough, chronic, paroxysmal, triggered by noxious odors or pressure in the external auditory canal Larynx \- Throat clearing \- Hoarse voice ABDOMEN Gastrointestinal \- Gastroesophageal reflux GENITOURINARY External Genitalia (Male) \- Impotence NEUROLOGIC Central Nervous System \- Cough syncope Peripheral Nervous System \- Sensory axonal neuropathy \- Distal sensory loss, upper and lower limbs \- Sensory loss more severe for pain and temperature \- Lancinating pains VOICE \- Hoarse voice MISCELLANEOUS \- Onset of cough in early adulthood \- Onset of sensory neuropathy in later adulthood ▲ Close
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE I, WITH COUGH AND GASTROESOPHAGEAL REFLUX | c1842586 | 2,472 | omim | https://www.omim.org/entry/608088 | 2019-09-22T16:08:16 | {"doid": ["0070148"], "mesh": ["C564296"], "omim": ["608088"], "orphanet": ["139564"], "synonyms": ["Alternative titles", "NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IB", "NEUROPATHY, HEREDITARY SENSORY, TYPE IB"]} |
Monocytic leukemia
SpecialtyOncology
Monocytic leukemia is a type of myeloid leukemia characterized by a dominance of monocytes in the marrow. When the monocytic cells are predominantly monoblasts, it can be subclassified into acute monoblastic leukemia.
Monocytic leukemia is almost always broken down into "acute" and "chronic":
* acute monocytic leukemia
* chronic myelomonocytic leukemia
## References[edit]
## External links[edit]
Classification
D
* ICD-10: C93
* ICD-9-CM: 206
* ICD-O: 9890/3-9894/3
This article about a neoplasm is a stub. You can help Wikipedia by expanding it.
* v
* t
* e
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Monocytic leukemia | c0153903 | 2,473 | wikipedia | https://en.wikipedia.org/wiki/Monocytic_leukemia | 2021-01-18T18:47:27 | {"umls": ["C0153903"], "wikidata": ["Q1313618"]} |
## Clinical Features
Hofmann et al. (1984) described isolated (solitary) bladder diverticulum in males of 3 and probably 4 generations. In most patients, the diverticulum was located near the vesicoureteral junction. Moderate sclerosis of the urethral sphincter with a prominent median bar of the prostate was a consistent finding. Symptoms varied from gross hematuria, diurnal frequency, infection and urinary hesitancy to only mild dysuria. One patient was entirely asymptomatic. The diverticula consisted mainly of mucosa covered only by a few strands of muscle. Bladder diverticula occur also in the Ehlers-Danlos syndrome (see 130000).
GU \- Solitary bladder diverticulum \- Urethral sphincter sclerosis \- Prominent prostate median bar \- Hematuria \- Diurnal frequency \- Urinary infection \- Urinary hesitancy \- Dysuria Inheritance \- Autosomal dominant ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| BLADDER DIVERTICULUM | c0156273 | 2,474 | omim | https://www.omim.org/entry/109820 | 2019-09-22T16:44:25 | {"doid": ["11353"], "mesh": ["C562406"], "omim": ["109820"], "icd-9": ["596.3"], "icd-10": ["N32.3"]} |
A number sign (#) is used with this entry because autosomal dominant mental retardation-5 (MRD5) is caused by heterozygous mutation in the SYNGAP1 gene (603384) on chromosome 6p21. Almost all reported cases have occurred de novo.
Description
MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Most patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some have acquired microcephaly (summary by Berryer et al., 2013).
Clinical Features
In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). All patients showed global developmental delay with delayed motor development, hypotonia, moderate to severe mental retardation, and severe language impairment. One patient had strabismus, and 2 had epilepsy. There were no other dysmorphic features.
Hamdan et al. (2011) reported 3 unrelated patients with MRD5. In addition to moderate to severe intellectual disability, the children also showed behavioral abnormalities, such as avoidance of other children and impulsivity, and mood problems, such as sullenness and rigidity. Two had well-controlled epilepsy and acquired microcephaly, and 1 had autism, thus expanding the phenotypic spectrum associated with SYNGAP1 mutations.
Berryer et al. (2013) reported 5 unrelated patients with MRD5. All presented with delayed development in the first years of life and all but 1 showed moderate to severe intellectual disability. Four patients had epilepsy, 3 had autism, and 3 had behavioral abnormalities. There were no notable dysmorphic features or structural brain abnormalities.
Carvill et al. (2013) reported 2 unrelated patients with epileptic encephalopathy, severe mental retardation, and autism spectrum disorder. One patient had onset of atypical absence seizures at age 3 years, followed by atonic seizures, focal dyscognitive seizures, and myoclonic jerks associated with EEG abnormalities. The other had onset of absence seizures at age 10 months, followed by myoclonic jerks. Both had delayed development and showed cognitive regression after seizure onset. Each patient carried a de novo heterozygous truncating mutation in the SYNGAP1 gene (603384.0009 and 603384.0010). Three additional unrelated patients with a similar phenotype, mental retardation associated with onset of multiple seizure types in the first years of life and developmental regression, also carried heterozygous truncating SYNGAP1 mutations, but DNA from one or both parents was not available to confirm that the mutations occurred de novo. Carvill et al. (2013) concluded that epileptic encephalopathy should be part of the phenotypic spectrum associated with SYNGAP1 mutations. These patients were identified from a large cohort of 500 patients with epileptic encephalopathy who underwent targeted sequencing of candidate genes. SYNGAP1 mutations accounted for 1% of cases.
Mignot et al. (2016) reported 17 unrelated affected individuals with loss-of-function mutations in the SYNGAP1 gene. All had delayed psychomotor development, with walking achieved in most by age 3 years. Speech delay was common, and 5 patients did not speak at age 10 years. Except for 1 patient who had a single seizure, all patients had epilepsy, particularly myoclonic epilepsy and absence seizures; about half of patients had pharmacoresistant seizures. Eight (50%) of 16 patients older than 3 had autism spectrum disorder with very poor communication skills. Additional common neurologic features included hypotonia, ataxia, and broad-based or clumsy gait. Brain imaging was either normal or showed nonspecific features. There were no apparent genotype/phenotype correlations.
Inheritance
Almost all reported cases of MRD5 have resulted from de novo mutations. However, Berryer et al. (2013) reported a fully affected patient who inherited the mutation from her mildly affected father; he was found to be mosaic for the mutation.
Molecular Genetics
In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003).
In 3 of 60 patients with nonsyndromic intellectual disability, including 30 with autism spectrum disorder and 9 with epilepsy, Hamdan et al. (2011) identified de novo heterozygous truncating mutations in the SYNGAP1 gene (see, e.g., 603384.0005 and 603384.0006).
Berryer et al. (2013) identified 5 different SYNGAP1 mutations (see, e.g., 603384.0007 and 603384.0008) in 5 unrelated patients with nonsyndromic intellectual disability. There were 3 truncating mutations and 2 missense mutations. These patients were identified by targeted sequencing of the SYNGAP1 gene in several cohorts including a total of 34 patients with nonsyndromic intellectual disability. Four of the mutations occurred de novo; 1 was inherited from a mildly affected parent who was mosaic for the mutation. None of the mutant proteins were detected in neuronal cells transfected with the mutations, suggesting decreased stability, even of the missense mutations. Studies in cortical pyramidal neurons showed that the missense mutations were unable to suppress activity-mediated ERK (176872), consistent with a loss of protein function.
Animal Model
Clement et al. (2012) found that haploinsufficiency for Syngap1 in mice accelerated the maturation of glutamatergic synapses in the hippocampus during the first few weeks of neonatal hippocampal development. Dendritic spines in pyramidal neurons grew larger in the mutant mice compared to wildtype mice during this critical developmental period, and the changes persisted into adulthood. There was a disruption in spine head size, with more mushroom-type spines and fewer stubby spines, the spine motility rates were decreased, and there were spine signaling abnormalities. These changes were accompanied by premature acquisition of functional AMPA receptors in the synapses. Syngap1 haploinsufficiency altered disrupted excitatory/inhibitory balance in the hippocampus, with increased excitation and increased seizure susceptibility. Changes occurred in neural networks that support cognition and behavior, such as the hippocampus, and these effects were linked to life-long intellectual disability and impaired memory. These studies provided a neurophysiologic mechanism linking abnormal glutamatergic synapse maturation during development to enduring abnormalities in behaviors indicative of neurodevelopmental disorders in humans.
INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly (in some patients) Neck \- Torticollis (in some patients) NEUROLOGIC Central Nervous System \- Hypotonia \- Delayed development \- Mental retardation, mild to severe \- Developmental regression \- Seizures \- EEG abnormalities \- Developmental regression \- Epileptic encephalopathy (in some patients) \- Normal brain MRI or CT scan Behavioral Psychiatric Manifestations \- Autism spectrum disorder \- Behavioral abnormalities MISCELLANEOUS \- Onset in first years of life \- Most mutations occur de novo MOLECULAR BASIS \- Caused by mutation in the synaptic Ras GTPase activating protein 1 gene (SYNGAP1, 603384.0001 ) ▲ Close
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| MENTAL RETARDATION, AUTOSOMAL DOMINANT 5 | c2675473 | 2,475 | omim | https://www.omim.org/entry/612621 | 2019-09-22T16:01:00 | {"doid": ["0070035"], "mesh": ["C567234"], "omim": ["612621"], "orphanet": ["178469"], "synonyms": [], "genereviews": ["NBK537721"]} |
Nausea caused by motion
For the album by Bright Eyes, see Motion Sickness.
Motion sickness
Other namesKinetosis, travel sickness, seasickness, airsickness, carsickness, simulation sickness, space motion sickness, space adaptation syndrome
A drawing of people with sea sickness from 1841
SpecialtyNeurology
SymptomsNausea, vomiting, cold sweat, increased salivation[1]
ComplicationsDehydration, electrolyte problems, lower esophageal tear[1]
CausesReal or perceived motion[1]
Risk factorsPregnancy, migraines, Meniere’s disease[1]
Diagnostic methodBased on symptoms[1]
Differential diagnosisBenign paroxysmal positional vertigo, vestibular migraine, stroke[1]
PreventionAvoidance of triggers[1]
TreatmentBehavioral measures, medications[2]
MedicationScapolamine, dimenhydrinate, dexamphetamine[2]
PrognosisGenerally resolve within a day[1]
FrequencyNearly all people with sufficient motion[2]
Motion sickness occurs due to a difference between actual and expected motion.[1] Symptoms commonly include nausea, vomiting, cold sweat, headache, sleepiness, yawning, loss of appetite, and increased salivation.[1] Complications may rarely include dehydration, electrolyte problems, or a lower esophageal tear.[1]
The cause of motion sickness is either real or perceived motion.[1] This may include from car travel, air travel, sea travel, space travel, or reality simulation.[1] Risk factors include pregnancy, migraines, and Meniere’s disease.[1] The diagnosis is based on symptoms.[1]
Treatment may include behavioral measures or medications.[2] Behavioral measures include keeping the head still and focusing on the horizon.[1] Three types of medications are useful: antimuscarinics such as scopolamine, H1 antihistamines such as dimenhydrinate, and amphetamines such as dexamphetamine.[2] Side effects, however, may limit the use of medications.[2] A number of medications used for nausea such as ondansetron are not effective for motion sickness.[2]
Nearly all people are affected with sufficient motion.[1] Susceptibility, however, is variable.[1] Women are more easily affected than men.[1] Motion sickness has been described since at least the time of Hippocrates.[1] "Nausea" is from the Greek naus meaning ship.[1]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Motion felt but not seen
* 2.1.1 Carsickness
* 2.1.2 Airsickness
* 2.1.3 Seasickness
* 2.1.4 Centrifuge motion sickness
* 2.1.5 Dizziness due to spinning
* 2.1.6 Virtual reality
* 2.2 Motion seen but not felt
* 2.2.1 Space motion sickness
* 2.2.2 Screen images
* 2.2.3 Virtual reality
* 2.3 Motion that is seen and felt
* 3 Pathophysiology
* 3.1 Sensory conflict theory
* 3.2 Neural mismatch
* 3.3 Defense against poisoning
* 3.4 Nystagmus hypothesis
* 4 Diagnosis
* 5 Treatment
* 5.1 Behavioral measures
* 5.2 Medication
* 5.3 Alternative medicine
* 6 Epidemiology
* 7 References
* 8 External links
## Signs and symptoms[edit]
Symptoms commonly include nausea, vomiting, cold sweat, headache, sleepiness, yawning, loss of appetite, and increased salivation.[1] Occasionally tiredness can last for hours to days an episode of motion sickness, known as "sopite syndrome".[1] Rarely severe symptoms such as the inability to walk, ongoing vomiting, or social isolation may occur.[1]
## Cause[edit]
Motion sickness can be divided into three categories:
1. Motion sickness caused by motion that is felt but not seen, as in terrestrial motion sickness;
2. Motion sickness caused by motion that is seen but not felt, as in space motion sickness;
3. Motion sickness caused when both systems detect motion but they do not correspond, as in either terrestrial or space motion sickness.
### Motion felt but not seen[edit]
In these cases, motion is sensed by the vestibular system and hence the motion is felt, but no motion or little motion is detected by the visual system, as in terrestrial motion sickness.
#### Carsickness[edit]
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A specific form of terrestrial motion sickness, being carsick is quite common and evidenced by disorientation while reading a map, a book, or a small screen during travel. Carsickness results from the sensory conflict arising in the brain from differing sensory inputs. Motion sickness is caused by a conflict between signals arriving in the brain from the inner ear, which forms the base of the vestibular system, the sensory apparatus that deals with movement and balance, and which detects motion mechanically. If someone is looking at a stationary object within a vehicle, such as a magazine, their eyes will inform their brain that what they are viewing is not moving. Their inner ears, however, will contradict this by sensing the motion of the vehicle.[3]
Varying theories exist as to cause. The sensory conflict theory notes that the eyes view motion while riding in the moving vehicle while other body sensors sense stillness, creating conflict between the eyes and inner ear. Another suggests the eyes mostly see the interior of the car which is motionless while the vestibular system of the inner ear senses motion as the vehicle goes around corners or over hills and even small bumps. Therefore, the effect is worse when looking down but may be lessened by looking outside of the vehicle.
In the early 20th century, Austro-Hungarian scientist Robert Barany observed the back and forth movement of the eyes of railroad passengers as they looked out the side windows at the scenery whipping by. He called it "railway nystagmus". Also called "optokinetic nystagmus". It causes nausea and vomiting. His findings were published in the journal Laeger, 83:1516, Nov.17, 1921.
#### Airsickness[edit]
Main article: Airsickness
Air sickness is a kind of terrestrial motion sickness induced by certain sensations of air travel.[4] It is a specific form of motion sickness and is considered a normal response in healthy individuals. It is essentially the same as carsickness but occurs in an airplane. An airplane may bank and tilt sharply, and unless passengers are sitting by a window, they are likely to see only the stationary interior of the plane due to the small window sizes and during flights at night. Another factor is that while in flight, the view out of windows may be blocked by clouds, preventing passengers from seeing the moving ground or passing clouds.
#### Seasickness[edit]
Seasickness is a form of terrestrial motion sickness characterized by a feeling of nausea and, in extreme cases, vertigo experienced after spending time on a boat.[4] It is essentially the same as carsickness, though the motion of a watercraft tends to be more regular. It is typically brought on by the rocking motion of the craft[5][6] or movement while the craft is immersed in water.[7] As with airsickness, it can be difficult to visually detect motion even if one looks outside the boat since water does not offer fixed points with which to visually judge motion. Poor visibility conditions, such as fog, may worsen seasickness. The greatest contributor to seasickness is the tendency for people being affected by the rolling or surging motions of the craft to seek refuge below decks, where they are unable to relate themselves to the boat's surroundings and consequent motion. Some sufferers of carsickness are resistant to seasickness and vice versa.[citation needed] Adjusting to the craft's motion at sea is called "gaining one's sea legs"; it can take a significant portion of the time spent at sea after disembarking to regain a sense of stability "post-sea legs".
#### Centrifuge motion sickness[edit]
Rotating devices such as centrifuges used in astronaut training and amusement park rides such as the Rotor, Mission: Space and the Gravitron can cause motion sickness in many people. While the interior of the centrifuge does not appear to move, one will experience a sense of motion.[dubious – discuss] In addition, centrifugal force can cause the vestibular system to give one the sense that downward is in the direction away from the center of the centrifuge rather than the true downward direction.
#### Dizziness due to spinning[edit]
When one spins and stops suddenly, fluid in the inner ear continues to rotate causing a sense of continued spinning while one's visual system no longer detects motion.
#### Virtual reality[edit]
Main article: Virtual reality sickness
Usually, VR programs would detect the motion of the user's head and adjust the rotation of vision to avoid dizziness. However, some cases such as system lagging or software crashing could cause lags in the screen updates. In such cases, even some small head motions could trigger the motion sickness by the defense mechanism mentioned below: the inner ear transmits to the brain that it senses motion, but the eyes tell the brain that everything is still. As a result of the incongruity, the brain concludes that the individual is hallucinating and further concludes that the hallucination is due to poison ingestion. The brain responds by inducing vomiting, to clear the supposed toxin.[8]
### Motion seen but not felt[edit]
In these cases, motion is detected by the visual system and hence the motion is seen, but no motion or little motion is sensed by the vestibular system. Motion sickness arising from such situations has been referred to as "visually induced motion sickness" (VIMS).[9]
#### Space motion sickness[edit]
Main article: Space adaptation syndrome
Zero gravity interferes with the vestibular system's gravity-dependent operations, so that the two systems, vestibular and visual, no longer provide a unified and coherent sensory representation. This causes unpleasant disorientation sensations often quite distinct from terrestrial motion sickness, but with similar symptoms. The symptoms may be more intense because a condition caused by prolonged weightlessness is usually quite unfamiliar.
Space motion sickness was effectively unknown during the earliest spaceflights because the very cramped conditions of the spacecraft allowed for only minimal bodily motion, especially head motion. Space motion sickness seems to be aggravated by being able to freely move around, and so is more common in larger spacecraft.[4] Around 60% of Space Shuttle astronauts currently experience it on their first flight; the first case of space motion sickness is now thought to be the Soviet cosmonaut Gherman Titov, in August 1961 onboard Vostok 2, who reported dizziness, nausea, and vomiting. The first severe cases were in early Apollo flights; Frank Borman on Apollo 8 and Rusty Schweickart on Apollo 9. Both experienced identifiable and quite unpleasant symptoms—in the latter case causing the mission plan to be modified.
#### Screen images[edit]
This type of terrestrial motion sickness is particularly prevalent when susceptible people are watching films presented on very large screens such as IMAX, but may also occur in regular format theaters or even when watching TV or playing games. For the sake of novelty, IMAX and other panoramic type theaters often show dramatic motions such as flying over a landscape or riding a roller coaster. This type of motion sickness can be prevented by closing one's eyes during such scenes.
In regular-format theaters, an example of a movie that caused motion sickness in many people is The Blair Witch Project. Theaters warned patrons of its possible nauseating effects, cautioning pregnant women in particular. Blair Witch was filmed with a handheld camcorder, which was subjected to considerably more motion than the average movie camera,[10] and lacks the stabilization mechanisms of steadicams.
Home movies, often filmed with a cell phone camera, also tend to cause motion sickness in those who view them. The person holding the cell phone or other camera usually is unaware of this as the recording is being made since the sense of motion seems to match the motion seen through the camera's viewfinder. Those who view the film afterward only see the movement, which may be considerable, without any sense of motion. Using the zoom function seems to contribute to motion sickness as well since zooming is not a normal function of the eye. The use of a tripod or a camera or cell phone with image stabilization while filming can reduce this effect.[citation needed]
#### Virtual reality[edit]
See also: Virtual reality sickness
Motion sickness due to virtual reality is very similar to simulation sickness and motion sickness due to films.[11] In virtual reality the effect is made more acute as all external reference points are blocked from vision, the simulated images are three-dimensional and in some cases stereo sound that may also give a sense of motion. The NADS-1, a simulator located at the National Advanced Driving Simulator, is capable of accurately stimulating the vestibular system with a 360-degree horizontal field of view and 13 degrees of freedom motion base.[12] Studies have shown that exposure to rotational motions in a virtual environment can cause significant increases in nausea and other symptoms of motion sickness.[13]
In a study conducted by the U.S. Army Research Institute for the Behavioral and Social Sciences in a report published May 1995 titled "Technical Report 1027 – Simulator Sickness in Virtual Environments", out of 742 pilot exposures from 11 military flight simulators, "approximately half of the pilots (334) reported post-effects of some kind: 250 (34%) reported that symptoms dissipated in less than one hour, 44 (6%) reported that symptoms lasted longer than four hours, and 28 (4%) reported that symptoms lasted longer than six hours. There were also four (1%) reported cases of spontaneously occurring flashbacks."[14]
### Motion that is seen and felt[edit]
When moving within a rotating reference frame such as in a centrifuge or environment where gravity is simulated with centrifugal force, the coriolis effect causes a sense of motion in the vestibular system that does not match the motion that is seen.
## Pathophysiology[edit]
There are various hypotheses that attempt to explain the cause of the condition.
### Sensory conflict theory[edit]
Contemporary sensory conflict theory, referring to "a discontinuity between either visual, proprioceptive, and somatosensory input, or semicircular canal and otolith input", is probably the most thoroughly studied.[15] According to this theory, when the brain presents the mind with two incongruous states of motion; the result is often nausea and other symptoms of disorientation known as motion sickness. Such conditions happen when the vestibular system and the visual system do not present a synchronized and unified representation of one's body and surroundings.
According to sensory conflict theory, the cause of terrestrial motion sickness is the opposite of the cause of space motion sickness. The former occurs when one perceives visually that one's surroundings are relatively immobile while the vestibular system reports that one's body is in motion relative to its surroundings.[4] The latter can occur when the visual system perceives that one's surroundings are in motion while the vestibular system reports relative bodily immobility (as in zero gravity.)
### Neural mismatch[edit]
A variation of the sensory conflict theory is known as neural mismatch, implying a mismatch occurring between ongoing sensory experience and long-term memory rather than between components of the vestibular and visual systems. This theory emphasizes "the limbic system in the integration of sensory information and long-term memory, in the expression of the symptoms of motion sickness, and the impact of anti-motion-sickness drugs and stress hormones on limbic system function. The limbic system may be the neural mismatch center of the brain."[16]
### Defense against poisoning[edit]
It has also been proposed that motion sickness could function as a defense mechanism against neurotoxins.[17] The area postrema in the brain is responsible for inducing vomiting when poisons are detected, and for resolving conflicts between vision and balance. When feeling motion but not seeing it (for example, in the cabin of a ship with no portholes), the inner ear transmits to the brain that it senses motion, but the eyes tell the brain that everything is still. As a result of the incongruity, the brain concludes that the individual is hallucinating and further concludes that the hallucination is due to poison ingestion. The brain responds by inducing vomiting, to clear the supposed toxin. Treisman's indirect argument has recently been questioned via an alternative direct evolutionary hypothesis, as well as modified and extended via a direct poison hypothesis.[8] The direct evolutionary hypothesis essentially argues that there are plausible means by which ancient real or apparent motion could have contributed directly to the evolution of aversive reactions, without the need for the co-opting of a poison response as posited by Treisman. Nevertheless, the direct poison hypothesis argues that there still are plausible ways in which the body's poison response system may have played a role in shaping the evolution of some of the signature symptoms that characterize motion sickness.
### Nystagmus hypothesis[edit]
Yet another theory, known as the nystagmus hypothesis,[18] has been proposed based on stimulation of the vagus nerve resulting from the stretching or traction of extra-ocular muscles co-occurring with eye movements caused by vestibular stimulation. There are three critical aspects to the theory: first is the close linkage between activity in the vestibular system, i.e., semicircular canals and otolith organs, and a change in tonus among various of each eye's six extra-ocular muscles. Thus, with the exception of voluntary eye movements, the vestibular and oculomotor systems are thoroughly linked. Second is the operation of Sherrington's Law[19] describing reciprocal inhibition between agonist-antagonist muscle pairs, and by implication the stretching of extraocular muscle that must occur whenever Sherrington's Law is made to fail, thereby causing an unrelaxed (contracted) muscle to be stretched. Finally, there is the critical presence of afferent output to the Vagus nerves as a direct result of eye muscle stretch or traction.[20] Thus, 10th nerve stimulation resulting from eye muscle stretch is proposed as the cause of motion sickness. The theory explains why labyrinthine-defective individuals are immune to motion sickness;[21][22] why symptoms emerge when undergoing various body-head accelerations; why combinations of voluntary and reflexive eye movements may challenge the proper operation of Sherrington's Law, and why many drugs that suppress eye movements also serve to suppress motion sickness symptoms.[23]
A recent theory [24] argues that the main reason motion sickness occurs is due to an imbalance in vestibular outputs favoring the semicircular canals (nauseogenic) vs. otolith organs (anti-nauseogenic). This theory attempts to integrate previous theories of motion sickness. For example, there are many sensory conflicts that are associated with motion sickness and many that are not, but those in which canal stimulation occurs in the absence of normal otolith function (e.g., in free fall) are the most provocative. The vestibular imbalance theory is also tied to the different roles of the otoliths and canals in autonomic arousal (otolith output more sympathetic).
## Diagnosis[edit]
The diagnosis is based on symptoms.[1] Other conditions that may present similarly include vestibular disorders such as benign paroxysmal positional vertigo and vestibular migraine and stroke.[1]
## Treatment[edit]
Treatment may include behavioral measures or medications.[2]
### Behavioral measures[edit]
Behavioral measures to decrease motion sickness include holding the head still and lying on the back.[2] Focusing on the horizon may also be useful.[1] Listening to music, mindful breathing, being the driver, and not reading while moving are other techniques.[1]
Habituation is the most effective technique but requires significant time.[1] It is often used by the military for pilots.[1] These techniques must be carried out at least every week to retain effectiveness.[1]
A head-worn, computer device with a transparent display can be used to mitigate the effects of motion sickness (and spatial disorientation) if visual indicators of the wearer’s head position are shown.[25] Such a device functions by providing the wearer with digital reference lines in their field of vision that indicate the horizon’s position relative to the user’s head. This is accomplished by combining readings from accelerometers and gyroscopes mounted in the device. This technology has been implemented in both standalone devices[26] and Google Glass.[27][28] In two NIH-backed studies, greater than 90% of people experienced a reduction in the symptoms of motion sickness while using this technology.[25] One promising looking treatment is for to wear LCD shutter glasses that create a stroboscopic vision of 4 Hz with a dwell of 10 milliseconds.[29]
### Medication[edit]
Three types of medications are useful: antimuscarinics such as scopolamine, H1 antihistamines such as dimenhydrinate, and amphetamines such as dexamphetamine.[2] Benefits are greater if used before the onset of symptoms or shortly after symptoms begin.[1] Side effects, however, may limit the use of medications.[2] A number of medications used for nausea such as ondansetron and metoclopramide are not effective in motion sickness.[2][1]
Scopolamine is the most effective medication.[1] Evidence is best for when it is used preventatively.[30] It is available as a skin patch.[1] Side effects may include blurry vision.[1]
Other effective first generation antihistamines include meclizine, promethazine, cyclizine, and cinnarizine.[1] In pregnancy meclizine and dimenhydrinate are generally felt to be safe.[1] Side effects include sleepiness.[1] Second generation antihistamines have not been found to be useful.[1]
Dextroamphetamine may be used together with an antihistamine or an antimuscarinic.[1] Concerns include their addictive potential.[1]
Those involved in high-risk activities, such as SCUBA diving, should evaluate the risks versus the benefits of medications.[31][32][33][34][35] Promethazine combined with ephedrine to counteract the sedation is known as "the Coast Guard cocktail".[36]
### Alternative medicine[edit]
Acupuncture has not been found to be useful.[2] Ginger root is commonly thought to be an effective anti-emetic, but it is ineffective in treating motion sickness.[37] Providing smells does not appear to have a significant effect on the rate of motion sickness.[2]
## Epidemiology[edit]
Roughly one-third of people are highly susceptible to motion sickness, and most of the rest get motion sick under extreme conditions. The rates of space motion sickness have been estimated at between forty and eighty percent of those who enter weightless orbit. Several factors influence susceptibility to motion sickness, including sleep deprivation and the cubic footage allocated to each space traveler. Studies indicate that women are more likely to be affected than men,[1] and that the risk decreases with advancing age. There is some evidence that people with Asian ancestry may develop motion sickness more frequently than people of European ancestry, and there are situational and behavioral factors, such as whether a passenger has a view of the road ahead, and diet and eating behaviors.[38]
## References[edit]
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2. ^ a b c d e f g h i j k l m n Golding, J. F. (2016). "Motion sickness". Handbook of Clinical Neurology. 137: 371–390. doi:10.1016/B978-0-444-63437-5.00027-3. ISBN 9780444634375. ISSN 0072-9752. PMID 27638085.
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4. ^ a b c d Benson, Alan J. (2002). "Motion Sickness" (PDF). In Kent B. Pandoff; Robert E. Burr (eds.). Medical Aspects of Harsh Environments. 2. Washington, D.C.: Borden Institute. pp. 1048–83. ISBN 978-0-16-051184-4. Retrieved 27 Mar 2017.
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6. ^ Shri Kamal Sharma (1992). Resource Utilization and Development: A Perspective Study of Madhya Pradesh, India. Northern Book Centre. pp. 1078–. ISBN 978-81-7211-032-1. Retrieved 30 June 2013.
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8. ^ a b Lawson, B. D. (2014). Motion sickness symptomatology and origins. Handbook of Virtual Environments: Design, Implementation, and Applications, 531–99.
9. ^ So, R.H.Y. and Ujike, H. (2010) Visually induced motion sickness, visual stress and photosensitive epileptic seizures: what do they have in common? Preface to the special issue. Applied Ergonomics, 41(4), pp. 491–93.
10. ^ Wax, Emily (30 July 1999). "The Dizzy Spell of 'Blair Witch Project'". The Washington Post. Retrieved 8 February 2017.
