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nord_957_1
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Symptoms of Perniosis
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Perniosis is characterized by inflammation of the small blood vessels caused by an abnormal reaction to the cold. It is characterized by a bluish-red discoloration of the skin that can cause pain, intense itching, burning/stinging, and swelling of the skin, especially as the body becomes warmer. The discoloration usually occurs on the fingers, toes, lower legs, heels, ears and nose; rarely it can appear on the thighs and buttocks. In severely affected individuals, there may be blister-like lesions (bullae) which may become ulcers if rubbed or irritated. This may result in infections or even scarring upon healing. Perniosis of the thighs is a form of perniosis that more commonly affects young females who wear tight fitting pants. It is characterized by red or bluish patches (plaques) on the skin. These plaques are distributed on the upper hip region and on the outside of the thighs and can cause swelling, burning, itching and occasionally ulceration.
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Symptoms of Perniosis. Perniosis is characterized by inflammation of the small blood vessels caused by an abnormal reaction to the cold. It is characterized by a bluish-red discoloration of the skin that can cause pain, intense itching, burning/stinging, and swelling of the skin, especially as the body becomes warmer. The discoloration usually occurs on the fingers, toes, lower legs, heels, ears and nose; rarely it can appear on the thighs and buttocks. In severely affected individuals, there may be blister-like lesions (bullae) which may become ulcers if rubbed or irritated. This may result in infections or even scarring upon healing. Perniosis of the thighs is a form of perniosis that more commonly affects young females who wear tight fitting pants. It is characterized by red or bluish patches (plaques) on the skin. These plaques are distributed on the upper hip region and on the outside of the thighs and can cause swelling, burning, itching and occasionally ulceration.
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nord_957_2
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Causes of Perniosis
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The exact cause of perniosis is unclear. It may be due to a root cause (primary), a consequence of a primary disease (secondary), such as a connective tissue disease or from abnormal proteins in the blood, or a disease of unknown causes (idiopathic). One hypothesis is that cold weather causes the small veins and arteries close to the skin to tighten or constrict. When the tissues are rewarmed, blood leaks into the tissue and causes the skin to swell. The swelling irritates the nerves and can cause pain. It is thought by some that the disorder may represent an allergic reaction or hypersensitivity to the cold. Prolonged exposure to the cold, insufficient protective clothing, and circulatory or cardiovascular diseases may also be causative factors. Tight clothing may decrease blood flow to the affected area causing a decrease in the skin’s temperature. Some cases are believed to be caused by genetic factors. Other suspected causes include nutrition, local infection, hormonal changes, and other systemic diseases. In the elderly, perniosis may be associated with an underlying systemic disease.
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Causes of Perniosis. The exact cause of perniosis is unclear. It may be due to a root cause (primary), a consequence of a primary disease (secondary), such as a connective tissue disease or from abnormal proteins in the blood, or a disease of unknown causes (idiopathic). One hypothesis is that cold weather causes the small veins and arteries close to the skin to tighten or constrict. When the tissues are rewarmed, blood leaks into the tissue and causes the skin to swell. The swelling irritates the nerves and can cause pain. It is thought by some that the disorder may represent an allergic reaction or hypersensitivity to the cold. Prolonged exposure to the cold, insufficient protective clothing, and circulatory or cardiovascular diseases may also be causative factors. Tight clothing may decrease blood flow to the affected area causing a decrease in the skin’s temperature. Some cases are believed to be caused by genetic factors. Other suspected causes include nutrition, local infection, hormonal changes, and other systemic diseases. In the elderly, perniosis may be associated with an underlying systemic disease.
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Perniosis
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nord_957_3
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Affects of Perniosis
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The incidence of perniosis is currently uncertain. Perniosis is seen more often in females than in males. More specifically, it is seen more often in women who are very thin or who have a low body mass index. Several articles in the medical literature focus on cases of perniosis in anorexic women. Individuals who smoke long-term or with poor circulation, are affected more frequently than the general population. This condition is more common in cold, damp climates than in dry ones. Many cases have been reported from Western Europe but cases have also been reported in the late winter to early spring in the coastal areas of North America. Symptoms usually begin before the age of 20 years. It does not commonly occur in children and elderly people.
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Affects of Perniosis. The incidence of perniosis is currently uncertain. Perniosis is seen more often in females than in males. More specifically, it is seen more often in women who are very thin or who have a low body mass index. Several articles in the medical literature focus on cases of perniosis in anorexic women. Individuals who smoke long-term or with poor circulation, are affected more frequently than the general population. This condition is more common in cold, damp climates than in dry ones. Many cases have been reported from Western Europe but cases have also been reported in the late winter to early spring in the coastal areas of North America. Symptoms usually begin before the age of 20 years. It does not commonly occur in children and elderly people.
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Perniosis
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nord_957_4
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Related disorders of Perniosis
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Symptoms of the following disorders can be similar to those of perniosis. Comparisons may be useful for a differential diagnosis:Raynaud’s disease, or Raynaud’s phenomenon, is a vascular disorder. It is characterized by spasms of arterioles, especially in the fingers and toes due to exposure to cold. Occasionally other areas of the body such as the nose and tongue may be affected. The intermittent attacks of pallor or bluish color of the fingers or toes are precipitated by exposure to cold and intensified by emotional upsets. Raynaud’s may occur alone or be secondary to other conditions.Chilblain lupus erythromatosus is a chronic and persistent form of lupus erythromatosus. It may be preceded by facial lesions, but most commonly affects the fingers, calves and heels of the feet. It is a disorder that affects mostly women and may progress to systemic lupus erythromatosus, which can affect the internal organs. Vasculitis is a common disorder characterized by an inflammation of the blood vessel walls. This inflammation causes a narrowing of the inside of the vessel and can obstruct the flow of blood to the tissues (ischemia). The lack of blood may cause tissue death (necrosis), formation of blood clots (thrombosis), or the weakening and ballooning of an artery, which can possibly rupture (aneurysm). (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)Cold urticaria is a chronic, reactive skin disorder. It is probably the most common form of physical urticaria. Major symptoms may include abnormal reddening of the skin (erythema), hives, and itching after skin exposure to cold temperatures. (For more information on this disorder, choose “Urticaria, Cold” as your search term in the Rare Disease Database.)Cellulitis is a bacterial infection of the skin. The skin is painful, red, swollen, and warm to the touch. Usually, the lower legs are affected, but it is normally only on one side (unilateral). This condition is treated with systemic antibiotics.Irritant contact dermatitis is a skin condition that primarily affects the hands. It is characterized by red, dry, rough, and chapped skin and can be caused by contact with an irritant (e.g. detergent), not by contact with the cold.Acute embolism to the lower extremities is a blood clot that causes decreased blood flow (ischemia) to the legs and/or feet. As a result, the skin can be painful, pale, and warm as the clot worsens. In addition, individuals may show signs of decreased pulse, numbness, or even paralysis to the affected area.Acrocyanosis is a condition that presents with chronic coolness and a purple discoloration of primarily the hands and feet. However, it may also affect the nose, ears, lips, and nipples. Cold temperatures can worsen symptoms.Aicardi-Goutières syndrome is a rare genetic disorder, which is associated with a mutation in the TREX1 gene. It presents in infancy and primarily affects women. Approximately 40% of children with syndrome present with pernio-like skin lesions.Cold panniculitis is inflammation of subcutaneous fat (adipose) tissue due to direct cold exposure, such as contact with popsicles. This condition is common in young children. It presents as red, hardened raised patches (plaques), which resolve in a few weeks. This disease may also be confirmed by removing a sample of tissue from an affected area and then testing the sample (biopsy).Cryofibrinogenemia is a condition in which the blood plasma forms a precipitate during cooling conditions (cryoprecipitate). This disease is confirmed by the presence of proteins in the plasma called cryofibrinogen and the absence of circulating proteins called cryoglobulins. It may lead to the blockage of a blood vessel (secondary vascular occlusion), purple-colored spots (purpura), or skin cell death (necrosis) in areas such as the hands, feet, ears, and nose.
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Related disorders of Perniosis. Symptoms of the following disorders can be similar to those of perniosis. Comparisons may be useful for a differential diagnosis:Raynaud’s disease, or Raynaud’s phenomenon, is a vascular disorder. It is characterized by spasms of arterioles, especially in the fingers and toes due to exposure to cold. Occasionally other areas of the body such as the nose and tongue may be affected. The intermittent attacks of pallor or bluish color of the fingers or toes are precipitated by exposure to cold and intensified by emotional upsets. Raynaud’s may occur alone or be secondary to other conditions.Chilblain lupus erythromatosus is a chronic and persistent form of lupus erythromatosus. It may be preceded by facial lesions, but most commonly affects the fingers, calves and heels of the feet. It is a disorder that affects mostly women and may progress to systemic lupus erythromatosus, which can affect the internal organs. Vasculitis is a common disorder characterized by an inflammation of the blood vessel walls. This inflammation causes a narrowing of the inside of the vessel and can obstruct the flow of blood to the tissues (ischemia). The lack of blood may cause tissue death (necrosis), formation of blood clots (thrombosis), or the weakening and ballooning of an artery, which can possibly rupture (aneurysm). (For more information on this disorder, choose “Vasculitis” as your search term in the Rare Disease Database.)Cold urticaria is a chronic, reactive skin disorder. It is probably the most common form of physical urticaria. Major symptoms may include abnormal reddening of the skin (erythema), hives, and itching after skin exposure to cold temperatures. (For more information on this disorder, choose “Urticaria, Cold” as your search term in the Rare Disease Database.)Cellulitis is a bacterial infection of the skin. The skin is painful, red, swollen, and warm to the touch. Usually, the lower legs are affected, but it is normally only on one side (unilateral). This condition is treated with systemic antibiotics.Irritant contact dermatitis is a skin condition that primarily affects the hands. It is characterized by red, dry, rough, and chapped skin and can be caused by contact with an irritant (e.g. detergent), not by contact with the cold.Acute embolism to the lower extremities is a blood clot that causes decreased blood flow (ischemia) to the legs and/or feet. As a result, the skin can be painful, pale, and warm as the clot worsens. In addition, individuals may show signs of decreased pulse, numbness, or even paralysis to the affected area.Acrocyanosis is a condition that presents with chronic coolness and a purple discoloration of primarily the hands and feet. However, it may also affect the nose, ears, lips, and nipples. Cold temperatures can worsen symptoms.Aicardi-Goutières syndrome is a rare genetic disorder, which is associated with a mutation in the TREX1 gene. It presents in infancy and primarily affects women. Approximately 40% of children with syndrome present with pernio-like skin lesions.Cold panniculitis is inflammation of subcutaneous fat (adipose) tissue due to direct cold exposure, such as contact with popsicles. This condition is common in young children. It presents as red, hardened raised patches (plaques), which resolve in a few weeks. This disease may also be confirmed by removing a sample of tissue from an affected area and then testing the sample (biopsy).Cryofibrinogenemia is a condition in which the blood plasma forms a precipitate during cooling conditions (cryoprecipitate). This disease is confirmed by the presence of proteins in the plasma called cryofibrinogen and the absence of circulating proteins called cryoglobulins. It may lead to the blockage of a blood vessel (secondary vascular occlusion), purple-colored spots (purpura), or skin cell death (necrosis) in areas such as the hands, feet, ears, and nose.
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Perniosis
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nord_957_5
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Diagnosis of Perniosis
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Diagnosis is determined by ruling out other conditions or diseases.Clinical Evaluations and Workup
The clinician will assess the individual for a history of prolonged cold exposure and conduct a physical examination, including a full skin examination to check for painful, itchy, red skin lesions on the extremities. An echocardiogram may be performed if an acute embolism is suspected. The clinician will also conduct a close examination of the process of rewarming the affected areas. The lesions should be self-limiting and resolve upon rewarming. The patient is also screened for autoimmune markers. Blood tests including a complete blood count, antinuclear antibodies, cryoglobulins, cryofibrinogen, cold agglutinins, antiphospholipid antibodies, and serum protein electrophoresis are performed to rule out other conditions. Skin biopsies are performed if the condition persists and an underlying systemic inflammatory disease is suspected.
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Diagnosis of Perniosis. Diagnosis is determined by ruling out other conditions or diseases.Clinical Evaluations and Workup
The clinician will assess the individual for a history of prolonged cold exposure and conduct a physical examination, including a full skin examination to check for painful, itchy, red skin lesions on the extremities. An echocardiogram may be performed if an acute embolism is suspected. The clinician will also conduct a close examination of the process of rewarming the affected areas. The lesions should be self-limiting and resolve upon rewarming. The patient is also screened for autoimmune markers. Blood tests including a complete blood count, antinuclear antibodies, cryoglobulins, cryofibrinogen, cold agglutinins, antiphospholipid antibodies, and serum protein electrophoresis are performed to rule out other conditions. Skin biopsies are performed if the condition persists and an underlying systemic inflammatory disease is suspected.
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Perniosis
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Therapies of Perniosis
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Treatment
First-line treatment and management of perniosis, consists of protecting the body from the cold and warming the affected areas slowly. For example, patients may benefit from wearing layered warm clothing, gloves, and socks. Individuals with perniosis should avoid scratching or rubbing the affected area to help avoid further damage to the skin. Treatment with medications is second-line, and limited efficacy has been shown. The calcium channel blocker drug nifedipine (Adalat) may be an effective treatment for severe cases in decreasing the duration, severity, and recurrence of the lesions. Nifedipine works by widening the blood vessels. Patients given extended-release nifedipine, taken 20 mg three times daily, reported fast symptom improvement. Topical corticosteroids, such as topical mometasone or betamethasone, may help relieve the intense itching.Treatment with intense pulsed light has been shown to reduce redness.Patients are also encouraged to stop smoking because smoking decreases the amount of oxygen delivered to wounds and slows down the healing process.
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Therapies of Perniosis. Treatment
First-line treatment and management of perniosis, consists of protecting the body from the cold and warming the affected areas slowly. For example, patients may benefit from wearing layered warm clothing, gloves, and socks. Individuals with perniosis should avoid scratching or rubbing the affected area to help avoid further damage to the skin. Treatment with medications is second-line, and limited efficacy has been shown. The calcium channel blocker drug nifedipine (Adalat) may be an effective treatment for severe cases in decreasing the duration, severity, and recurrence of the lesions. Nifedipine works by widening the blood vessels. Patients given extended-release nifedipine, taken 20 mg three times daily, reported fast symptom improvement. Topical corticosteroids, such as topical mometasone or betamethasone, may help relieve the intense itching.Treatment with intense pulsed light has been shown to reduce redness.Patients are also encouraged to stop smoking because smoking decreases the amount of oxygen delivered to wounds and slows down the healing process.
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Perniosis
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nord_958_0
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Overview of Perrault Syndrome
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Perrault syndrome is a rare genetic disorder which causes sensorineural hearing loss in both males and females and ovarian dysfunction in females. Only about 100 cases have been reported, mostly in females. Hearing loss is present at birth or early childhood and may be progressive, but the disease is usually diagnosed in females in early adulthood due to a late puberty. In females, the ovaries do not function normally to begin puberty despite having an otherwise normal set of chromosomes (46,XX karyotype). Male fertility is normal, but females may not be able to conceive naturally, depending on the severity. A diagnosis is usually made after imaging shows a uterus but no functional ovaries and the karyotype of 46,XX. The hearing loss from birth is irreversible and may progressively get worse, warranting the need for a hearing aid or cochlear implant. Affected females may have primary ovarian insufficiency (POI), resulting in an early menopause before 40 years old, or some degree of ovary dysfunction. As a result, it may be difficult or impossible to conceive naturally and most women with Perrault syndrome will require an endocrinologist to manage hormone levels. Life expectancy is normal.
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Overview of Perrault Syndrome. Perrault syndrome is a rare genetic disorder which causes sensorineural hearing loss in both males and females and ovarian dysfunction in females. Only about 100 cases have been reported, mostly in females. Hearing loss is present at birth or early childhood and may be progressive, but the disease is usually diagnosed in females in early adulthood due to a late puberty. In females, the ovaries do not function normally to begin puberty despite having an otherwise normal set of chromosomes (46,XX karyotype). Male fertility is normal, but females may not be able to conceive naturally, depending on the severity. A diagnosis is usually made after imaging shows a uterus but no functional ovaries and the karyotype of 46,XX. The hearing loss from birth is irreversible and may progressively get worse, warranting the need for a hearing aid or cochlear implant. Affected females may have primary ovarian insufficiency (POI), resulting in an early menopause before 40 years old, or some degree of ovary dysfunction. As a result, it may be difficult or impossible to conceive naturally and most women with Perrault syndrome will require an endocrinologist to manage hormone levels. Life expectancy is normal.
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Perrault Syndrome
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Symptoms of Perrault Syndrome
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The most common symptoms of Perrault syndrome include:
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Symptoms of Perrault Syndrome. The most common symptoms of Perrault syndrome include:
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Causes of Perrault Syndrome
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Perrault syndrome is caused by changes (mutations) in six genes: CLPP, ERAL1, HARS2, HSD17B4, LARS2, or TWNK. Mutations in one of these genes have been identified in about 40% of patients. The cause is unknown in the other 60% of patients. Perrault syndrome is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Perrault Syndrome. Perrault syndrome is caused by changes (mutations) in six genes: CLPP, ERAL1, HARS2, HSD17B4, LARS2, or TWNK. Mutations in one of these genes have been identified in about 40% of patients. The cause is unknown in the other 60% of patients. Perrault syndrome is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Perrault Syndrome
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Affects of Perrault Syndrome
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Fewer than 100 cases of Perrault syndrome have been diagnosed, making it extremely rare (<1 in 1 million). A family history of this disease is the greatest known risk, particularly if the genetic mutation is identified.
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Affects of Perrault Syndrome. Fewer than 100 cases of Perrault syndrome have been diagnosed, making it extremely rare (<1 in 1 million). A family history of this disease is the greatest known risk, particularly if the genetic mutation is identified.
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Perrault Syndrome
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Related disorders of Perrault Syndrome
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Turner syndrome – also causes ovarian dysfunction but affected females have a 45,XO karyotypeSwyer syndrome – also causes ovarian dysfunction but affected females have a 46,XY karyotypeCongenital cytomegaloviral infection (cCMV) – may cause hearing loss at birth due to a viral infection during pregnancyBronchiootorenal (BOR) syndrome – may cause hearing loss at birth, but due to malformations during development which also affect the kidneysX-linked deafness 2 (DFNX2) – causes a different type of hearing loss at birth, affecting the bone rather than the nervous system
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Related disorders of Perrault Syndrome. Turner syndrome – also causes ovarian dysfunction but affected females have a 45,XO karyotypeSwyer syndrome – also causes ovarian dysfunction but affected females have a 46,XY karyotypeCongenital cytomegaloviral infection (cCMV) – may cause hearing loss at birth due to a viral infection during pregnancyBronchiootorenal (BOR) syndrome – may cause hearing loss at birth, but due to malformations during development which also affect the kidneysX-linked deafness 2 (DFNX2) – causes a different type of hearing loss at birth, affecting the bone rather than the nervous system
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Perrault Syndrome
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nord_958_5
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Diagnosis of Perrault Syndrome
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The diagnosis of Perrault syndrome is based on the early hearing loss and ovarian dysfunction in females with a normal 46,XX set of chromosomes. Genetic testing for mutations in the six known causative genes can help to confirm the diagnosis, but more commonly the exact cause will be unknown. Since males with Perrault syndrome tend to only experience hearing loss, they may not receive a diagnosis unless they also have a sister with Perrault syndrome.Clinical Testing and Work-up
Newborn infants may show the first signs of Perrault syndrome if they fail newborn hearing screening tests. Older children might be diagnosed with hearing loss based on an audiogram. Due to its rarity, clinicians would not likely suspect Perrault syndrome until they have also found ovarian dysfunction causing late puberty in a young adult woman. Clinical testing may include blood tests, hearing tests, pelvic imaging, genetic testing and neurological exams. A care team may include audiologists, otolaryngologists, endocrinologists, gynecologists, geneticists and neurologists. Once the diagnosis is made, these clinicians can help manage the hearing loss, hormone levels and fertility issues involved in Perrault syndrome.
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Diagnosis of Perrault Syndrome. The diagnosis of Perrault syndrome is based on the early hearing loss and ovarian dysfunction in females with a normal 46,XX set of chromosomes. Genetic testing for mutations in the six known causative genes can help to confirm the diagnosis, but more commonly the exact cause will be unknown. Since males with Perrault syndrome tend to only experience hearing loss, they may not receive a diagnosis unless they also have a sister with Perrault syndrome.Clinical Testing and Work-up
Newborn infants may show the first signs of Perrault syndrome if they fail newborn hearing screening tests. Older children might be diagnosed with hearing loss based on an audiogram. Due to its rarity, clinicians would not likely suspect Perrault syndrome until they have also found ovarian dysfunction causing late puberty in a young adult woman. Clinical testing may include blood tests, hearing tests, pelvic imaging, genetic testing and neurological exams. A care team may include audiologists, otolaryngologists, endocrinologists, gynecologists, geneticists and neurologists. Once the diagnosis is made, these clinicians can help manage the hearing loss, hormone levels and fertility issues involved in Perrault syndrome.
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Perrault Syndrome
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nord_958_6
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Therapies of Perrault Syndrome
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There is no cure for Perrault syndrome and treatment focuses on remedying the symptoms of hearing loss, hormone imbalance and infertility. Depending on the severity of hearing loss, an audiologist or ENT physician may recommend hearing aids, cochlear implants or vibrotactile devices. Routine hearing checks are important to determine if the hearing loss is getting worse. An endocrinologist can induce normal puberty in young women and then supplement the proper hormones to maintain a normal menstrual cycle. Most women with Perrault syndrome meet with their endocrinologists every three months when starting puberty, once a year when receiving hormone supplementation and every five years to check bone density changes as a result of hormone supplementation.For women with primary ovarian insufficiency (POI), a clinician may recommend freezing their eggs since menopause happens early. Women with shrunken ovaries (ovarian dysgenesis) may not be able to conceive naturally but may be able to have children using in-vitro fertilization since they have a functioning uterus.
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Therapies of Perrault Syndrome. There is no cure for Perrault syndrome and treatment focuses on remedying the symptoms of hearing loss, hormone imbalance and infertility. Depending on the severity of hearing loss, an audiologist or ENT physician may recommend hearing aids, cochlear implants or vibrotactile devices. Routine hearing checks are important to determine if the hearing loss is getting worse. An endocrinologist can induce normal puberty in young women and then supplement the proper hormones to maintain a normal menstrual cycle. Most women with Perrault syndrome meet with their endocrinologists every three months when starting puberty, once a year when receiving hormone supplementation and every five years to check bone density changes as a result of hormone supplementation.For women with primary ovarian insufficiency (POI), a clinician may recommend freezing their eggs since menopause happens early. Women with shrunken ovaries (ovarian dysgenesis) may not be able to conceive naturally but may be able to have children using in-vitro fertilization since they have a functioning uterus.
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Perrault Syndrome
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nord_959_0
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Overview of Pertussis
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Pertussis is a highly contagious acute respiratory disease caused by the bacteria Bordetella pertussis. This disease has 3 stages: catarrhal, paroxysmal, and convalescent. The symptoms of the catarrhal stage are mild and may go unnoticed. The paroxysmal stage of Pertussis is characterized by episodes of coughing with a distinctive “whooping” sound when breathing in (inspiration). This characteristic cough gives the disease its common name, Whooping Cough. During the convalescent stage, episodes of coughing are less frequent and symptoms improve. The incidence of Pertussis has diminished greatly with widespread use of the DPT vaccine (Diphtheria Pertussis Tetanus), but in certain areas of the United States outbreaks have occurred periodically in recent years.
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Overview of Pertussis. Pertussis is a highly contagious acute respiratory disease caused by the bacteria Bordetella pertussis. This disease has 3 stages: catarrhal, paroxysmal, and convalescent. The symptoms of the catarrhal stage are mild and may go unnoticed. The paroxysmal stage of Pertussis is characterized by episodes of coughing with a distinctive “whooping” sound when breathing in (inspiration). This characteristic cough gives the disease its common name, Whooping Cough. During the convalescent stage, episodes of coughing are less frequent and symptoms improve. The incidence of Pertussis has diminished greatly with widespread use of the DPT vaccine (Diphtheria Pertussis Tetanus), but in certain areas of the United States outbreaks have occurred periodically in recent years.