11. ^ "Combating VR Sickness: Debunking Myths And Learning What Really Works". ARVI Games.
12. ^ "The National Advanced Driving Simulator – The NADS-1". Nads-sc.uiowa.edu. Retrieved 2014-03-02.
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17. ^ Motion sickness: an evolutionary hypothesis
18. ^ Ebenholtz SM, Cohen MM, Linder BJ (November 1994). "The possible role of nystagmus in motion sickness: a hypothesis". Aviat Space Environ Med. 65 (11): 1032–35. PMID 7840743.
19. ^ Sherrington, C.S. (1893). "Further experimental note on the correlation of action of antagonistic muscles". Proceedings of the Royal Society. B53 (1693): 407–20. Bibcode:1893RSPS...53..407S. doi:10.1136/bmj.1.1693.1218. PMC 2403312. PMID 20754272.
20. ^ Milot JA, Jacob JL, Blanc VF, Hardy JF (December 1983). "The oculocardiac reflex in strabismus surgery". Can. J. Ophthalmol. 18 (7): 314–17. PMID 6671149.
21. ^ Kennedy, R.S.; Graybiel, A.; McDonough, R.C.; Beckwith, F.D. (1968). "Symptomatology under storm conditions in the North Atlantic in control subjects and in persons with bilateral labyrinthine defects". Acta Oto-Laryngologica. 66 (1–6): 533–40. doi:10.3109/00016486809126317. hdl:2060/19650024320. PMID 5732654.
22. ^ Cheung BS, Howard IP, Money KE (June 1991). "Visually-induced sickness in normal and bilaterally labyrinthine-defective subjects". Aviat Space Environ Med. 62 (6): 527–31. PMID 1859339.
23. ^ Ebenholtz, S.M.Oculomotor Systems and Perception. Cambridge University Press, 2005, 148–53
24. ^ Previc, F.H. (2018). "An intravestibular theory of motion sickness". Aerospace Medicine and Human Performance. 89 (2): 130–40. doi:10.3357/AMHP.4946.2018. ISSN 2375-6314. PMID 29463358.
25. ^ a b Krueger WW (January 2011). "Controlling motion sickness and spatial disorientation and enhancing vestibular rehabilitation with a user-worn see-through display". Laryngoscope. 121 Suppl 2: S17–35. doi:10.1002/lary.21373. PMC 4769875. PMID 21181963.
26. ^ "Air Force to examine AdviTech's motion-sickness product for combat pilots". San Antonio Business Journal. Nov 10, 2010. Retrieved 15 July 2014.
27. ^ "BCMC, LLC". Retrieved 15 July 2014.
28. ^ "Google Glass Treating Motion Sickness". YouTube.com. Retrieved 15 July 2014.
29. ^ Reschke, MF; Somers, JT; Ford, G (January 2006). "Stroboscopic vision as a treatment for motion sickness: strobe lighting vs. shutter glasses". Aviation, Space, and Environmental Medicine. 77 (1): 2–7. PMID 16422446.
30. ^ Spinks A, Wasiak J (2011). "Scopolamine (hyoscine) for preventing and treating motion sickness". The Cochrane Database of Systematic Reviews (6): CD002851. doi:10.1002/14651858.CD002851.pub4. hdl:10072/19480. PMC 7138049. PMID 21678338.
31. ^ Schwartz, Henry JC; Curley, Michael D (1986). "Transdermal Scopolamine in the Hyperbaric Environment". United States Navy Experimental Diving Unit Technical Report. Retrieved 2008-05-09.
32. ^ Lawson, B. D.; McGee, H. A.; Castaneda, M. A.; Golding, J. F.; Kass, S. J.; McGrath, C. M. (2009). Evaluation of Several Common Antimotion Sickness Medications and Recommendations Concerning Their Potential Usefulness During Special Operations. (No. NAMRL-09-15) (Report). Pensacola, Florida.: Naval aerospace medical research laboratory. Archived from the original on 2016-04-27. Retrieved 2017-02-07.
33. ^ Bitterman N, Eilender E, Melamed Y (May 1991). "Hyperbaric oxygen and scopolamine". Undersea Biomedical Research. 18 (3): 167–74. PMID 1853467. Archived from the original on 2008-08-20. Retrieved 2008-05-09.
34. ^ Williams TH, Wilkinson AR, Davis FM, Frampton CM (March 1988). "Effects of transcutaneous scopolamine and depth on diver performance". Undersea Biomedical Research. 15 (2): 89–98. PMID 3363755. Retrieved 2008-05-09.
35. ^ Arieli R, Shupak A, Shachal B, Shenedrey A, Ertracht O, Rashkovan G (1999). "Effect of the anti-motion-sickness medication cinnarizine on central nervous system oxygen toxicity". Undersea and Hyperbaric Medicine. 26 (2): 105–09. PMID 10372430. Retrieved 2008-05-09.
36. ^ East Carolina University Department of Diving & Water Safety. "Seasickness: Information and Treatment" (PDF).
37. ^ Brainard A, Gresham C (2014). "Prevention and treatment of motion sickness". Am Fam Physician. 90 (1): 41–46. PMID 25077501.
38. ^ Hromatka BS, Tung JY, Kiefer AK, Do CB, Hinds DA, Eriksson N (May 2015). "Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis". Hum. Mol. Genet. 24 (9): 2700–08. doi:10.1093/hmg/ddv028. PMC 4383869. PMID 25628336.
## External links[edit]
Look up motion sickness in Wiktionary, the free dictionary.
Wikimedia Commons has media related to Motion sickness.
* Davis, Christopher J.; Lake-Bakaar, Gerry V.; Grahame-Smith, David G. (2012). Nausea and Vomiting: Mechanisms and Treatment. Springer Science & Business Media. p. 123. ISBN 978-3-642-70479-6.
* Motion Sickness from MedlinePlus
* Motion Sickness Educational Video
Classification
D
* ICD-10: T75.3
* ICD-9-CM: 994.6
* OMIM: 158280
* MeSH: D009041
* DiseasesDB: 11908
External resources
* eMedicine: article/2060606
* v
* t
* e
Motion sickness
Types
* Airsickness
* Seasickness
* Simulator sickness
* Ski sickness
* Space adaptation syndrome
* Virtual reality sickness
Medicine treatment
* Bonine
* Cinnarizine
* Dramamine
* Marezine
* Promethazine
* Transdermscop
Related
* Bárány chair
* Sickness bag
* v
* t
* e
Consequences of external causes
Temperature
Elevated
Hyperthermia
Heat syncope
Reduced
Hypothermia
Immersion foot syndromes
Trench foot
Tropical immersion foot
Warm water immersion foot
Chilblains
Frostbite
Aerosol burn
Cold intolerance
Acrocyanosis
Erythrocyanosis crurum
Radiation
Radiation poisoning
Radiation burn
Chronic radiation keratosis
Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy
Radiation acne
Radiation-induced cancer
Radiation recall reaction
Radiation-induced erythema multiforme
Radiation-induced hypertrophic scar
Radiation-induced keloid
Radiation-induced morphea
Air
* Hypoxia/Asphyxia
* Barotrauma
* Aerosinusitis
* Decompression sickness
* High altitude
* Altitude sickness
* Chronic mountain sickness
* Death zone
* HAPE
* HACE
Food
* Starvation
Maltreatment
* Physical abuse
* Sexual abuse
* Psychological abuse
Travel
* Motion sickness
* Seasickness
* Airsickness
* Space adaptation syndrome
Adverse effect
* Hypersensitivity
* Anaphylaxis
* Angioedema
* Allergy
* Arthus reaction
* Adverse drug reaction
Other
* Electrical injury
* Drowning
* Lightning injuries
Ungrouped
skin conditions
resulting from
physical factors
* Dermatosis neglecta
* Pinch mark
* Pseudoverrucous papules and nodules
* Sclerosing lymphangitis
* Tropical anhidrotic asthenia
* UV-sensitive syndrome
environmental skin conditions
Electrical burn
frictional/traumatic/sports
Black heel and palm
Equestrian perniosis
Jogger's nipple
Pulling boat hands
Runner's rump
Surfer's knots
Tennis toe
Vibration white finger
Weathering nodule of ear
Wrestler's ear
Coral cut
Painful fat herniation
Uranium dermatosis
iv use
Skin pop scar
Skin track
Slap mark
Pseudoacanthosis nigricans
Narcotic dermopathy
* v
* t
* e
Underwater diving
* Diving modes
* Atmospheric pressure diving
* Freediving
* Saturation diving
* Scuba diving
* Snorkeling
* Surface oriented diving
* Surface-supplied diving
* Unmanned diving
Diving equipment
* Cleaning and disinfection of personal diving equipment
* Human factors in diving equipment design
Basic equipment
* Diving mask
* Snorkel
* Swimfin
Breathing gas
* Bailout gas
* Bottom gas
* Breathing air
* Decompression gas
* Emergency gas supply
* Heliox
* Nitrox
* Oxygen
* Travel gas
* Trimix
Buoyancy and
trim equipment
* Buoyancy compensator
* Power inflator
* Dump valve
* Diving weighting system
* Ankle weights
* Integrated weights
* Trim weights
* Weight belt
Decompression
equipment
* Decompression buoy
* Decompression cylinder
* Decompression trapeze
* Dive computer
* Diving shot
* Jersey upline
* Jonline
Diving suit
* Atmospheric diving suit
* Dry suit
* Sladen suit
* Standard diving suit
* Rash vest
* Wetsuit
* Dive skins
* Hot-water suit
Helmets
and masks
* Anti-fog
* Diving helmet
* Free-flow helmet
* Lightweight demand helmet
* Orinasal mask
* Reclaim helmet
* Shallow water helmet
* Standard diving helmet
* Diving mask
* Band mask
* Full-face mask
* Half mask
Instrumentation
* Bottom timer
* Depth gauge
* Dive computer
* Dive timer
* Diving watch
* Helium release valve
* Pneumofathometer
* Submersible pressure gauge
Mobility
equipment
* Diving bell
* Closed bell
* Wet bell
* Diving stage
* Swimfin
* Monofin
* PowerSwim
* Towboard
Diver
propulsion
vehicle
* Advanced SEAL Delivery System
* Cosmos CE2F series
* Dry Combat Submersible
* Human torpedo
* Motorised Submersible Canoe
* Necker Nymph
* R-2 Mala-class swimmer delivery vehicle
* SEAL Delivery Vehicle
* Shallow Water Combat Submersible
* Siluro San Bartolomeo
* Wet Nellie
* Wet sub
Safety
equipment
* Alternative air source
* Octopus regulator
* Pony bottle
* Bolt snap
* Buddy line
* Dive light
* Diver's cutting tool
* Diver's knife
* Diver's telephone
* Through-water communications
* Diving bell
* Diving safety harness
* Emergency gas supply
* Bailout block
* Bailout bottle
* Lifeline
* Screw gate carabiner
* Emergency locator beacon
* Rescue tether
* Safety helmet
* Shark-proof cage
* Snoopy loop
* Navigation equipment
* Distance line
* Diving compass
* Dive reel
* Line marker
* Surface marker buoy
* Silt screw
Underwater
breathing
apparatus
* Atmospheric diving suit
* Diving cylinder
* Burst disc
* Diving cylinder valve
* Diving helmet
* Reclaim helmet
* Diving regulator
* Mechanism of diving regulators
* Regulator malfunction
* Regulator freeze
* Single-hose regulator
* Twin-hose regulator
* Full face diving mask
Open-circuit
scuba
* Scuba set
* Bailout bottle
* Decompression cylinder
* Independent doubles
* Manifolded twin set
* Scuba manifold
* Pony bottle
* Scuba configuration
* Sidemount
* Sling cylinder
Diving
rebreathers
* Carbon dioxide scrubber
* Carleton CDBA
* CDLSE
* Cryogenic rebreather
* CUMA
* DSEA
* Dolphin
* Electro-galvanic oxygen sensor
* FROGS
* Halcyon PVR-BASC
* Halcyon RB80
* IDA71
* Interspiro DCSC
* KISS
* LAR-5
* LAR-6
* LAR-V
* LARU
* Porpoise
* Ray
* Siebe Gorman CDBA
* Siva
* Viper
Surface-supplied
diving equipment
* Air line
* Diver's umbilical
* Diving air compressor
* Gas panel
* Hookah
* Scuba replacement
* Sea Trek
* Snuba
* Standard diving dress
Escape set
* Davis Submerged Escape Apparatus
* Momsen lung
* Steinke hood
* Submarine Escape Immersion Equipment
*
Diving
equipment
manufacturers
* AP Diving
* Apeks
* Aqua Lung America
* Aqua Lung/La Spirotechnique
* Beuchat
* René Cavalero
* Cis-Lunar
* Cressi-Sub
* Dacor
* DESCO
* Dive Xtras
* Divex
* Diving Unlimited International
* Drägerwerk
* Fenzy
* Maurice Fernez
* Technisub
* Oscar Gugen
* Heinke
* HeinrichsWeikamp
* Johnson Outdoors
* Mares
* Morse Diving
* Nemrod
* Oceanic Worldwide
* Porpoise
* Sub Sea Systems
* Shearwater Research
* Siebe Gorman
* Submarine Products
* Suunto
Diving support equipment
Access equipment
* Boarding stirrup
* Diver lift
* Diving bell
* Diving ladder
* Diving platform (scuba)
* Diving stage
* Downline
* Jackstay
* Launch and recovery system
* Messenger line
* Moon pool
Breathing gas
handling
* Air filtration
* Activated carbon
* Hopcalite
* Molecular sieve
* Silica gel
* Booster pump
* Carbon dioxide scrubber
* Cascade filling system
* Diver's pump
* Diving air compressor
* Diving air filter
* Water separator
* High pressure breathing air compressor
* Low pressure breathing air compressor
* Gas blending
* Gas blending for scuba diving
* Gas panel
* Gas reclaim system
* Gas storage bank
* Gas storage quad
* Gas storage tube
* Helium analyzer
* Nitrox production
* Membrane gas separation
* Pressure swing adsorption
* Oxygen analyser
* Oxygen compatibility
Decompression
equipment
* Built-in breathing system
* Decompression tables
* Diving bell
* Bell cursor
* Closed bell
* Clump weight
* Launch and recovery system
* Wet bell
* Diving chamber
* Diving stage
* Recreational Dive Planner
* Saturation system
Platforms
* Dive boat
* Canoe and kayak diving
* Combat Rubber Raiding Craft
* Liveaboard
* Subskimmer
* Diving support vessel
* HMS Challenger (K07)
Underwater
habitat
* Aquarius Reef Base
* Continental Shelf Station Two
* Helgoland Habitat
* Jules' Undersea Lodge
* Scott Carpenter Space Analog Station
* SEALAB
* Tektite habitat
Remotely operated
underwater vehicles
* 8A4-class ROUV
* ABISMO
* Atlantis ROV Team
* CURV
* Deep Drone
* Épaulard
* Global Explorer ROV
* Goldfish-class ROUV
* Kaikō ROV
* Kaşif ROUV
* Long-Term Mine Reconnaissance System
* Mini Rover ROV
* OpenROV
* ROV KIEL 6000
* ROV PHOCA
* Scorpio ROV
* Sea Dragon-class ROV
* Seabed tractor
* Seafox drone
* Seahorse ROUV
* SeaPerch
* SJT-class ROUV
* T1200 Trenching Unit
* VideoRay UROVs
Safety equipment
* Diver down flag
* Diving shot
* Hyperbaric lifeboat
* Hyperbaric stretcher
* Jackstay
* Jonline
* Reserve gas supply
General
* Diving spread
* Air spread
* Saturation spread
* Hot water system
* Sonar
* Underwater acoustic positioning system
* Underwater acoustic communication
Freediving
Activities
* Aquathlon
* Apnoea finswimming
* Freediving
* Haenyeo
* Pearl hunting
* Ama
* Snorkeling
* Spearfishing
* Underwater football
* Underwater hockey
* Underwater ice hockey
* Underwater rugby
* Underwater target shooting
Competitions
* Nordic Deep
* Vertical Blue
* Disciplines
* Constant weight (CWT)
* Constant weight without fins (CNF)
* Dynamic apnea (DYN)
* Dynamic apnea without fins (DNF)
* Free immersion (FIM)
* No-limits apnea (NLT)
* Static apnea (STA)
* Skandalopetra diving
* Variable weight apnea (VWT)
* Variable weight apnea without fins
Equipment
* Diving mask
* Diving suit
* Hawaiian sling
* Polespear
* Snorkel (swimming)
* Speargun
* Swimfins
* Monofin
* Water polo cap
Freedivers
* Deborah Andollo
* Peppo Biscarini
* Sara Campbell
* Derya Can Göçen
* Goran Čolak
* Carlos Coste
* Robert Croft
* Mandy-Rae Cruickshank
* Yasemin Dalkılıç
* Leonardo D'Imporzano
* Flavia Eberhard
* Şahika Ercümen
* Emma Farrell
* Francisco Ferreras
* Pierre Frolla
* Flavia Eberhard
* Mehgan Heaney-Grier
* Elisabeth Kristoffersen
* Loïc Leferme
* Enzo Maiorca
* Jacques Mayol
* Audrey Mestre
* Karol Meyer
* Stéphane Mifsud
* Alexey Molchanov
* Natalia Molchanova
* Dave Mullins
* Patrick Musimu
* Guillaume Néry
* Herbert Nitsch
* Umberto Pelizzari
* Annelie Pompe
* Michal Risian
* Stig Severinsen
* Tom Sietas
* Aharon Solomons
* Martin Štěpánek
* Walter Steyn
* Tanya Streeter
* William Trubridge
* Devrim Cenk Ulusoy
* Danai Varveri
* Alessia Zecchini
* Nataliia Zharkova
Hazards
* Barotrauma
* Drowning
* Freediving blackout
* Deep-water blackout
* Shallow-water blackout
* Hypercapnia
* Hypothermia
Historical
* Ama
* Octopus wrestling
* Swimming at the 1900 Summer Olympics – Men's underwater swimming
Organisations
* AIDA International
* Scuba Schools International
* Australian Underwater Federation
* British Freediving Association
* Confédération Mondiale des Activités Subaquatiques
* Fédération Française d'Études et de Sports Sous-Marins
* Performance Freediving International
Professional diving
Occupations
* Ama
* Commercial diver
* Commercial offshore diver
* Hazmat diver
* Divemaster
* Diving instructor
* Diving safety officer
* Diving superintendent
* Diving supervisor
* Haenyeo
* Media diver
* Police diver
* Public safety diver
* Scientific diver
* Underwater archaeologist
Military diving
* Army engineer diver
* Clearance diver
* Frogman
* List of military diving units
* Royal Navy ships diver
* Special Boat Service
* United States military divers
* U.S. Navy diver
* U.S.Navy master diver
* United States Navy SEALs
* Underwater Demolition Team
Underwater work
* Commercial offshore diving
* Dive leader
* Diver training
* Recreational diver training
* Hyperbaric welding
* Media diving
* Nondestructive testing
* Pearl hunting
* Police diving
* Potable water diving
* Public safety diving
* Scientific diving
* Ships husbandry
* Sponge diving
* Submarine pipeline
* Underwater archaeology
* Archaeology of shipwrecks
* Underwater construction
* Offshore construction
* Underwater demolition
* Underwater photography
* Underwater search and recovery
* Underwater videography
Salvage diving
* SS Egypt
* Kronan
* La Belle
* SS Laurentic
* RMS Lusitania
* Mars
* Mary Rose
* USS Monitor
* HMS Royal George
* Vasa
Diving contractors
* COMEX
* Helix Energy Solutions Group
Tools & equipment
* Abrasive waterjet
* Airlift
* Baited remote underwater video
* In-water surface cleaning
* Brush cart
* Cavitation cleaning
* Pressure washing
* Pigging
* Lifting bag
* Remotely operated underwater vehicle
* Thermal lance
* Tremie
* Water jetting
Underwater
weapons
* Limpet mine
* Speargun
* Hawaiian sling
* Polespear
Underwater
firearm
* Gyrojet
* Mk 1 Underwater Defense Gun
* Powerhead
* Underwater pistols
* Heckler & Koch P11
* SPP-1 underwater pistol
* Underwater revolvers
* AAI underwater revolver
* Underwater rifles
* ADS amphibious rifle
* APS underwater rifle
* ASM-DT amphibious rifle
Recreational diving
Specialties
* Altitude diving
* Cave diving
* Deep diving
* Ice diving
* Muck diving
* Open-water diving
* Rebreather diving
* Sidemount diving
* Solo diving
* Technical diving
* Underwater photography
* Wreck diving
Diver
organisations
* British Sub-Aqua Club (BSAC)
* Cave Divers Association of Australia (CDAA)
* Cave Diving Group (CDG)
* Comhairle Fo-Thuinn (CFT)
* Confédération Mondiale des Activités Subaquatiques (CMAS)
* Federación Española de Actividades Subacuáticas (FEDAS)
* Fédération Française d'Études et de Sports Sous-Marins (FFESSM)
* International Association for Handicapped Divers (IAHD)
* National Association for Cave Diving (NACD)
* Woodville Karst Plain Project (WKPP)
Diving tourism
industry
* Dive center
* Environmental impact of recreational diving
* Scuba diving tourism
* Shark tourism
* Sinking ships for wreck diving sites
Diving events
and festivals
* Diversnight
* Underwater Bike Race
Recreational
dive sites
Reef diving
regions
* Aliwal Shoal Marine Protected Area
* Arrecifes de Cozumel National Park
* Edmonds Underwater Park
* Great Barrier Reef
* iSimangaliso Marine Protected Area
* Poor Knights Islands
* Table Mountain National Park Marine Protected Area
Reef dive
sites
* Artificial reef
* Gibraltar Artificial Reef
* Shark River Reef
* Osborne Reef
* Fanadir
* Gamul Kebir
* Palancar Reef
* Underwater artworks
* Cancún Underwater Museum
* Christ of the Abyss
* Molinere Underwater Sculpture Park
Wreck diving
regions
* Chuuk Lagoon
* Edmonds Underwater Park
* Finger Lakes Underwater Preserve Association
* Maritime Heritage Trail – Battle of Saipan
* Michigan Underwater Preserves
* Robben Island Marine Protected Area
* Table Mountain National Park Marine Protected Area
* Tulagi
* Tulamben
* Whitefish Point Underwater Preserve
* Wreck Alley, San Diego
Wreck dive
sites
* HMS A1
* HMS A3
* USS Aaron Ward
* Abessinia
* Aeolian Sky
* Albert C. Field
* Andrea Doria
* Antilla
* Antilles
* Aquila
* USS Arkansas
* Bianca C.
* SS Binnendijk
* HMS Boadicea
* Booya
* HMSAS Bloemfontein
* Breda
* HMAS Brisbane
* HMHS Britannic
* Bungsberg
* HMAS Canberra
* Carl D. Bradley
* Carnatic
* SMS Dresden
* Dunraven
* Eastfield
* HMT Elk
* Ellengowan
* RMS Empress of Ireland
* HMS Falmouth
* Fifi
* SS Francisco Morazan
* Fujikawa Maru
* Fumizuki
* SATS General Botha
* USNS General Hoyt S. Vandenberg
* HMS Ghurka
* Glen Strathallan
* SAS Good Hope
* Gothenburg
* Herzogin Cecilie
* Hilma Hooker
* Hispania
* HMS Hood
* HMAS Hobart
* Igara
* James Eagan Layne
* Captain Keith Tibbetts
* King Cruiser
* SMS Kronprinz
* Kyarra
* HMS Laforey
* USAT Liberty
* Louis Sheid
* USS LST-507
* SMS Markgraf
* Mikhail Lermontov
* HMS M2
* Maine
* Maloja
* HMS Maori
* Marguerite
* SS Mauna Loa
* USAT Meigs
* Mendi
* USCGC Mohawk
* Mohegan
* RMS Moldavia
* HMS Montagu
* MV RMS Mulheim
* Nagato
* Oceana
* USS Oriskany
* Oslofjord
* P29
* P31
* Pedernales
* Persier
* HMAS Perth
* SAS Pietermaritzburg
* Piłsudski
* Pool Fisher
* HMS Port Napier
* Preußen
* President Coolidge
* PS Queen Victoria
* Radaas
* Rainbow Warrior
* RMS Rhone
* Rondo
* Rosehill
* Rotorua
* Royal Adelaide
* Royal Charter
* Rozi
* HMS Safari
* Salem Express
* USS Saratoga
* USS Scuffle
* HMS Scylla
* HMS Sidon
* USS Spiegel Grove
* Stanegarth
* Stanwood
* Stella
* HMAS Swan
* USS Tarpon
* Thesis
* Thistlegorm
* Toa Maru
* Torrey Canyon
* SAS Transvaal
* U-40
* U-352
* U-1195
* Um El Faroud
* Varvassi
* Walter L M Russ
* Washingtonian (1913)
* HMNZS Wellington
* USS Yancey
* Yongala
* Zenobia
* Zealandia
* Zingara
Cave diving
sites
* Blauhöhle
* Chinhoyi Caves
* Devil's Throat at Punta Sur
* Engelbrecht Cave
* Fossil Cave
* Jordbrugrotta
* Piccaninnie Ponds
* Pluragrotta
* Pollatoomary
* Sistema Ox Bel Ha
* Sistema Sac Actun
* Sistema Dos Ojos
* Sistema Nohoch Nah Chich
Freshwater
dives
* Dutch Springs
* Ewens Ponds
* Little Blue Lake
Training sites
* Capernwray Dive Centre
* Deepspot
* National Diving and Activity Centre
* Stoney Cove
Open ocean
diving
* Blue-water diving
* Black-water diving
Diving safety
* Human factors in diving equipment design
* Human factors in diving safety
* Life-support system
* Safety-critical system
* Scuba diving fatalities
Diving
hazards
* List of diving hazards and precautions
* Environmental
* Current
* Delta-P
* Entanglement hazard
* Overhead
* Silt out
* Wave action
* Equipment
* Freeflow
* Use of breathing equipment in an underwater environment
* Failure of diving equipment other than breathing apparatus
* Single point of failure
* Physiological
* Cold shock response
* Decompression
* Nitrogen narcosis
* Oxygen toxicity
* Seasickness
* Uncontrolled decompression
* Diver behaviour and competence
* Lack of competence
* Overconfidence effect
* Panic
* Task loading
* Trait anxiety
* Willful violation
Consequences
* Barotrauma
* Decompression sickness
* Drowning
* Hypothermia
* Hypoxia
* Hypercapnia
* Hyperthermia
Diving
procedures
* Ascending and descending
* Emergency ascent
* Boat diving
* Canoe and kayak diving
* Buddy diving
* buddy check
* Decompression
* Decompression practice
* Pyle stop
* Ratio decompression
* Dive briefing
* Dive log
* Dive planning
* Scuba gas planning
* Diver communications
* Diving hand signals
* Diving line signals
* Diver voice communications
* Diver rescue
* Diver training
* Doing It Right
* Drift diving
* Gas blending for scuba diving
* Night diving
* Solo diving
* Water safety
Risk
management
* Checklist
* Hazard identification and risk assessment
* Hazard analysis
* Job safety analysis
* Risk assessment
* Risk control
* Hierarchy of hazard controls
* Incident pit
* Lockout–tagout
* Permit To Work
* Redundancy
* Safety data sheet
* Situation awareness
Diving team
* Bellman
* Chamber operator
* Diver medical technician
* Diver's attendant
* Diving supervisor
* Diving systems technician
* Gas man
* Life support technician
* Stand-by diver
Equipment
safety
* Breathing gas quality
* Testing and inspection of diving cylinders
* Hydrostatic test
* Sustained load cracking
* Diving regulator
* Breathing performance of regulators
Occupational
safety and
health
* Approaches to safety
* Job safety analysis
* Risk assessment
* Toolbox talk
* Housekeeping
* Association of Diving Contractors International
* Code of practice
* Contingency plan
* Diving regulations
* Emergency procedure
* Emergency response plan
* Evacuation plan
* Hazardous Materials Identification System
* Hierarchy of hazard controls
* Administrative controls
* Engineering controls
* Hazard elimination
* Hazard substitution
* Personal protective equipment
* International Marine Contractors Association
* Occupational hazard
* Biological hazard
* Chemical hazard
* Physical hazard
* Psychosocial hazard
* Occupational hygiene
* Exposure assessment
* Occupational exposure limit
* Workplace health surveillance
* Safety culture
* Code of practice
* Diving safety officer
* Diving superintendent
* Health and safety representative
* Operations manual
* Safety meeting
* Standard operating procedure
Diving medicine
Diving
disorders
* List of signs and symptoms of diving disorders
* Cramp
* Motion sickness
* Surfer's ear
Pressure
related
* Alternobaric vertigo
* Barostriction
* Barotrauma
* Air embolism
* Aerosinusitis
* Barodontalgia
* Dental barotrauma
* Pulmonary barotrauma
* Compression arthralgia
* Decompression illness
* Dysbarism
Oxygen
* Freediving blackout
* Hyperoxia
* Hypoxia
* Oxygen toxicity
Inert gases
* Avascular necrosis
* Decompression sickness
* Isobaric counterdiffusion
* Taravana
* Dysbaric osteonecrosis
* High-pressure nervous syndrome
* Hydrogen narcosis
* Nitrogen narcosis
Carbon dioxide
* Hypercapnia
* Hypocapnia
Breathing gas
contaminants
* Carbon monoxide poisoning
Immersion
related
* Asphyxia
* Drowning
* Hypothermia
* Immersion diuresis
* Instinctive drowning response
* Laryngospasm
* Salt water aspiration syndrome
* Swimming-induced pulmonary edema
Treatment
* Demand valve oxygen therapy
* First aid
* Hyperbaric medicine
* Hyperbaric treatment schedules
* In-water recompression
* Oxygen therapy
* Therapeutic recompression
Personnel
* Diving Medical Examiner
* Diving Medical Practitioner
* Diving Medical Technician
* Hyperbaric nursing
Screening
* Atrial septal defect
* Effects of drugs on fitness to dive
* Fitness to dive
* Psychological fitness to dive
Research
Researchers in
diving physiology
and medicine
* Arthur J. Bachrach
* Albert R. Behnke
* Paul Bert
* George F. Bond
* Robert Boyle
* Albert A. Bühlmann
* John R. Clarke
* Guybon Chesney Castell Damant
* Kenneth William Donald
* William Paul Fife
* John Scott Haldane
* Robert William Hamilton Jr.