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Pertussis
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Symptoms of Pertussis
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Pertussis is a highly contagious disease that typically lasts for approximately 6 to 10 weeks. The symptoms are more severe in infants or in individuals who have never been immunized against the disease. There are three recognized stages of the disease: catarrhal, paroxysmal, and convalescent.The incubation period for Pertussis is 7 to 10 days. During the first or catarrhal stage of the disease, the symptoms are mild and may go unnoticed or be confused with the common cold or influenza. Symptoms may include a general feeling of ill health (malaise), a runny nose (rhinorrhea), sneezing, and/or tearing of the eyes (lacrimation). Some affected people may experience a slight elevation in temperature (low-grade fever). Toward the end of this phase, a cough develops that becomes increasingly more persistent, especially at night.The paroxysmal stage of Pertussis is characterized by recurring intense episodes of coughing. An episode or “paroxysm” consists of a series of coughs in rapid succession with increasing intensity. The last cough in the series is followed by a large inspiration that produces a characteristic “whoop” sound. During these coughing episodes, affected individuals find it difficult to draw air into the lungs (inspiration) between coughs. Typically, people with Pertussis cough up (expectorate) large amounts of thick mucus, which may cause vomiting (post-pertussis emesis). Other symptoms during an attack may include bulging eyes, prominent veins in the neck, protrusion of the tongue, and/or excessive salivation. Aspiration of mucous into the lungs may cause bacterial pneumonia. Infections of the middle ear (otitis media) may also occur during this stage of the disease.The convalescent stage of Pertussis begins approximately 4 weeks after onset of the disease. Episodes of coughing become less frequent and not as severe. Slow recovery begins during this phase of the disease. Occasionally episodes of coughing may recur for months.The coughing associated with Pertussis may cause a sudden increase in the pressure within the blood vessels of the nose and/or eyes. This may lead to nosebleeds (epistaxis) and the appearance of red blood vessels in the white of the eyes (scleral hemorrhage). Other more severe complications may include seizures, a collapsed lung (atelectasis), abnormal enlargement and destruction of the bronchi and bronchial tubes (bronchiectasis), the escape of air from the lungs into the surrounding soft tissues (subcutaneous emphysema), and/or a hernia in the area of the groin (inguinal hernia). Bacterial superinfection and, in rare cases, acute inflammation of the brain (encephalitis) may also occur.
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Symptoms of Pertussis. Pertussis is a highly contagious disease that typically lasts for approximately 6 to 10 weeks. The symptoms are more severe in infants or in individuals who have never been immunized against the disease. There are three recognized stages of the disease: catarrhal, paroxysmal, and convalescent.The incubation period for Pertussis is 7 to 10 days. During the first or catarrhal stage of the disease, the symptoms are mild and may go unnoticed or be confused with the common cold or influenza. Symptoms may include a general feeling of ill health (malaise), a runny nose (rhinorrhea), sneezing, and/or tearing of the eyes (lacrimation). Some affected people may experience a slight elevation in temperature (low-grade fever). Toward the end of this phase, a cough develops that becomes increasingly more persistent, especially at night.The paroxysmal stage of Pertussis is characterized by recurring intense episodes of coughing. An episode or “paroxysm” consists of a series of coughs in rapid succession with increasing intensity. The last cough in the series is followed by a large inspiration that produces a characteristic “whoop” sound. During these coughing episodes, affected individuals find it difficult to draw air into the lungs (inspiration) between coughs. Typically, people with Pertussis cough up (expectorate) large amounts of thick mucus, which may cause vomiting (post-pertussis emesis). Other symptoms during an attack may include bulging eyes, prominent veins in the neck, protrusion of the tongue, and/or excessive salivation. Aspiration of mucous into the lungs may cause bacterial pneumonia. Infections of the middle ear (otitis media) may also occur during this stage of the disease.The convalescent stage of Pertussis begins approximately 4 weeks after onset of the disease. Episodes of coughing become less frequent and not as severe. Slow recovery begins during this phase of the disease. Occasionally episodes of coughing may recur for months.The coughing associated with Pertussis may cause a sudden increase in the pressure within the blood vessels of the nose and/or eyes. This may lead to nosebleeds (epistaxis) and the appearance of red blood vessels in the white of the eyes (scleral hemorrhage). Other more severe complications may include seizures, a collapsed lung (atelectasis), abnormal enlargement and destruction of the bronchi and bronchial tubes (bronchiectasis), the escape of air from the lungs into the surrounding soft tissues (subcutaneous emphysema), and/or a hernia in the area of the groin (inguinal hernia). Bacterial superinfection and, in rare cases, acute inflammation of the brain (encephalitis) may also occur.
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Causes of Pertussis
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Pertussis is an infectious disease caused by the gram-negative coccobacillus, Bordetella pertussis. Pertussis is a highly contagious disease via droplets in the air from the respiratory tract of infected individuals. Transmission occurs during the catarrhal stage and during the first 2 to 3 weeks of the paroxysmal phase.
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Causes of Pertussis. Pertussis is an infectious disease caused by the gram-negative coccobacillus, Bordetella pertussis. Pertussis is a highly contagious disease via droplets in the air from the respiratory tract of infected individuals. Transmission occurs during the catarrhal stage and during the first 2 to 3 weeks of the paroxysmal phase.
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Affects of Pertussis
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Pertussis occurs most frequently and severely in young children. Adolescents and adults tend to experience much less severe symptoms, and sometimes the disease may not even be recognized as Pertussis. For reasons that are not fully understood, slightly more females than males are affected.Pertussis occurs in all geographic locations throughout the world. There is no seasonal pattern to outbreaks of the disease. The World Health Organization (WHO) has estimated that 60 million cases of Pertussis occur worldwide each year. Approximately 500,000 to 1,000,000 individuals develop life-threatening complications because of Pertussis.The Pertussis vaccine (DPT vaccination) has been in widespread use since the late 1940s. Since that time, the incidence of Pertussis has fallen dramatically from 250,000 cases per year in the United States. Recently, the CDC reported that pertussis affected about 1,900 infants per year between 1994 and 1996. However, the Pertussis vaccine is not 100 percent effective in preventing the disease. In widespread outbreaks of Pertussis, individuals' susceptibility to this infection increases with the amount of time that has elapsed since their last immunization. The Centers for Disease Control (CDC) in Atlanta, GA suggest that the small risk of severe reactions associated with the DPT vaccine is negligible when compared to the possible severity of the disease itself. The risk of serious complications is estimated to be 1 in 100,000 to 300,000 for the vaccine as opposed to 1 in 9,500 for the disease itself. The American Academy of Pediatrics has reported near epidemic local outbreaks of Pertussis in at least 10 geographic areas in the United States during recent years. In most of these areas, parents have not permitted immunization of their children against Pertussis because of the possible complications of vaccine.
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Affects of Pertussis. Pertussis occurs most frequently and severely in young children. Adolescents and adults tend to experience much less severe symptoms, and sometimes the disease may not even be recognized as Pertussis. For reasons that are not fully understood, slightly more females than males are affected.Pertussis occurs in all geographic locations throughout the world. There is no seasonal pattern to outbreaks of the disease. The World Health Organization (WHO) has estimated that 60 million cases of Pertussis occur worldwide each year. Approximately 500,000 to 1,000,000 individuals develop life-threatening complications because of Pertussis.The Pertussis vaccine (DPT vaccination) has been in widespread use since the late 1940s. Since that time, the incidence of Pertussis has fallen dramatically from 250,000 cases per year in the United States. Recently, the CDC reported that pertussis affected about 1,900 infants per year between 1994 and 1996. However, the Pertussis vaccine is not 100 percent effective in preventing the disease. In widespread outbreaks of Pertussis, individuals' susceptibility to this infection increases with the amount of time that has elapsed since their last immunization. The Centers for Disease Control (CDC) in Atlanta, GA suggest that the small risk of severe reactions associated with the DPT vaccine is negligible when compared to the possible severity of the disease itself. The risk of serious complications is estimated to be 1 in 100,000 to 300,000 for the vaccine as opposed to 1 in 9,500 for the disease itself. The American Academy of Pediatrics has reported near epidemic local outbreaks of Pertussis in at least 10 geographic areas in the United States during recent years. In most of these areas, parents have not permitted immunization of their children against Pertussis because of the possible complications of vaccine.
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Related disorders of Pertussis
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Symptoms of the following disorders can be similar to those of Pertussis. Comparisons may be useful for a differential diagnosis:Acute Bronchitis is a common respiratory disease characterized by inflammation of the bronchi and bronchial tubes. Symptoms may include a persistent cough accompanied by abundant mucous discharge (sputum), fever, and/or back pain. Bronchitis is caused by the spread of an upper respiratory infection into the bronchi and may occur along with other diseases such as measles, pertussis, and/or diphtheria.Influenza is a highly contagious common infectious disease of the respiratory tract caused by a virus and transmitted by airborne droplet infection. The symptoms of Influenza are often similar to those of the catarrhal stage of Pertussis including sore throat, excessive mucous, cough, fever, general weakness, and/or muscle pains.Other bacteria that are related to the Bordetella pertussis may cause symptoms that are very similar to those of Pertussis. These bacteria include Bordetella parapertussis and Bordetella bronchiseptica.
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Related disorders of Pertussis. Symptoms of the following disorders can be similar to those of Pertussis. Comparisons may be useful for a differential diagnosis:Acute Bronchitis is a common respiratory disease characterized by inflammation of the bronchi and bronchial tubes. Symptoms may include a persistent cough accompanied by abundant mucous discharge (sputum), fever, and/or back pain. Bronchitis is caused by the spread of an upper respiratory infection into the bronchi and may occur along with other diseases such as measles, pertussis, and/or diphtheria.Influenza is a highly contagious common infectious disease of the respiratory tract caused by a virus and transmitted by airborne droplet infection. The symptoms of Influenza are often similar to those of the catarrhal stage of Pertussis including sore throat, excessive mucous, cough, fever, general weakness, and/or muscle pains.Other bacteria that are related to the Bordetella pertussis may cause symptoms that are very similar to those of Pertussis. These bacteria include Bordetella parapertussis and Bordetella bronchiseptica.
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Diagnosis of Pertussis
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The diagnosis of Pertussis may be confirmed by isolating the organism Bordetella pertussis from the sputum of an affected individual. These sputum samples are best obtained using a cotton swab that is placed through the nose into the rear portion of the throat (posterior pharynx). The paroxysmal phase of Pertussis is associated with very high levels of white cells in the blood (i.e., lymphocytosis).
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Diagnosis of Pertussis. The diagnosis of Pertussis may be confirmed by isolating the organism Bordetella pertussis from the sputum of an affected individual. These sputum samples are best obtained using a cotton swab that is placed through the nose into the rear portion of the throat (posterior pharynx). The paroxysmal phase of Pertussis is associated with very high levels of white cells in the blood (i.e., lymphocytosis).
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Therapies of Pertussis
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PreventionThe most important treatment for Pertussis is prevention. The DPT vaccine is provided to infants and although there may be some discomfort from the injection, it is generally safe and effective. There may be extremely rare but serious adverse reactions in some children. These should be immediately brought to the attention of a physician when they begin to appear.An acellular vaccine, which is made with part of the bacterium that causes Pertussis rather than the whole bacterium, is available for vaccination of infants. Known as Tripedia, the vaccine is manufactured by Connaught Laboratories. It is hoped that this acellular vaccine will produce fewer side effects (e.g., fever, seizures, etc.) than cellular vaccines.Adverse reactions have been associated with the Diphtheria Pertussis Tetanus (DPT) vaccination and the risk for these reactions increases with age. In most circumstances, vaccination is not recommended for children over the age of seven years. Adverse reactions may be local or systemic. Local reactions may include pain, skin redness (erythema), and/or swelling. Elevated temperature is a common systemic reaction to the pertussis vaccine. In some rare cases, a fever of over 104.9F degrees has been reported. Other very rare complications have included seizures, shock, and severe hypersensitivity reactions (anaphylaxis). The most severe complication of the DPT vaccination is the very rare occurrence of brain inflammation (encephalopathy). (For more information on these allergic reactions, choose “Anaphylaxis” as your search term in the Rare Disease Database.)A new combined vaccine, known as Certiva, for diphtheria, tetanus, and acellular pertussis (DTaP) has been approved by the Food and Drug Administration (FDA) as a preventative measure against these illnesses. For more information, contact:NIH/National Institute of Child Health and Human Development9000 Rockville PikeBuilding 31 Rm 2a32, Msc 2425Bethesda, M. 20892Tel: (301) 496-5133Fax: (301) 496-7101Website: http://www.nih.gov/nichd/TreatmentThe treatment of Pertussis involves the administration of antibiotic drugs that help to clear the bacteria from the throat of affected individuals, usually within three to four days. By the fourth day of treatment, the disease is no longer contagious. Erythromycin is the antibiotic drug of choice and is routinely given because it halts transmission of the disease to others. A course of antibiotic therapy may also be prescribed to those individuals who have been in close contact with affected individuals, especially children. The combination of trimethoprim-sulfamethoxazole is an alternative antibiotic therapy that is given to those who cannot tolerate erythromycin.Recently, the Centers for Disease Control (CDC) reported that erythromycin may caus. pyloric stenosis, a severe stomach disorder, in some babies. Pyloric stenosis blocks digestion and causes projectile vomiting. However, while CDC urges physicians and parents to be aware of this potentially serious side-effect, it does not recommend that physicians stop prescribing erythromycin for Pertussis.Seriously ill infants with Pertussis should be kept in a dark and quiet room. They should be disturbed as little as possible to help prevent frequent episodes of severe coughing. Close attention should be paid to the nutritional needs of the infant, since poor nutrition can contribute significantly to complications. Small meals should be given as frequently as possible. Expectorant cough mixtures, cough suppressants, and sedatives are of little value and should be used cautiously or not at all.Hospitalization may be recommended for seriously ill infants with Pertussis. Parenteral fluid (IV) therapy may be required to replace salt and water loss if vomiting is severe. Careful suctioning of the throat may become necessary to clear excessive mucous secretions. When suctioning is not able to clear the airway, a surgical procedure may be performed to create a temporary opening into the throat (tracheostomy). A tube is then inserted into this opening, through which oxygen is supplied to the lungs. Oxygen may also be administered to affected infants if their skin and mucous membranes have a bluish discoloration (cyanotic) after the removal of secretions from the throat. This type of intensive supportive care may be lifesaving in very severe cases of Pertussis.