* Leonard Erskine Hill
* Brian Andrew Hills
* Felix Hoppe-Seyler
* Christian J. Lambertsen
* Simon Mitchell
* Charles Momsen
* John Rawlins R.N.
* Charles Wesley Shilling
* Edward D. Thalmann
* Jacques Triger
Diving medical
research
organisations
* Aerospace Medical Association
* Divers Alert Network (DAN)
* Diving Diseases Research Centre (DDRC)
* Diving Medical Advisory Council (DMAC)
* European Diving Technology Committee (EDTC)
* European Underwater and Baromedical Society (EUBS)
* National Board of Diving and Hyperbaric Medical Technology
* Naval Submarine Medical Research Laboratory
* Royal Australian Navy School of Underwater Medicine
* Rubicon Foundation
* South Pacific Underwater Medicine Society (SPUMS)
* Southern African Underwater and Hyperbaric Medical Association (SAUHMA)
* Undersea and Hyperbaric Medical Society (UHMS)
* United States Navy Experimental Diving Unit (NEDU)
Law
* Civil liability in recreational diving
* Diving regulations
* Duty of care
* List of legislation regulating underwater diving
* Investigation of diving accidents
* UNESCO Convention on the Protection of the Underwater Cultural Heritage
History of underwater diving
* History of decompression research and development
* History of scuba diving
* List of researchers in underwater diving
* Timeline of diving technology
* Underwater diving in popular culture
Archeological
sites
* SS Commodore
* USS Monitor
* Queen Anne's Revenge
* Whydah Gally
Underwater art
and artists
* The Diver
* Jason deCaires Taylor
Engineers
and inventors
* William Beebe
* Georges Beuchat
* John R. Clarke
* Jacques Cousteau
* Charles Anthony Deane
* John Deane
* Ted Eldred
* Henry Fleuss
* Émile Gagnan
* Joseph-Martin Cabirol
* Christian J. Lambertsen
* Yves Le Prieur
* John Lethbridge
* Ernest William Moir
* Joseph Salim Peress
* Auguste Piccard
* Willard Franklyn Searle
* Augustus Siebe
* Jacques Triger
Equipment
* Aqua-Lung
* RV Calypso
* SP-350 Denise
* Nikonos
* Porpoise regulator
* Standard diving dress
* Vintage scuba
Military and
covert operations
* Raid on Alexandria (1941)
* Sinking of the Rainbow Warrior
Scientific projects
* 1992 cageless shark-diving expedition
* Mission 31
Incidents
Dive boat incidents
* Sinking of MV Conception
* Fire on MV Red Sea Aggressor
Diver rescues
* Alpazat cave rescue
* Tham Luang cave rescue
Early diving
* John Day (carpenter)
* Charles Spalding
* Ebenezer Watson
Freediving fatalities
* Loïc Leferme
* Audrey Mestre
* Nicholas Mevoli
* Natalia Molchanova
Offshore
diving incidents
* Byford Dolphin diving bell accident
* Drill Master diving accident
* Star Canopus diving accident
* Stena Seaspread diving accident
* Venture One diving accident
* Waage Drill II diving accident
* Wildrake diving accident
Professional
diving fatalities
* Roger Baldwin
* John Bennett
* Victor F. Guiel Jr.
* Craig M. Hoffman
* Peter Henry Michael Holmes
* Johnson Sea Link accident
* Edwin Clayton Link
* Gerard Anthony Prangley
* Pier Skipness
* Robert John Smyth
* Albert D. Stover
* Richard A. Walker
* Lothar Michael Ward
* Joachim Wendler
* Bradley Westell
* Arne Zetterström
Scuba diving
fatalities
* Ricardo Armbruster
* Allan Bridge
* David Bright
* Berry L. Cannon
* Cotton Coulson
* Cláudio Coutinho
* E. Yale Dawson
* Deon Dreyer
* Milan Dufek
* Sheck Exley
* Maurice Fargues
* Fernando Garfella Palmer
* Guy Garman
* Steve Irwin
* Jim Jones
* Henry Way Kendall
* Artur Kozłowski
* Chris and Chrissy Rouse
* Kirsty MacColl
* Agnes Milowka
* François de Roubaix
* Dave Shaw
* Wesley C. Skiles
* Dewey Smith
* Rob Stewart
* Esbjörn Svensson
* Josef Velek
Publications
Manuals
* NOAA Diving Manual
* U.S. Navy Diving Manual
* Basic Cave Diving: A Blueprint for Survival
* Underwater Handbook
* Bennett and Elliott's physiology and medicine of diving
* Encyclopedia of Recreational Diving
* The new science of skin and scuba diving
* Professional Diver's Handbook
* Basic Scuba
Standards and
Codes of Practice
* Code of Practice for Scientific Diving (UNESCO)
* DIN 7876
* IMCA Code of Practice for Offshore Diving
* ISO 24801 Recreational diving services — Requirements for the training of recreational scuba divers
General non-fiction
* The Darkness Beckons
* Goldfinder
* The Last Dive
* Shadow Divers
* The Silent World: A Story of Undersea Discovery and Adventure
Research
* List of Divers Alert Network publications
Dive guides
*
Training and registration
Diver
training
* Competence and assessment
* Competency-based learning
* Refresher training
* Skill assessment
* Diver training standard
* Diving instructor
* Diving school
* Occupational diver training
* Commercial diver training
* Military diver training
* Public safety diver training
* Scientific diver training
* Recreational diver training
* Introductory diving
* Teaching method
* Muscle memory
* Overlearning
* Stress exposure training
Skills
* Combat sidestroke
* Diver navigation
* Diver trim
* Ear clearing
* Frenzel maneuver
* Valsalva maneuver
* Finning techniques
* Scuba skills
* Buddy breathing
* Low impact diving
* Diamond Reef System
* Surface-supplied diving skills
* Underwater searches
Recreational
scuba
certification
levels
Core diving skills
* Advanced Open Water Diver
* Autonomous diver
* CMAS* scuba diver
* CMAS** scuba diver
* Introductory diving
* Low Impact Diver
* Master Scuba Diver
* Open Water Diver
* Supervised diver
Leadership skills
* Dive leader
* Divemaster
* Diving instructor
* Master Instructor
Specialist skills
* Rescue Diver
* Solo diver
Diver training
certification
and registration
organisations
* European Underwater Federation (EUF)
* International Diving Regulators and Certifiers Forum (IDRCF)
* International Diving Schools Association (IDSA)
* International Marine Contractors Association (IMCA)
* List of diver certification organizations
* National Oceanic and Atmospheric Administration (NOAA)
* Nautical Archaeology Society
* Universal Referral Program
* World Recreational Scuba Training Council (WRSTC)
Commercial diver
certification
authorities
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Motion sickness | c0026603 | 2,476 | wikipedia | https://en.wikipedia.org/wiki/Motion_sickness | 2021-01-18T18:29:09 | {"mesh": ["D009041"], "umls": ["C0026603"], "wikidata": ["Q309067"]} |
## Cloning and Expression
Diskin et al. (2009) identified the NBPF23 gene within a copy number variation (CNV) region on chromosome 1q21.1 associated with susceptibility to neuroblastoma (NBLST6; 613017). Real-time quantitative RT-PCR detected highest levels of NBPF23 expression in fetal brain and fetal sympathetic ganglia samples from early gestation, consistent with NBPF23 being expressed in early sympathicoadrenal development. Diskin et al. (2009) stated that there are 3 clusters of NBPF genes on chromosome 1 within areas of segmental duplication. The encoded proteins are recently evolved and primate-specific, share significant homology, and contain highly conserved domains (DUF1220) that are thought to be neuronal-specific.
Mapping
Diskin et al. (2009) mapped the NBPF23 gene to chromosome 1q21.1 based on sequence alignment of a mapped EST.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| NEUROBLASTOMA BREAKPOINT FAMILY, MEMBER 17, PSEUDOGENE | None | 2,477 | omim | https://www.omim.org/entry/612970 | 2019-09-22T16:00:09 | {"omim": ["612970"], "synonyms": ["Alternative titles", "NEUROBLASTOMA BREAKPOINT FAMILY, MEMBER 23, PSEUDOGENE"]} |
## Summary
### Clinical characteristics.
EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) is characterized by abnormalities in the posterior fossa and degeneration of the anterior horn cells. At birth, skeletal muscle weakness manifests as hypotonia (sometimes with congenital joint contractures) and poor feeding. In persons with prolonged survival, spasticity, dystonia, and seizures become evident. Within the first year of life respiratory insufficiency and swallowing difficulties are common. Intellectual disability is severe. Life expectancy ranges from a few weeks to adolescence. To date, 82 individuals (from 58 families) with EXOSC3-PCH have been described.
### Diagnosis/testing.
The diagnosis of EXOSC3-PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and is confirmed by the presence of biallelic EXOSC3 pathogenic variants identified by molecular genetic testing.
### Management.
Treatment of manifestations: No specific therapy is available. Treatment is symptomatic. Contractures and scoliosis are managed by passive or active movement and bracing as needed. Aspiration risk and seizures are managed in a routine manner. Education is adapted to the level of cognitive abilities.
Surveillance: Regular examinations to address: growth and nutritional status (including problems with feeding and risk of aspiration); respiratory function; joint contractures and scoliosis. Observation for and management of epileptic seizures.
### Genetic counseling.
EXOSC3-PCH is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EXOSC3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Once the EXOSC3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
## Diagnosis
### Suggestive Findings
Diagnosis of EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH) should be suspected in children with severe neurologic impairment and characteristic findings on brain imaging.
#### Neurologic Findings
Common
* Hypotonia (onset is usually at birth, but a later onset is possible)
* Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes
* Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival
* Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations)
Less common
* Joint contractures (can be present at birth or develop later)
* Swallowing insufficiency
* Ophthalmologic findings of:
* Small or pale optic discs indicative of optic atrophy
* Nystagmus
* Strabismus
* Seizures
#### Brain MRI Findings Consistent with Pontocerebellar Hypoplasia Type 1 (PCH1) *
Common
* Hypoplasia and/or atrophy of the cerebellum in varying degrees
* Hypoplasia and/or atrophy of the pons in varying degrees
* Cerebellar vermis and cerebellar hemispheres equally affected
Less common
* Intracerebellar cysts [Eggens et al 2014]
* Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia
* See Nomenclature.
#### Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
### Establishing the Diagnosis
The diagnosis of EXOSC3 pontocerebellar hypoplasia is established in a proband with suggestive findings and biallelic EXOSC3 pathogenic variants identified by molecular genetic testing (see Table 1).
Note: Identification of biallelic EXOSC3 variants of uncertain significance (or identification of one known EXOSC3 pathogenic variant and one EXOSC3 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of EXOSC3-PHC has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
#### Option 1
Single-gene testing. Sequence analysis of EXOSC3 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A cerebellar hypoplasia multigene panel that includes EXOSC3 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. Of note, given the rarity of EXOSC3-PCH, some panels for cerebellar hypoplasia may not include this gene. (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
Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in EXOSC3 Pontocerebellar Hypoplasia
View in own window
Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
EXOSC3Sequence analysis 3~99% 4
Deletion/duplication analysis 5Partial-gene deletion in 1 person 6
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants.
3\.
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.
4\.
Wan et al [2012], Rudnik-Schöneborn et al [2013], Zanni et al [2013], Eggens et al [2014]
5\.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
6\.
Eggens et al [2014]
## Clinical Characteristics
## Differential Diagnosis
Key disorders to consider in the differential diagnosis of pontocerebellar hypoplasia type 1 (PCH1) include EXOSC8-, SLC25A46-, and VRK1-related PCH1, PCH2/4 (TSEN54-related PCH), spinal muscular atrophy type 1, PCH10, and PCH12 (see Table 2).
PCH1. About 50% of individuals with PCH1 have pathogenic variants in EXOSC3 (i.e., EXOSC3-PCH). In children with EXOSC3-PCH, neonatal death, delayed nerve conduction velocities, and congenital respiratory and feeding difficulties occur less frequently than in those without identifiable EXOSC3 pathogenic variants [Rudnik-Schöneborn et al 2014].
PCH2/4. Dyskinesias and seizures are common in PCH2, the most common type of PCH. PCH4 is a severe form of PCH2, often with congenital contractures and polyhydramnios. In children with EXOSC3-PCH, central motor findings (together with the typical brain MRI findings of cerebellar or pontocerebellar hypoplasia) may falsely suggest a diagnosis of PCH2. Compared to findings in EXOSC3-PCH, the findings in PCH2 are:
* No abnormalities of the spinal cord (whereas in PCH1 anterior horn cells are involved);
* Attenuation of the pons on brain MRI (whereas in PCH1 the pons can be unaffected).
### Table 2.
Genes of Interest in the Differential Diagnosis of EXOSC3 Pontocerebellar Hypoplasia
View in own window
Gene(s)Phenotype/
DisorderMOIBrain MRI FindingsClinical Characteristics
Key differential diagnosis disorders (in order of relevance)
EXOSC8
SLC25A46
VRK1PCH1 1, 2ARPontine atrophy may not be present in some individuals.
* Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth
* Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. 3
TSEN54TSEN54-PCH (PCH2, 4, & 5)AR
* Severe pontocerebellar hypoplasia w/relative sparing of pons
* Profound supratentorial atrophy in PCH4
* Generalized clonus, impaired swallowing, dystonia, chorea, progressive microcephaly in PCH2
* PCH4 is a severe type of PCH2, w/congenital contractures & polyhydramnios.
SMN1Spinal muscular atrophy type 1ARNormal
* Early-onset (birth-6 mos) disease is characterized by muscle weakness & lack of motor development.
* Cognitive function is normal.
* EMG reveals denervation; muscle biopsy shows grouped atrophy.
CLP1PCH10 (OMIM 615803)ARMild cerebellar atrophy/hypoplasiaVery rare disorder characterized by DD, microcephaly, spasticity, axonal motor & sensory neuropathy, abnormal muscle tone, seizures, motor neuron degeneration
COASYPCH12 (OMIM 618266)ARPrenatal-onset microcephaly; hypoplasia of cerebellum, brain stem, spinal cordSevere prenatal-onset PCH, microcephaly, arthrogryposis w/hypoplasia of spinal cord & brain stem, multiple congenital contractures, polyhydramnios, motor neuron degeneration
Other disorders to consider (in alphabetic order by gene)
B3GALNT2
B4GAT1
DAG1
FKRP
FKTN
GMPPB
ISPD
LARGE1
POMGNT1
POMGNT2
POMK
POMT1
POMT2
RXYLT1 4Alpha-dystroglycanopathiesARWide spectrum of brain malformations incl cobblestone lissencephaly & hydrocephalusMuscle weakness & ophthalmologic abnormalities
CASKID & microcephaly w/pontine & cerebellar hypoplasia (See CASK Disorders.)XLNeocortical dysplasia (simplified gyral pattern, thin brain stem w/flattening of pons) & severe cerebellar hypoplasia (PCH)
* Heterozygous females have severe or profound ID & structural brain anomalies incl mild congenital microcephaly & severe postnatal microcephaly.
* Hemizygous males are more severely affected.
CHMP1APCH8 1ARMRI findings similar to PCH1BMicrocephaly, delayed walking, variable foot deformities, chorea, dystonic posturing, impaired cognition
PCLOPCH3 1AR
>40 genes (e.g., PMM2 5)Congenital disorders of glycosylation (CDG) (See also PMM2-CDG (CDG-Ia).)AR
(XL)Pontocerebellar hypoplasia w/superimposed atrophy, delayed myelinationDysmorphic features, ataxia; organ failure in neonatal period
RARS2PCH6 1AR
* Very rare
* ↑ CSF lactate concentration
RELNLissencephaly 2 (OMIM 257320)ARClassic lissencephaly w/coexistent cerebellar & pontine hypoplasia
SEPSECSPCH2 1ARProgressive cerebello-cerebral atrophy closely resembles mild PCH.Clinical findings closely resemble mild PCH2.
TOE1PCH7 1ARPCHDisorders of sex development
VLDLRVLDLR cerebellar hypoplasiaARGross cerebellar hypoplasia, flat ventral pons, simplified gyriAtaxia & ID
AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked
1\.
van Dijk et al [2018]
2\.
OMIM Phenotypic Series: Pontocerebellar hypoplasia
3\.
Children with EXOSC3 pathogenic variants other than c.395A>C (p.Asp132Ala) have a more severe phenotype that includes severe pontine and cerebellar hypoplasia, joint contractures, and death in infancy.
4\.
OMIM Phenotypic Series: Muscular dystrophy-dystroglycanopathy, type A
5\.
PMM2-CDG (CDG-Ia) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides.
Other conditions to consider in the differential diagnosis
* Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [Forman et al 2005]
* Pontocerebellar hypoplasia in extremely premature infants (gestational age <28 weeks); an acquired phenocopy to be considered [Volpe 2009, Pierson & Al Sufiani 2016]
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with EXOSC3 pontocerebellar hypoplasia (EXOSC3-PCH), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
### Table 3.
Recommended Evaluations Following Initial Diagnosis of EXOSC3 Pontocerebellar Hypoplasia
View in own window
System/ConcernEvaluationComment
ConstitutionalMeasure length & weight.See Gastrointestinal/Feeding if evidence of failure to thrive.
Gastrointestinal/
FeedingGastroenterology / nutrition / feeding team evalAssess swallowing & feeding to determine safety of oral vs gastrostomy feeding.
RespiratoryAssess airway & pulmonary function & secretion management.Consult pulmonologist.
NeurologicEval by pediatric neurologistAssess for:
* Evidence of severe generalized clonus;
* Chorea, spasticity;
* Seizures (to incl EEG);
* Impaired central vision.
Hearing lossEval by audiologist
VisionEval by pediatric ophthalmologist
* Assess visual acuity.
* Fundoscopy to assess optic nerve
MusculoskeletalMultidisciplinary neuromuscular clinic assessment by orthopedist, physical medicine, OT/PTTo incl assessment of:
* Contractures, clubfoot, & kyphoscoliosis
* Need for positioning devices
Palliative careRefer to palliative care specialist.When deemed appropriate by family & care providers
Genetic
counselingBy genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of EXOSC3-PCH to facilitate medical & personal decision making
Family support/
resourcesAssess:
* Use of community or online resources incl Parent to Parent;
* Need for social work involvement for parental support;
* Need for home nursing referral.
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist
1\.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
### Treatment of Manifestations
No specific treatment for EXOSC3-PCH exists; the goals are to maximize function and reduce complications.
Ideally, each affected individual is managed by a multidisciplinary team of relevant specialists including developmental pediatricians, neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see Table 4).
### Table 4.
Treatment of Manifestations in Individuals with EXOSC3 Pontocerebellar Hypoplasia
View in own window
Manifestation/
ConcernTreatmentConsiderations/Other
SeizuresPer standard practiceBy neurologist experienced in epilepsy management
IrritabilityNoneOften related to chorea (involuntary movements)
MusculoskeletalMultidisciplinary neuromuscular clinic physical medicine, OT/PT
* Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices.
* Alternative casting/splinting & stretching
OrthopedicsManage contractures, clubfoot, scoliosis w/bracing &/or surgical intervention.
Feeding/DysphagiaGastroenterology / nutrition / feeding teamModify food consistency to ↓ aspiration risk &/or consider NG feeding & gastrostomy.
SpeechSpeech/language evalConsider involving speech therapist & OT to improve communication skills.
Respiratory
* Manage pulmonary complications.
* Treatment of respiratory infections
Per treating pulmonologist
NeurodevelopmentalEarly intervention / individual education program based on needsSee Developmental Delay / Intellectual Disability Management Issues.
NG = nasogastric; OT = occupational therapy, PT = physical therapy
#### Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
* IEP services:
* An IEP provides specially designed instruction and related services to children who qualify.
* IEP services will be reviewed annually to determine whether any changes are needed.
* As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
* Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
* PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
* As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
* A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
* Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
* Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
### Surveillance
### Table 5.
Recommended Surveillance for Individuals with EXOSC3 Pontocerebellar Hypoplasia
View in own window
System/ConcernEvaluationFrequency
RespiratoryAssess airway & pulmonary function & secretion management.Monitoring of respiratory function may be necessary to detect sleep apnea.
Gastrointestinal/
Feeding
* Aspiration risk & nutritional status
* Monitor for constipation.
Annually; more frequently if needed
Musculoskeletal
* PT/OT eval
* Assess for contractures, scoliosis, foot deformities.
* Hip/spine x-rays
Neurologic
* Monitor those w/seizures as clinically indicated.
* Monitor for dystonia & choreic movements.
DevelopmentMonitor developmental milestones
Family support/
resourcesFamily needs
OT = occupational therapy, PT = physical therapy
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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
| EXOSC3 Pontocerebellar Hypoplasia | None | 2,478 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK236968/ | 2021-01-18T21:28:48 | {"synonyms": ["Pontocerebellar Hypoplasia Type 1B (PCH1B)"]} |
## Summary
### Clinical characteristics.
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
### Diagnosis/testing.
NS is diagnosed on clinical grounds by observation of key features. Affected individuals have normal chromosome studies. Molecular genetic testing identifies a pathogenic variant in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 and RIT1 each in 5%, and KRAS in fewer than 5%. Other reported genes – in which pathogenic variants have been found to cause Noonan syndrome in fewer than 1% of cases – include BRAF, LZTR1, MAP2K1, and NRAS. Several additional genes associated with a Noonan-syndrome-like phenotype in fewer than ten individuals have been identified.
### Management.
Treatment of manifestations: Cardiovascular anomalies in NS are usually treated as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. Treatment for serious bleeding is guided by knowledge of the specific factor deficiency or platelet aggregation anomaly. Growth hormone (GH) treatment increases growth velocity.
Surveillance: Monitoring of anomalies found in any system, especially cardiovascular abnormalities.
### Genetic counseling.
NS is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant NS have a de novo pathogenic variant, an affected parent is recognized in 30%-75% of families. The risk to sibs of a proband with autosomal dominant NS depends on the genetic status of the parents: if a parent is affected, the risk is 50%; when the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%). Each child of an individual with autosomal dominant Noonan syndrome has a 50% chance of inheriting the pathogenic variant. NS caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner. The parents of an individual with autosomal recessive NS are typically heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be asymptomatic or have mild features of NS. If both parents are heterozygous for one LZTR1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of having one LZTR1 pathogenic variant (which can be associated with mild NS features), and a 25% chance of being unaffected and not a carrier. Prenatal testing is possible if the NS-related pathogenic variant(s) have been identified in an affected family member.
## Diagnosis
### Suggestive Findings
Noonan syndrome (NS) should be suspected in individuals with the following key features:
* Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in the adult. Key features found irrespective of age include low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; and eyes that are often wide-spaced, downslanted, and with epicanthal folds and fullness or droopiness of the upper eyelids (ptosis).
Note: See the National Human Genome Research Institute (NHGRI) Atlas of Human Malformation Syndromes (scroll to ATLAS IMAGES) for photographs of individuals with Noonan syndrome from diverse ethnic backgrounds.
* Short stature
* Congenital heart defect, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy
* Developmental delay of variable degree
* Broad or webbed neck
* Unusual chest shape with superior pectus carinatum, inferior pectus excavatum
* Widely set nipples
* Cryptorchidism in males
* Other:
* Coagulation defects. Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time) may show abnormalities. Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction.
* Lymphatic dysplasias of the lungs, intestines, and/or lower extremities
Diagnostic criteria developed by van der Burgt in 1997 were published in van der Burgt [2007]. While they have not been used extensively in North America, they are of particular value in the research domain, and are embedded in management guidelines developed by Dyscerne in the United Kingdom [Noonan Syndrome Guideline Development Group 2010]. This clinical management guideline also provides details of recommended baseline investigations and age-specific management. Similar recommendations are provided in Romano et al [2010] and Roberts et al [2013].
### Establishing the Diagnosis
The diagnosis of NS is established in a proband with a heterozygous pathogenic variant in one of the genes listed in Table 1 or biallelic pathogenic variants in LZTR1 idenfitied by molecular genetic testing. Testing approaches can include use of a multigene panel, serial single-gene testing, and more comprehensive genomic testing:
* A multigene panel that includes the genes listed in Table1 and other genes of interest (see Differential Diagnosis) is the test of choice for an individual suspected of having Noonan syndrome. Because of significant phenotypic overlap with cardiofaciocutaneous syndrome and Costello syndrome, most available panels include the genes for these diagnoses, too. 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.
* Serial single-gene testing can be considered if panel testing is not feasible. Approximately 50% of individuals with NS have a pathogenic missense variant in PTPN11; therefore, single-gene testing starting with PTPN11 would be the next best first test. Appropriate serial single-gene testing if PTPN11 testing is not diagnostic can be determined by the individual's phenotype (e.g., RIT1 if there is hypertrophic cardiomyopathy, SHOC2 if there is a loose anagen hair phenotype, LZTR1 if autosomal recessive inheritance is suspected); however, continued sequential single-gene testing is not recommended as it is more costly than panel testing.
Since Noonan syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to result in a diagnosis; however, rare cases have been reported for some genes (see Table 1).
* More comprehensive genomic testing (when available) including exome sequencing or genome sequencing may be considered if use of a multigene panel and/or serial single-gene testing fails to confirm a diagnosis in an individual with features of NS.
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 Noonan Syndrome (NS)
View in own window
Gene 1Proportion of NS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detected by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
PTPN1150% 5Nearly 100%Rare duplication, 6 diagnosis of NS questioned 7
SOS110%-13% 8100%Unknown 9
RAF15% 10Nearly 100%One reported case w/a duplication, 11 diagnosis of NS questioned 7
One reported case of a deletion 12
RIT15% 10100%Unknown 9
KRAS<5% 13100%Unknown 9
NRAS8 individuals & 4 families 14100%Unknown 9
BRAF<2% 15100%Unknown 9
MAP2K1<2% 16100%Unknown 9
LZTR1Unknown 17100%Unknown 9
Others 18NA
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
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.
5\.
Tartaglia et al [2002]
6\.
Shchelochkov et al [2008], Graham et al [2009], Chen et al [2014a]
7\.
Lissewski et al [2015]
8\.
Approximately 16%-20% of individuals with a clinical diagnosis of Noonan syndrome who do not have an identified PTPN11 pathogenic variant are found to have an SOS1 pathogenic variant [Roberts et al 2007, Tartaglia et al 2007].
9\.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
10\.
Aoki et al [2016]
11\.
Luo et al [2012]
12\.
Sana et al [2014]
13\.
Schubbert et al [2006], Brasil et al [2010]
14\.
De Filippi et al [2009], Cirstea et al [2010], Runtuwene et al [2011], Denayer et al [2012], Kraoua et al [2012], Ekvall et al [2015]
15\.
Sarkozy et al [2009]
16\.
Nava et al [2007]
17\.
Yamamoto et al [2015], Johnston et al [2018], Jacquinet et al [2019], Nakaguma et al [2019], Pagnamenta et al [2019], Perin et al [2019], Umeki et al [2019]
18\.
Recent reports have implicated several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each including RRAS (2 probands) [Flex et al 2014], RASA2 (3 probands) [Chen et al 2014b], A2ML1 (3 probands) [Vissers et al 2015], SOS2 (8 probands) [Cordeddu et al 2015, Yamamoto et al 2015], and MRAS (5 probands) [Higgins et al 2017, Motta et al 2019, Suzuki et al 2019].
## Clinical Characteristics
### Clinical Description
Prenatal features. Advanced paternal age has been observed in cohorts with simplex NS [Tartaglia et al 2004a]. Common perinatal findings include: polyhydramnios; lymphatic dysplasia including increased nuchal translucency and cystic hygroma; relative macrocephaly; and cardiac and renal anomalies [Myers et al 2014]. In chromosomally normal fetuses with increased nuchal translucency, it is estimated that 5%-15% have PTPN11-associated NS [Bakker et al 2014].
Growth. Birth weight is usually normal, although edema may cause a transient increase. Infants with NS frequently have feeding difficulties. This period of failure to thrive is self-limited, although poor weight gain may persist for up to 18 months.
Length at birth is usually normal. Postnatal growth failure is often obvious from the first year of life [Otten & Noordam 2009]. Mean height then follows the third centile from ages two to four years until puberty, when below-average growth velocity and an attenuated adolescent growth spurt tend to occur. As bone maturity is usually delayed, prolonged growth into the 20s is possible.
Final adult height approaches the lower limit of normal: 161-167 cm in males and 150-155 cm in females. Growth curves have been developed from these cross-sectional retrospective data. One study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [Noonan et al 2003].
Decreased IGF-I- and IGF-binding protein 3, together with low responses to provocation, suggest impaired growth hormone release, or disturbance of the growth hormone / insulin-like growth factor I axis, in many affected persons. Mild growth hormone resistance related to a post-receptor signaling defect, which may be partially compensated for by elevated growth hormone secretion, is reported in individuals with NS and a PTPN11 pathogenic variant [Binder et al 2005]. See Management for discussion of growth hormone (GH) treatment.
Cardiovascular. Significant bias in the frequency of congenital heart disease may exist because many clinicians have in the past required the presence of cardiac anomalies for diagnosis of NS. The frequency of congenital heart disease is estimated at between 50% and 80%.
* Pulmonary valve stenosis, often with dysplasia, is the most common anomaly in NS, found in 20%-50% of affected individuals; it may be isolated or associated with other cardiovascular defects.
* Hypertrophic cardiomyopathy is found in 20% to 30% of individuals with NS. It usually presents early in life: the median age at diagnosis is five months and more than 50% of individuals with NS and hypertrophic cardiomyopathy are diagnosed by age six months [Hickey et al 2011, Wilkinson et al 2012].
* Other structural defects frequently observed include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Coarctation of the aorta is more common than previously thought [Noonan 2005b].
* An electrocardiographic abnormality is documented in approximately 90% of individuals with NS and may be present without concomitant structural defects. Extreme right axis deviation with superior counterclockwise frontal QRS loop, superior or left axis deviation, or left anterior hemiblock or an RSR' pattern in lead V1 are common findings [Sharland et al 1992].
Psychomotor development. Early developmental milestones may be delayed, likely in part as a result of the combination of joint hyperextensibility and hypotonia. The average age for sitting unsupported is around ten months and for walking is 21 months [Sharland et al 1992]. About 50% of school-age children meet diagnostic criteria for a developmental coordination disorder [Lee et al 2005a] and impaired manual dexterity is significantly correlated with verbal and nonverbal intellectual functioning [Pierpont et al 2009].
Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [Lee et al 2005a] and 10%-15% require special education [van der Burgt et al 1999]. Intellectual abilities are, in general, mildly lowered in children with NS. IQ scores below 70 are seen in 6%-23% across studies [van der Burgt et al 1999, Pierpont et al 2015]. Studies conflict with regard to strength in verbal vs nonverbal performance and no clear pattern has emerged [Lee et al 2005a, Pierpont et al 2009]. There may be a specific cognitive disability, either in verbal or praxic reasoning, requiring a special academic strategy and school placement.
Articulation deficiency is common (72%) but usually responds well to speech therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies. The average age at first words is around 15 months and simple two-word phrases emerge on average from age 31 to 32 months [Pierpont et al 2010a].
A study of the language phenotype of children and adults with NS showed that language impairments in general are more common in NS than in the general population and, when present, are associated with a higher risk for reading and spelling difficulties [Pierpont et al 2010b]. Language is significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonologic memory. No specific aspect of language was selectively affected in those with NS.
There is emerging evidence that attention and executive functioning are one of the most common neuropsychological challenges for children with NS [Pierpont et al 2015]. Studies that rely on screening measures rather than comprehensive diagnostic assessments suggest that children with NS are at heightened risk for autism spectrum disorders; however, further research is needed [Pierpont 2016].
Psychological health. Few details of psychological health in Noonan syndrome are reported. No particular syndrome of behavioral disability or psychopathology is observed, and self-esteem is comparable to age-related peers [Lee et al 2005a]. Noonan [2005a] has documented problems in a cohort of 51 adults: depression was found in 23%, and occasional substance abuse and bipolar disease was reported. Similar findings were not reported in a large UK cohort followed over many years [Shaw et al 2007].
Detailed psychological assessment of a group of 11 affected individuals identified anxiety, panic attacks, social introversion, impoverished self-awareness, and marked difficulties in identifying and expressing feelings and emotions (alexithymia) [Verhoeven et al 2008]. This same research team suggests that in adulthood mild problems in attention, organizational skills, psychosocial immaturity, and alexithymia may be found, and thus assessment of social cognition and personality may be appropriate [Wingbermuehle et al 2009]. In one study of adults with NS, 49% reported that they had been diagnosed and treated for depression and/or anxiety [Smpokou et al 2012].
Genitourinary. Renal abnormalities, generally mild, are present in 11% of individuals with NS. Dilatation of the renal pelvis is most common. Duplex collecting systems, minor rotational anomalies, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, unilateral renal ectopia, and bilateral cysts with scarring are reported less commonly.
Male pubertal development and subsequent fertility may be normal, delayed, or inadequate. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60% to 80% of males; however, a study of male gonadal function identified Sertoli cell dysfunction in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotropic hypogonadism [Marcus et al 2008].
Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years. Normal fertility is the rule.
Facial features. Differences in facial appearance, albeit subtle at certain ages, are a key clinical feature:
* In the neonate, tall forehead, hypertelorism with downslanting palpebral fissures, low-set, posteriorly rotated ears with a thickened helix, a deeply grooved philtrum with high, wide peaks to the vermilion border of the upper lip, and a short neck with excess nuchal skin and low posterior hairline are found.
* In infancy, eyes are prominent, with horizontal palpebral fissures, hypertelorism, and full or ptotic upper eyelids. The nose has a depressed root, wide base, and bulbous tip.
* In childhood, facial appearance is often lacking in affect or expression, as in an individual with a myopathy.
* By adolescence, facial shape is an inverted triangle, wide at the forehead and tapering to a pointed chin. Eyes are less prominent and features are sharper. The neck lengthens, accentuating skin webbing or prominence of the trapezius muscle.
* In the older adult, nasolabial folds are prominent, and the skin appears transparent and wrinkled.
Bleeding diathesis. Most persons with NS have a history of abnormal bleeding or bruising. Early studies reported that about one third of all individuals with NS have one or more coagulation defects with subsequent studies suggesting a lower rate of coagulopathy [Derbent et al 2010]. The coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences. A variety of small studies have shown that while 50%-89% of those with NS have either a history of bleeding and/or abnormal hemostatic lab results, only 10%-42% have both [reviewed in Briggs & Dickerman 2012].
Lymphatic. Varied lymphatic abnormalities are described in individuals with NS. They may be localized or widespread, prenatal, and/or postnatal. Dorsal limb (top of the foot and back of the hand) lymphedema is most common. Less common findings include: intestinal, pulmonary, or testicular lymphangiectasia; chylous effusions of the pleural space and/or peritoneum; and localized lymphedema of the scrotum or vulva.
Prenatal features suggestive of Noonan syndrome, likely of a lymphatic nature, include: transient or persistent cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis [Gandhi et al 2004, Yoshida et al 2004b, Joó et al 2005].
Ocular. Ocular abnormalities including strabismus, refractive errors, amblyopia, and nystagmus occur in up to 95% of affected individuals. Anterior segment and fundus changes are less common. There are case reports of keratoconus and axenfeld anomaly [Lee & Sakhalkar 2014, Guerin et al 2015].
Dermatologic. Skin differences, particularly follicular keratosis over extensor surfaces and face, are relatively common and may occasionally be as severe as those found in cardiofaciocutaneous syndrome (see Differential Diagnosis).
Café au lait spots and lentigines are described in NS more frequently than in the general population (see Noonan syndrome with multiple lentigines discussion in Genetically Related Disorders).
Other
* Arnold-Chiari I malformation. Eleven cases of Arnold-Chiari malformation have been reported in the medical literature, although the true incidence in NS is not known [Keh et al 2013, Mitsuhara et al 2014, Zarate et al 2014, Ejarque et al 2015].
* Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.
* Juvenile myelomonocytic leukemia (JMML). Individuals with Noonan syndrome and a germline pathogenic variant in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course.
* Other malignancies. One study of individuals with Noonan syndrome caused by a pathogenic variant in PTPN11 supports a threefold increased risk of malignancy [Jongmans et al 2011].
* Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [Hasle 2009, Jongmans et al 2011].
* Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [Denayer et al 2010, Jongmans et al 2010]. Three embryonal rhabdomyosarcomas (ERMS) caused by a germline SOS1 pathogenic variant have been reported [Denayer et al 2010, Hastings et al 2010, Jongmans et al 2010]. One with obstructive jaundice involved the biliary ampulla/duodenum; one the bladder; and one the urachus. Three additional cases of ERMS and NS (of the orbit, vagina, and abdomen) were reported; genotype was not determined [Khan et al 1995, Jung et al 2003, Moschovi et al 2007].
* Overall risk of malignancy. Kratz et al reported on a cohort of 632 individuals with molecularly confirmed NS (inclusive of Noonan syndrome with multiple lentigines) and found four cases of JMML, two of brain tumor, two of ALL, and one neuroblastoma, and calculated a childhood cancer standardized incidence ratio of 8.1 [Kratz et al 2015]. Individuals with NS are at an eightfold greater risk of developing a childhood cancer than are those without NS.
* Myeloproliferative disorders, either transient or more fulminant, can also occur in infants with Noonan syndrome [Kratz et al 2005].
* Noonan-like / multiple giant-cell lesion syndrome. The giant-cell granulomas and bone and joint anomalies in Noonan-like / multiple giant-cell lesion syndrome are recognized to be part of the Noonan syndrome spectrum. They can resemble cherubism, an autosomal dominant disorder caused by pathogenic variants in SH3BP2 (see Cherubism), lesions observed in neurofibromatosis (see Neurofibromatosis Type 1), or lesions observed in the Ramon syndrome with juvenile rheumatoid arthritis (polyarticular pigmented villonodular synovitis).
Noonan-like / multiple giant-cell lesion syndrome is caused by pathogenic variants in PTPN11 [Jafarov et al 2005, Wolvius et al 2006] and SOS1 [Beneteau et al 2009, Neumann et al 2009]. One family with Noonan-like / multiple giant-cell lesion syndrome has a PTPN11 pathogenic variant reported in Noonan syndrome without giant cell lesions [Tartaglia et al 2002]; thus, additional genetic factors may be necessary for the giant cell proliferation to occur.
These multiple giant cell lesions are also recognized in persons with cardiofaciocutaneous syndrome caused by mutation of BRAF and MEK1 [Neumann et al 2009]. Thus dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant-cell lesion formation, arguing against the existence of Noonan-like / multiple giant-cell lesion syndrome as a separate entity.
### Genotype-Phenotype Correlations
PTPN11. Analysis of a large cohort of individuals with Noonan syndrome (NS) [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 pathogenic variants are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with NS caused by PTPN11 abnormalities.
Additional cohort analyses have linked PTPN11 pathogenic variants to short stature, pectus deformity, easy bruising, characteristic facial appearance [Yoshida et al 2004a, Zenker et al 2004], and cryptorchidism [Jongmans et al 2004]. In contradistinction, the study of Allanson et al [2010] failed to establish any facial phenotype-genotype correlation.
The presence or absence of a pathogenic variant in PTPN11 does not affect the likelihood of developmental delay, although individuals with the p.Asn308Asp pathogenic variant are said to be more likely to receive normal education [Jongmans et al 2004].
Germline pathogenic variants at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [Niihori et al 2005].
The post-receptor signaling defect causing mild growth hormone resistance in individuals with NS and a PTPN11 pathogenic variant [Binder et al 2005] leads to reduced efficacy of short-term growth hormone (GH) treatment in individuals with a PTPN11 pathogenic variant [Binder et al 2005, Ferreira et al 2005, Limal et al 2006]. However, careful review of height data reveals that individuals with a PTPN11 pathogenic variant presented with more severe short stature and, therefore, reached a lower final height despite a similar height gain [Noordam et al 2008].
An in-frame three-nucleotide PTPN11 deletion (p.Gly60del) in a female infant with severe features of Noonan syndrome, including hydrops fetalis and juvenile myelomonocytic leukemia [Yoshida et al 2004a], has been reported. The p.Asp61del three-nucleotide PTPN11 deletion has also been reported in a child with typical rather than severe NS [Lee et al 2005b].
SOS1. Tartaglia et al [2007] concluded that the phenotype in 22 individuals with NS who had an SOS1 pathogenic variant fell within the spectrum of NS, but emphasized the more frequent occurrence of ectodermal abnormalities and a greater likelihood of normal development and stature in these individuals compared to others with NS. In a companion paper, Roberts et al [2007] reported that 14 individuals with NS who had a SOS1 pathogenic variant did not differ in development and stature from other individuals with NS. Cardiac septal defects were found more frequently than in individuals with NS and pathogenic variants in PTPN11. The study did not make specific mention of ectodermal findings.
Pierpont et al [2009] have studied intellectual abilities in Noonan syndrome and report that individuals with SOS1 pathogenic variants generally have average or higher-level skills.
RAF1. Studies emphasize a striking correlation with hypertrophic cardiomyopathy, with 95% of affected individuals with a RAF1 pathogenic variant showing this feature, in comparison with the overall prevalence in NS of 18%. This suggests that pathologic cardiomyocyte hypertrophy occurs because of increased RAS signaling. Multiple nevi, lentigines, and/or café au lait spots were reported in one third of people with RAF1-associated NS.
KRAS. The phenotype associated with pathogenic variants in KRAS tends to be atypical, with greater likelihood and severity of intellectual disability [Zenker et al 2007] in these individuals than in others with NS. Kratz et al [2009] reported the somewhat unusual feature of craniosynostosis in two unrelated probands with NS and a pathogenic missense KRAS variant.
NRAS. Few individuals with an NRAS pathogenic variant have been reported. The clinical features appear to be typical with no particular or distinctive phenotype observed [Cirstea et al 2010].
BRAF, MAP2K1. The rare individuals with a pathogenic variant in BRAF or MAP2K1 also appear to have features of classic Noonan syndrome, albeit with florid ectodermal manifestations [Nava et al 2007, Nyström et al 2008, Sarkozy et al 2009].
RIT1. Compared to the prevalence of hypertrophic cardiomyopathy overall in NS (20%), there is an overrepresentation of HCM in individuals with a pathogenic variant in RIT1 (70%-75%) [Aoki et al 2013, Yaoita et al 2016]. Analysis of affected individuals also suggests a high prevalence of perinatal abnormalities, high birth weight, relative macrocephaly, curly hair, hyperpigmentation, and wrinkled palms and soles but lower prevalence of short stature, pectus deformity, or intellectual disability [Bertola et al 2014, Yaoita et al 2016].
LZTR1. Overall, the features reported in individuals with NS caused by either heterozygous or biallelic pathogenic variants in LZTR1 are those commonly seen in individuals with NS of other genetic causes, including typical facial features, pulmonary valve stenosis, hypertrophic cardiomyopathy, short stature, and developmental delay. A more in-depth evaluation of the phenotype of those with a heterozygous pathogenic variant or biallelic pathogenic variants in LZTR1 suggests increased prevalence of hypertrophic cardiomyopathy in those with biallelic pathogenic variants (19/26 with biallelic pathogenic variants vs 5/26 with a heterozygous pathogenic variant) [Pagnamenta et al 2019].
### Penetrance
Penetrance of NS is difficult to determine because of ascertainment bias and variable expressivity with frequent subtlety of features. Many affected adults are diagnosed only after the birth of a more obviously affected infant.
### Nomenclature
An early term for NS, "male Turner syndrome," incorrectly implied that the condition would not be found in females.
In 1949, Otto Ullrich reported affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term "Bonnevie-Ullrich syndrome" became popular, particularly in Europe.
### Prevalence
NS is common and reported to occur in between 1:1,000 and 1:2,500 persons. Mild expression is likely to be overlooked.
## Differential Diagnosis
Turner syndrome, found only in females, is differentiated from Noonan syndrome (NS) by demonstration of a sex chromosome abnormality on cytogenetic studies in individuals with Turner syndrome. The phenotype of Turner syndrome is actually quite different from that of NS, when one considers face, heart, development, and kidneys. In Turner syndrome, renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.
Like NS, Watson syndrome (OMIM 193520) is characterized by short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes (e.g., café au lait patches). The Watson syndrome phenotype also overlaps with that of neurofibromatosis 1; the two are now known to be allelic [Allanson et al 1991].
Cardiofaciocutaneous (CFC) syndrome and NS have the greatest overlap in features. CFC syndrome has similar cardiac and lymphatic findings [Noonan 2001, Armour & Allanson 2008]. In CFC syndrome, intellectual disability is usually more severe, with a higher likelihood of structural central nervous system anomalies; skin pathology is more florid; gastrointestinal problems are more severe and long lasting; and bleeding diathesis is rare. Facial appearance tends to be coarser, dolichocephaly and absent eyebrows are more frequently seen, and blue eyes are less commonly seen. To date, the four genes in which mutation is known to cause CFC syndrome are BRAF (~75%), MAP2K1 and MAP2K2 (~25%), and KRAS (<2%-3%). Rarely, individuals have a pathogenic variant in a gene usually associated with Noonan syndrome [Narumi et al 2008, Nyström et al 2008].
Costello syndrome shares features with both NS and CFC [Hennekam 2003, Gripp et al 2006, Kerr et al 2006]. Many individuals with Costello syndrome have been studied molecularly; no PTPN11 pathogenic variant has been identified [Tartaglia et al 2003a, Tröger et al 2003]. Germline pathogenic variants occurring most commonly in exon 2 of the HRAS proto-oncogene have been shown to cause Costello syndrome [Aoki et al 2005].
Noonan syndrome-like disorder with loose anagen hair (OMIM 607721). Germline pathogenic variants in SHOC2 usually lead to a phenotype of Noonan-like features; a small proportion of those affected have the classic Noonan syndrome phenotype [Kerr, personal experience]. The recurrent pathogenic missense SHOC2 variant, 4A>G, has been found in a subgroup with features of NS but also growth hormone deficiency; distinctive hyperactive behavior that improves with age in most; hair anomalies including easily pluckable, sparse, thin slow-growing hair (loose anagen hair); darkly pigmented skin with eczema or ichthyosis; hypernasal voice; and an overrepresentation of mitral valve dysplasia and septal defects in comparison with classic NS [Cordeddu et al 2009]. Sequence analysis of all exons detects a pathogenic variant in about 5% of individuals with Noonan syndrome. Most have the classic loose anagen hair [Cordeddu et al 2009].
Noonan syndrome-like disorder with or without JMML (OMIM 613563). Germline pathogenic variants in CBL cause a variable phenotype characterized by a relatively high frequency of neurologic features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism [Martinelli et al 2010, Niemeyer et al 2010, Martinelli et al 2015].
Due to the significant phenotypic overlap with classic NS, most RASopathy diagnostic gene panels include testing for the common SHOC2 variant and CBL gene sequencing.
Other. NS should be distinguished from other syndromes/conditions with developmental delay, short stature, congenital heart defects, and distinctive facies, especially the following:
* Williams syndrome
* Aarskog syndrome (OMIM 100050)
* In utero exposure to alcohol or primidone
Neurofibromatosis 1 (NF1) shares some features with NS, including short stature, learning difficulties, and café au lait patches. Infrequently, affected individuals also have a NS-like facial appearance. This could be caused by chance concurrence of NS and NF1 [Colley et al 1996, Bertola et al 2005]. However, most often it appears to be a NS-like facial appearance in an individual with a pathogenic variant in NF1, sometimes in the presence of a variant NF1 phenotype [Stevenson et al 2006, Nyström et al 2009].
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Noonan syndrome (NS), the following evaluations are recommended:
* Complete physical and neurologic examination
* Plotting of growth parameters on NS growth charts
* Cardiac evaluation with echocardiography and electrocardiography
* Ophthalmologic evaluation
* Hearing evaluation
* Coagulation screen to include CBC with differential, PT/PTT (repeat after 12 months if age <12 months at the time of first screening [Romano et al 2010, Roberts et al 2013]
* Renal ultrasound examination; urinalysis if the urinary tract is anomalous
* Clinical and radiographic assessment of spine and rib cage
* Brain and cervical spine MRI if neurologic symptoms are present
* Multidisciplinary developmental evaluation
* Consultation with a clinical geneticist and/or genetic counselor
### Treatment of Manifestations
Treatment of the complications of Noonan syndrome is generally standard and does not differ from treatment in the general population.
Management guidelines have been developed by Dyscerne, a European consortium [Noonan Syndrome Guideline Development Group 2010] (full text); a separate set has been published by an American consortium working with the Noonan Syndrome Support Group [Romano et al 2010] and in the Lancet [Roberts et al 2013].
Treatment of cardiovascular anomalies is generally the same as in the general population. Pulmonary valve stenosis treated with percutaneous balloon pulmonary valvuloplasty has a higher reintervention rate vs pulmonary valve stenosis without NS [Prendiville et al 2014]. There is substantial early mortality associated with hypertrophic cardiomyopathy; infants presenting before age six months in congestive heart failure have the worst prognosis (2-year survival of 30%) [Hickey et al 2011, Wilkinson et al 2012].
Developmental disabilities should be addressed by early intervention programs and individualized education strategies.
The bleeding diathesis in Noonan syndrome can have a variety of causes. Specific treatment for serious bleeding may be guided by knowledge of a factor deficiency or platelet aggregation anomaly. Factor VIIa has been successfully used to control bleeding caused by hemophilia, von Willebrand disease, thrombocytopenia, and thrombasthenia. It has also been used in an infant with Noonan syndrome whose platelet count and prothrombin and partial thromboplastin times were normal, to control severe postoperative blood loss resulting from gastritis [Tofil et al 2005].
Studies of growth hormone (GH) treatment have been published from the UK, Japan [Ogawa et al 2004], the Netherlands [Noordam 2007, Noordam et al 2008], Sweden [Osio et al 2005], and the United States [Romano et al 2009].
* The rationale for GH treatment of individuals with Noonan syndrome includes:
* Significant short stature compared with normal peers;
* Possible impairment of the GH-insulin-like-growth-factor type I (GH-IGF-I) axis; and
* Documented response to GH treatment in studies.
* In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal.
* No standard dose has been established; no correlation between dosage used and final height is apparent.
* Short stature due to Noonan syndrome is an FDA-approved indication for growth hormone treatment.
Short- and long-term studies have demonstrated a consistent and significant increase in height velocity in children with Noonan syndrome who have been treated [Osio et al 2005, Noordam et al 2008, Romano et al 2009].
The increase in height SD varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [Osio et al 2005, Noordam et al 2008, Dahlgren 2009].
Subsequent studies have shown that children with prepubertal NS growth hormone deficiency have been shown to increase their growth rate with growth hormone therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic growth hormone deficiency [Lee et al 2015, Zavras et al 2015].
### Surveillance
If anomalies are found in any system (see Evaluations Following Initial Diagnosis), periodic follow up should be planned and lifelong monitoring may be necessary; for example, periodic eye examination if a refraction error or strabismus is found, urinalysis if there are structural abnormalities of the collecting system. Despite the apparent increased incidence of hematologic and solid tumor malignancies, no surveillance strategies have been evaluated or recommended.
### Agents/Circumstances to Avoid
Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis.
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
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| Noonan Syndrome | c0028326 | 2,479 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1124/ | 2021-01-18T21:07:32 | {"mesh": ["D009634"], "synonyms": []} |
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Ileitis
SpecialtyGastroenterology
Ileitis is an inflammation of the ileum, a portion of the small intestine. Crohn's ileitis is a type of Crohn's disease affecting the ileum. Ileitis is caused by the bacterium Lawsonia intracellularis. Inflammatory bowel disease does not associate with Lawsonia intracellularis infection.
## References[edit]
## External links[edit]
Classification
D
* ICD-10: K50.0 \- K52.9
* MeSH: D007079
* SNOMED CT: 52457000
* v
* t
* e
Diseases of the digestive system
Upper GI tract
Esophagus
* Esophagitis
* Candidal
* Eosinophilic
* Herpetiform
* Rupture
* Boerhaave syndrome
* Mallory–Weiss syndrome
* UES
* Zenker's diverticulum
* LES
* Barrett's esophagus
* Esophageal motility disorder
* Nutcracker esophagus
* Achalasia
* Diffuse esophageal spasm
* Gastroesophageal reflux disease (GERD)
* Laryngopharyngeal reflux (LPR)
* Esophageal stricture
* Megaesophagus
* Esophageal intramural pseudodiverticulosis
Stomach
* Gastritis
* Atrophic
* Ménétrier's disease
* Gastroenteritis
* Peptic (gastric) ulcer
* Cushing ulcer
* Dieulafoy's lesion
* Dyspepsia
* Pyloric stenosis
* Achlorhydria
* Gastroparesis
* Gastroptosis
* Portal hypertensive gastropathy
* Gastric antral vascular ectasia
* Gastric dumping syndrome
* Gastric volvulus
* Buried bumper syndrome
* Gastrinoma
* Zollinger–Ellison syndrome
Lower GI tract
Enteropathy
Small intestine
(Duodenum/Jejunum/Ileum)
* Enteritis
* Duodenitis
* Jejunitis
* Ileitis
* Peptic (duodenal) ulcer
* Curling's ulcer
* Malabsorption: Coeliac
* Tropical sprue
* Blind loop syndrome
* Small bowel bacterial overgrowth syndrome
* Whipple's
* Short bowel syndrome
* Steatorrhea
* Milroy disease
* Bile acid malabsorption
Large intestine
(Appendix/Colon)
* Appendicitis
* Colitis
* Pseudomembranous
* Ulcerative
* Ischemic
* Microscopic
* Collagenous
* Lymphocytic
* Functional colonic disease
* IBS
* Intestinal pseudoobstruction / Ogilvie syndrome
* Megacolon / Toxic megacolon
* Diverticulitis/Diverticulosis/SCAD
Large and/or small
* Enterocolitis
* Necrotizing
* Gastroenterocolitis
* IBD
* Crohn's disease
* Vascular: Abdominal angina
* Mesenteric ischemia
* Angiodysplasia
* Bowel obstruction: Ileus
* Intussusception
* Volvulus
* Fecal impaction
* Constipation
* Diarrhea
* Infectious
* Intestinal adhesions
Rectum
* Proctitis
* Radiation proctitis
* Proctalgia fugax
* Rectal prolapse
* Anismus
Anal canal
* Anal fissure/Anal fistula
* Anal abscess
* Hemorrhoid
* Anal dysplasia
* Pruritus ani
GI bleeding
* Blood in stool
* Upper
* Hematemesis
* Melena
* Lower
* Hematochezia
Accessory
Liver
* Hepatitis
* Viral hepatitis
* Autoimmune hepatitis
* Alcoholic hepatitis
* Cirrhosis
* PBC
* Fatty liver
* NASH
* Vascular
* Budd–Chiari syndrome
* Hepatic veno-occlusive disease
* Portal hypertension
* Nutmeg liver
* Alcoholic liver disease
* Liver failure
* Hepatic encephalopathy
* Acute liver failure
* Liver abscess
* Pyogenic
* Amoebic
* Hepatorenal syndrome
* Peliosis hepatis
* Metabolic disorders
* Wilson's disease
* Hemochromatosis
Gallbladder
* Cholecystitis
* Gallstone / Cholelithiasis
* Cholesterolosis
* Adenomyomatosis
* Postcholecystectomy syndrome
* Porcelain gallbladder
Bile duct/
Other biliary tree
* Cholangitis
* Primary sclerosing cholangitis
* Secondary sclerosing cholangitis
* Ascending
* Cholestasis/Mirizzi's syndrome
* Biliary fistula
* Haemobilia
* Common bile duct
* Choledocholithiasis
* Biliary dyskinesia
* Sphincter of Oddi dysfunction
Pancreatic
* Pancreatitis
* Acute
* Chronic
* Hereditary
* Pancreatic abscess
* Pancreatic pseudocyst
* Exocrine pancreatic insufficiency
* Pancreatic fistula
Other
Hernia
* Diaphragmatic
* Congenital
* Hiatus
* Inguinal
* Indirect
* Direct
* Umbilical
* Femoral
* Obturator
* Spigelian
* Lumbar
* Petit's
* Grynfeltt-Lesshaft
* Undefined location
* Incisional
* Internal hernia
* Richter's
Peritoneal
* Peritonitis
* Spontaneous bacterial peritonitis
* Hemoperitoneum
* Pneumoperitoneum
This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it.
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*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
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| Ileitis | c0020877 | 2,480 | wikipedia | https://en.wikipedia.org/wiki/Ileitis | 2021-01-18T18:31:34 | {"mesh": ["D007079"], "umls": ["C0020877"], "wikidata": ["Q3796380"]} |
A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-14 (CMS14) is caused by homozygous mutation in the ALG2 gene (607905) on chromosome 9q22.
Description
Congenital myasthenic syndrome-14 is an autosomal recessive neuromuscular disorder characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. There is no respiratory or cardiac involvement. Treatment with anticholinesterase medication may be beneficial (summary by Cossins et al., 2013).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
Clinical Features
Cossins et al. (2013) reported 4 sibs, born of consanguineous Saudi Arabian parents, with onset of a slowly progressive muscle disorder within the first 2 years of life. The patients showed delayed motor milestones, hypotonia, and absent reflexes. The 3 older patients had progressive deterioration and became wheelchair-bound in the second decade; the youngest had not achieved ambulation. There was proximal greater than distal muscle weakness and mild facial weakness, but no ophthalmoplegia. All patients had pes planus and high-arched palate, and the 3 older sibs showed knee contractures and distal joint laxity. Mild learning difficulty was also apparent. Electrophysiologic studies of 2 patients showed decremental compound muscle action potentials (CMAP) in response to repetitive nerve stimulation, consistent with myasthenia, and increased jitter. Muscle biopsy of 1 patient showed variation in fiber size with type 1 fiber predominance. An unrelated man, born of consanguineous Italian parents, developed progressive proximal muscle weakness at age 4 years. He was diagnosed with myasthenia in his teens and showed favorable response to pyridostigmine. At age 60 years, he had limited walking ability with a waddling gait, lumbar lordosis, scapular winging, and Gowers sign; facial and neck muscles were strong and there was no ptosis.
Monies et al. (2014) reported 3 young adult patients from an extended consanguineous Saudi Arabian family with a form of congenital limb-girdle myopathy. All had onset of progressive proximal muscle weakness between 2 and 4 years of age after learning how to walk independently, although 1 had delayed motor development and hypotonia. Two patients became wheelchair-bound in their teens, whereas the third was still ambulatory at age 33 years. Both upper and lower limbs were affected, with proximal weakness greater than distal weakness. Other features included lordosis and scoliosis, but there were no bulbar symptoms or respiratory insufficiency. Electrophysiologic studies showed a decrement of the CMAP on repetitive nerve stimulation. Muscle biopsies performed on 2 patients showed myopathic features with type 1 fiber predominance, ragged-red fibers, and subsarcolemmal accumulation of normal mitochondria. These findings supported a mitochondrial myopathy combined with a neuromuscular junction disorder. Laboratory studies showed mildly increased serum creatine kinase in 1 patient and marginally increased carbohydrate-deficient transferrin (190000) in 1 patient.
Inheritance
The transmission pattern of CMS14 in the families reported by Cossins et al. (2013) and Monies et al. (2014) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 4 sibs, born of consanguineous Saudi Arabian parents, with CMS14, Cossins et al. (2013) identified a homozygous ins/del mutation in the ALG2 gene (607905.0003). The mutation was found by a combination of linkage analysis and whole-exome sequencing. An unrelated patient of Italian descent was homozygous for a different mutation in the ALG2 gene (V68G; 607905.0004). Although ALG2 is involved in glycosylation, transferrin glycosylation was not abnormal in the patients, suggesting that the mutations resulted in only a modest impairment of N-linked glycosylation.