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Therapies of Pertussis. PreventionThe most important treatment for Pertussis is prevention. The DPT vaccine is provided to infants and although there may be some discomfort from the injection, it is generally safe and effective. There may be extremely rare but serious adverse reactions in some children. These should be immediately brought to the attention of a physician when they begin to appear.An acellular vaccine, which is made with part of the bacterium that causes Pertussis rather than the whole bacterium, is available for vaccination of infants. Known as Tripedia, the vaccine is manufactured by Connaught Laboratories. It is hoped that this acellular vaccine will produce fewer side effects (e.g., fever, seizures, etc.) than cellular vaccines.Adverse reactions have been associated with the Diphtheria Pertussis Tetanus (DPT) vaccination and the risk for these reactions increases with age. In most circumstances, vaccination is not recommended for children over the age of seven years. Adverse reactions may be local or systemic. Local reactions may include pain, skin redness (erythema), and/or swelling. Elevated temperature is a common systemic reaction to the pertussis vaccine. In some rare cases, a fever of over 104.9F degrees has been reported. Other very rare complications have included seizures, shock, and severe hypersensitivity reactions (anaphylaxis). The most severe complication of the DPT vaccination is the very rare occurrence of brain inflammation (encephalopathy). (For more information on these allergic reactions, choose “Anaphylaxis” as your search term in the Rare Disease Database.)A new combined vaccine, known as Certiva, for diphtheria, tetanus, and acellular pertussis (DTaP) has been approved by the Food and Drug Administration (FDA) as a preventative measure against these illnesses. For more information, contact:NIH/National Institute of Child Health and Human Development9000 Rockville PikeBuilding 31 Rm 2a32, Msc 2425Bethesda, M. 20892Tel: (301) 496-5133Fax: (301) 496-7101Website: http://www.nih.gov/nichd/TreatmentThe treatment of Pertussis involves the administration of antibiotic drugs that help to clear the bacteria from the throat of affected individuals, usually within three to four days. By the fourth day of treatment, the disease is no longer contagious. Erythromycin is the antibiotic drug of choice and is routinely given because it halts transmission of the disease to others. A course of antibiotic therapy may also be prescribed to those individuals who have been in close contact with affected individuals, especially children. The combination of trimethoprim-sulfamethoxazole is an alternative antibiotic therapy that is given to those who cannot tolerate erythromycin.Recently, the Centers for Disease Control (CDC) reported that erythromycin may caus. pyloric stenosis, a severe stomach disorder, in some babies. Pyloric stenosis blocks digestion and causes projectile vomiting. However, while CDC urges physicians and parents to be aware of this potentially serious side-effect, it does not recommend that physicians stop prescribing erythromycin for Pertussis.Seriously ill infants with Pertussis should be kept in a dark and quiet room. They should be disturbed as little as possible to help prevent frequent episodes of severe coughing. Close attention should be paid to the nutritional needs of the infant, since poor nutrition can contribute significantly to complications. Small meals should be given as frequently as possible. Expectorant cough mixtures, cough suppressants, and sedatives are of little value and should be used cautiously or not at all.Hospitalization may be recommended for seriously ill infants with Pertussis. Parenteral fluid (IV) therapy may be required to replace salt and water loss if vomiting is severe. Careful suctioning of the throat may become necessary to clear excessive mucous secretions. When suctioning is not able to clear the airway, a surgical procedure may be performed to create a temporary opening into the throat (tracheostomy). A tube is then inserted into this opening, through which oxygen is supplied to the lungs. Oxygen may also be administered to affected infants if their skin and mucous membranes have a bluish discoloration (cyanotic) after the removal of secretions from the throat. This type of intensive supportive care may be lifesaving in very severe cases of Pertussis.
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Overview of Peutz Jeghers Syndrome
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SummaryPeutz Jeghers syndrome (PJS) is an autosomal dominant genetic condition affecting around 1/50,000 and 1/200,000 individuals. Symptoms usually appear during the first decade of life and begin with spots of dark skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers as well as inside the mouth (oral mucosa) and around the anus (perianal). Multiple benign polyps called hamartomas also begin to grow in the gastrointestinal tract of affected individuals around that age. These polyps are located throughout the gastrointestinal tract and can cause nausea, vomiting, abdominal pain, intestinal obstruction and rectal bleeding. Abdominal surgery or endoscopic procedures might be necessary to remove polyps (polypectomy) to prevent polyps-related complications, such as folding of the intestine into itself (intussusception). Affected individuals have an increased risk for intestinal and other cancers. Frequent medical examination and testing is necessary to allow early detection of polyps and cancer.IntroductionPeutz Jeghers syndrome is part of a heterogeneous group of disorders, known as hamartomatous polyposis syndromes that involve the growth of multiple polyps in the gastrointestinal tract of affected individuals. It was first described in a pair of twin sisters with dark pigment spots on their lips and oral mucosa by Dr. J.T. Connor in 1895. These symptoms were attributed to a familial syndrome in 1921, when Dr. Jan Peutz described four affected siblings. The syndrome was then defined as a distinct entity by Dr. Harold Jeghers in 1949 when he described 10 cases and was subsequently named Peutz Jeghers syndrome in 1954 by Dr. Andre Bruwer. The gene causing PJS (STK-11/LKB1) was identified in 1998 and allows early detection of the disease and screening of family members.
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Overview of Peutz Jeghers Syndrome. SummaryPeutz Jeghers syndrome (PJS) is an autosomal dominant genetic condition affecting around 1/50,000 and 1/200,000 individuals. Symptoms usually appear during the first decade of life and begin with spots of dark skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers as well as inside the mouth (oral mucosa) and around the anus (perianal). Multiple benign polyps called hamartomas also begin to grow in the gastrointestinal tract of affected individuals around that age. These polyps are located throughout the gastrointestinal tract and can cause nausea, vomiting, abdominal pain, intestinal obstruction and rectal bleeding. Abdominal surgery or endoscopic procedures might be necessary to remove polyps (polypectomy) to prevent polyps-related complications, such as folding of the intestine into itself (intussusception). Affected individuals have an increased risk for intestinal and other cancers. Frequent medical examination and testing is necessary to allow early detection of polyps and cancer.IntroductionPeutz Jeghers syndrome is part of a heterogeneous group of disorders, known as hamartomatous polyposis syndromes that involve the growth of multiple polyps in the gastrointestinal tract of affected individuals. It was first described in a pair of twin sisters with dark pigment spots on their lips and oral mucosa by Dr. J.T. Connor in 1895. These symptoms were attributed to a familial syndrome in 1921, when Dr. Jan Peutz described four affected siblings. The syndrome was then defined as a distinct entity by Dr. Harold Jeghers in 1949 when he described 10 cases and was subsequently named Peutz Jeghers syndrome in 1954 by Dr. Andre Bruwer. The gene causing PJS (STK-11/LKB1) was identified in 1998 and allows early detection of the disease and screening of family members.
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Symptoms of Peutz Jeghers Syndrome
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PJS is characterized by the growth of multiple benign polyps called hamartomas on the mucous lining of the gastrointestinal system and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus (perianal). These melanocytic macules can appear as early as the first year of life and are present in most affected children under five years of age. They tend to fade away with age and might completely disappear in puberty or adulthood, although they tend to persist in the oral mucosa. Polyps also begin to grow within the first years of life, but associated symptoms typically arise between 10 to 30 years of age. Around half of patients with PJS have to undergo surgery by age 18 because of polyps-related complication. Polyps most often tend to develop in the small intestine (in the jejunum, specifically) but can also arise in the stomach and large intestine. Rarely, polyps can grow outside the gastrointestinal tract and affect the ureters, bladder, lungs, bronchi, and gallbladder. Gastrointestinal polyps can cause abdominal pain, vomiting, diarrhea, intestinal obstruction and rectal bleeding, which can lead to anemia. They can also provoke folding of the intestine into itself (intussusception), which can lead to severe abdominal pain and emergency surgery. Individuals with Peutz Jeghers syndrome are at a highly increased risk of developing gastrointestinal and other cancers including breast, cervical, uterine, pancreas, and lung. The lifetime risk of developing cancer in affected individuals can be as high as 93%. Individuals that develop cancer are usually affected around their fifth decade of life (age 40-49). Affected females have an increased risk for a benign ovarian tumor called SCTAT (sex cord tumors with annular tumors) for which symptoms may include irregular or heavy periods or early puberty. Usually before age 20, affected males can develop a tumor in the testes, called Sertoli cells carcinoma that secretes estrogen and can lead to breast development (gynecomastia).
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Symptoms of Peutz Jeghers Syndrome. PJS is characterized by the growth of multiple benign polyps called hamartomas on the mucous lining of the gastrointestinal system and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus (perianal). These melanocytic macules can appear as early as the first year of life and are present in most affected children under five years of age. They tend to fade away with age and might completely disappear in puberty or adulthood, although they tend to persist in the oral mucosa. Polyps also begin to grow within the first years of life, but associated symptoms typically arise between 10 to 30 years of age. Around half of patients with PJS have to undergo surgery by age 18 because of polyps-related complication. Polyps most often tend to develop in the small intestine (in the jejunum, specifically) but can also arise in the stomach and large intestine. Rarely, polyps can grow outside the gastrointestinal tract and affect the ureters, bladder, lungs, bronchi, and gallbladder. Gastrointestinal polyps can cause abdominal pain, vomiting, diarrhea, intestinal obstruction and rectal bleeding, which can lead to anemia. They can also provoke folding of the intestine into itself (intussusception), which can lead to severe abdominal pain and emergency surgery. Individuals with Peutz Jeghers syndrome are at a highly increased risk of developing gastrointestinal and other cancers including breast, cervical, uterine, pancreas, and lung. The lifetime risk of developing cancer in affected individuals can be as high as 93%. Individuals that develop cancer are usually affected around their fifth decade of life (age 40-49). Affected females have an increased risk for a benign ovarian tumor called SCTAT (sex cord tumors with annular tumors) for which symptoms may include irregular or heavy periods or early puberty. Usually before age 20, affected males can develop a tumor in the testes, called Sertoli cells carcinoma that secretes estrogen and can lead to breast development (gynecomastia).
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Causes of Peutz Jeghers Syndrome
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Peutz Jeghers syndrome is an autosomal dominant genetic condition caused by mutations in the STK11/LKB1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Approximately 60-78% of individuals with PJS have an affected relative. Around 80-94% of PJS patients have an identified mutation in the STK11 gene, which means that other genes are possibly involved in the disease. More than 200 disease-causing (pathogenic) mutations have been reported and the penetrance of these mutations is thought to be 100%, meaning that an individual carrying a pathogenic mutation will necessarily develop the disease.The STK11 gene produces a protein that is involved in the regulation of cell division and programmed cell death (apoptosis). It also interacts with p53, a major tumor suppression protein. Pathogenic mutations in STK11 lead to either cessation or dysfunction of protein production by the gene and uncontrolled cell growth, which can in turn lead to the development of benign polyps (hamartomas) and cancer.The dark pigmented spots (melanocytic macules) are thought to be caused by inflammation and blockage of melanin migration from cells where it is produced (melanocytes) to cells forming the outermost layer of the skin (keratinocytes).
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Causes of Peutz Jeghers Syndrome. Peutz Jeghers syndrome is an autosomal dominant genetic condition caused by mutations in the STK11/LKB1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Approximately 60-78% of individuals with PJS have an affected relative. Around 80-94% of PJS patients have an identified mutation in the STK11 gene, which means that other genes are possibly involved in the disease. More than 200 disease-causing (pathogenic) mutations have been reported and the penetrance of these mutations is thought to be 100%, meaning that an individual carrying a pathogenic mutation will necessarily develop the disease.The STK11 gene produces a protein that is involved in the regulation of cell division and programmed cell death (apoptosis). It also interacts with p53, a major tumor suppression protein. Pathogenic mutations in STK11 lead to either cessation or dysfunction of protein production by the gene and uncontrolled cell growth, which can in turn lead to the development of benign polyps (hamartomas) and cancer.The dark pigmented spots (melanocytic macules) are thought to be caused by inflammation and blockage of melanin migration from cells where it is produced (melanocytes) to cells forming the outermost layer of the skin (keratinocytes).