In 3 patients from a large consanguineous Saudi Arabian Bedouin family with limb-girdle myasthenia, Monies et al. (2014) identified the same homozygous ins/del mutation in exon 1 of the ALG2 gene as that found by Cossins et al. (2013). Both families originated from the same small village, suggestive of a founder mutation.
INHERITANCE \- Autosomal recessive HEAD & NECK Mouth \- High-arched palate (in some patients) CHEST Ribs Sternum Clavicles & Scapulae \- Scapular winging (in some patients) SKELETAL \- Joint contractures (in some patients) \- Distal joint laxity (in some patients) Spine \- Lordosis (in some patients) \- Scoliosis (in some patients) Feet \- Pes planus (in some patients) MUSCLE, SOFT TISSUES \- Myasthenia \- Limb-girdle muscle weakness \- Muscle weakness, proximal greater than distal \- Gower sign \- Lower and upper limbs affected \- Hypotonia (in some patients) \- Decremental response of compound muscle action potential on repetitive nerve stimulation \- Jitter \- Muscle biopsy shows type 1 fiber predominance \- Ragged-red fibers (in some patients) \- Subsarcolemmal accumulation of normal mitochondria (in some patients) \- Tubular aggregates (in some patients) NEUROLOGIC Central Nervous System \- Delayed motor development (in some patients) \- Waddling gait \- Learning difficulties, mild (1 family) LABORATORY ABNORMALITIES \- Mildly increased serum creatine kinase (in some patients) \- Serum transferrin shows normal or mild hypo-glycosylation MISCELLANEOUS \- Onset in first decade \- Slowly progressive \- Some patients may become wheelchair-bound \- Favorable response to anticholinesterase medication \- Three unrelated families have been reported (last curated February 2015) MOLECULAR BASIS \- Cause by mutation in the homolog of the S. cerevisiae ALG2 gene (ALG2, 607905.0003 ) ▲ Close
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| MYASTHENIC SYNDROME, CONGENITAL, 14 | c0751882 | 2,481 | omim | https://www.omim.org/entry/616228 | 2019-09-22T15:49:30 | {"doid": ["0110669"], "mesh": ["D020294"], "omim": ["616228"], "orphanet": ["353327", "590"], "synonyms": ["Alternative titles", "MYASTHENIC SYNDROME, CONGENITAL, WITH TUBULAR AGGREGATES 3"], "genereviews": ["NBK1168"]} |
Loss of visual acuity associated with illness or aging
Acute visual loss
Other namesAcute vision loss
A Snellen chart, which is frequently used for visual acuity testing
Acute visual loss is a rapid loss of the ability to see. It is caused by many ocular conditions like retinal detachment, glaucoma, macular degeneration, and giant cell arteritis, etc.
Play media
Video explanation (script)[1]
## Contents
* 1 Main causes
* 1.1 Retinal detachment
* 1.2 Glaucoma
* 1.3 Macular degeneration
* 1.4 Giant cell arteritis
* 1.5 Vascular occlusions
* 1.6 Vitreous hemorrhage
* 1.7 Hyphema
* 2 References
## Main causes[edit]
### Retinal detachment[edit]
Main article: Retinal detachment
Retinal detachment should be considered if there were preceding flashes or floaters, or if there is a new visual field defect in one eye.[2][3] If treated early enough, retinal tear and detachment can have a good outcome.[2]
### Glaucoma[edit]
Main article: Glaucoma
Angle-closure glaucoma should be considered if there is painful loss of vision with a red eye, nausea or vomiting.[4] The eye pressure will be very high typically greater than 40 mmHg.[5] Emergent laser treatment to the iris may prevent blindness.[4]
### Macular degeneration[edit]
Main article: Macular degeneration
Wet macular degeneration should be considered in older people with new distortion of their vision with bleeding in the macula.[6][7] Vision can often be regained with prompt eye injections with anti-VEGF agents.[6]
### Giant cell arteritis[edit]
Main article: Giant-cell arteritis
Giant cell arteritis should be considered in an older person with jaw claudication, temporal pain, and tiredness.[8] Placing the person on steroids might save both their vision and decrease their risk of stroke.[9] Without treatment a person can quickly go blind in both eyes.[10]
### Vascular occlusions[edit]
* Central retinal artery occlusion: CRAO is characterized by painless, acute vision loss in one eye.[11]
* Central retinal vein occlusion: CRVO causes sudden, painless vision loss that can be mild to severe. [12]
* Branch retinal vein occlusion: sudden painless vision loss or visual field defect are the main symptom of BRVO. [13]
* Branch retinal artery occlusion: BRAO may also cause acute painless loss of vision. [14]
### Vitreous hemorrhage[edit]
Main article: Vitreous hemorrhage
It is one of the most common causes of acute or subacute decrease in vision. [15]
### Hyphema[edit]
Main article: Hyphema
Blood in the anterior chamber of the eye is known as hyphema. Severe hyphema covering pupillary area can cause sudden decrease in vision.
## References[edit]
1. ^ "Acute Visual Loss - MEDSKL". medskl.com. Retrieved 23 January 2019. (Video's script with inline references)
2. ^ a b Fraser, S; Steel, D (24 November 2010). "Retinal detachment". BMJ Clinical Evidence. 2010. PMC 3275330. PMID 21406128.
3. ^ "Facts About Retinal Detachment". National Eye Institute. October 2009. Archived from the original on 28 July 2016. Retrieved 26 July 2016.
4. ^ a b "Facts About Glaucoma". National Eye Institute. Archived from the original on 28 March 2016. Retrieved 29 March 2016.
5. ^ Simcock, Peter; Burger, Andre (2015). Fast Facts: Ophthalmology. Karger Medical and Scientific Publishers. p. 25. ISBN 9781908541727.
6. ^ a b "Facts About Age-Related Macular Degeneration". National Eye Institute. June 2015. Archived from the original on 22 December 2015. Retrieved 21 December 2015.
7. ^ Brown, Thomas Andrew; Shah, Sonali J. (2013). USMLE Step 1 Secrets3: USMLE Step 1 Secrets. Elsevier Health Sciences. p. 576. ISBN 978-0323085144.
8. ^ "Giant Cell Arteritis". National Institute of Arthritis and Musculoskeletal and Skin Diseases. 13 April 2017. Archived from the original on 22 October 2017. Retrieved 21 October 2017.
9. ^ "Giant Cell Arteritis". National Institute of Arthritis and Musculoskeletal and Skin Diseases. 13 April 2017. Retrieved 19 October 2018.
10. ^ Solomon, Caren G.; Weyand, Cornelia M.; Goronzy, Jörg J. (2014). "Giant-Cell Arteritis and Polymyalgia Rheumatica". New England Journal of Medicine. 371 (1): 50–7. doi:10.1056/NEJMcp1214825. PMC 4277693. PMID 24988557.
11. ^ Varma DD, Cugati S, Lee AW, Chen CS (June 2013). "A review of central retinal artery occlusion: clinical presentation and management". Eye. 27 (6): 688–97. doi:10.1038/eye.2013.25. PMC 3682348. PMID 23470793.
12. ^ "Eye Strokes: CRAO, BRVO And Other Retinal Artery And Vein Occlusions".
13. ^ Musa Abdelaziz, MD, Mahdi Rostamizadeh, Baseer Ahmad, MD. "Branch retinal vein occlusion".CS1 maint: multiple names: authors list (link)
14. ^ Matthew Santos, Robert H. Janigian, Jr. M.D. "Branch retinal artery occlusion".CS1 maint: multiple names: authors list (link)
15. ^ John P. Berdahl, MD, and Prithvi Mruthyunjaya, MD. "Vitreous Hemorrhage: Diagnosis and Treatment".CS1 maint: multiple names: authors list (link)
* 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
| Acute visual loss | c0155002 | 2,482 | wikipedia | https://en.wikipedia.org/wiki/Acute_visual_loss | 2021-01-18T18:29:26 | {"umls": ["C0155002"], "wikidata": ["Q11789224"]} |
A number sign (#) is used with this entry because of evidence that short-rib thoracic dysplasia-11 with or without polydactyly (SRTD11) is caused by homozygous or compound heterozygous mutation in the WDR34 gene (613363) on chromosome 9q34.
Description
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013).
There is phenotypic overlap with the cranioectodermal dysplasias (see CED1, 218330).
For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
Clinical Features
Tuysuz et al. (2009) reported 13 patients with a clinical diagnosis of Jeune syndrome from 11 families and emphasized the phenotypic variability of the disorder, particularly regarding prognosis. The diagnosis was established in the prenatal period in 4 patients, infancy in 6 patients, and childhood in 3 patients. Two affected fetuses were terminated. The living patients all had small thorax deformity, classified as bell-shaped or long narrow, varying degrees of mesomelic shortness, and mild to severe brachydactyly. Tuysuz et al. (2009) classified them into 3 groups according to clinical features: 7 with severe pulmonary involvement; 1 with renal failure; and 2 with a milder form of the disorder. The degree of respiratory distress varied from negligible to fatal and improved with age. Short stature was sometimes present at birth but also developed in the postnatal period. Patients with severe pulmonary involvement had a bell-shaped thorax and mild brachydactyly; the patient with renal involvement had a long narrow thorax and severe brachydactyly, whereas those with mild involvement presented with polydactyly and moderate to severe brachydactyly. Important radiologic findings included metaphyseal widening and trident appearance of the acetabular margin, which improved with age in 2 older patients. Other radiologic features included high handlebar clavicles, shortness of the metacarpals and second and distal phalanges, and hypoplastic ileum. In the follow-up period, 8 had respiratory distress, which was lethal in 6 before age 2 years, and 1 died of chronic renal failure at age 13. None had ocular involvement, ectodermal dysplasia, or cardiac or urogenital anomalies.
Huber et al. (2013) studied a consanguineous Algerian family in which 3 sibs had short-rib thoracic dysplasia. The proband was diagnosed with SRPS type III, or severe ATD, by ultrasound at 23 weeks of gestation due to the findings of micromelia, curved femurs, and short thorax. The proband died on day 7 of life from respiratory insufficiency, and abnormal skeletal findings were confirmed by postnatal radiographs that showed long narrow thorax with short ribs, shortened tubular bones, round metaphyseal ends with lateral spike, and trident appearance of the acetabular roof. The second case was a suspected recurrence and the pregnancy was terminated at 26 weeks of gestation. The third case was diagnosed at 20 weeks of gestation and was stillborn at 42 weeks of gestation.
Mapping
In a consanguineous Algerian family in which 3 sibs had short-rib thoracic dysplasia, Huber et al. (2013) performed genomewide homozygosity mapping and identified a single region of homozygosity shared by the 3 sibs on chromosome 9, obtaining a lod score of 2.4 (theta = 0) between markers D9S1819 and D9S1847. Analysis of SNP genotypes narrowed the critical region to a 3.6-Mb interval bounded by rs2798429 and rs10114591 at 9q34.11.
Molecular Genetics
In 3 affected individuals from a consanguineous Algerian family with short-rib thoracic dysplasia mapping to chromosome 9q34.11, in whom mutation in the IFT80 (611177) and DYNC2H1 (603297) genes had been excluded, Huber et al. (2013) identified homozygosity for a missense mutation in the candidate gene WDR34 (613363.0001). Whole-exome analysis in 1 of the affected individuals confirmed that the WDR34 variant was the only homozygous variant in the chromosome 9 region. Sequencing of WDR34 combined with whole-exome analysis in 30 independent patients with short-rib thoracic dysplasia in the ATD/SRPS III phenotype spectrum revealed another 2 patients with homozygous missense mutations in WDR34 (613363.0002; 613363.0003) and 1 who was compound heterozygous for a missense mutation (613363.0004) and a splice site mutation (613363.0005). The mutations cosegregated with disease in each family and were not found in controls. Only 1 of the 6 patients with WDR34 mutations exhibited polydactyly; there were no visceral anomalies apart from hypotrophic lungs in 1 patient, and none had cleft lip/palate.
Schmidts et al. (2013) performed whole-exome sequencing in 61 unrelated individuals diagnosed with Jeune syndrome based on classic clinical and radiologic findings, primarily short ribs with a small or narrow thorax and small ilia with acetabular spurs. Biallelic mutations in the WDR34 gene (see, e.g., 613363.0003 and 613363.0006-613363.0007) were identified in 6 of the probands, 1 of whom had previously been reported by Tuysuz et al. (2009). Screening of 52 more patients with a clinical diagnosis of Jeune/ATD revealed 4 patients from 3 families with biallelic variants in WDR34 (see, e.g., 613363.0008-613363.0009). Schmidts et al. (2013) stated that because most patients did not survive beyond the neonatal period due to a severe respiratory phenotype, it was difficult to predict the degree of renal, hepatic, or retinal involvement associated with WDR34 mutations; however, 1 patient who was alive at 8 years of age had been diagnosed with rod-cone dystrophy, indicating that retinal degeneration may occur. In addition, the authors noted that in this study, mutations in WDR34 accounted for approximately 10% of all cases of ATD, making it the most commonly mutated gene after DYNC2H1 in this disease.
INHERITANCE \- Autosomal recessive GROWTH Weight \- Obesity (rare) HEAD & NECK Eyes \- Rod-cone dystrophy (rare) RESPIRATORY Lung \- Respiratory insufficiency \- Recurrent respiratory infections CHEST External Features \- Long, narrow thorax \- Bell-shaped thorax Ribs Sternum Clavicles & Scapulae \- Short, horizontal ribs \- Handlebar clavicles ABDOMEN External Features \- Protruding abdomen GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism (rare) Kidneys \- Dilated renal pelvis (rare) \- Dilated calyces (rare) \- Nephrocalcinosis (rare) SKELETAL Pelvis \- Trident acetabulum with spurs \- Squared iliac wings \- Irregular sciatic notches Limbs \- Short long bones \- Mild bowing of humeri and femora Hands \- Brachydactyly \- Postaxial polydactyly (rare) NEUROLOGIC Central Nervous System \- Speech and language delay (rare) PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios (rare) MISCELLANEOUS \- Most patients die in the neonatal period due to respiratory insufficiency MOLECULAR BASIS \- Caused by mutation in the WD-repeat containing protein 34 gene (WDR34, 613363.0001 ) ▲ 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
| SHORT-RIB THORACIC DYSPLASIA 11 WITH OR WITHOUT POLYDACTYLY | c0432197 | 2,483 | omim | https://www.omim.org/entry/615633 | 2019-09-22T15:51:22 | {"doid": ["0110095"], "mesh": ["C537602"], "omim": ["615633"], "orphanet": ["93271", "474"]} |
fundoscopy demonstrating age-related macular degeneration.
A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision.[1]
## Forms of maculopathies[edit]
* Age-Related Macular Degeneration is a degenerative maculopathy associated with progressive sight loss. It is characterised by changes in pigmentation in the Retinal Pigment Epithelium, the appearance of drusen on the retina of the eye and choroidal neovascularization. AMD has two forms; 'dry' or atrophic/non-exudative AMD, and 'wet' or exudative/neovascular AMD.
* Malattia Leventinese (or Doyne’s honeycomb retinal dystrophy) is another maculopathy with a similar pathology to wet AMD.
* Cellophane Maculopathy A fine glistening membrane forms over the macula, obscuring the vision.[2]
## See also[edit]
* EFEMP1 \- a gene thought to be involved with Malattia Leventinese
* Robert Walter Doyne \- the British Ophthalmologist after whom Malattia Leventinese is named
* Age-Related Macular Degeneration
* Retinitis Pigmentosa
* Malattia Leventinese
## References[edit]
1. ^ Kanski JJ. Clinical Ophthalmology: A Systematic Approach. 6th edition 2007.
2. ^ Handbook of Ocular Disease Management: Epiretinal membrane Archived 2008-04-28 at the Wayback Machine Retrieved on 2008-05-14
* 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
| Maculopathy | c0730362 | 2,484 | wikipedia | https://en.wikipedia.org/wiki/Maculopathy | 2021-01-18T18:47:42 | {"wikidata": ["Q3842207"]} |
## Clinical Features
Freundlich et al. (1981) studied an Israeli-Arab family in which the parents were first cousins and 4 of 11 sibs had a pellagra-like rash with neurologic manifestations. They thoroughly studied 1 sib, a 14-year-old boy who had first been admitted at age 13 months with a red, scaly rash over the face, upper chest, hands, and legs. The rash disappeared with nicotinamide therapy. During childhood the pellagra-like skin rash recurred several times and was each time cured by nicotinamide. At age 14 years he showed, in addition to rash, confusion, diplopia, dysarthria, and ataxia. Again all clinical abnormalities cleared with nicotinamide. Laboratory findings excluded Hartnup disease: amino aciduria and indicanuria were absent, as was any evidence of tryptophan malabsorption. Tryptophan loading did not induce tryptophanuria and did not increase excretion of xanthurenic or kynurenic acids. The authors suggested that the affected sibs have a genetically determined block in tryptophan degradation.
Salih et al. (1985) likewise described a pellagra-like condition, which they interpreted as a 'new' hereditary defect of tryptophan metabolism, in a Sudanese family with consanguinity. The condition manifested itself as a pellagra-like skin rash within 8 weeks of birth, with signs of cerebellar ataxia and developmental retardation. Cataracts developed early. The authors stated in the abstract that none of 10 affected children had survived beyond 2 years of age; yet the illustrative case that they describe in detail died at the age of 31 months. In the pedigree illustrated, affected males and females occurred in 3 sibships of the highly consanguineous kindred. There appeared to be impairment in the synthesis of quinolinic acid and nicotinamide nucleotides from tryptophan. Hartnup disease (234500) is a disorder of tryptophan metabolism with pellagra-like light-sensitive rash and cerebellar ataxia.
Eyes \- Early cataracts Neuro \- Confusion \- Diplopia \- Dysarthria \- Ataxia \- Developmental retardation Inheritance \- Autosomal recessive Misc \- Clinical abnormalities clear with nicotinamide Lab \- No aminoaciduria or indicanuria \- No tryptophan malabsorption or tryptophanuria \- Impaired synthesis of quinolinic acid and nicotinamide nucleotides from tryptophan \- Defect in degradation of tryptophan Skin \- Pellagra-like rash \- Red, scaly rash of face, upper chest, hands, and legs ▲ 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
| PELLAGRA-LIKE SYNDROME | c1850052 | 2,485 | omim | https://www.omim.org/entry/260650 | 2019-09-22T16:23:37 | {"mesh": ["C538352"], "omim": ["260650"], "orphanet": ["2837"], "synonyms": []} |
Post-thrombotic syndrome
Other namespostphlebitic syndrome, venous stress disorder
Person with post-thrombotic syndrome and leg ulcers
SpecialtyHematology
Post-thrombotic syndrome (PTS), also called postphlebitic syndrome and venous stress disorder is a medical condition that may occur as a long-term complication of deep vein thrombosis (DVT).
## Contents
* 1 Signs and symptoms
* 2 Cause
* 3 Risk factors
* 4 Diagnosis
* 5 Prevention
* 6 Treatment
* 6.1 Upper extremities
* 7 Epidemiology
* 8 Socioeconomic
* 9 Research directions
* 10 References
* 11 External links
## Signs and symptoms[edit]
Signs and symptoms of PTS in the leg may include:[1]
* pain (aching or cramping)
* heaviness
* itching or tingling
* swelling (edema)
* varicose veins
* brownish or reddish skin discoloration
* ulcer
These signs and symptoms may vary among patients and over time. With PTS, these symptoms typically are worse after walking or standing for long periods of time and improve with resting or elevating the leg.[1]
PTS lowers a person's quality of life after DVT, specifically with regards to physical and psychological symptoms and limitations in daily activities.[2][3][4]
## Cause[edit]
Despite ongoing research, the cause of PTS is not entirely clear. Inflammation is thought to play a role[5][6] as well as damage to the venous valves from the thrombus itself. This valvular incompetence combined with persistent venous obstruction from thrombus increases the pressure in veins and capillaries. Venous hypertension induces a rupture of small superficial veins, subcutaneous hemorrhage[7] and an increase of tissue permeability. That is manifested by pain, swelling, discoloration, and even ulceration.[8]
## Risk factors[edit]
The following factors increase the risk of developing PTS:[9][10][11][12][13][14][15]
* age > 65
* proximal DVT
* a second DVT in same leg as first DVT (recurrent ipsilateral DVT)
* persistent DVT symptoms 1 month after DVT diagnosis
* obesity
* poor quality of anticoagulation control (i.e. dose too low) during the first 3 months of treatment
## Diagnosis[edit]
When physicians find a DVT in the clinical history of their patients, a postthrombotic syndrome is possible if the patients have suggestive symptoms. Ultrasonography for deep venous thrombosis must be performed to evaluate the situation: the degree of obstruction by clots, the location of these clots, and the detection of deep and/or superficial venous insufficiency.[16][17] Since signs and symptoms of DVT and PTS may be quite similar, a diagnosis of PTS should be delayed for 3–6 months after DVT diagnosis so an appropriate diagnosis can be made.[1]
## Prevention[edit]
Prevention of PTS begins with prevention of initial and recurrent DVT. For people hospitalized at high-risk of DVT, prevention methods may include early ambulation, use of compression stockings or electrostimulation devices, and/or anticoagulant medications.[18] Elastic compression stockings may reduce the occurrence of PTS after clinically confirmed DVT.[19]
Increasingly, catheter-directed thrombolysis has been employed. This is a procedure in which a vascular interventionist will break up a clot using a variety of methods.
For people who have already had a single DVT event, the best way to prevent a second DVT is appropriate anticoagulation therapy.[20]
A second prevention approach may be weight loss for those who are overweight or obese. Increased weight can put more stress and pressure on leg veins, and can predispose patients to developing PTS.[13]
## Treatment[edit]
Treatment options for PTS include proper leg elevation, compression therapy with elastic stockings, or electrostimulation devices, pharmacotherapy (pentoxifylline), herbal remedies (such as horse chestnut, rutosides), and wound care for leg ulcers.[1][21]
The benefits of compression bandages is unclear. They may be useful to treat edemas.[7]
### Upper extremities[edit]
Patients with upper-extremity DVT may develop upper-extremity PTS, but the incidence is lower than that for lower-extremity PTS (15-25%).[22][23] No treatment or prevention methods are established, but patients with upper-extremity PTS may wear a compression sleeve for persistent symptoms.[20]
## Epidemiology[edit]
PTS can affect 23-60% of patients in the two years following DVT of the leg. Of those, 10% may go on to develop severe PTS, involving venous ulcers.[24]
## Socioeconomic[edit]
Treatment of PTS adds significantly to the cost of treating DVT. The annual health care cost of PTS in the United States has been estimated at $200 million, with costs over $3800 per patient in the first year alone, and increasing with disease severity.[24][25] PTS also causes lost work productivity: people with severe PTS and venous ulcers lose up to 2 work days per year.[26]
## Research directions[edit]
The field of PTS still holds many unanswered questions that are important targets for more research. Those include
* Fully defining the pathophysiology of PTS, including the role of inflammation and residual thrombus after completion of an appropriate duration of anticoagulant therapy
* Developing a PTS risk prediction model
* Role of thrombolytic ("clot-busting") drugs in PTS prevention
* Defining the true efficacy of elastic compression stockings for PTS prevention (and if effective, elucidating the minimum compression strength necessary and the optimal timing and duration of compression therapy)
* Whether PTS prevention methods are necessary for patients with asymptomatic or distal DVT
* Additional treatment options for PTS with demonstrated safety and efficacy (compression and pharmacologic therapies)[citation needed]
## References[edit]
1. ^ a b c d Kahn SR (November 2009). "How I treat postthrombotic syndrome". Blood. 114 (21): 4624–31. doi:10.1182/blood-2009-07-199174. PMID 19741190.
2. ^ Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis" Arch Intern Med 2002;162:1144-8.
3. ^ Kahn SR, M'Lan CE, Lamping DL, Kurz X, Bérard A, Abenhaim L (December 2004). "The influence of venous thromboembolism on quality of life and severity of chronic venous disease". Journal of Thrombosis and Haemostasis. 2 (12): 2146–51. doi:10.1111/j.1538-7836.2004.00957.x. PMID 15613019.
4. ^ Kahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, et al. (July 2008). "Determinants of health-related quality of life during the 2 years following deep vein thrombosis". Journal of Thrombosis and Haemostasis. 6 (7): 1105–12. doi:10.1111/j.1538-7836.2008.03002.x. PMID 18466316.
5. ^ Shbaklo H, Holcroft CA, Kahn SR (March 2009). "Levels of inflammatory markers and the development of the post-thrombotic syndrome". Thrombosis and Haemostasis. 101 (3): 505–12. doi:10.1160/TH08-08-0511. PMID 19277412.
6. ^ Roumen-Klappe EM, Janssen MC, Van Rossum J, Holewijn S, Van Bokhoven MM, Kaasjager K, et al. (April 2009). "Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study". Journal of Thrombosis and Haemostasis. 7 (4): 582–7. doi:10.1111/j.1538-7836.2009.03286.x. PMID 19175493.
7. ^ a b Pirard D, Bellens B, Vereecken P (March 2008). "The post-thrombotic syndrome - a condition to prevent". Dermatology Online Journal. 14 (3): 13. PMID 18627714.
8. ^ Vedantham S (2009). "Valvular dysfunction and venous obstruction in the post-thrombotic syndrome". Thrombosis Research. 123 Suppl 4 (Suppl 4): S62-5. doi:10.1016/s0049-3848(09)70146-x. PMID 19303507.
9. ^ Tick LW, Kramer MH, Rosendaal FR, Faber WR, Doggen CJ (December 2008). "Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis". Journal of Thrombosis and Haemostasis. 6 (12): 2075–81. doi:10.1111/j.1538-7836.2008.03180.x. PMID 18983518.
10. ^ Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. (July 1996). "The long-term clinical course of acute deep venous thrombosis". Annals of Internal Medicine. 125 (1): 1–7. doi:10.7326/0003-4819-125-1-199607010-00001. PMID 8644983.
11. ^ Shbaklo H, Kahn SR (September 2008). "Long-term prognosis after deep venous thrombosis". Current Opinion in Hematology. 15 (5): 494–8. doi:10.1097/moh.0b013e32830abde2. PMID 18695373.
12. ^ Kahn SR, Kearon C, Julian JA, Mackinnon B, Kovacs MJ, Wells P, et al. (April 2005). "Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis". Journal of Thrombosis and Haemostasis. 3 (4): 718–23. doi:10.1111/j.1538-7836.2005.01216.x. PMID 15733061.
13. ^ a b Ageno W, Piantanida E, Dentali F, Steidl L, Mera V, Squizzato A, et al. (February 2003). "Body mass index is associated with the development of the post-thrombotic syndrome". Thrombosis and Haemostasis. 89 (2): 305–9. doi:10.1055/s-0037-1613447. PMID 12574811.
14. ^ van Dongen CJ, Prandoni P, Frulla M, Marchiori A, Prins MH, Hutten BA (May 2005). "Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome". Journal of Thrombosis and Haemostasis. 3 (5): 939–42. doi:10.1111/j.1538-7836.2005.01333.x. PMID 15869588.
15. ^ Kahn SR, Ginsberg JS (January 2004). "Relationship between deep venous thrombosis and the postthrombotic syndrome". Archives of Internal Medicine. 164 (1): 17–26. doi:10.1001/archinte.164.1.17. PMID 14718318.
16. ^ Masuda EM, Kessler DM, Kistner RL, Eklof B, Sato DT (July 1998). "The natural history of calf vein thrombosis: lysis of thrombi and development of reflux". Journal of Vascular Surgery. 28 (1): 67–73, discussion 73–4. doi:10.1016/s0741-5214(98)70201-0. PMID 9685132.
17. ^ Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C (May 2009). "Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization". Journal of Thrombosis and Haemostasis. 7 (5): 879–83. doi:10.1111/j.1538-7836.2009.03294.x. PMID 19175497.
18. ^ Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW (June 2008). "Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest (8th ed.). 133 (6 Suppl): 381S–453S. doi:10.1378/chest.08-0656. PMID 18574271.
19. ^ Appelen D, van Loo E, Prins MH, Neumann MH, Kolbach DN (September 2017). Cochrane Vascular Group (ed.). "Compression therapy for prevention of post-thrombotic syndrome". The Cochrane Database of Systematic Reviews. 9: CD004174. doi:10.1002/14651858.CD004174.pub3. PMC 6483721. PMID 28950030.
20. ^ a b Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)" Chest 2008;133:454S-545S.
21. ^ Vazquez SR, Freeman A, VanWoerkom RC, Rondina MT (November 2009). "Contemporary issues in the prevention and management of postthrombotic syndrome". The Annals of Pharmacotherapy. 43 (11): 1824–35. doi:10.1345/aph.1m185. PMC 3245967. PMID 19737994.
22. ^ Elman EE, Kahn SR (2006). "The post-thrombotic syndrome after upper extremity deep venous thrombosis in adults: a systematic review". Thrombosis Research. 117 (6): 609–14. doi:10.1016/j.thromres.2005.05.029. PMID 16002126.
23. ^ Prandoni P, Bernardi E, Marchiori A, Lensing AW, Prins MH, Villalta S, et al. (August 2004). "The long term clinical course of acute deep vein thrombosis of the arm: prospective cohort study". BMJ. 329 (7464): 484–5. doi:10.1136/bmj.38167.684444.3a. PMC 515197. PMID 15256419.
24. ^ a b Ashrani AA, Heit JA (November 2009). "Incidence and cost burden of post-thrombotic syndrome". Journal of Thrombosis and Thrombolysis. 28 (4): 465–76. doi:10.1007/s11239-009-0309-3. PMC 4761436. PMID 19224134.
25. ^ Caprini JA, Botteman MF, Stephens JM, Nadipelli V, Ewing MM, Brandt S, et al. (2003). "Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States". Value in Health. 6 (1): 59–74. doi:10.1046/j.1524-4733.2003.00204.x. PMID 12535239.