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Affects of Peutz Jeghers Syndrome
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Peutz Jeghers syndrome is a rare disorder that affects males and females in equal numbers and can occur in any racial or ethnic group. The birth prevalence of PJS is estimated to be between 1/50,000 and 1/200,000. Limited evidence shows that the disease might be more prevalent in certain countries such as the Netherlands and China. Women are at a higher risk of developing cancer compared to men, as PJS increases the likelihood of developing breast, ovarian, cervical, and uterine cancer.
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Affects of Peutz Jeghers Syndrome. Peutz Jeghers syndrome is a rare disorder that affects males and females in equal numbers and can occur in any racial or ethnic group. The birth prevalence of PJS is estimated to be between 1/50,000 and 1/200,000. Limited evidence shows that the disease might be more prevalent in certain countries such as the Netherlands and China. Women are at a higher risk of developing cancer compared to men, as PJS increases the likelihood of developing breast, ovarian, cervical, and uterine cancer.
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Related disorders of Peutz Jeghers Syndrome
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Symptoms of the following disorders can be similar to those of Peutz-Jeghers syndrome. Comparisons may be useful for a differential diagnosis: Juvenile polyposis syndrome is an autosomal dominant genetic disorder characterized by a specific type of hamartomatous polyp referred to as a juvenile polyp . Most polyps are benign but affected individuals are at an increased risk for colon and other cancers.Serrated polyposis syndrome is an autosomal dominant genetic disorder characterized by a specific type of polyp referred to as a serrated (saw-tooth) polyp located in the colorectum. Most polyps are benign but serrated polyposis is associated with an increased personal and family history of colorectal cancer.Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by mutations in the APC gene. (For more information on this disorder, choose “familial adenomatous polyposis” as your search term in the Rare Disease Database.)Turcot syndrome is a rare inherited disorder characterized by the association of benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract with tumors of the central nervous system. Symptoms associated with polyp formation may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. Affected individuals may also experience neurological symptoms, depending upon the type, size and location of the associated brain tumor. Researchers believe that Turcot syndrome is a variant of familial adenomatous polyposis or Lynch syndrome (hereditary nonpolyposis colorectal cancer). (For more information on this disorder, choose “Turcot syndrome” as your search term in the Rare Disease Database.)Hereditary mixed polyposis syndrome is an autosomal dominant genetic disorder characterized by the development of multiple types of polyps (atypical juvenile polyps, hyperplastic polyps, sessile serrated adenomas, and adenomatous polyps) in the gastrointestinal tract. Affected individuals are at an increased risk for colorectal cancer.The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations in the PTEN tumor suppressor gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Findings in PHTS also include increased risk for certain types of cancer and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age. (For more information on this disorder, choose “PTEN hamartoma tumor syndrome” as your search term in the Rare Disease Database.)Cronkhite-Canada syndrome (CCS) is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss, and nail growth problems. CCS occurs primarily in the older population (average age 59) and predominantly occurs in males. It is considered to be an acquired, not hereditary, disease. (For more information on this disorder, choose “Cronkhite-Canada syndrome” as your search term in the Rare Disease Database.)Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic disorder characterized by an increased risk of developing a specific form of thyroid cancer (medullary thyroid carcinoma) and benign tumors affecting additional glands of the endocrine system. Individuals with one particular type of the syndrome, called MEN2B, can develop benign growths arising from nerve cells called ganglion cells (ganglioneuromatosis). These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation, and an abnormally enlarged colon (megacolon). Affected infants often fail to gain weight and grow at the expected rate for age and sex (failure to thrive). (For more information on this disorder, choose “multiple endocrine neoplasia type 2” as your search term in the Rare Disease Database.)Carney complex is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common in individuals with Carney complex and, most often, are found in the heart where they can potentially cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. A wide variety of endocrine abnormalities potentially can occur in Carney complex affecting a variety of glands. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi). (For more information on this disorder, choose “Carney complex” as your search term in the Rare Disease Database.)
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Related disorders of Peutz Jeghers Syndrome. Symptoms of the following disorders can be similar to those of Peutz-Jeghers syndrome. Comparisons may be useful for a differential diagnosis: Juvenile polyposis syndrome is an autosomal dominant genetic disorder characterized by a specific type of hamartomatous polyp referred to as a juvenile polyp . Most polyps are benign but affected individuals are at an increased risk for colon and other cancers.Serrated polyposis syndrome is an autosomal dominant genetic disorder characterized by a specific type of polyp referred to as a serrated (saw-tooth) polyp located in the colorectum. Most polyps are benign but serrated polyposis is associated with an increased personal and family history of colorectal cancer.Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by mutations in the APC gene. (For more information on this disorder, choose “familial adenomatous polyposis” as your search term in the Rare Disease Database.)Turcot syndrome is a rare inherited disorder characterized by the association of benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract with tumors of the central nervous system. Symptoms associated with polyp formation may include diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain, and weight loss. Affected individuals may also experience neurological symptoms, depending upon the type, size and location of the associated brain tumor. Researchers believe that Turcot syndrome is a variant of familial adenomatous polyposis or Lynch syndrome (hereditary nonpolyposis colorectal cancer). (For more information on this disorder, choose “Turcot syndrome” as your search term in the Rare Disease Database.)Hereditary mixed polyposis syndrome is an autosomal dominant genetic disorder characterized by the development of multiple types of polyps (atypical juvenile polyps, hyperplastic polyps, sessile serrated adenomas, and adenomatous polyps) in the gastrointestinal tract. Affected individuals are at an increased risk for colorectal cancer.The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations in the PTEN tumor suppressor gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Findings in PHTS also include increased risk for certain types of cancer and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age. (For more information on this disorder, choose “PTEN hamartoma tumor syndrome” as your search term in the Rare Disease Database.)Cronkhite-Canada syndrome (CCS) is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss, and nail growth problems. CCS occurs primarily in the older population (average age 59) and predominantly occurs in males. It is considered to be an acquired, not hereditary, disease. (For more information on this disorder, choose “Cronkhite-Canada syndrome” as your search term in the Rare Disease Database.)Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic disorder characterized by an increased risk of developing a specific form of thyroid cancer (medullary thyroid carcinoma) and benign tumors affecting additional glands of the endocrine system. Individuals with one particular type of the syndrome, called MEN2B, can develop benign growths arising from nerve cells called ganglion cells (ganglioneuromatosis). These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation, and an abnormally enlarged colon (megacolon). Affected infants often fail to gain weight and grow at the expected rate for age and sex (failure to thrive). (For more information on this disorder, choose “multiple endocrine neoplasia type 2” as your search term in the Rare Disease Database.)Carney complex is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common in individuals with Carney complex and, most often, are found in the heart where they can potentially cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. A wide variety of endocrine abnormalities potentially can occur in Carney complex affecting a variety of glands. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi). (For more information on this disorder, choose “Carney complex” as your search term in the Rare Disease Database.)
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Peutz Jeghers Syndrome
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Diagnosis of Peutz Jeghers Syndrome
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A clinical diagnosis of Peutz Jeghers syndrome can be made when any one of the following criteria is present:The melanocytic macules can be identified with a physical examination. Polyps can be detected by endoscopy, x-ray examination, or wireless capsule endoscopy and are classified as PJS polyps by microscopic examination.Genetic testing for the identification of disease-causing (pathogenic) mutations in the STK11 gene is recommended when any one of the following criteria is present:Genetic testing is particularly useful when a pathogenic mutation has already been identified in a family. The penetrance of the STK11 gene mutation is thought to be 100% (which means that someone with a pathogenic mutation has a 100% chance of developing the disease), so genetic testing can give a definite diagnosis before symptoms appear. About half of PJS patients are diagnosed with genetic testing before the appearance of symptoms.
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Diagnosis of Peutz Jeghers Syndrome. A clinical diagnosis of Peutz Jeghers syndrome can be made when any one of the following criteria is present:The melanocytic macules can be identified with a physical examination. Polyps can be detected by endoscopy, x-ray examination, or wireless capsule endoscopy and are classified as PJS polyps by microscopic examination.Genetic testing for the identification of disease-causing (pathogenic) mutations in the STK11 gene is recommended when any one of the following criteria is present:Genetic testing is particularly useful when a pathogenic mutation has already been identified in a family. The penetrance of the STK11 gene mutation is thought to be 100% (which means that someone with a pathogenic mutation has a 100% chance of developing the disease), so genetic testing can give a definite diagnosis before symptoms appear. About half of PJS patients are diagnosed with genetic testing before the appearance of symptoms.
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Peutz Jeghers Syndrome
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Therapies of Peutz Jeghers Syndrome
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Treatment
A consultation with a clinical geneticist or genetic counselor should be offered. As there is no cure for Peutz Jeghers syndrome, treatment is mostly focused on surveillance and control of symptoms. After initial diagnosis, it is recommended that individuals older than 8 years or having symptoms undergo endoscopic and small bowel examination. The latter can be done with magnetic resonance imaging of the intestines (magnetic resonance enterography, MRE) or by swallowing a capsule that records internal images from inside the gastrointestinal tract (video capsule endoscopy, VCE). Gynecologic and breast examination are also recommended for women older than 18 years. Testicular examination is recommended for men. Following initial workup after the diagnosis, endoscopy, colonoscopy, and small bowel examination should be performed every 2-3 years to detect polyps and potential tumors. An annual mammogram is recommended for women. Testicular ultrasound can be done every two years for men.As PJS increases the risk of breast, uterine, and ovarian cancer, it is possible for affected women to undergo preventive mastectomy, hysterectomy or salpingo-oophorectomy (surgical removal of the breasts, uterus, and fallopian tubes and ovaries, respectively).Polyps over 1 cm in size are removed with endoscopic techniques to avoid polyps-related complications such as bleeding and intussusception. These complications might require surgical interventions to be corrected. If a patient undergoes surgery, endoscopic removal of polyps (polypectomy) is performed at the same time as surgery to reduce the risk of recurrence of complications and surgery.In cases where dark pigmented spots (melanocytic macules) have a greatly negative psychological impact on affected individuals, they can be partially removed with laser treatment.
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Therapies of Peutz Jeghers Syndrome. Treatment
A consultation with a clinical geneticist or genetic counselor should be offered. As there is no cure for Peutz Jeghers syndrome, treatment is mostly focused on surveillance and control of symptoms. After initial diagnosis, it is recommended that individuals older than 8 years or having symptoms undergo endoscopic and small bowel examination. The latter can be done with magnetic resonance imaging of the intestines (magnetic resonance enterography, MRE) or by swallowing a capsule that records internal images from inside the gastrointestinal tract (video capsule endoscopy, VCE). Gynecologic and breast examination are also recommended for women older than 18 years. Testicular examination is recommended for men. Following initial workup after the diagnosis, endoscopy, colonoscopy, and small bowel examination should be performed every 2-3 years to detect polyps and potential tumors. An annual mammogram is recommended for women. Testicular ultrasound can be done every two years for men.As PJS increases the risk of breast, uterine, and ovarian cancer, it is possible for affected women to undergo preventive mastectomy, hysterectomy or salpingo-oophorectomy (surgical removal of the breasts, uterus, and fallopian tubes and ovaries, respectively).Polyps over 1 cm in size are removed with endoscopic techniques to avoid polyps-related complications such as bleeding and intussusception. These complications might require surgical interventions to be corrected. If a patient undergoes surgery, endoscopic removal of polyps (polypectomy) is performed at the same time as surgery to reduce the risk of recurrence of complications and surgery.In cases where dark pigmented spots (melanocytic macules) have a greatly negative psychological impact on affected individuals, they can be partially removed with laser treatment.
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Peutz Jeghers Syndrome
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nord_961_0
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Overview of Pfeiffer Syndrome
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Pfeiffer syndrome is a rare genetic disorder characterized by premature fusion of certain skull bones (craniosynostosis) and broad and medially deviated thumbs and great toes. Most affected individuals also have differences to their midface (protruding eyes) and conductive hearing loss. Three forms of Pfeiffer syndrome are recognized, of which types II and III are the more serious. Pfeiffer syndrome is an autosomal dominant condition associated with changes (pathogenic variants or mutations) in the genes fibroblast growth factor receptor-2 (FGFR2) and fibroblast growth factor receptor-1 (FGFR1). Pfeiffer syndrome is now known to be a member of a group of conditions caused by variants in the FGFR genes including Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans and Muenke syndrome. (For more information on these conditions, please see the Related Disorders section below.)