26. ^ Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K (March 1997). "Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden". Annals of Internal Medicine. 126 (6): 454–7. doi:10.7326/0003-4819-126-6-199703150-00006. PMID 9072931.
## External links[edit]
Classification
D
* ICD-10: I87.0
* MeSH: D054070
* v
* t
* e
Cardiovascular disease (vessels)
Arteries, arterioles
and capillaries
Inflammation
* Arteritis
* Aortitis
* Buerger's disease
Peripheral artery disease
Arteriosclerosis
* Atherosclerosis
* Foam cell
* Fatty streak
* Atheroma
* Intermittent claudication
* Critical limb ischemia
* Monckeberg's arteriosclerosis
* Arteriolosclerosis
* Hyaline
* Hyperplastic
* Cholesterol
* LDL
* Oxycholesterol
* Trans fat
Stenosis
* Carotid artery stenosis
* Renal artery stenosis
Other
* Aortoiliac occlusive disease
* Degos disease
* Erythromelalgia
* Fibromuscular dysplasia
* Raynaud's phenomenon
Aneurysm / dissection /
pseudoaneurysm
* torso: Aortic aneurysm
* Abdominal aortic aneurysm
* Thoracic aortic aneurysm
* Aneurysm of sinus of Valsalva
* Aortic dissection
* Aortic rupture
* Coronary artery aneurysm
* head / neck
* Intracranial aneurysm
* Intracranial berry aneurysm
* Carotid artery dissection
* Vertebral artery dissection
* Familial aortic dissection
Vascular malformation
* Arteriovenous fistula
* Arteriovenous malformation
* Telangiectasia
* Hereditary hemorrhagic telangiectasia
Vascular nevus
* Cherry hemangioma
* Halo nevus
* Spider angioma
Veins
Inflammation
* Phlebitis
Venous thrombosis /
Thrombophlebitis
* primarily lower limb
* Deep vein thrombosis
* abdomen
* Hepatic veno-occlusive disease
* Budd–Chiari syndrome
* May–Thurner syndrome
* Portal vein thrombosis
* Renal vein thrombosis
* upper limb / torso
* Mondor's disease
* Paget–Schroetter disease
* head
* Cerebral venous sinus thrombosis
* Post-thrombotic syndrome
Varicose veins
* Gastric varices
* Portacaval anastomosis
* Caput medusae
* Esophageal varices
* Hemorrhoid
* Varicocele
Other
* Chronic venous insufficiency
* Chronic cerebrospinal venous insufficiency
* Superior vena cava syndrome
* Inferior vena cava syndrome
* Venous ulcer
Arteries or veins
* Angiopathy
* Macroangiopathy
* Microangiopathy
* Embolism
* Pulmonary embolism
* Cholesterol embolism
* Paradoxical embolism
* Thrombosis
* Vasculitis
Blood pressure
Hypertension
* Hypertensive heart disease
* Hypertensive emergency
* Hypertensive nephropathy
* Essential hypertension
* Secondary hypertension
* Renovascular hypertension
* Benign hypertension
* Pulmonary hypertension
* Systolic hypertension
* White coat hypertension
Hypotension
* Orthostatic hypotension
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Post-thrombotic syndrome | c0032807 | 2,486 | wikipedia | https://en.wikipedia.org/wiki/Post-thrombotic_syndrome | 2021-01-18T18:56:35 | {"mesh": ["D054070", "D011186"], "umls": ["C0032807"], "wikidata": ["Q382091"]} |
A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-2 (PEOA2) is caused by heterozygous mutation in the nuclear-encoded ANT1 gene (SLC25A4; 103220) on chromosome 4q35.
Heterozygous mutation in the SLC25A4 gene can also cause autosomal dominant mitochondrial DNA depletion syndrome-12A (MTDPS12A; 617184), and homozygous mutation in the SLC25A4 gene causes autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B; 615418).
Description
Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (Filosto et al., 2003; Luoma et al., 2004).
PEO caused by mutations in the POLG gene are associated with more complicated phenotypes than those forms caused by mutations in the ANT1 or C10ORF2 genes (Lamantea et al., 2002).
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).
Clinical Features
Kaukonen et al. (1996, 1999) reported several Italian adPEO families. All patients had progressive external ophthalmoplegia and ptosis, but no generalized muscle weakness. Age at onset was approximately 35 years. Several affected family members had sensorineural hearing loss. Two subjects had goiter associated with hypo- or hyperthyroidism. Two elderly subjects suffered from dementia manifesting as impairment of cognitive functions, with no affective component. An increased serum lactate level at rest was detected in 1 patient. A typical example of a patient in this family was a 67-year-old woman with ptosis and ophthalmoplegia, bilateral hearing loss, and hyperthyroidism with goiter. Her standard electromyogram was myopathic, and nerve conduction-velocity studies were normal. Multiple mtDNA deletions were detected in an analysis of muscle biopsy from the biceps brachialis. Histologic analysis of her muscle sample showed that 3% of the fibers were ragged red and 5% showed partial COX deficiency (see 220110). No elevation of lactic acid was detected at rest or after standard exercise, and her serum CPK level was within the normal range. Respiratory chain analysis showed slightly reduced activities of complexes III and IV (65 to 70% of the mean of controls), whereas activities of complexes I and II were within the normal range.
Mapping
In an Italian family with adPEO, Kaukonen et al. (1999) mapped the disease locus, formerly designated 'PEO3,' to a 13.5-cM interval between markers D4S2920 and D4S2924 on chromosome 4q34-q35. The results yielded 2-point and multipoint lod scores of 3.51 and 4.7, respectively. In 3 Italian families with autosomal dominant PEO, Kaukonen et al. (1996) found linkage to a locus on chromosome 3p (formerly designated 'PEO2'). However, in a reanalysis of these families, Kaukonen et al. (2000) failed to find significant lod scores to the locus on chromosome 3p (highest new multipoint lod score of 2.85). Further haplotype analysis did not support the existence of an adPEO locus on chromosome 3, and a mutation in the ANT1 gene (103220.0001) on 4q35 was later identified in these families (see Kaukonen et al., 2000).
Molecular Genetics
In affected members of 5 4q-linked Italian families with adPEO reported by Kaukonen et al. (1996, 1999), Kaukonen et al. (2000) identified a heterozygous mutation in the ANT1 gene (103220.0001). The affected families originated from the Romagna County of Italy, suggesting a founder effect. Except for a lack of cardiac symptoms, the features of the patients resembled those in Ant1 knockout mice (Graham et al., 1997).
In 3 members of a Greek family with PEOA2, Napoli et al. (2001) identified a heterozygous mutation in the SLC25A4 gene (103220.0003). The mutation was absent in several unaffected family members and in Italian and Greek controls.
Hirano and DiMauro (2001) reviewed the molecular genetics of progressive external ophthalmoplegia and classified the specific disease type according to mutation in the autosomal ANT1, C10ORF2, and POLG genes as well as in multiple mitochondrial genes.
Lamantea et al. (2002) stated that mutations in the ANT1 and C10ORF2 gene account for approximately 4% and 35% of familial adPEO cases, respectively. Mutations in the POLG gene are the most frequent cause of all forms of familial PEO, accounting for approximately 45% of cases.
INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Sensorineural hearing loss has been reported Eyes \- External ophthalmoplegia, progressive (PEO) \- Ptosis MUSCLE, SOFT TISSUES \- Facial muscle weakness \- Generalized muscle weakness (less common) \- Exercise intolerance (less common) \- EMG shows myopathic changes \- Muscle biopsy shows ragged red fibers \- Muscle biopsy shows multiple mitochondrial DNA (mtDNA) deletions \- Muscle biopsy shows decreased activity of cytochrome c oxidase \- Electron microscopy shows subsarcolemmal accumulations of abnormally shaped mitochondria LABORATORY ABNORMALITIES \- Serum lactate is usually normal MISCELLANEOUS \- Adult onset (before 50 years) \- Progressive disorder \- Genetic heterogeneity (see 157640 ) \- SLC25A4 mutations account for approximately 4% of all PEO cases MOLECULAR BASIS \- Caused by mutation in the solute carrier family 25 (mitochondrial carrier) member 4 gene (SLC25A4, 103220.0001 ) ▲ 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
| PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 2 | c1834846 | 2,487 | omim | https://www.omim.org/entry/609283 | 2019-09-22T16:06:20 | {"mesh": ["C563575"], "omim": ["157640", "609283"], "orphanet": ["254892"], "synonyms": ["adPEO", "Alternative titles", "PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL DOMINANT 2"], "genereviews": ["NBK487393"]} |
## Clinical Features
Turnpenny et al. (1994, 1995) reported a 4-generation Scottish family in which several members had ectodermal dysplasia predominantly affecting the teeth, but also involving the hair and skin. Hypo/oligodontia of the secondary dentition was characteristic by late adolescence, but 2 individuals had multiple natal teeth. Flexural acanthosis nigricans during childhood and early adolescence was present in some affected women. Heat tolerance was variable, but all subjects sweated. Scalp hair was thin and slow growing (except in affected women during pregnancy), and body hair was scanty. Nails were normal. Although some manifestations resembled those in the Clouston syndrome (129500), Turnpenny et al. (1994) suggested that these cases represent a distinct form of ectodermal dysplasia.
Inheritance
The pedigree pattern in the family with ectodermal dysplasia reported by Turnpenny et al. (1995) was consistent with autosomal dominant inheritance.
INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (5th-10th percentile) HEAD & NECK Head \- Relative macrocephaly Eyes \- Thin, sparse eyebrows \- Thin, sparse eyelashes Teeth \- Multiple natal teeth \- Hypodontia (secondary teeth) \- Oligodontia (secondary teeth) SKELETAL Skull \- Hyperostosis of cranial vault SKIN, NAILS, & HAIR Skin \- Flexural acanthosis nigricans (females, childhood-early adolescence) \- Normal sweating capacity \- Hypoplastic pilosebaceous units \- Hypoplastic sweat glands Nails \- Normal nails (majority) Hair \- Thin, slow-growing scalp hair \- Scant axillary hair \- Scant pubic hair \- Flaked, cracked, missing cuticular scales \- Thin, sparse eyebrows \- Thin, sparse eyelashes MISCELLANEOUS \- Variable heat tolerance \- Acanthosis nigricans fades during adolescence and reappears in pregnancy \- Scalp hair quality improves during pregnancy ▲ Close
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*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| ECTODERMAL DYSPLASIA WITH NATAL TEETH, TURNPENNY TYPE | c1832444 | 2,488 | omim | https://www.omim.org/entry/601345 | 2019-09-22T16:15:12 | {"mesh": ["C563347"], "omim": ["601345"], "orphanet": ["69083"], "synonyms": ["Alternative titles", "ECTODERMAL DYSPLASIA, HAIR/TOOTH TYPE"]} |
A rare ophthalmic disorder characterized by inflammation of the posterior uveal tract (retina and choroid), due to an infectious etiology. Presenting symptoms are decreased visual acuity, visual field defects, floaters, photopsia, photophobia, and occasionally pain. Signs on examination include conjunctival injection, keratic precipitates, retrolental cells, inflammatory infiltrates on the retina, macular edema, and peripheral retinal neovascularization, among others. Complications (such as cataracts, band keratopathy, glaucoma, cystoid macula edema, and retinal detachment) may lead to permanent vision loss.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Infectious posterior uveitis | None | 2,489 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=279919 | 2021-01-23T17:46:14 | {"icd-10": ["H30.9"]} |
Fear of cats
Ailurophobia
Other namesfelinophobia, elurophobia, felinophobia
Pronunciation
* ai-loor-oh-FOH-be-uh
SpecialtyPsychology
Ailurophobia is a type of specific phobia: the persistent, excessive fear of cats.[1] The name comes from the Greek words αἴλουρος (ailouros), 'cat' and φόβος (phóbos), 'fear'. Other names include felinophobia,[2] elurophobia,[2] and cat phobia.[2] A person with such a fear is known as an ailurophobe.
## Contents
* 1 Description
* 2 Treatment
* 3 In popular culture
* 4 See also
* 5 References
* 6 Further reading
## Description[edit]
The exact cause of ailurophobia is unclear; it may be due to experiencing a previous attack by a cat or witnessing someone else be attacked, but genetic and environmental factors may also play a part. Specific phobias, especially animal phobias, often develop in childhood.[3]
An ailurophobe may experience panic and fear when thinking about cats, including imagining the possibility of encountering a cat, inadvertently making physical contact with a cat, even seeing depictions of cats in the media. They may experience extreme anxiety and fear when hearing meowing, hissing, or similar sounds made by cats.[3]
Big cats such as lions or tigers can also trigger the stimuli associated with the phobia.[4] This phobia, in relation to big cats, may have biological (or even evolutionary) origin. There is evidence that the Australopithecus (ancestor of the genus Homo) were prey of Dinofelis, a feline of the extinct Machairodontinae subfamily. In size they were between a modern leopard and a lion, with most about the size of a jaguar (70 cm tall and up to 120 kg). However, analysis of carbon isotope ratios in specimens from Swartkrans indicates that Dinofelis' preferentially hunted grazing animals. The main predators of hominids in the environment at that time were most likely leopards and fellow machairodont Megantereon, whose carbon isotope ratios showed more indication of preying on hominids.[5]
## Treatment[edit]
Exposure therapy is one of the most effective treatments.[3] One strongly motivated patient was able to recover using this method, by slowly becoming accustomed to cat fur, under therapist supervision, by first touching varying types of velvet, then becoming accustomed to a toy kitten, and finally a live kitten, which the patient subsequently adopted. As the kitten grew, she also became less afraid of full-grown cats.[6]
Systematic desensitization is a specific type of exposure therapy that involves learning relaxation techniques to help manage feelings of fear and anxiety during exposure therapy. Eventually, these exercises can also help form new associations, such as eliciting a relaxation response instead of a stress response when confronted by a cat.[3]
There are not any medications specifically designed to treat phobias, but some can help with short-term management of symptoms. These include:[3]
* Beta-blockers. Beta-blockers help with physical symptoms of anxiety, such as increased heart rate and dizziness. They are generally taken before going into a situation that triggers physical symptoms.
* Benzodiazepines. These are sedatives that also help decrease anxiety symptoms. While they can be helpful, they also have a high risk of addiction.
* D-cycloserine (DCS). This is a drug that may help enhance the benefits of exposure therapy.
## In popular culture[edit]
In the 1965 animated television special A Charlie Brown Christmas, the character Lucy lists a number of phobias to Charlie Brown and incorrectly states, "If you’re afraid of cats, you have ailurophasia."[7] The word-forming element "-phasia" is a scientific Greek suffix used to form the names of disorders and phenomena relating to words and speech, such as cryptophasia, aphasia, dysphasia, and schizophasia.[8]
In the 1934 horror film, The Black Cat, the protagonist portrayed by Bela Lugosi suffers from an extreme version of the phobia.
In the 1969 horror film, Eye of the Cat, where the protagonist planning the murder of an elderly woman has a fear of cats.
In the 1988 anime City Hunter 2, the character Umibozu has a fear of cats.
In the 1989 anime Ranma 1/2, the main character Ranma Saotome has a fear of cats.
In the movie series The Mummy, the main antagonist Imhotep has a fear of cats, since he is a living corpse and cats have associations as guardians of the underworld in Egyptian mythology.
In the 2016 anime High School Fleet the character Mashiro Munetani has a fear of cats.
In the 2017 anime Nyanko Days, the character Arashi Iketani has a fear of cats.
The title character in the comic strip Big Nate has ailurophobia.
The character Robbie Jackson, in the BBC soap opera EastEnders has the condition.
In the game Minecraft, the Creeper will run away from cats and ocelots.
In The Elder Scrolls IV: Shivering Isles, the expansion to the video game The Elder Scrolls IV: Oblivion, an orc named Ushnar gro-Shadborgob is deathly afraid of cats and the humanoid feline Khajiits.
In the show Impractical Jokers, Sal Vulcano is deathly afraid of cats. The other jokers sometimes use cats in his "punishments".
In the fith series of Schitt’s Creek, the Moira Rose character talks of ailurophobes in the episode ‘Roadkill’.
## See also[edit]
* List of phobias
## References[edit]
1. ^ London, Louis S. (January 1952). "Ailurophobia and ornithophobia: Cat phobia and bird phobia". The Psychiatric Quarterly. 26 (1–4): 365–371. doi:10.1007/BF01568473. PMID 14949213.
2. ^ a b c Szasz, Thomas. A lexicon of lunacy: metaphoric malady, moral responsibility, and psychiatry. p. 68.
3. ^ a b c d e "Ailurophobia, or Fear of Cats: Symptoms, Causes, Treatment". Healthline. Retrieved 22 January 2020.
4. ^ Freeman, H. L.; D. C. Kendrick (August 1960). "A case of cat phobia. Treatment by a method derived from experimental psychology". BMJ. 2 (5197): 497–502. doi:10.1136/bmj.2.5197.497. PMC 2097085. PMID 13824737.
5. ^ "Dinofelis – hominid hunter or misunderstood feline?". www.maropeng.co.za.
6. ^ Freeman, H. L.; D. C. Kendrick (August 1960). "A case of cat phobia. Treatment by a method derived from experimental psychology". BMJ. 2 (5197): 497–502. doi:10.1136/bmj.2.5197.497. PMC 2097085. PMID 13824737.
7. ^ Schulz, Charles. "A Charlie Brown Christmas" (PDF). Ashley River Creative Arts Elementary School. Archived from the original (PDF) on 10 September 2016. Retrieved 18 June 2016.
8. ^ See -phasia at Wiktionary.
## Further reading[edit]
* Crawford, Nelson Antrim (1934). "Cats Holy and Profane". Psychoanalytic Review. 21: 168–179. Retrieved 9 April 2009.
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Ailurophobia | None | 2,490 | wikipedia | https://en.wikipedia.org/wiki/Ailurophobia | 2021-01-18T18:41:56 | {"wikidata": ["Q405385"]} |
## Summary
### Clinical characteristics.
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), and eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence. Life expectancy is variable. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA).
### Diagnosis/testing.
The diagnosis of FAHN is established in a proband with suggestive findings and typically by identification of biallelic FA2H pathogenic variants on molecular genetic testing; however, on occasion uniparental disomy (UDP) is causative.
### Management.
Treatment of manifestations: Symptomatic treatment focuses primarily on the dystonia, which can be debilitating. Therapies used with varying success include the oral medications baclofen, tizanidine, dantrolene, and anticholinergics; injection of botulinum toxin targeting abnormal co-contraction of selected muscle groups; and ablative pallidotomy or thalamotomy. Attention should be given to nutritional status and feeding.
Independence should be encouraged when possible through use of adaptive aids (e.g., walker or wheelchair for gait abnormalities, augmentative communication devices) and appropriate community resources (e.g., financial services, programs for the visually impaired, special education).
Surveillance: Regular assessment of nutritional status and swallowing, vision, mobility and environmental adaptations, speech, and communication needs.
### Genetic counseling.
Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism: FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner; FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a de novo event and is unlikely to recur.
Autosomal recessive inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.
## Diagnosis
### Suggestive Findings
Fatty acid hydroxylase-associated neurodegeneration (FAHN) should be considered in individuals with the following clinical findings, neuroimaging findings, and family history (see Figure 1).
#### Figure 1.
Neuroimaging features of FAHN (A) vs PKAN (B) The two forms of NBIA share T2-weighted / gradient-echo hypointensity. Distinguishing features include diffuse cerebral atrophy (seen in FAHN) and central globus pallidus T2-weighted hyperintensity (seen in (more...)
Clinical findings
* Onset within the first or second decade of life
* Corticospinal tract involvement:
* Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
* Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
* Movement disorder including one or both of the following:
* Dystonia
* Ataxia
* Dysarthria
* Dysphagia
* Eye findings:
* Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
* In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
* Epilepsy
* Cognitive decline
Neuroimaging findings. Brain MRI findings typically may include (in order of likelihood):
* On T2-weighted images: variable unilateral or bilateral symmetric white matter hyperintensity that may affect both periventricular and subcortical white matter, and may become confluent with time. U-fibers and cerebellar white matter appear to be affected to a lesser degree.
* Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord
* Thinning of the corpus callosum
* Optic atrophy
* T2-weighted hypointensity of the globus pallidus (may display blooming on T2*-weighted images).
Note: T2-weighted hypointensity coupled with an extrapyramidal movement disorder and intellectual decline is suggestive of a neurodegeneration with brain iron accumulation (NBIA) disorder (see Differential Diagnosis). The "eye of the tiger" sign, pathognomonic for pantothenate kinase-associated neurodegeneration (PKAN), another form of NBIA, is not seen in FAHN.
Family history is consistent with autosomal recessive inheritance, including parental consanguinity.
### Establishing the Diagnosis
The diagnosis of FAHN is established in a proband with suggestive findings and biallelic FA2H pathogenic variants on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with findings indistinguishable from other neurodegenerative disorders with pyramidal and extrapyramidal involvement are more likely to be diagnosed with comprehensive genomic testing (see Option 2).
#### Option 1
When the phenotypic and imaging findings suggest the diagnosis of FAHN or a similar type of neurodegeneration with brain iron accumulation (see NBIA Overview), molecular genetic testing is most often a multigene panel.
A multigene panel that includes FA2H 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 neurodegenerative disorders with pyramidal and extrapyramidal involvement, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
### Table 1.
Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
View in own window
Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
FA2HSequence analysis 3>95% 4
Gene-targeted deletion/duplication analysis 5See footnote 6
Uniparental disomy (UPD) analysis 7See footnote 8
1\.
See Table A. Genes and Databases for chromosome locus and protein.
2\.
See Molecular Genetics for information on allelic variants detected in this gene.
3\.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4\.
Kruer et al [2010]
5\.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6\.
One reported to date [Pierson et al 2012]
7\.
Various methods can detect UPD in an apparent FA2H homozygote. Testing may require parental blood specimens.
8\.
Four probands from nonconsanguineous families had uniparental disomy (UPD, maternal or paternal) [Soehn et al 2016]. For probands with apparent homozygous FA2H pathogenic variants and no evidence of large gene deletions, parental testing and/or investigation of the proband for UPD are recommended. The presence of UPD will alter recurrence risks (see Genetic Counseling).
## Clinical Characteristics
### Clinical Description
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. FAHN is a subtype of neurodegeneration with brain iron accumulation (NBIA) but is also included under the classifications of leukodystrophies and hereditary spastic paraplegias.
Of note, leukodystrophy and hereditary spastic paraplegia 35 (HSP35), two phenotypes previously considered distinct disorders based on clinical findings [Dick et al 2008, Edvardson et al 2008], are now included in the phenotypic spectrum of FAHN based on molecular genetic findings [Dick et al 2010, Kruer et al 2010].
The most frequent presenting finding is a subtle change in gait that may lead to increasingly frequent falls. This typically occurs in childhood or adolescence and may be the result of focal dystonia and/or corticospinal tract involvement.
The degree of spasticity resulting from corticospinal tract involvement can vary among persons with FAHN. Individuals affected to a lesser degree may develop spastic paraparesis but retain the ability to walk, while individuals with more severe disease may demonstrate a spastic quadriplegic pattern of disability and lose their ability to ambulate, instead relying on a wheelchair.
Dystonia may begin focally (e.g., affecting one foot) but typically spreads to assume a generalized pattern. The degree of dystonia seen in FAHN is generally milder than that in other forms of NBIA, such as PKAN, in which status dystonicus occurs.
Ataxia typically begins in childhood or adolescence and may emerge along with dystonia and/or spasticity. The ataxia that occurs in FAHN may affect both axial and appendicular function and, along with both dystonia and spasticity, can markedly impair gait.
Dysarthria may be prominent in FAHN. In some individuals, expressive speech can be impaired to the point of anarthria. Dysphagia, potentially necessitating gastrostomy tube placement, can also occur.
Optic atrophy in FAHN may begin as a subtle loss of visual acuity in childhood, but may progress to the point of functional blindness. The oculomotor abnormalities seen in FAHN may impair functional vision as well.
A few individuals with FAHN and peripheral neuropathy have been reported [Donkervoort et al 2014, Zaki et al 2015].
Seizures are not typically seen in the early stages of disease, but may occur later in the disease course. When present, seizures (which tend to be complex partial or generalized) are typically infrequent and respond relatively well to anticonvulsants.
While progressive intellectual impairment occurs in most persons with FAHN, more information on the cognitive phenotype and natural history are needed. Serial assessments have documented cognitive decline in two individuals [Tonelli et al 2012]. One report suggests a psychiatric component to FAHN based on findings of anxiety, depression, and bipolar disorder in affected sibs [Magariello et al 2017].
Although the neurodegeneration in FAHN is progressive, declines may be intermittent and punctuated by periods of relative clinical stability. However, lost skills are not usually regained. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence.
Life expectancy. Although premature death often occurs in the 20s or 30s secondary to a combination of nutrition-related immunodeficiency and respiratory compromise, life expectancy is variable.
Neuropathologic features for FAHN have not yet been reported. Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes.
### Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed for pathogenic variants in FA2H.
### Nomenclature
Historically, the FA2H-related phenotype has been classified as either a genetic leukodystrophy [Vanderver et al 2015] or a hereditary spastic paraplegia (SPG35) (see OMIM 612319) [Dick et al 2008, Soehn et al 2016].
The authors prefer to refer to the FA2H-related phenotype as fatty acid hydroxylase-associated neurodegeneration because this term refers to the genetic basis of the disorder and encompasses all clinical classifications.
### Prevalence
No reliable prevalence data are available. However, the prevalence is estimated to be lower than one in 1,000,000.
## Differential Diagnosis
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a neurodegenerative disorder that shows clinical overlap with other early-onset neurodegenerative disorders. Disorders that may exhibit clinical and neuroimaging features similar to those seen in FAHN are summarized in Table 2.
### Table 2.
Disorders to Consider in the Differential Diagnosis of FAHN
View in own window
PhenotypeDisorderGene(s)MOIAdditional Clinical & MRI Features of Differential Diagnosis Disorder
Overlapping w/FAHNDistinguishing from FAHN
Other NBIA disordersMPANC19orf12AR
* Cognitive decline
* Progressive spasticity & dystonia
* Optic atrophy
* Hyperintense streaking of medial medullary lamina often observed on T2-weighted MRI
* Parkinsonism developing in later disease
PKANPANK2ARProgressive dystonia & dysarthria
* "Eye of the tiger" sign
* More severe dystonia
Juvenile PLAN (atypical NAD)PLA2G6AR
* Progressive spasticity & dystonia
* Optic atrophy
* Cognitive decline
* Cerebellar atrophy
* Fewer cerebellar findings
* Apparent claval hypertrophy
CoPANCOASYARChildhood-onset gait abnormalities w/cognitive/psychiatric features
* More prominent extrapyramidal signs
* Pallidal iron
Neurodegenerative mineral deposition disorderWilson diseaseATP7BAR
* Gait disturbance
* Spasticity
* Dystonia
* T2-weighted hypointensity of globus pallidus
* Kayser-Fleischer rings
* Liver disease (most common 1st manifestation of Wilson disease in children)
Clinical mimics w/spasticity, dystonia, ataxia, or combination
Hereditary ataxiaFriedreich ataxiaFXNAR
* Spastic paraplegia
* Dysarthria
* Optic atrophy
* Peripheral neuropathy
* Cerebellar atrophy
* More prominent early gait ataxia (cerebellar & proprioceptive)
* Absence of early spasticity
* Cardiomyopathy
* Diabetes mellitus in later stages
* Prominent cervical cord atrophy & only later-onset cerebellar atrophy on MRI
ARSACSSACSAR
* Early childhood spastic ataxia
* Oculomotor abnormalities
* Teenage-onset of seizures
* Unsteady at onset of gait
* Hypermyelinated retinal fibers
* Polyneuropathy
PLP1 null syndrome (see PLP1-related disorders)PLP1XLChildhood-onset spasticity & ataxiaMultifocal demyelinating polyneuropathy
Spastic paraplegia 2 (see PLP1-related disorders)PLP1XL
* Childhood-onset spasticity ± ataxia
* Nystagmus
* Preserved cognition
* Milder course
Spastic paraplegia 44GJC2AR
* Spasticity
* Hyperreflexia
* Intention tremor
* Preservation of basal ganglia & no cerebellar atrophy
* Diffuse hypomyelination on MRI
Spastic paraplegia 11SPG11AR
* Spastic paraparesis
* Mild cognitive delay
* Cerebellar & bulbar involvement
* Periventricular white matter abnormalities & thin corpus callosum on MRI
More frequent peripheral neuropathy
Spastic paraplegia 15ZFYVE26AR
Arylsulfatase A deficiency (juvenile metachromatic leukodystrophy)ARSAAR
* Early childhood motor regression
* Spasticity
* Dysarthria
* Behavior & cognitive ability decline first
* More frequent peripheral neuropathy
* Periventricular demyelination on MRI
Hypomyelination with atrophy of the basal ganglia and cerebellum (see TUBB4A-Related Leukodystrophy)TUBB4AAR
* Variable-onset motor regression w/spasticity
* Dystonia
* Bulbar & cerebellar dysfunction
* Cerebellar atrophy on MRI
* More prominent extrapyramidal features
* Diffuse hypomyelination, atrophy of caudate & putamen, preservation of globus pallidus on MRI
POLR3-related leukodystrophyPOLR3A
POLR3B
POLR3CAR
* Spasticity
* Tremor
* Extrapyramidal symptoms
* MRI: thin corpus callosum w/ cerebellar atrophy.