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Overview of Pfeiffer Syndrome. Pfeiffer syndrome is a rare genetic disorder characterized by premature fusion of certain skull bones (craniosynostosis) and broad and medially deviated thumbs and great toes. Most affected individuals also have differences to their midface (protruding eyes) and conductive hearing loss. Three forms of Pfeiffer syndrome are recognized, of which types II and III are the more serious. Pfeiffer syndrome is an autosomal dominant condition associated with changes (pathogenic variants or mutations) in the genes fibroblast growth factor receptor-2 (FGFR2) and fibroblast growth factor receptor-1 (FGFR1). Pfeiffer syndrome is now known to be a member of a group of conditions caused by variants in the FGFR genes including Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans and Muenke syndrome. (For more information on these conditions, please see the Related Disorders section below.)
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Pfeiffer Syndrome
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Symptoms of Pfeiffer Syndrome
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Infants with Pfeiffer syndrome type I have craniosynostosis that causes the head to appear short and tall (turribrachycephaly). Additional features may include a high, full forehead; underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); an underdeveloped upper jaw (hypoplastic maxilla), with a prominent lower jaw; and dental abnormalities. Intelligence is usually normal. There is usually some degree of hearing loss, which is more commonly conductive rather than sensorineural. Pfeiffer syndrome type II is characterized by a more severe form of craniosynostosis (cloverleaf skull), with more severe hand and foot anomalies and additional malformations of the limbs. In infants with Pfeiffer syndrome type II, premature closure of the fibrous joints (cranial sutures) between several bones in the skull causes the skull to have a “tri-lobed” appearance (cloverleaf skull deformity, or Kleeblattschadel type craniosynostosis). In addition, this form of craniosynostosis is often associated with hydrocephalus, a condition in which the normal flow of cerebrospinal fluid (CSF) is altered, leading to abnormal widening (dilatation) of the spaces within the brain (ventricles) causing accumulation of CSF in the skull and increased pressure on the brain. Characteristic craniofacial features associated with Pfeiffer syndrome type II may include an abnormally high, broad forehead; severe protrusion of the eyes (ocular proptosis); an unusually flat middle portion of the face (midface hypoplasia); a “beak-shaped” nose; and downwardly displaced ears. Besides craniofacial features, some may have abnormalities in the structure of segments of the spinal column. Affected infants may also exhibit fixation and lack of mobility (ankylosis) of the elbow joints and/or, in some people, various malformations of certain internal organs in the abdomen (visceral anomalies). In addition, infants with Pfeiffer syndrome type II often experience impaired mental development and neurological problems due to severe involvement of the brain, and/or hypoxia due to problems with breathing. Without appropriate treatment, the physical abnormalities associated with the disorder may lead to life-threatening complications during infancy. Severe obstructive sleep apnea is common. Additionally, closure of the tracheal cartilage (tracheal cartilaginous sleeve) can worsen breathing problems. Individuals with Pfeiffer syndrome type III have symptoms and findings similar to those present in Pfeiffer syndrome type II, with the exception of the cloverleaf skull deformity. Additional characteristics associated with Pfeiffer syndrome type III include a shortened base of the skull (anterior cranial base); the abnormal presence of certain teeth at birth (natal teeth); severe protrusion of the eyes (ocular proptosis) due to shallowness of the bony cavities that accommodate the eyeballs (orbit); and/or various malformations of certain internal organs in the abdominal area (visceral anomalies). As in type II, individuals with Pfeiffer syndrome type III often experience impaired mental development and severe neurological problems and may develop potentially life-threatening complications early in life without appropriate treatment.
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Symptoms of Pfeiffer Syndrome. Infants with Pfeiffer syndrome type I have craniosynostosis that causes the head to appear short and tall (turribrachycephaly). Additional features may include a high, full forehead; underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); an underdeveloped upper jaw (hypoplastic maxilla), with a prominent lower jaw; and dental abnormalities. Intelligence is usually normal. There is usually some degree of hearing loss, which is more commonly conductive rather than sensorineural. Pfeiffer syndrome type II is characterized by a more severe form of craniosynostosis (cloverleaf skull), with more severe hand and foot anomalies and additional malformations of the limbs. In infants with Pfeiffer syndrome type II, premature closure of the fibrous joints (cranial sutures) between several bones in the skull causes the skull to have a “tri-lobed” appearance (cloverleaf skull deformity, or Kleeblattschadel type craniosynostosis). In addition, this form of craniosynostosis is often associated with hydrocephalus, a condition in which the normal flow of cerebrospinal fluid (CSF) is altered, leading to abnormal widening (dilatation) of the spaces within the brain (ventricles) causing accumulation of CSF in the skull and increased pressure on the brain. Characteristic craniofacial features associated with Pfeiffer syndrome type II may include an abnormally high, broad forehead; severe protrusion of the eyes (ocular proptosis); an unusually flat middle portion of the face (midface hypoplasia); a “beak-shaped” nose; and downwardly displaced ears. Besides craniofacial features, some may have abnormalities in the structure of segments of the spinal column. Affected infants may also exhibit fixation and lack of mobility (ankylosis) of the elbow joints and/or, in some people, various malformations of certain internal organs in the abdomen (visceral anomalies). In addition, infants with Pfeiffer syndrome type II often experience impaired mental development and neurological problems due to severe involvement of the brain, and/or hypoxia due to problems with breathing. Without appropriate treatment, the physical abnormalities associated with the disorder may lead to life-threatening complications during infancy. Severe obstructive sleep apnea is common. Additionally, closure of the tracheal cartilage (tracheal cartilaginous sleeve) can worsen breathing problems. Individuals with Pfeiffer syndrome type III have symptoms and findings similar to those present in Pfeiffer syndrome type II, with the exception of the cloverleaf skull deformity. Additional characteristics associated with Pfeiffer syndrome type III include a shortened base of the skull (anterior cranial base); the abnormal presence of certain teeth at birth (natal teeth); severe protrusion of the eyes (ocular proptosis) due to shallowness of the bony cavities that accommodate the eyeballs (orbit); and/or various malformations of certain internal organs in the abdominal area (visceral anomalies). As in type II, individuals with Pfeiffer syndrome type III often experience impaired mental development and severe neurological problems and may develop potentially life-threatening complications early in life without appropriate treatment.
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Pfeiffer Syndrome
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Causes of Pfeiffer Syndrome
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Pfeiffer syndrome type I is associated with variants in FGFR1 and FGFR2. Pfeiffer syndrome type II and type III are associated with variants in FGFR2. Pfeiffer syndrome is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Essentially all cases of Pfeiffer syndrome type II and type III have resulted from new mutations. Advanced paternal age is associated with an increased risk for new mutations for Pfeiffer syndrome. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Pfeiffer Syndrome. Pfeiffer syndrome type I is associated with variants in FGFR1 and FGFR2. Pfeiffer syndrome type II and type III are associated with variants in FGFR2. Pfeiffer syndrome is an autosomal dominant genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Essentially all cases of Pfeiffer syndrome type II and type III have resulted from new mutations. Advanced paternal age is associated with an increased risk for new mutations for Pfeiffer syndrome. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Pfeiffer Syndrome
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Affects of Pfeiffer Syndrome
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The incidence of all types of Pfeiffer syndrome is approximately 1/100,000.
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Affects of Pfeiffer Syndrome. The incidence of all types of Pfeiffer syndrome is approximately 1/100,000.
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Pfeiffer Syndrome
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Related disorders of Pfeiffer Syndrome
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Apert syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the head that lead to distinctive facial features. In addition, the hands and/or feet may be webbed (syndactyly) and in some cases, intellectual disability may also be present. Babies born with Apert syndrome have fibrous joints between bones of the skull (sutures) that close prematurely (craniosynostosis). The pressure of continued brain growth distorts various bones of the skull and the face. The skull is forced into one of several characteristic shapes. Often the head appears abnormally pointed at the top (acrocephaly). The distortion of the skull plates creates changes in the facial bones leading to characteristic facial abnormalities, such as widely spaced eyes (ocular hypertelorism), abnormal protrusion of the eyes (exophthalmos), underdevelopment of midfacial regions (midface hypoplasia), and/or a narrow roof of the mouth (palate). Malformations of the hands and feet may include unusually broad thumbs and great toes, short fingers, and/or partial to complete fusion (syndactyly) of certain fingers and toes (digits). Most commonly, there is complete fusion of bones within the second to the fourth fingers and the presence of a single common nail (“mitten-like” syndactyly). Apert syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose “Apert” as your search term in the Rare Disease Database.)Crouzon syndrome is a rare genetic disorder that may be evident at birth (congenital) or during infancy. The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities may vary greatly in range and severity from person to person, including among affected family members. However, in most infants with Crouzon syndrome, the fibrous joints between certain bones of the skull (cranial sutures) close prematurely (craniosynostosis). In addition, facial abnormalities typically include unusual bulging or protrusion of the eyeballs (proptosis) due to shallow eye cavities (orbits); outward deviation of one of the eyes (divergent strabismus or exotropia); widely spaced eyes (ocular hypertelorism); and a small, underdeveloped upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). The presence of normal appearing hands and feet distinguishes Crouzon syndrome from Pfeiffer syndrome. Crouzon syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose “Crouzon as your search term in the Rare Disease Database.) Crouzon syndrome with acanthosis nigricans is a rare genetic disorder characterized by the signs and symptoms of Crouzon syndrome in combination with thick, dark areas in the skin folds (acathosis nigricans). This condition follows autosomal dominant inheritance and is associated with specific variants in FGFR3. Jackson-Weiss syndrome is an extremely rare genetic disorder characterized by craniosynostosis; an unusually flat middle portion of the face (midface hypoplasia); abnormally broad great toes; and/or webbing or fusion (syndactyly) of the second and third toes. The range and severity of symptoms and findings may vary greatly from person to person, including within affected family members (kindreds). Jackson-Weiss syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose “Jackson-Weiss” as your search term in the Rare Disease Database.) Beare-Stevenson syndrome is an extremely rare genetic disorder characterized by craniosynostosis, skin abnormalities called cutis gyrata and acanthosis nigricans and intellectual disability. Cutis gyrata are patches of skin with a furrowed and wrinkled appearance and are found most often on the face, near the ears and on the palms of hands and soles of feet. Acanthosis nigricans are patches of thick, dark areas in the skin folds. Genital and anal abnormalities may also be present. Beare-Stevenson syndrome is an autosomal dominant genetic condition associated with variants in the FGFR2 gene. Muenke syndrome is a rare genetic disorder characterized by premature fusion of skull bones over the top of the head from ear to ear (coronal craniosynostosis). Other symptoms can be similar to those of other disorders caused by FGFR variants. Muenke syndrome is an autosomal dominant genetic condition associated with a specific single variant in FGFR3. Some individuals with this specific FGFR3 variant do not have symptoms of the disorder. FGFR2-related isolated coronal synostosis is an autosomal dominant genetic disorder characterized by premature fusion of skull bones over the top of the head from ear to ear (coronal craniosynostosis) and no other major abnormalities. Many children also have hypertelorism as well. This condition follows autosomal dominant inheritance and is associated with variants in FGFR2.