* Cerebellar features predominate
* Abnormal dentition
* Endocrine abnormalities
* ± Myopia
* Hypomyelination pattern on MRI
Other disordersJuvenile & chronic hexosaminidase A deficiencyHEXAAR
* Childhood or later onset spasticity, ataxia, & seizures
* ± Optic atrophy
* ± Cerebellar atrophy
* ± Retinitis pigmentosa
* Juvenile form more aggressive
GTP cyclohydrolase 1-deficient dopa-responsive dystoniaGCH1ARChildhood-onset gait abnormalities, spasticity, & brisk reflexes
* Diurinal fluctuation
* Improvement w/low-dose levodopa
* MRI: normal
AD = autosomal dominant; AR = autosomal recessive; ARSACS = autosomal recessive spastic ataxia of Charlevoix Saguenay; MOI = mode of inheritance; NBIA = neurodegeneration with brain iron accumulation; XL = X-linked
## Management
### Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
### Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
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System/ConcernEvaluationComment
EyesOphthalmologic evaluationTo incl visual acuity & examination for optic atrophy or eye movement abnormalities
FeedingMultidisciplinary team evaluationAttention to nutritional status & feeding
MusculoskeletalPhysical & occupational therapyMobility & self-help skills
NeurologicNeurologic evaluationFor dystonia, ataxia, spasticity; incl EEG if question of seizures.
Miscellaneous/
OtherDevelopmental assessmentTo incl motor, general cognitive, & vocational skills
Speech & language pathologistSpeech & communication, augmentative devices
Consultation w/clinical geneticist &/or genetic counselor
### Treatment of Manifestations
#### Eyes
Refer those with visual impairment to appropriate community resources.
#### Feeding
Once swallowing evaluation and nutrition assessments indicate that the individual cannot maintain adequate nutrition and/or avoid the risk of aspiration with oral feeding, gastrostomy tube placement is indicated.
#### Neurologic
Pharmacologic and surgical interventions are focused on palliation of symptoms.
Dystonia and spasticity can be debilitating. Symptomatic treatments used with varying success include the following:
* Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
* Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
* Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [Justesen et al 1999].
Ataxia. Therapies for cerebellar ataxia can include use of weighted gloves to assist with dysmetria. Note that riluzole, recently recommended for cerebellar ataxia [Ristori et al 2010], has not to the authors' knowledge undergone a therapeutic trial in FAHN.
Seizures. Seizures respond well to traditional management with antiepileptic drugs.
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
#### Motor Dysfunction
Gross motor dysfunction
* Physical therapy is recommended to maximize mobility.
* Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
#### Global Developmental Disability / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
* In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
* Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
* Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
* Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
### Surveillance
The following should be performed on a regular basis:
* Swallowing evaluation, nutrition assessment, and monitoring of height and weight to screen for evidence of worsening nutritional status
* Ophthalmologic assessment with particular attention to visual acuity.
* Assessment of mobility, self-help skills, and activities of daily living and need for adaptive devices
* Assessment of speech and communication needs
### Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
### Therapies Under Investigation
Iron chelation. Interest in iron chelation has reemerged as trials using deferiprone have been published in other disorders of brain iron accumulation, including Friedreich ataxia [Boddaert et al 2007] and superficial siderosis [Levy & Llinas 2011]. Deferiprone can cross the blood-brain barrier and remove intracellular iron. A multicenter, placebo controlled, double-blind trial comparing the efficacy and safety of 18 months of treatment with deferiprone versus placebo in patients with PKAN was completed in January of 2017 (see Clinical Trials). Data is currently being analyzed. Results, when published, may be generalizable to other NBIA disorders. However, long-term clinical trials of deferiprone in specific forms of NBIA will be necessary to further assess safety and efficacy.
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.
*[v]: View this template
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*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Fatty Acid Hydroxylase-Associated Neurodegeneration | c3668943 | 2,491 | gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK56080/ | 2021-01-18T21:26:05 | {"mesh": ["C580102"], "synonyms": []} |
A number sign (#) is used with this entry because this disorder is caused by copy number increase of a small region on distal chromosome Xq28. One report has identified a 0.3-Mb region of Xq28 (chrX:153.2-153.5 Mb, NCBI36) containing at least 11 genes and including the GDI1 gene (300104), which is mutated in MRX41 (300849). Two additional reports have identified a more distal 0.5-Mb region (chrX:153.7-154.2 Mb (NCBI36/hg19)) containing at least 8 genes and including the RAB39B gene (300774), which is mutated in MRX72 (300271).
Clinical Features
Vandewalle et al. (2009) reported 4 families with X-linked mental retardation. The first family was of Belgian origin and had 4 affected males in 2 generations. All had normal growth, moderate mental retardation, and variable mild dysmorphic features, including mild 2-3 toe syndactyly, ataxic gait, and strabismus. The second family was of German origin and consisted of 2 affected brothers. The older brother was of average gestational size but was very floppy and was found to have a classic Dandy-Walker malformation, with cerebellar hypoplasia and agenesis of the corpus callosum. He developed seizures at 15 months of age and was microcephalic. Dysmorphic features included large ears, upslanting palpebral fissures, epicanthal folds, and thin lips. His brother also had a Dandy-Walker malformation, with agenesis of the cerebellar vermis and hypoplasia of the corpus callosum. At 19 months he had not developed seizures but had microcephaly. The third family reported by Vandewalle et al. (2009) was of Spanish origin and was reported as case 6 by Madrigal et al. (2007). The index case was born to nonconsanguineous parents at 8 months of pregnancy complicated by an acute pancreatitis. He developed neonatal seizures and cyanotic crises, and was hospitalized for 10 days. Imaging of his brain showed ventricular dilatation and large asymmetric cisterna magna. Gross motor milestones were within normal range. His speech development was delayed. At age 7, he had mild dysmorphic features with microcephaly, a high palate, medial eyebrow flare, and prominent ears. His IQ was 58. Neurologic examination was normal. No clinical details were available for 2 maternal brothers who were institutionalized. The fourth family was a sporadic case born to healthy, unrelated German parents. He had mild global psychomotor delay and did not begin walking until 20 months of age. Mild dysmorphic features were present, including brachycephaly, broad forehead, hypotelorism, and epicanthus inversus, more pronounced at the left side. He had a rather flat midface with flat nasal root and a short philtrum. He had a high palate and a small chin. Head circumference was at the 25th percentile.
In addition to mental retardation and dysmorphic features, Vandewalle et al. (2009) found ventricular aberrations in 2 families. A large fourth ventricle was seen in family 1, and a ventricular dilatation in family 3.
Cytogenetics
El-Hattab et al. (2011) reported 4 boys, including 2 brothers, with intellectual disability and behavioral disorders associated with a recurrent approximately 0.5-Mb duplication of chromosome Xq28 identified through array CGH. The duplications spanned chrX:153.7-154.2 Mb (NCBI36/hg19), and were confirmed by FISH analysis. All 3 mothers, who were more mildly affected with learning difficulties, also carried the duplication. X-chromosome inactivation studies showed skewed patterns in all 3 of the mothers, 2 with preferential inactivation of the normal chromosome and 1 with preferential inactivation of the duplicated chromosome. DNA sequence analysis showed that the breakpoints occurred within the directly oriented low-copy repeat (LCR) regions int22h-1 and int22h-2, which are in or close to the F8 gene (300841). The duplicated region contained 9 genes, including RAB39B (300774), but not GDI1 (300104). All 4 boys with the duplication had cognitive impairment, aggressive and/or hyperactive behavior, recurrent ear infections or pneumonia, and mildly dysmorphic facial features, including high forehead, upper eyelid fullness, broad nasal bridge, and thick lower lip. A mother and daughter from a fourth family were found to carry a heterozygous reciprocal deletion of Xq28 with 100% skewed X-chromosome inactivation of the chromosome with the deletion. Neither had intellectual disability, but the daughter came to attention for hyperactivity, inattentiveness, and sensory integration difficulties. The mother had a history of 2 spontaneous abortions, which El-Hattab et al. (2011) postulated may indicate that the deletion is lethal to males in utero.
Vanmarsenille et al. (2014) reported 4 male patients, including 2 brothers, with intellectual disability associated with a recurrent approximately 0.5-Mb duplication at distal chromosome Xq28 (chrX: 154.1-154.6 (hg19)). The duplications were apparently the same as those reported by El-Hattab et al. (2011), and the breakpoints involved the int22h-1 and int22h-2 LCRs. The duplicated region was distal to and did not include the GDI1 gene. Cell lines from 2 of the patients showed increased mRNA expression of BRCC3 (300617), VBP1 (300133), and RAB39B. The patients had behavioral or psychiatric problems, including schizophrenia in 1, and variable dysmorphic features, such as high forehead, large ears, deep-set eyes, and thin upper lip. Vanmarsenille et al. (2014) noted that point mutations in the RAB39B gene can cause X-linked mental retardation-72 (MRX72; 300271). Overexpression of Rab39b in mouse primary hippocampal neurons resulted in a significant decrease in neuronal branching as well as a decrease in the number of synapses compared to controls. These findings led Vanmarsenille et al. (2014) to conclude that increased dosage of the RAB39B gene causes disturbed neuronal development leading to cognitive impairment.
Molecular Genetics
In 4 families with X-linked mental retardation, Vandewalle et al. (2009) identified copy number gain of an identical 0.3-Mb region at chromosome Xq28 that included 18 annotated genes. Of these, RPL10 (312173), ATP6AP1 (300197), and GDI1 (300104) are expressed in brain. Vandewalle et al. (2009) considered GDI1 the most likely candidate gene in the region, as its copy number correlated perfectly with severity of clinical features and mutations in GDI1 have been found to cause mental retardation. Families 1 and 3 carried 3 copies of GDI1, family 2 carried 5, and family 4, 2. Vandewalle et al. (2009) noted that the duplicated region of chromosome Xq28 harbored by affected individuals did not contain the MECP2 gene (300005) and is thus distinct from the duplicated region associated with MECP2 duplication syndrome (300260). Clinical features also differ.
Fusco et al. (2010) commented on the paper by Vandewalle et al. (2009). They differed with the conclusion of Vandewalle et al. (2009) that increased GDI1 expression is likely to be responsible for the mental retardation seen in this duplication syndrome, and considered the IKBKG gene (300248), also in the interval, to be likely to play a role in the mental retardation associated with this duplication. Fusco et al. (2010) concluded that the presence of high repetitive DNA sequence families, low copy repeats (LCRs), and a nonprocessed pseudogene sequence in the Xq28 region can enhance homologous recombination, and that several studies had pointed out the ability of L1 and L2 copies to recombine giving rise to both pathologic and nonpathologic structural variants. The recombinant alleles reported by Vandewalle et al. (2009) fit very well with these previous findings. In addition, Fusco et al. (2010) wondered whether any other gene in the duplicated region may play a role in the mental retardation phenotype described by the authors and, in particular, favored the analysis of IKBKG because it is located exactly in the recombination region, and because studies had suggested that any upregulation or decreased expression may cause cellular dysfunction, and thus disease, in a tissue (brain)-specific manner. Froyen (2010) replied to Fusco et al. (2010) on behalf of Vandewalle et al. (2009).
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| CHROMOSOME Xq28 DUPLICATION SYNDROME | c1846058 | 2,492 | omim | https://www.omim.org/entry/300815 | 2019-09-22T16:19:33 | {"mesh": ["C537723"], "omim": ["300815"], "orphanet": ["293939", "1762"], "synonyms": ["Distal dup(X)q(28)", "Distal trisomy Xq28"], "genereviews": ["NBK349624"]} |
Tourette syndrome is a complex disorder characterized by repetitive, sudden, and involuntary movements or noises called tics. Tics usually appear in childhood, and their severity varies over time. In most cases, tics become milder and less frequent in late adolescence and adulthood.
Tourette syndrome involves both motor tics, which are uncontrolled body movements, and vocal or phonic tics, which are outbursts of sound. Some motor tics are simple and involve only one muscle group. Simple motor tics, such as rapid eye blinking, shoulder shrugging, or nose twitching, are usually the first signs of Tourette syndrome. Motor tics also can be complex (involving multiple muscle groups), such as jumping, kicking, hopping, or spinning.
Vocal tics, which generally appear later than motor tics, also can be simple or complex. Simple vocal tics include grunting, sniffing, and throat-clearing. More complex vocalizations include repeating the words of others (echolalia) or repeating one's own words (palilalia). The involuntary use of inappropriate or obscene language (coprolalia) is possible, but uncommon, among people with Tourette syndrome.
In addition to frequent tics, people with Tourette syndrome are at risk for associated problems including attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, depression, and problems with sleep.
## Frequency
Although the exact incidence of Tourette syndrome is uncertain, it is estimated to affect 1 to 10 in 1,000 children. This disorder occurs in populations and ethnic groups worldwide, and it is more common in males than in females.
## Causes
A variety of genetic and environmental factors likely play a role in causing Tourette syndrome. Most of these factors are unknown, and researchers are studying risk factors before and after birth that may contribute to this complex disorder. Scientists believe that tics may result from changes in brain chemicals (neurotransmitters) that are responsible for producing and controlling voluntary movements.
Mutations involving the SLITRK1 gene have been identified in a small number of people with Tourette syndrome. This gene provides instructions for making a protein that is active in the brain. The SLITRK1 protein probably plays a role in the development of nerve cells, including the growth of specialized extensions (axons and dendrites) that allow each nerve cell to communicate with nearby cells. It is unclear how mutations in the SLITRK1 gene can lead to this disorder.
Most people with Tourette syndrome do not have a mutation in the SLITRK1 gene. Because mutations have been reported in so few people with this condition, the association of the SLITRK1 gene with this disorder has not been confirmed. Researchers suspect that changes in other genes, which have not been identified, are also associated with Tourette syndrome.
### Learn more about the gene associated with Tourette syndrome
* SLITRK1
## Inheritance Pattern
The inheritance pattern of Tourette syndrome is unclear. Although the features of this condition can cluster in families, many genetic and environmental factors are likely to be involved. Among family members of an affected person, it is difficult to predict who else may be at risk of developing the condition.
Tourette syndrome was previously thought to have an autosomal dominant pattern of inheritance, which suggests that one mutated copy of a gene in each cell would be sufficient to cause the condition. Several decades of research have shown that this is not the case. Almost all cases of Tourette syndrome probably result from a variety of genetic and environmental factors, not changes in a single gene.
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*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Tourette syndrome | c0040517 | 2,493 | medlineplus | https://medlineplus.gov/genetics/condition/tourette-syndrome/ | 2021-01-27T08:25:35 | {"gard": ["7783"], "mesh": ["D005879"], "omim": ["137580"], "synonyms": []} |
Neonatal inflammatory skin and bowel disease is a rare, life-threatening, autoinflammatory syndrome with immune deficiency disorder characterized by early-onset, life-long inflammation, affecting the skin and bowel, associated with recurrent infections. Patients present perioral and perianal psoriasiform erythema and papular eruption with pustules, failure to thrive associated with chronic malabsorptive diarrhea, intercurrent gastrointestinal infections and feeding troubles, as well as absent, short or broken hair and trichomegaly. Recurrent cutaneous and pulmonary infections lead to recurrent blepharitis, otitis externa and bronchiolitis.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Neonatal inflammatory skin and bowel disease | c3280501 | 2,494 | orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=294023 | 2021-01-23T18:18:37 | {"omim": ["614328", "616069"]} |
This article relies largely or entirely on a single source. Relevant discussion may be found on the talk page. Please help improve this article by introducing citations to additional sources.
Find sources: "Precancerous condition" – news · newspapers · books · scholar · JSTOR (July 2012)
Precancerous condition
Other namesPremalignant condition, precancer, premalignancy, dysplasia, intraepithelial neoplasm, carcinoma in situ
Micrograph of high grade squamous intraepithelial lesion, a precancerous condition of the uterine cervix. Pap stain.
SpecialtyOncology
A precancerous condition is a condition or lesion involving abnormal cells which are associated with an increased risk of developing into cancer.[1][2][3] Clinically, precancerous conditions encompass a variety of conditions or lesions with an increased risk of developing into cancer. Some of the most common precancerous conditions include certain colon polyps, which can progress into colon cancer, monoclonal gammopathy of undetermined significance, which can progress into multiple myeloma or myelodysplastic syndrome.[4] and cervical dysplasia, which can progress into cervical cancer.[5] Pathologically, precancerous lesions can range from benign neoplasias, which are tumors which do not invade neighboring normal tissues or spread to distant organs, to dysplasia,[1] which involves collections of abnormal cells which in some cases have an increased risk of progressing to anaplasia and invasive cancer. Sometimes the term "precancer" is also used for carcinoma in situ, which is a noninvasive cancer that has not progressed to an aggressive, invasive stage. As with other precancerous conditions, not all carcinoma in situ will progress to invasive disease.
## Contents
* 1 Classification
* 2 Signs and symptoms
* 3 Causes
* 4 Pathophysiology
* 5 Examples
* 5.1 Skin
* 5.2 Breast
* 5.3 Head and neck/oral
* 5.4 Gastrointestinal
* 5.5 Gynecological
* 5.6 Urological
* 5.7 Hematological
* 6 References
* 7 External links
## Classification[edit]
The term precancerous or premalignant condition may refer to certain conditions, such as monoclonal gammopathy of unknown significance, or to certain lesions, such as colorectal adenoma (colon polyps), which have the potential to progress into cancer (see: Malignant transformation). Premalignant lesions are morphologically atypical tissue which appear abnormal when viewed under the microscope, and which are more likely to progress to cancer than normal tissue.[6] Precancerous conditions and lesions affect a variety of organ systems, including the skin, oral cavity, stomach, colon, and hematological system. Some authorities also refer to hereditary genetic conditions which predispose to developing cancer, such as hereditary nonpolyposis colorectal cancer, as a precancerous condition, as individuals with these conditions have a much higher risk of developing cancer in certain organs.[3]
## Signs and symptoms[edit]
The signs and symptoms of precancerous conditions differ based on the organ affected. In many cases, individuals with precancerous conditions do not experience any symptoms. Precancerous conditions of the skin or oral cavity often appear as visible lesions without associated pain or discomfort,[6] while precancerous conditions of the hematological system are typically asymptomatic, or in the case of monoclonal gammopathy of unknown significance, may rarely cause numbness and tingling in the hands and feet or difficulty with balance[7] (see: peripheral neuropathy).
## Causes[edit]
Main article: Causes of cancer
In many cases, risk factors for precancerous conditions and lesions are the same risk factors that predispose individuals to a specific cancer. For example, individuals with cervical or anal infection with oncogenic, or cancer causing, strains of human papilloma virus (HPV) are at elevated risk for cervical and anal cancers,[8] respectively, as well as for cervical and anal dysplasia.[8] Similarly, sun exposure is an important risk factor for both actinic keratosis[9] as well as skin cancer. However, in many cases, precancerous conditions or lesions can be sporadic and idiopathic in nature, meaning that they are not associated with a hereditary genetic predisposition to the particular cancer, nor with a direct causative agent or other identifiable cause.[10]
## Pathophysiology[edit]
Main article: Carcinogenesis
Stepwise progression from normal tissue to precancerous lesion to invasive cancer
The pathophysiology of precancerous lesions is thought to be similar to that of cancer, and varies depending on the disease site and type of lesion.[11] It is thought that cancer is preceded by a clinically silent premalignant phase during which oncogenic genetic and epigenetic alterations accumulate. The duration of this premalignant phase can vary from cancer to cancer and from individual to individual.[10]
## Examples[edit]
### Skin[edit]
* actinic keratosis[12]
* Bowen's disease (intraepidermal carcinoma/squamous carcinoma in situ)
* dyskeratosis congenita
### Breast[edit]
* ductal carcinoma in situ
* Sclerosing adenosis
* Small duct papilloma
### Head and neck/oral[edit]
* oral submucous fibrosis
* erythroplakia
* lichen planus (oral)
* leukoplakia
* proliferative verrucous leukoplakia[6]
* stomatitis nicotina[13]
### Gastrointestinal[edit]
* Barrett's esophagus
* atrophic gastritis
* colon polyp
* Plummer-Vinson syndrome (sideropenic dysphagia)[6]
* hereditary nonpolyposis colorectal cancer[6]
* Ulcerative colitis
* Crohn's disease
### Gynecological[edit]
* cervical dysplasia (cervical intraepithelial neoplasm, CIN)
* vaginal intraepithelial neoplasm (VAIN)[14]
* anal dysplasia (also see: anal cancer)
* lichen sclerosus
* Bowen's disease (penile or vulvar)[15]
* erythroplasia of Queyrat[15]
### Urological[edit]
* bladder carcinoma in situ[16]
### Hematological[edit]
* monoclonal gammopathy of unknown significance
## References[edit]
1. ^ a b "NCI Dictionary of Cancer Terms". National Cancer Institute. 2011-02-02. Retrieved 2018-03-28.
2. ^ "Precancerous conditions of the colon or rectum". Canadian cancer society. Retrieved 2018-03-19.
3. ^ a b "Precancerous conditions of the esophagus". Canadian cancer society. Retrieved 2018-03-19.
4. ^ Korde N, Kristinsson SY, Landgren O (May 2011). "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies". Blood. 117 (21): 5573–81. doi:10.1182/blood-2011-01-270140. PMC 3316455. PMID 21441462.
5. ^ "Precancerous conditions of the cervix". Canadian cancer society. Retrieved 2018-03-19.
6. ^ a b c d e Yardimci G, Kutlubay Z, Engin B, Tuzun Y (December 2014). "Precancerous lesions of oral mucosa". World Journal of Clinical Cases. 2 (12): 866–72. doi:10.12998/wjcc.v2.i12.866. PMC 4266835. PMID 25516862.
7. ^ "MGUS - MGUS Multiple Myeloma - MGUS Myeloma -Monoclonal Gammopathy". Multiple Myeloma Research Foundation. Archived from the original on 2017-07-10. Retrieved 2018-03-28.
8. ^ a b Roberts JR, Siekas LL, Kaz AM (February 2017). "Anal intraepithelial neoplasia: A review of diagnosis and management". World Journal of Gastrointestinal Oncology. 9 (2): 50–61. doi:10.4251/wjgo.v9.i2.50. PMC 5314201. PMID 28255426.
9. ^ "Actinic keratosis - Symptoms and causes". Mayo Clinic. Retrieved 2018-03-28.
10. ^ a b Willimsky G, Czéh M, Loddenkemper C, Gellermann J, Schmidt K, Wust P, Stein H, Blankenstein T (July 2008). "Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness". The Journal of Experimental Medicine. 205 (7): 1687–700. doi:10.1084/jem.20072016. PMC 2442645. PMID 18573907.
11. ^ Hyndman IJ (April 2016). "Review: the Contribution of both Nature and Nurture to Carcinogenesis and Progression in Solid Tumours". Cancer Microenvironment. 9 (1): 63–9. doi:10.1007/s12307-016-0183-4. PMC 4842185. PMID 27066794.
12. ^ "Actinic Keratosis". skincancer.org. Retrieved 2018-03-19.
13. ^ Neville BW, Day TA (July 2002). "Oral cancer and precancerous lesions". Ca. 52 (4): 195–215. doi:10.3322/canjclin.52.4.195. PMID 12139232. S2CID 3238352.
14. ^ "What Is Vaginal Cancer?". www.cancer.org. Retrieved 2018-03-28.
15. ^ a b Arya M, Kalsi J, Kelly J, Muneer A (March 2013). "Malignant and premalignant lesions of the penis". BMJ. 346: f1149. doi:10.1136/bmj.f1149. PMID 23468288. S2CID 33771829.
16. ^ "Bladder Cancer Staging | Bladder Cancer Stages". www.cancer.org. Retrieved 2018-03-28.
## External links[edit]
Classification
D
* MeSH: D011230
Look up premalignant or precancerous in Wiktionary, the free dictionary.
* v
* t
* e
Overview of tumors, cancer and oncology
Conditions
Benign tumors
* Hyperplasia
* Cyst
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Malignant progression
* Dysplasia
* Carcinoma in situ
* Cancer
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* Primary tumor
* Sentinel lymph node
Topography
* Head and neck (oral, nasopharyngeal)
* Digestive system
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* Endocrine system
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Other
* Precancerous condition
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Staging/grading
* TNM
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Misc.
* Research
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*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Precancerous condition | c0032927 | 2,495 | wikipedia | https://en.wikipedia.org/wiki/Precancerous_condition | 2021-01-18T18:48:59 | {"mesh": ["D011230"], "umls": ["C0032927"], "wikidata": ["Q1088163"]} |
Shigellosis
Other namesBacillary dysentery, Marlow syndrome
Shigella seen in a stool sample
SpecialtyInfectious disease
SymptomsDiarrhea, fever, abdominal pain[1]
ComplicationsReactive arthritis, sepsis, seizures, hemolytic uremic syndrome[1]
Usual onset1–2 days post exposure[1]
DurationUsually 5–7 days[1]
CausesShigella[1]
Diagnostic methodStool culture[1]
PreventionHandwashing[1]
TreatmentDrinking fluids and rest[1]
MedicationAntibiotics (severe cases)[1]
Frequency>80 million[2]
Deaths700,000[2]
Shigellosis is an infection of the intestines caused by Shigella bacteria.[1][3] Symptoms generally start one to two days after exposure and include diarrhea, fever, abdominal pain, and feeling the need to pass stools even when the bowels are empty.[1] The diarrhea may be bloody.[1] Symptoms typically last five to seven days and it may take several months before bowel habits return entirely to normal.[1] Complications can include reactive arthritis, sepsis, seizures, and hemolytic uremic syndrome.[1]
Shigellosis is caused by four specific types of Shigella.[2] These are typically spread by exposure to infected feces.[1] This can occur via contaminated food, water, or hands or sexual contact.[1][4] Contamination may be spread by flies or when changing diapers (nappies).[1] Diagnosis is by stool culture.[1]
The risk of infection can be reduced by properly washing the hands.[1] There is no vaccine.[1] Shigellosis usually resolves without specific treatment.[1] Sufficient fluids by mouth and rest is recommended.[1] Bismuth subsalicylate may help with the symptoms; however, medications that slow the bowels such as loperamide are not recommended.[1] In severe cases antibiotics may be used but resistance is common.[1][5] Commonly used antibiotics include ciprofloxacin and azithromycin.[1]
Globally shigellosis occurs in at least 80 million people and results in about 700,000 deaths a year.[2] Most cases occur in the developing world.[2] Young children are most commonly affected.[1] Outbreaks of disease may occur in childcare settings and schools.[1] It is also relatively common among travelers.[1] In the United States about half a million cases occur a year.[1]
## Contents
* 1 Signs and symptoms
* 2 Cause
* 2.1 Bacteria
* 2.2 Transmission
* 3 Mechanism
* 4 Diagnosis
* 5 Prevention
* 5.1 Vaccine
* 6 Treatment
* 6.1 Antibiotics
* 7 Epidemiology
* 8 See also
* 9 References
* 10 External links
## Signs and symptoms[edit]
Signs and symptoms may range from mild abdominal discomfort to full-blown dysentery characterized by cramps, diarrhea, with slimy-consistent stools, fever, blood, pus, or mucus in stools or tenesmus.[6][7] Onset time is 12 to 96 hours, and recovery takes 5 to 7 days.[8] Infections are associated with mucosal ulceration, rectal bleeding, and drastic dehydration. Reactive arthritis and hemolytic uremic syndrome are possible sequelae that have been reported in the aftermath of shigellosis.[citation needed]
The most common neurological symptom includes seizures.[9]
## Cause[edit]
### Bacteria[edit]
Shigellosis is caused by a bacterial infection with Shigella,[1] a bacterium that is genetically similar to and was once classified as E. coli.[10] There are three serogroups and one serotype of Shigella:
* Shigella flexneri
* Shigella boydii
* Shigella dysenteriae and
* Shigella sonnei (serotype)[1]
The probability of being infected by any given strain of Shigella varies around the world. For instance, S. sonnei is the most common in the United States, while S. dysenteriae and S. boydii are rare in the U.S.[1]
### Transmission[edit]
Shigella is transmitted through the fecal-oral route of individuals infected with the disease, whether or not they are exhibiting symptoms.[1][11] Long-term carriers of the bacteria are rare.[11] Apart from humans, the bacteria can also infect primates.[12]
## Mechanism[edit]
Upon ingestion, the bacteria pass through the gastrointestinal tract until they reach the small intestine. There they begin to multiply until they reach the large intestine.[13] In the large intestine, the bacteria cause cell injury and the beginning stages of Shigellosis via two main mechanisms: direct invasion of epithelial cells in the large intestine and production of enterotoxin 1 and enterotoxin 2.[13]
Unlike other bacteria, Shigella is not destroyed by the gastric acid in the stomach. As a result, it takes only 10 to 200 cells to cause an infection.[13] This infectious dose is several order of magnitudes smaller than that of other species of bacteria (e.g. Cholera, caused by the bacterium Vibrio cholerae, has an infectious dose between 108 and 1011 cells).[14]
## Diagnosis[edit]
The diagnosis of shigellosis is made by isolating the organism from diarrheal fecal sample cultures. Shigella species are negative for motility and are generally not lactose fermenters, but S. sonnei can ferment lactose.[15] They typically do not produce gas from carbohydrates (with the exception of certain strains of S. flexneri) and tend to be overall biochemically inert. Shigella should also be urea hydrolysis negative. When inoculated to a triple sugar iron slant, they react as follows: K/A, gas -, and H2S -. Indole reactions are mixed, positive and negative, with the exception of S. sonnei, which is always indole negative. Growth on Hektoen enteric agar produces bluish-green colonies for Shigella and bluish-green colonies with black centers for Salmonella.[citation needed]
## Prevention[edit]
Simple precautions can be taken to prevent getting shigellosis: wash hands before handling food and thoroughly cook all food before eating. The primary prevention methods are improved sanitation and personal and food hygiene, but a low-cost and efficacious vaccine would complement these methods.[16]
Since shigellosis is spread very quickly among children, keeping infected children out of daycare for 24 hours after their symptoms have disappeared, will decrease the occurrence of shigellosis in daycares.[17]
### Vaccine[edit]
Currently, no licensed vaccine targeting Shigella exists. Several vaccine candidates for Shigella are in various stages of development including live attenuated, conjugate, ribosomal, and proteosome vaccines.[16][18][19] Shigella has been a longstanding World Health Organization target for vaccine development, and sharp declines in age-specific diarrhea/dysentery attack rates for this pathogen indicate that natural immunity does develop following exposure; thus, vaccination to prevent the disease should be feasible. Shigellosis is resistant to many antibiotics used to treat the disease,[20] so vaccination is an important part of the strategy to reduce morbidity and mortality.[16]
## Treatment[edit]
Treatment consists mainly of replacing fluids and salts lost because of diarrhea. Replacement by mouth is satisfactory for most people, but some may need to receive fluids intravenously. Antidiarrheal drugs (such as diphenoxylate or loperamide) may prolong the infection and should not be used.[21]
### Antibiotics[edit]
Antibiotics should only be used in severe cases or for certain populations with mild symptoms (elderly, immunocompromised, food service industry workers, child care workers). For Shigella-associated diarrhea, antibiotics shorten the length of infection,[22] but they are usually avoided in mild cases because many Shigella strains are becoming resistant to common antibiotics.[23] Furthermore, effective medications are often in short supply in developing countries, which carry the majority of the disease burden from Shigella. Antidiarrheal agents may worsen the sickness, and should be avoided.[24]
In most cases, the disease resolves within four to eight days without antibiotics. Severe infections may last three to six weeks. Antibiotics, such as trimethoprim-sulfamethoxazole, ciprofloxacin may be given when the person is very young or very old, when the disease is severe, or when the risk of the infection spreading to other people is high. Additionally, ampicillin (but not amoxicillin) was effective in treating this disease previously, but now the first choice of drug is pivmecillinam.[25]
## Epidemiology[edit]
Insufficient data exist,[26] but it is estimated to have caused the death of 34,000 children under the age of five in 2013, and 40,000 deaths in people over five years of age.[16] Shigella also causes about 580,000 cases annually among travelers and military personnel from industrialized countries.[27]
An estimated 500,000 cases of shigellosis occur annually in the United States.[20] Infants, the elderly, and the critically ill are susceptible to the most severe symptoms of disease, but all humans are susceptible to some degree. Individuals with acquired immune deficiency syndrome (AIDS) are more frequently infected with Shigella.[28] Shigellosis is a more common and serious condition in the developing world; fatality rates of shigellosis epidemics in developing countries can be 5–15%.[29]
Orthodox Jewish communities (OJCs) are a known risk group for shigellosis; Shigella sonnei is cyclically epidemic in these communities in Israel, with sporadic outbreaks occurring elsewhere in among these communities. "Through phylogenetic and genomic analysis, we showed that strains from outbreaks in OJCs outside of Israel are distinct from strains in the general population and relate to a single multidrug-resistant sublineage of S. sonnei that prevails in Israel. Further Bayesian phylogenetic analysis showed that this strain emerged approximately 30 years ago, demonstrating the speed at which antimicrobial drug–resistant pathogens can spread widely through geographically dispersed, but internationally connected, communities."[30]
## See also[edit]
* Gastroenteritis
* Shiga-like toxin
* Shiga toxin
* Traveler's diarrhea
## References[edit]
1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag "General Information| Shigella – Shigellosis | CDC". www.cdc.gov. 3 August 2016. Archived from the original on 16 April 2017. Retrieved 20 April 2017.