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Related disorders of Pfeiffer Syndrome. Apert syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the head that lead to distinctive facial features. In addition, the hands and/or feet may be webbed (syndactyly) and in some cases, intellectual disability may also be present. Babies born with Apert syndrome have fibrous joints between bones of the skull (sutures) that close prematurely (craniosynostosis). The pressure of continued brain growth distorts various bones of the skull and the face. The skull is forced into one of several characteristic shapes. Often the head appears abnormally pointed at the top (acrocephaly). The distortion of the skull plates creates changes in the facial bones leading to characteristic facial abnormalities, such as widely spaced eyes (ocular hypertelorism), abnormal protrusion of the eyes (exophthalmos), underdevelopment of midfacial regions (midface hypoplasia), and/or a narrow roof of the mouth (palate). Malformations of the hands and feet may include unusually broad thumbs and great toes, short fingers, and/or partial to complete fusion (syndactyly) of certain fingers and toes (digits). Most commonly, there is complete fusion of bones within the second to the fourth fingers and the presence of a single common nail (“mitten-like” syndactyly). Apert syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose “Apert” as your search term in the Rare Disease Database.)Crouzon syndrome is a rare genetic disorder that may be evident at birth (congenital) or during infancy. The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities may vary greatly in range and severity from person to person, including among affected family members. However, in most infants with Crouzon syndrome, the fibrous joints between certain bones of the skull (cranial sutures) close prematurely (craniosynostosis). In addition, facial abnormalities typically include unusual bulging or protrusion of the eyeballs (proptosis) due to shallow eye cavities (orbits); outward deviation of one of the eyes (divergent strabismus or exotropia); widely spaced eyes (ocular hypertelorism); and a small, underdeveloped upper jaw (hypoplastic maxilla), with protrusion of the lower jaw (relative mandibular prognathism). The presence of normal appearing hands and feet distinguishes Crouzon syndrome from Pfeiffer syndrome. Crouzon syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose “Crouzon as your search term in the Rare Disease Database.) Crouzon syndrome with acanthosis nigricans is a rare genetic disorder characterized by the signs and symptoms of Crouzon syndrome in combination with thick, dark areas in the skin folds (acathosis nigricans). This condition follows autosomal dominant inheritance and is associated with specific variants in FGFR3. Jackson-Weiss syndrome is an extremely rare genetic disorder characterized by craniosynostosis; an unusually flat middle portion of the face (midface hypoplasia); abnormally broad great toes; and/or webbing or fusion (syndactyly) of the second and third toes. The range and severity of symptoms and findings may vary greatly from person to person, including within affected family members (kindreds). Jackson-Weiss syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose “Jackson-Weiss” as your search term in the Rare Disease Database.) Beare-Stevenson syndrome is an extremely rare genetic disorder characterized by craniosynostosis, skin abnormalities called cutis gyrata and acanthosis nigricans and intellectual disability. Cutis gyrata are patches of skin with a furrowed and wrinkled appearance and are found most often on the face, near the ears and on the palms of hands and soles of feet. Acanthosis nigricans are patches of thick, dark areas in the skin folds. Genital and anal abnormalities may also be present. Beare-Stevenson syndrome is an autosomal dominant genetic condition associated with variants in the FGFR2 gene. Muenke syndrome is a rare genetic disorder characterized by premature fusion of skull bones over the top of the head from ear to ear (coronal craniosynostosis). Other symptoms can be similar to those of other disorders caused by FGFR variants. Muenke syndrome is an autosomal dominant genetic condition associated with a specific single variant in FGFR3. Some individuals with this specific FGFR3 variant do not have symptoms of the disorder. FGFR2-related isolated coronal synostosis is an autosomal dominant genetic disorder characterized by premature fusion of skull bones over the top of the head from ear to ear (coronal craniosynostosis) and no other major abnormalities. Many children also have hypertelorism as well. This condition follows autosomal dominant inheritance and is associated with variants in FGFR2.
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Pfeiffer Syndrome
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Diagnosis of Pfeiffer Syndrome
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The diagnosis of Pfeiffer syndrome is based on clinical findings. Molecular genetic testing for FGFR1 and FGFR2 gene variants is available if the diagnosis is uncertain.
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Diagnosis of Pfeiffer Syndrome. The diagnosis of Pfeiffer syndrome is based on clinical findings. Molecular genetic testing for FGFR1 and FGFR2 gene variants is available if the diagnosis is uncertain.
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Pfeiffer Syndrome
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Therapies of Pfeiffer Syndrome
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Treatment
The treatment of Pfeiffer syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; surgeons; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); neurologists; ophthalmologists; specialists who assess and treat hearing problems (audiologists); and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively. Specific therapies for Pfeiffer syndrome are symptomatic and supportive. Because craniosynostosis and, in some cases, associated hydrocephalus may result in abnormally increased pressure within the skull (intracranial pressure) and on the brain, early surgery may be advised to correct craniosynostosis and, in the case of hydrocephalus, to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Early corrective and reconstructive surgery may also be performed in infants with Pfeiffer syndrome to help correct certain associated craniofacial differences (e.g., midface hypoplasia, facial asymmetry, nasal abnormalities, ocular proptosis due to shallow orbits). The results of such craniofacial surgery may vary, but often produce a significant decrease in ocular symptoms and breathing problems. These surgeries can temporarily worsen velopharyngeal insufficiency, making speaking and swallowing more difficult, but this resolves with time. Airway compromise can also occur, especially in very young children. This causes low oxygen levels that can, if unrecognized and untreated, result in brain damage. In many cases, particularly those with a tracheal cartilaginous sleeve, a surgical airway (tracheostomy) may be necessary. In addition, in some affected individuals, reconstructive surgery may be performed to help correct ear malformations and/or specialized hearing aids may be used to improve conductive hearing loss.In some individuals with Pfeiffer syndrome, surgery may also be conducted to help correct syndactyly and/or other skeletal malformations and improve function and mobility. Physical therapy and additional orthopedic and supportive measures may also be used to help further improve an affected individual’s mobility. The surgical procedure(s) performed to correct certain craniofacial, audiological, digital, and/or skeletal abnormalities associated with the disorder will depend upon the severity and location of the anatomical abnormalities and their associated symptoms.
Early intervention may be important to ensure that children with Pfeiffer syndrome reach their potential. Special services that may be beneficial to affected children include special social support, physical therapy, speech therapy, and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families. In addition, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any symptoms and physical characteristics that may be potentially associated with Pfeiffer syndrome.
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Therapies of Pfeiffer Syndrome. Treatment
The treatment of Pfeiffer syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; surgeons; physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists); neurologists; ophthalmologists; specialists who assess and treat hearing problems (audiologists); and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively. Specific therapies for Pfeiffer syndrome are symptomatic and supportive. Because craniosynostosis and, in some cases, associated hydrocephalus may result in abnormally increased pressure within the skull (intracranial pressure) and on the brain, early surgery may be advised to correct craniosynostosis and, in the case of hydrocephalus, to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. Early corrective and reconstructive surgery may also be performed in infants with Pfeiffer syndrome to help correct certain associated craniofacial differences (e.g., midface hypoplasia, facial asymmetry, nasal abnormalities, ocular proptosis due to shallow orbits). The results of such craniofacial surgery may vary, but often produce a significant decrease in ocular symptoms and breathing problems. These surgeries can temporarily worsen velopharyngeal insufficiency, making speaking and swallowing more difficult, but this resolves with time. Airway compromise can also occur, especially in very young children. This causes low oxygen levels that can, if unrecognized and untreated, result in brain damage. In many cases, particularly those with a tracheal cartilaginous sleeve, a surgical airway (tracheostomy) may be necessary. In addition, in some affected individuals, reconstructive surgery may be performed to help correct ear malformations and/or specialized hearing aids may be used to improve conductive hearing loss.In some individuals with Pfeiffer syndrome, surgery may also be conducted to help correct syndactyly and/or other skeletal malformations and improve function and mobility. Physical therapy and additional orthopedic and supportive measures may also be used to help further improve an affected individual’s mobility. The surgical procedure(s) performed to correct certain craniofacial, audiological, digital, and/or skeletal abnormalities associated with the disorder will depend upon the severity and location of the anatomical abnormalities and their associated symptoms.
Early intervention may be important to ensure that children with Pfeiffer syndrome reach their potential. Special services that may be beneficial to affected children include special social support, physical therapy, speech therapy, and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families. In addition, thorough clinical evaluations may be important in family members of diagnosed individuals to detect any symptoms and physical characteristics that may be potentially associated with Pfeiffer syndrome.
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Overview of PHACE Syndrome
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SummaryPHACE syndrome is a rare disorder that affects multiple systems of the body. This disorder is characterized by an association of several different abnormalities that occur together with greater frequency than would otherwise be expected. The term PHACE is an acronym; each letter stands for a word. The acronym comes from the first letter of some of the more common signs and symptoms of this disorder. PHACE stands for: (P)osterior fossa and other structural brain malformations; large (H)emangiomas of the face, neck, and/or scalp; anatomical anomalies of the cerebral or cervical (A)rteries; (C)ardiac anomalies/(C)oarctation of the aorta; and (E)ye abnormalities. If sternal anomalies are present, sometimes the term PHACES syndrome is used, with (S) standing for (S)ternal anomalies. The disorder occurs with much greater frequency in girls than boys. The specific symptoms and their severity can vary greatly from one individual to another. Most affected children will not exhibit all of the major symptoms potentially associated with this disorder. Some children with only develop mild problems associated with the disorder, while others will develop serious complications that greatly impact quality of life. The exact cause of PHACE syndrome is not known. PHACE syndrome was first identified in the medical literature in 1996.
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Overview of PHACE Syndrome. SummaryPHACE syndrome is a rare disorder that affects multiple systems of the body. This disorder is characterized by an association of several different abnormalities that occur together with greater frequency than would otherwise be expected. The term PHACE is an acronym; each letter stands for a word. The acronym comes from the first letter of some of the more common signs and symptoms of this disorder. PHACE stands for: (P)osterior fossa and other structural brain malformations; large (H)emangiomas of the face, neck, and/or scalp; anatomical anomalies of the cerebral or cervical (A)rteries; (C)ardiac anomalies/(C)oarctation of the aorta; and (E)ye abnormalities. If sternal anomalies are present, sometimes the term PHACES syndrome is used, with (S) standing for (S)ternal anomalies. The disorder occurs with much greater frequency in girls than boys. The specific symptoms and their severity can vary greatly from one individual to another. Most affected children will not exhibit all of the major symptoms potentially associated with this disorder. Some children with only develop mild problems associated with the disorder, while others will develop serious complications that greatly impact quality of life. The exact cause of PHACE syndrome is not known. PHACE syndrome was first identified in the medical literature in 1996.