2. ^ a b c d e Guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1 (PDF). WHO. 2005. p. 2. ISBN 978-9241593304. Archived (PDF) from the original on 21 August 2017. Retrieved 20 April 2017.
3. ^ "Factsheet about shigellosis". European Centre for Disease Prevention and Control.
4. ^ Antibiotic Resistance Threats in the United States, 2019 (PDF). CDC. 2019. p. 9.
5. ^ "Update – CDC Recommendations for Managing and Reporting Shigella Infections with Possible Reduced Susceptibility to Ciprofloxacin". emergency.cdc.gov. 7 June 2018. Retrieved 16 June 2018.
6. ^ "Shigellosis". The Merck Manual Home Health Handbook. Archived from the original on 4 January 2012. Retrieved 10 February 2012.
7. ^ Niyogi, SK (April 2005). "Shigellosis". Journal of Microbiology (Seoul, Korea). 43 (2): 133–43. PMID 15880088.
8. ^ "Symptoms of Shigella Infection". About Shigella. Marler Clark. Archived from the original on 8 January 2012. Retrieved 10 February 2012.
9. ^ "Diarrhoeal Diseases: Shigellosis". Initiative for Vaccine Research. World Health Organization. Archived from the original on 15 December 2008. Retrieved 11 May 2012.
10. ^ Devanga Ragupathi, NK; Muthuirulandi Sethuvel, DP; Inbanathan, FY; Veeraraghavan, B (21 January 2018). "Accurate differentiation of Escherichia coli and Shigella serogroups: challenges and strategies". New Microbes New Infect. 21: 58–62. doi:10.1016/j.nmni.2017.09.003. PMC 5711669. PMID 29204286.
11. ^ a b "Shigellosis (Bacillary Dysentery)". Merck Manual Professional Version. Retrieved 16 March 2018.
12. ^ Bowen, Anna (31 May 2017). "Travelers' Health, Chapter 3, Shigellosis (CDC)". Retrieved 17 March 2018.
13. ^ a b c Aslam, A; Gossman, WG (14 February 2018). Shigella (Shigellosis). Treasure Island, FL: StatPearls. PMID 29493962.
14. ^ Nelson, EJ; Harris, JB; Glenn Morris, Jr., J; Calderwood, SB; Camilli, A (October 2009). "Cholera transmission: the host, pathogen and bacteriophage dynamic". Nat Rev Microbiol. 7 (10): 693–702. doi:10.1038/nrmicro2204. PMC 3842031. PMID 19756008.
15. ^ Ito, Hideo; Kido, Nobuo; Arakawa, Yoshichika; Ohta, Michio; Sugiyama, Tsuyoshi; Kato, Nobuo (1991). "Possible mechanisms underlying the slow lactose fermentation phenotype in Shigella spp". Applied and Environmental Microbiology. 57 (10): 2912–7. doi:10.1128/AEM.57.10.2912-2917.1991. PMC 183896. PMID 1746953.
16. ^ a b c d Mani, Sachin; Wierzba, Thomas; Walker, Richard I. (2016). "Status of vaccine research and development for Shigella". Vaccine. 34 (26): 2887–2894. doi:10.1016/j.vaccine.2016.02.075. PMID 26979135.
17. ^ mayo clinic "Shigella infection - Symptoms and causes". Archived from the original on 6 September 2015. Retrieved 14 September 2015.
18. ^ "WHO vaccine pipeline tracker". World Health Organization. Archived from the original on 25 July 2016. Retrieved 29 July 2016.
19. ^ "Vaccine Research And Development: New strategies for accelerating Shigella vaccine development" (PDF). Weekly Epidemiological Record. 72 (11): 73–80. 14 March 1997. PMID 9115858. Archived (PDF) from the original on 19 May 2009. Retrieved 10 February 2012.
20. ^ a b US Centers for Disease Control and Prevention. "Shigella – Shigellosis". Archived from the original on 24 July 2016. Retrieved 29 July 2016.
21. ^ "How can Shigella infections be treated?". Shigellosis: General Information. Centers for Disease Control and Prevention. 17 January 2019. Archived from the original on 8 February 2016.
22. ^ Christopher, Prince RH; David, Kirubah V; John, Sushil M; Sankarapandian, Venkatesan; Christopher, Prince RH (2010). "Antibiotic therapy for Shigella dysentery". The Cochrane Database of Systematic Reviews (8): CD006784. doi:10.1002/14651858.CD006784.pub4. PMC 6532574. PMID 20687081.
23. ^ Kahsay, AG; Muthupandian, S (30 August 2016). "A review on Sero diversity and antimicrobial resistance patterns of Shigella species in Africa, Asia and South America, 2001-2014". BMC Research Notes. 9 (1): 422. doi:10.1186/s13104-016-2236-7. PMC 5004314. PMID 27576729.
24. ^ "How can Shigella infections be treated?". Shigellosis: General Information. Centers for Disease Control and Prevention. Archived from the original on 11 February 2012. Retrieved 11 February 2012.
25. ^ Katzung, Bertram G. (2007). Basic and Clinical Pharmacology. New York, NY: McGraw Hill Medical. p. 733. ISBN 978-0-07-145153-6.
26. ^ Ram, PK; Crump JA; Gupta SK; Miller MA; Mintz ED (2008). "Analysis of Data Gaps Pertaining to Shigella Infections in Low and Medium Human Development Index Countries, 1984–2005". Epidemiology and Infection. 136 (5): 577–603. doi:10.1017/S0950268807009351. PMC 2870860. PMID 17686195.
27. ^ World Health Organization (2006). State of the art of new vaccine research and development (PDF). Archived (PDF) from the original on 4 March 2016.
28. ^ Angulo, Frederick J.; Swerdlow, David L. (1995). "Bacterial Enteric Infections in Persons Infected with Human Immunodeficiency Virus". Clinical Infectious Diseases. 21 (Supplement 1): S84–S93. doi:10.1093/clinids/21.supplement_1.s84. PMID 8547518.
29. ^ Todar, Kenneth. "Shigella and Shigellosis". Todar's Online Textbook of Bacteriology. Archived from the original on 9 February 2012. Retrieved 10 February 2012.
30. ^ Baker, K; et al. (September 2016). "Travel- and Community-Based Transmission of Multidrug-Resistant Shigella sonnei Lineage among International Orthodox Jewish Communities". Emerg Infect Dis. 22 (9): 1545–1553. doi:10.3201/eid2209.151953. PMC 4994374. PMID 27532625.
## External links[edit]
* CDC's Shigellosis Page
* Vaccine Resource Library: Shigellosis and enterotoxigenic Escherichia coli (ETEC)
Classification
D
* ICD-10: A03
* ICD-9-CM: 004
* MeSH: D004405
External resources
* MedlinePlus: 000295
* eMedicine: med/2112
* Patient UK: Shigellosis
* v
* t
* e
Proteobacteria-associated Gram-negative bacterial infections
α
Rickettsiales
Rickettsiaceae/
(Rickettsioses)
Typhus
* Rickettsia typhi
* Murine typhus
* Rickettsia prowazekii
* Epidemic typhus, Brill–Zinsser disease, Flying squirrel typhus
Spotted
fever
Tick-borne
* Rickettsia rickettsii
* Rocky Mountain spotted fever
* Rickettsia conorii
* Boutonneuse fever
* Rickettsia japonica
* Japanese spotted fever
* Rickettsia sibirica
* North Asian tick typhus
* Rickettsia australis
* Queensland tick typhus
* Rickettsia honei
* Flinders Island spotted fever
* Rickettsia africae
* African tick bite fever
* Rickettsia parkeri
* American tick bite fever
* Rickettsia aeschlimannii
* Rickettsia aeschlimannii infection
Mite-borne
* Rickettsia akari
* Rickettsialpox
* Orientia tsutsugamushi
* Scrub typhus
Flea-borne
* Rickettsia felis
* Flea-borne spotted fever
Anaplasmataceae
* Ehrlichiosis: Anaplasma phagocytophilum
* Human granulocytic anaplasmosis, Anaplasmosis
* Ehrlichia chaffeensis
* Human monocytotropic ehrlichiosis
* Ehrlichia ewingii
* Ehrlichiosis ewingii infection
Rhizobiales
Brucellaceae
* Brucella abortus
* Brucellosis
Bartonellaceae
* Bartonellosis: Bartonella henselae
* Cat-scratch disease
* Bartonella quintana
* Trench fever
* Either B. henselae or B. quintana
* Bacillary angiomatosis
* Bartonella bacilliformis
* Carrion's disease, Verruga peruana
β
Neisseriales
M+
* Neisseria meningitidis/meningococcus
* Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia
M−
* Neisseria gonorrhoeae/gonococcus
* Gonorrhea
ungrouped:
* Eikenella corrodens/Kingella kingae
* HACEK
* Chromobacterium violaceum
* Chromobacteriosis infection
Burkholderiales
* Burkholderia pseudomallei
* Melioidosis
* Burkholderia mallei
* Glanders
* Burkholderia cepacia complex
* Bordetella pertussis/Bordetella parapertussis
* Pertussis
γ
Enterobacteriales
(OX−)
Lac+
* Klebsiella pneumoniae
* Rhinoscleroma, Pneumonia
* Klebsiella granulomatis
* Granuloma inguinale
* Klebsiella oxytoca
* Escherichia coli: Enterotoxigenic
* Enteroinvasive
* Enterohemorrhagic
* O157:H7
* O104:H4
* Hemolytic-uremic syndrome
* Enterobacter aerogenes/Enterobacter cloacae
Slow/weak
* Serratia marcescens
* Serratia infection
* Citrobacter koseri/Citrobacter freundii
Lac−
H2S+
* Salmonella enterica
* Typhoid fever, Paratyphoid fever, Salmonellosis
H2S−
* Shigella dysenteriae/sonnei/flexneri/boydii
* Shigellosis, Bacillary dysentery
* Proteus mirabilis/Proteus vulgaris
* Yersinia pestis
* Plague/Bubonic plague
* Yersinia enterocolitica
* Yersiniosis
* Yersinia pseudotuberculosis
* Far East scarlet-like fever
Pasteurellales
Haemophilus:
* H. influenzae
* Haemophilus meningitis
* Brazilian purpuric fever
* H. ducreyi
* Chancroid
* H. parainfluenzae
* HACEK
Pasteurella multocida
* Pasteurellosis
* Actinobacillus
* Actinobacillosis
Aggregatibacter actinomycetemcomitans
* HACEK
Legionellales
* Legionella pneumophila/Legionella longbeachae
* Legionnaires' disease
* Coxiella burnetii
* Q fever
Thiotrichales
* Francisella tularensis
* Tularemia
Vibrionaceae
* Vibrio cholerae
* Cholera
* Vibrio vulnificus
* Vibrio parahaemolyticus
* Vibrio alginolyticus
* Plesiomonas shigelloides
Pseudomonadales
* Pseudomonas aeruginosa
* Pseudomonas infection
* Moraxella catarrhalis
* Acinetobacter baumannii
Xanthomonadaceae
* Stenotrophomonas maltophilia
Cardiobacteriaceae
* Cardiobacterium hominis
* HACEK
Aeromonadales
* Aeromonas hydrophila/Aeromonas veronii
* Aeromonas infection
ε
Campylobacterales
* Campylobacter jejuni
* Campylobacteriosis, Guillain–Barré syndrome
* Helicobacter pylori
* Peptic ulcer, MALT lymphoma, Gastric cancer
* Helicobacter cinaedi
* Helicobacter cellulitis
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Shigellosis | c0302361 | 2,496 | wikipedia | https://en.wikipedia.org/wiki/Shigellosis | 2021-01-18T18:46:02 | {"gard": ["4818"], "mesh": ["D004405"], "umls": ["C0302361"], "orphanet": ["810"], "wikidata": ["Q327298"]} |
Von Deimling and de Looze (1983) characterized butyrylesterase-1 in 14 mammalian species including man. They could not group it with any of the known esterases within the system of enzymes recommended by the International Union for Biochemistry (IUB) and therefore proposed that this enzyme be assigned to a new esterase subclass.
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| BUTYRYLESTERASE 1 | c1861981 | 2,497 | omim | https://www.omim.org/entry/113960 | 2019-09-22T16:43:55 | {"omim": ["113960"]} |
A number sign (#) is used with this entry because of evidence that Hartsfield syndrome (HRTFDS) is caused by heterozygous mutation in the FGFR1 gene (136350) on chromosome 8p11.
Description
Hartsfield syndrome classically refers to the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur (Vilain et al., 2009). The disorder involves midline and limb field defects (Zechi-Ceide et al., 2009).
See also ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC; 129900), which shows phenotypic similarities.
Clinical Features
Hartsfield et al. (1984) reported a male infant born with multiple congenital anomalies, including lobar holoprosencephaly, ectrodactyly, and cleft lip/palate, who died at age 7 days. He also had hypertelorism, depressed nose, low-set and posteriorly rotated ears, and craniosynostosis. Radiographic analysis showed loss of digits on both the hands and feet and absence of the right radius. Postmortem analysis of the brain showed only partial separation of the cerebral hemispheres, hypoplasia of the posterior corpus callosum, absence of the septum pellucidum, fusion of the frontal lobes, and absence of the olfactory bulbs and tracts.
Young et al. (1992) reported a male fetus with features similar to those reported in the affected infant by Hartsfield et al. (1984). Routine ultrasonography at age 18 weeks showed lobar holoprosencephaly and facial and limb abnormalities. Postmortem examination showed cleft lip and palate, telecanthus, low-set ears, and ectrodactyly with syndactyly of the hands and feet. The skull frontal bones were small, the forebrain was fused anteriorly, and the olfactory bulbs were absent.
Konig et al. (2003) described a male patient, born of healthy, unrelated parents, with lobar holoprosencephaly, ectrodactyly, and cleft lip/palate. In addition, the patient developed hypernatremia and severe psychomotor retardation. Konig et al. (2003) identified 6 previously reported cases, all sporadic. They noted phenotypic overlap with the EEC syndrome (see 129900).
Vilain et al. (2009) reported 5 unrelated males with a phenotype most consistent with a diagnosis of Hartsfield syndrome. One was terminated as a fetus, and the others had mental retardation. One patient had arhinencephaly, a mild expression of the holoprosencephaly, and vermian hypoplasia. The 4 other patients had semilobar or lobar holoprosencephaly and hypoplasia or agenesis of the corpus callosum. Four had cleft lip and or palate. All patients had ectrodactyly, which was variable and ranged from 1 or 2 digits on the hands and feet to only duplicated thumbs. Two patients had central diabetes insipidus and hypogonadotropic hypogonadism. Variable features included hyper- or hypotelorism, abnormalities of ear morphology, and cryptorchidism, All patients had a normal karyotype. In a review of the 11 patients reported in the literature, Vilain et al. (2009) noted the variable phenotypic expression, but stated that holoprosencephaly and ectrodactyly are the only constant dysmorphic findings.
Zechi-Ceide et al. (2009) reported an affected 3-year-old boy. As an infant, he had a broad nasal bridge, megalocornea, cleft lip/palate, prominent ears, ectopic testes, and small penis. There were multiple digital anomalies: in the hand, the left second and third digits and the right third digit were hypoplastic; both feet had 3 toes, large halluces, and complete 4/5 cutaneous syndactyly. He showed poor growth and severe psychomotor retardation with no language development and poor head control at age 3 years. Skeletal studies showed multiple abnormalities of the bones of the hands, wrist, and feet, as well as absence of posterior arches of T1-T3 of the spine. Brain MRI showed semilobar holoprosencephaly with fusion of the frontal lobes, absence of the frontal horns of the lateral ventricles, abnormal frontal lobe gyration, agenesis of the corpus callosum, abnormal basal ganglia, and a hypoplastic brain stem.
Inheritance
Konig et al. (2003) noted that all 7 reported patients with holoprosencephaly, bilateral cleft lip/palate, and ectrodactyly were male, pointing to X-linked inheritance. However, autosomal dominant inheritance was demonstrated by Simonis et al. (2013) (see MOLECULAR GENETICS).
Molecular Genetics
Simonis et al. (2013) performed exome sequencing in 4 of the unrelated male patients with Hartsfield syndrome previously reported by Vilain et al. (2009) and identified missense mutations in the FGFR1 gene (see, e.g., 136350.0030 and 136350.0031) in all 4 patients. Sequencing of the FGFR1 gene in another male patient and a female patient with Hartsfield syndrome as well as in a female fetus with features of the disorder revealed mutations in the 2 patients (see, e.g., 136350.0032) but not in the female fetus. Simonis et al. (2013) noted that the fetus exhibited features that deviated substantially from those of FGFR1 mutation-positive patients with Hartsfield syndrome and might represent another diagnostic entity. Two of the patients were homozygotes; the parents of 1 of these patients were found to be heterozygous for the mutation (see 136350.0031) and were reportedly asymptomatic and spontaneously fertile. The parents of the other homozygote were unavailable for testing. Simonis et al. (2013) concluded that FGFR1 is the most prevalent, if not the sole gene causing Hartsfield syndrome.
### Exclusion Studies
In the affected male they reported, Konig et al. (2003) excluded mutation in regions of the p63 gene (603273) in which mutations had been identified in EEC3 (604292).
In a patient with the disorder, Zechi-Ceide et al. (2009) excluded mutations in the SHH (600725), TGIF (602630), SIX3 (603714), GLI2 (165230), TP73L (603273), and DHCR7 (602858) genes.
INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Ears \- Low-set ears \- Posteriorly rotated ears Eyes \- Epicanthal folds \- Hypertelorism \- Hypotelorism Nose \- Broad nose Mouth \- Cleft lip \- Cleft palate GENITOURINARY External Genitalia (Male) \- Small penis \- Hypospadias Internal Genitalia (Male) \- Cryptorchidism SKELETAL Skull \- Hypoplastic frontal bones \- Craniosynostosis (reported in 1 patient) Hands \- Ectrodactyly \- Syndactyly Feet \- Ectrodactyly \- Syndactyly NEUROLOGIC Central Nervous System \- Lobar holoprosencephaly \- Hypotonia, neonatal \- Psychomotor retardation, severe \- Vermian hypoplasia \- Agenesis of the corpus callosum ENDOCRINE FEATURES \- Gonadotropin deficiency \- Diabetes insipidus LABORATORY ABNORMALITIES \- Hypernatremia MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor receptor 1 gene (FGFR1, 136350.0030 ) ▲ 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
| HARTSFIELD SYNDROME | c1845146 | 2,498 | omim | https://www.omim.org/entry/615465 | 2019-09-22T15:52:05 | {"mesh": ["C564484"], "omim": ["615465"], "orphanet": ["2117"], "synonyms": ["Alternative titles", "HOLOPROSENCEPHALY, ECTRODACTYLY, AND BILATERAL CLEFT LIP/PALATE"], "genereviews": ["NBK349073"]} |
Trisomy 8
Chromosome 8
SpecialtyMedical genetics
Trisomy 8 causes Warkany syndrome 2,[1] a human chromosomal disorder caused by having three copies (trisomy) of chromosome 8. It can appear with or without mosaicism.
## Contents
* 1 Characteristics
* 1.1 Other conditions
* 2 Diagnosis
* 3 See also
* 4 References
* 5 External links
## Characteristics[edit]
Complete trisomy 8 causes severe effects on the developing fetus and can be a cause of miscarriage.[2][3] Complete trisomy 8 is usually an early lethal condition, whereas trisomy 8 mosaicism is less severe and individuals with a low proportion of affected cells may exhibit a comparatively mild range of physical abnormalities and developmental delay.[4] Individuals with trisomy 8 mosaicism are more likely to survive into childhood and adulthood, and exhibit a characteristic and recognizable pattern of developmental abnormalities. Common findings include retarded psychomotor development, moderate to severe mental retardation, variable growth patterns which can result in either abnormally short or tall stature, an expressionless face, and many musculoskeletal, visceral, and eye abnormalities, as well as other anomalies.[5] A deep plantar furrow is considered to be pathognomonic of this condition, especially when seen in combination with other associated features.[6] The type and severity of symptoms are dependent upon the location and proportion of trisomy 8 cells compared to normal cells.
### Other conditions[edit]
Trisomy 8 mosaicism affects wide areas of chromosome 8 containing many genes, and can thus be associated with a range of symptoms.
* Mosaic trisomy 8 has been reported in rare cases of Rothmund–Thomson syndrome, a genetic disorder associated with the DNA helicase RECQL4 on chromosome 8q24.3. The syndrome is "characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease".[7]
* Some individuals trisomic for chromosome 8 were deficient in production of coagulation factor VII due to a factor 7 regulation gene (F7R) mapped to 8p23.3-p23.1.[8]
* Trisomy and other rearrangements of chromosome 8 have also been found in tricho–rhino–phalangeal syndrome.[9]
* Small regions of chromosome 8 trisomy and monosomy are also created by recombinant chromosome 8 syndrome (San Luis Valley syndrome), causing anomalies associated with tetralogy of Fallot, which results from recombination between a typical chromosome 8 and one carrying a parental paracentric inversion.[10]
* Trisomy is also found in some cases of chronic myeloid leukaemia, potentially as a result of karyotypic instability caused by the bcr:abl fusion gene.
## Diagnosis[edit]
The simplest and easiest way to detect trisomy 8 is by a Karyotype,a photograph representing all chromosomes of a cell in an orderly manner. Amniocentesis is also a technique for diagnosis. Samples from the Amniotic Liquid is taken from a fetus, cultured,then analyzed by a Karyotype. If the photograph shows 3 copies of chromosome 8 instead of 2,then the individual has trisomy 8.
## See also[edit]
* Warkany syndrome 1
## References[edit]
1. ^ Diseases Database (DDB): 32656
2. ^ Riccardi VM (1977). "Trisomy 8: an international study of 70 patients". Birth Defects Orig. Artic. Ser. 13 (3C): 171–84. PMID 890109.
3. ^ Chen, Chih-Ping; Chen, Ming; Pan, Yi-Ju; Su, Yi-Ning; Chern, Schu-Rern; Tsai, Fuu-Jen; Chen, Yu-Ting; Wang, Wayseen (2011). "Prenatal diagnosis of mosaic trisomy 8: Clinical report and literature review". Taiwanese Journal of Obstetrics and Gynecology. 50 (3): 331–338. doi:10.1016/j.tjog.2011.07.013. ISSN 1028-4559.
4. ^ Jones, K. L. (2005). Smith's Recognizable Patterns of Human Malformation. (6th ed.). Philadelphia: W. B. Sanders Company.
5. ^ Riccardi VM (1977). "Trisomy 8: an international study of 70 patients". Birth Defects Orig. Artic. Ser. 13 (3C): 171–84. PMID 890109.
6. ^ Lai CC (1975). "Trisomy 8 syndrome". Clin. Orthop. Relat. Res. 110: 238–43. doi:10.1097/00003086-197507000-00034. PMID 1157389.
7. ^ "MIM ID #268400 ROTHMUND-THOMSON SYNDROME; RTS". NCBI/OMIM.
8. ^ "MIM ID *134450 FACTOR VII REGULATOR; F7R". NCBI/OMIM.
9. ^ "MIM ID #190350 TRICHORHINOPHALANGEAL SYNDROME, TYPE I; TRPS1". NCBI/OMIM.
10. ^ "MIM ID #179613 RECOMBINANT CHROMOSOME 8 SYNDROME". NCBI/OMIM.
## External links[edit]
Classification
D
* ICD-10: Q92
* ICD-9-CM: 758
* MeSH: D014314
* DiseasesDB: 32656
* U.S. National Library of Medicine: Warkany Syndrome 2
* v
* t
* e
Chromosome abnormalities
Autosomal
Trisomies/Tetrasomies
* Down syndrome
* 21
* Edwards syndrome
* 18
* Patau syndrome
* 13
* Trisomy 9
* Tetrasomy 9p
* Warkany syndrome 2
* 8
* Cat eye syndrome/Trisomy 22
* 22
* Trisomy 16
Monosomies/deletions
* (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome)
* 1
* Wolf–Hirschhorn syndrome
* 4
* Cri du chat syndrome/Chromosome 5q deletion syndrome
* 5
* Williams syndrome
* 7
* Jacobsen syndrome
* 11
* Miller–Dieker syndrome/Smith–Magenis syndrome
* 17
* DiGeorge syndrome
* 22
* 22q11.2 distal deletion syndrome
* 22
* 22q13 deletion syndrome
* 22
* genomic imprinting
* Angelman syndrome/Prader–Willi syndrome (15)
* Distal 18q-/Proximal 18q-
X/Y linked
Monosomy
* Turner syndrome (45,X)
Trisomy/tetrasomy,
other karyotypes/mosaics
* Klinefelter syndrome (47,XXY)
* XXYY syndrome (48,XXYY)
* XXXY syndrome (48,XXXY)
* 49,XXXYY
* 49,XXXXY
* Triple X syndrome (47,XXX)
* Tetrasomy X (48,XXXX)
* 49,XXXXX
* Jacobs syndrome (47,XYY)
* 48,XYYY
* 49,XYYYY
* 45,X/46,XY
* 46,XX/46,XY
Translocations
Leukemia/lymphoma
Lymphoid
* Burkitt's lymphoma t(8 MYC;14 IGH)
* Follicular lymphoma t(14 IGH;18 BCL2)
* Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH)
* Anaplastic large-cell lymphoma t(2 ALK;5 NPM1)
* Acute lymphoblastic leukemia
Myeloid
* Philadelphia chromosome t(9 ABL; 22 BCR)
* Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1)
* Acute promyelocytic leukemia t(15 PML,17 RARA)
* Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1)
Other
* Ewing's sarcoma t(11 FLI1; 22 EWS)
* Synovial sarcoma t(x SYT;18 SSX)
* Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB)
* Myxoid liposarcoma t(12 DDIT3; 16 FUS)
* Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS)
* Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1)
Other
* Fragile X syndrome
* Uniparental disomy
* XX male syndrome/46,XX testicular disorders of sex development
* Marker chromosome
* Ring chromosome
* 6; 9; 14; 15; 18; 20; 21, 22
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[c.]: circa
*[AA]: Adrenergic agonist
*[AD]: Acetaldehyde dehydrogenase
*[HAART]: highly active antiretroviral therapy
*[Ki]: Inhibitor constant
*[nM]: nanomolars
*[MOR]: μ-opioid receptor
*[DOR]: δ-opioid receptor
*[KOR]: κ-opioid receptor
*[SERT]: Serotonin transporter
*[NET]: Norepinephrine transporter
*[NMDAR]: N-Methyl-D-aspartate receptor
*[M:D:K]: μ-receptor:δ-receptor:κ-receptor
*[ND]: No data
*[NOP]: Nociceptin receptor
*[BMI]: body mass index
*[OCD]: Obsessive-compulsive disorder
*[SSRIs]: Selective serotonin reuptake inhibitors
*[SNRIs]: Serotonin–norepinephrine reuptake inhibitors
*[TCAs]: Tricyclic antidepressants
*[MAOIs]: Monoamine oxidase inhibitors
*[MSNs]: medium spiny neurons
*[CREB]: cAMP response element-binding protein
| Trisomy 8 | c0432412 | 2,499 | wikipedia | https://en.wikipedia.org/wiki/Trisomy_8 | 2021-01-18T19:03:02 | {"mesh": ["C537942"], "icd-10": ["Q92"], "wikidata": ["Q2454191"]} |
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