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Symptoms of PHACE Syndrome
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Although researchers have been able to establish diagnostic criteria with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the relatively small number of identified cases, the lack of large clinical studies, and the possibility of multiple genes influencing the phenotype prevent physicians from developing a “one size fits all” description of PHACE and its prognosis. Therefore, it is important to note that every person is unique and that most affected individuals will not have all of the symptoms discussed below. The most noticeable sign associated with PHACE syndrome is often a hemangioma, which is an overgrowth of blood vessels that may appear as a red, purple, or blue birthmark. In these children, a hemangioma most often occurs on the face, head or neck. They may not be present or may be barely noticeable at birth, and become apparent and grow, sometimes quickly, in the weeks to months after birth. They usually become large, measuring more than 5 centimeters (approximately 2 inches). They can be one large area of discoloration or can consist of many smaller lesions in one area of the face, head, or neck. Hemangiomas can damage the skin causing sores (ulceration) or alter the appearance of facial features. If a hemangioma breaks open, it can be extremely painful. Hemangiomas can be superficial (only affecting the upper layers of the skin) or deep (extending deeper in the skin or in the fat layers). Hemangiomas may also be found in the internal organs of the body. Depending on the exact location of a hemangioma, it can affect vision, hearing or breathing. A hemangioma located near the subglottic airway, the area of the throat just below the vocal cords, can cause potentially life-threatening airway obstruction. Affected individuals may have a wheezing or noisy way of breathing (stridor). Some affected infants and children will have structural abnormalities of the brain, particularly in a region of the brain known as the posterior fossa. The posterior fossa is located near the base of the skull and contains the cerebellum, pons, and medulla oblongata. The cerebellum is the area of the brain that controls coordination and balance, and is also involved in cognition and behavior. Underdevelopment of the cerebellum, called cerebellar hypoplasia, is common. Cerebellar hypoplasia usually occurs on the same side of the body as the hemangioma (ipsilateral). Another common structural brain abnormality is a Dandy-Walker malformation (DWM), which occurs during embryonic development of the cerebellum and 4th ventricle. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by underdevelopment (small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the posterior fossa. DWM is sometimes (20-80%) associated with hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can lead to neurological impairment.Abnormalities affecting the cerebral arteries are another common finding. Arteries are major blood vessels in the body; they carry oxygen-filled blood away from the heart to the rest of the body. Approximately 80-90% of individuals have abnormalities of the medium-sized arteries of the head and neck. These abnormalities include malformation (dysplasia) or narrowing of the blood vessels. Sometimes, a blood vessel may follow an abnormal (aberrant) path through the head and neck. Specific abnormalities can include severe underdevelopment or absence (agenesis) of the carotid or vertebral arteries or abnormal persistence of embryonic blood vessels. The two carotid arteries are the main blood vessels that supply blood to the front and middle parts of the brain. Narrowing of the arteries may get progressively worse, putting affected children and individuals at risk for a stroke due to lack of blood flow to the brain. Sometimes, seizures or loss of feeling on one side of the body (hemiparesis) can be the initial sign of blood vessel problems. The abnormalities affecting the arteries may progress to resemble a disorder called Moyamoya disease. This is a progressive disorder that affects the blood vessels in the brain (cerebrovasculature). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. Inadequate blood supply then leads to reduced oxygen delivery to the brain. One of the outcomes can be a stroke, symptoms of which include paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attack, or “TIA”). Twitching or seizures can also result. Some affected infants and children have abnormalities affecting the heart and aortic arch. The aortic arch is where the aorta is connected to the heart; the aorta travels upward away from the heart before traveling downward (forming an arch). Common abnormalities can include coarctation of the aorta, aberrant subclavian artery, and ventricular septal defects. Coarctation of the aorta is a condition in which there is narrowing of the aorta, the main artery that supplies blood to the body. The severity of the condition can range from mild to severe. Coarctation of the aorta can cause high pressure in the left ventricle, the chamber of the heart that pumps blood into the aorta. Because the heart is forced to work harder to try and pump blood, this can lead to overgrowth (hypertrophy) of and damage to the heart muscle. The subclavian arteries are the arteries that supply blood to the arms. Aberrant subclavian arteries do not follow the normal path in the body that these arteries usually follow. This condition can potentially cause serious complications including a vascular ring. A vascular ring is an abnormality in which the aorta or one of its branches forms a ring around the windpipe (trachea) and the tube that carries food from the mouth to the stomach (esophagus). There are different types of vascular rings. Some symptoms that can occur include difficulty swallowing, difficulty eating or drinking, noisy breathing, difficulty breathing or a persistent cough. A ventricular septal defect is when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles. The size of this ‘hole’ will determine whether any symptoms are present, and how severe these symptoms may be. Individuals with PHACE syndrome are at risk of developing an aneurysm. This is when the walls of an artery bulge or balloon outward. Depending on its size and location, an aneurysm can cause a variety of symptoms. Aneurysms can also rupture, which can cause serious complications. Individuals with PHACE syndrome may also have a variety of eye abnormalities including underdevelopment of the main nerve that transmits nerve impulses from the eye to the brain to form images (optic nerve), morning glory disc anomaly, persistent hyperplastic primary vitreous, and the formation of a staphyloma, which is the abnormal protrusion or ‘pushing out’ of uveal tissue through a weak point in the eyeball. The uvea is the middle, colored (pigmented) layer of tissue of the eye. Morning glory disc anomaly is a birth defect involving the optic disc, the raised area where the optic nerves leave the retina. It is characterized by an abnormally-shaped optic disc, which ends up resembling a flower called a “morning glory.” Morning glory disc anomaly can cause poor vision and poor clarity of vision. Persistent hyperplastic primary vitreous is a birth defect in which embryonic blood vessels within the eye do not regress as they normally do. This can potentially cause vision problems. Less common findings include abnormally small eyes (microphthalmia), congenital cataracts, improper development of the cornea in which it blends into the white of the eye (sclerocornea), and a cleft of missing tissue in the colored portion of the eye (iris), which is called a coloboma. Third nerve palsy and Horner syndrome have also been reported in children with PHACE syndrome. The third cranial nerve controls muscles that move the eye, and also controls the constriction of the pupil, position of the upper eyelid, and the ability of the eye to focus. Symptoms of third nerve palsy can include double vision and drooping of the upper eyelid. Horner syndrome is a condition caused by abnormalities of the nerve pathway that runs from the brain to the eye and face on one side of the body. Horner syndrome is characterized by a persistently small pupil (miosis), drooping of the eyelid (ptosis), and little to no sweating on the affected side of the face (anhidrosis). PHACE syndrome can be associated with abnormalities affecting the breastbone (sternum) including partial or complete absence of the sternum. Sometimes, there is a split or groove in the sternum (sternal cleft) usually due to the sternum failing to fuse properly. On the skin of the breastbone, there may be small indentations or pits, or small, raised bumps (papules). Some infants or children have a scar-like line that extends upward from the bellybutton (supraumbilical raphe). Affected infants and children may experience delays in attaining speech and language abilities or difficulty swallowing (dysphagia). Children with PHACE syndrome often experience headaches. These headaches tend to be more severe and more frequent than in children without the disorder. Migraines may also occur and can result in vomiting and sensitivity to light (photophobia). Some individuals have dental problems including underdevelopment (hypoplasia) of the enamel of the teeth, discoloration of the enamel, and enamel that may chip easily. Affected individuals may also have endocrine abnormalities. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Affected individuals may experience decreased production of hormones made by the pituitary gland (hypopituitarism) or hormones made from the thyroid gland (hypothyroidism). Hypothyroidism may be present at birth or may be acquired during infancy or childhood and is characterized by poor growth (growth deficiency). Other signs of hypothyroidism can include weakness, fatigue, cold intolerance, and weight gain. Hypopituitarism is characterized by underdevelopment of the ovaries in females and the testes in males (hypogonadotropic hypogonadism) and late-onset adrenal insufficiency, in which the adrenal gland does not produce enough of the hormone cortisol. This can cause unintended weight loss, muscle weakness, fatigue, and low blood pressure. Some individuals may develop hearing loss. This may be because of a hemangioma forming in the auditory canal or affecting the auditory nerve. They are two main types of hearing loss: conductive and sensorineural. Conductive hearing loss is when there is a failure of sound to be conducted from the outer ear to the middle ear. Sensorineural hearing loss is when there is an impaired ability of the nerves of the ear to transmit sensory input from the inner ear to the brain. Mixed hearing loss is a combination of both. There are additional abnormalities that have been reported in individuals with PHACE syndrome. These additional abnormalities include Tetralogy of Fallot, ectopia cordis, and patent foreman ovale; arteriovenous malformations or arteriovenous fistula; malformations in the development of the outer layer of the cerebrum (abnormal cortical development); and the presence of thyroid tissue outside of its normal location (ectopic thyroid). For more information on these conditions, choose the specific condition name as your search term in the Rare Disease Database, or visit the organizations listed in the Resources section of this report.
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Symptoms of PHACE Syndrome. Although researchers have been able to establish diagnostic criteria with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the relatively small number of identified cases, the lack of large clinical studies, and the possibility of multiple genes influencing the phenotype prevent physicians from developing a “one size fits all” description of PHACE and its prognosis. Therefore, it is important to note that every person is unique and that most affected individuals will not have all of the symptoms discussed below. The most noticeable sign associated with PHACE syndrome is often a hemangioma, which is an overgrowth of blood vessels that may appear as a red, purple, or blue birthmark. In these children, a hemangioma most often occurs on the face, head or neck. They may not be present or may be barely noticeable at birth, and become apparent and grow, sometimes quickly, in the weeks to months after birth. They usually become large, measuring more than 5 centimeters (approximately 2 inches). They can be one large area of discoloration or can consist of many smaller lesions in one area of the face, head, or neck. Hemangiomas can damage the skin causing sores (ulceration) or alter the appearance of facial features. If a hemangioma breaks open, it can be extremely painful. Hemangiomas can be superficial (only affecting the upper layers of the skin) or deep (extending deeper in the skin or in the fat layers). Hemangiomas may also be found in the internal organs of the body. Depending on the exact location of a hemangioma, it can affect vision, hearing or breathing. A hemangioma located near the subglottic airway, the area of the throat just below the vocal cords, can cause potentially life-threatening airway obstruction. Affected individuals may have a wheezing or noisy way of breathing (stridor). Some affected infants and children will have structural abnormalities of the brain, particularly in a region of the brain known as the posterior fossa. The posterior fossa is located near the base of the skull and contains the cerebellum, pons, and medulla oblongata. The cerebellum is the area of the brain that controls coordination and balance, and is also involved in cognition and behavior. Underdevelopment of the cerebellum, called cerebellar hypoplasia, is common. Cerebellar hypoplasia usually occurs on the same side of the body as the hemangioma (ipsilateral). Another common structural brain abnormality is a Dandy-Walker malformation (DWM), which occurs during embryonic development of the cerebellum and 4th ventricle. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by underdevelopment (small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the posterior fossa. DWM is sometimes (20-80%) associated with hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can lead to neurological impairment.Abnormalities affecting the cerebral arteries are another common finding. Arteries are major blood vessels in the body; they carry oxygen-filled blood away from the heart to the rest of the body. Approximately 80-90% of individuals have abnormalities of the medium-sized arteries of the head and neck. These abnormalities include malformation (dysplasia) or narrowing of the blood vessels. Sometimes, a blood vessel may follow an abnormal (aberrant) path through the head and neck. Specific abnormalities can include severe underdevelopment or absence (agenesis) of the carotid or vertebral arteries or abnormal persistence of embryonic blood vessels. The two carotid arteries are the main blood vessels that supply blood to the front and middle parts of the brain. Narrowing of the arteries may get progressively worse, putting affected children and individuals at risk for a stroke due to lack of blood flow to the brain. Sometimes, seizures or loss of feeling on one side of the body (hemiparesis) can be the initial sign of blood vessel problems. The abnormalities affecting the arteries may progress to resemble a disorder called Moyamoya disease. This is a progressive disorder that affects the blood vessels in the brain (cerebrovasculature). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. Inadequate blood supply then leads to reduced oxygen delivery to the brain. One of the outcomes can be a stroke, symptoms of which include paralysis of the face, arms or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attack, or “TIA”). Twitching or seizures can also result. Some affected infants and children have abnormalities affecting the heart and aortic arch. The aortic arch is where the aorta is connected to the heart; the aorta travels upward away from the heart before traveling downward (forming an arch). Common abnormalities can include coarctation of the aorta, aberrant subclavian artery, and ventricular septal defects. Coarctation of the aorta is a condition in which there is narrowing of the aorta, the main artery that supplies blood to the body. The severity of the condition can range from mild to severe. Coarctation of the aorta can cause high pressure in the left ventricle, the chamber of the heart that pumps blood into the aorta. Because the heart is forced to work harder to try and pump blood, this can lead to overgrowth (hypertrophy) of and damage to the heart muscle. The subclavian arteries are the arteries that supply blood to the arms. Aberrant subclavian arteries do not follow the normal path in the body that these arteries usually follow. This condition can potentially cause serious complications including a vascular ring. A vascular ring is an abnormality in which the aorta or one of its branches forms a ring around the windpipe (trachea) and the tube that carries food from the mouth to the stomach (esophagus). There are different types of vascular rings. Some symptoms that can occur include difficulty swallowing, difficulty eating or drinking, noisy breathing, difficulty breathing or a persistent cough. A ventricular septal defect is when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles. The size of this ‘hole’ will determine whether any symptoms are present, and how severe these symptoms may be. Individuals with PHACE syndrome are at risk of developing an aneurysm. This is when the walls of an artery bulge or balloon outward. Depending on its size and location, an aneurysm can cause a variety of symptoms. Aneurysms can also rupture, which can cause serious complications. Individuals with PHACE syndrome may also have a variety of eye abnormalities including underdevelopment of the main nerve that transmits nerve impulses from the eye to the brain to form images (optic nerve), morning glory disc anomaly, persistent hyperplastic primary vitreous, and the formation of a staphyloma, which is the abnormal protrusion or ‘pushing out’ of uveal tissue through a weak point in the eyeball. The uvea is the middle, colored (pigmented) layer of tissue of the eye. Morning glory disc anomaly is a birth defect involving the optic disc, the raised area where the optic nerves leave the retina. It is characterized by an abnormally-shaped optic disc, which ends up resembling a flower called a “morning glory.” Morning glory disc anomaly can cause poor vision and poor clarity of vision. Persistent hyperplastic primary vitreous is a birth defect in which embryonic blood vessels within the eye do not regress as they normally do. This can potentially cause vision problems. Less common findings include abnormally small eyes (microphthalmia), congenital cataracts, improper development of the cornea in which it blends into the white of the eye (sclerocornea), and a cleft of missing tissue in the colored portion of the eye (iris), which is called a coloboma. Third nerve palsy and Horner syndrome have also been reported in children with PHACE syndrome. The third cranial nerve controls muscles that move the eye, and also controls the constriction of the pupil, position of the upper eyelid, and the ability of the eye to focus. Symptoms of third nerve palsy can include double vision and drooping of the upper eyelid. Horner syndrome is a condition caused by abnormalities of the nerve pathway that runs from the brain to the eye and face on one side of the body. Horner syndrome is characterized by a persistently small pupil (miosis), drooping of the eyelid (ptosis), and little to no sweating on the affected side of the face (anhidrosis). PHACE syndrome can be associated with abnormalities affecting the breastbone (sternum) including partial or complete absence of the sternum. Sometimes, there is a split or groove in the sternum (sternal cleft) usually due to the sternum failing to fuse properly. On the skin of the breastbone, there may be small indentations or pits, or small, raised bumps (papules). Some infants or children have a scar-like line that extends upward from the bellybutton (supraumbilical raphe). Affected infants and children may experience delays in attaining speech and language abilities or difficulty swallowing (dysphagia). Children with PHACE syndrome often experience headaches. These headaches tend to be more severe and more frequent than in children without the disorder. Migraines may also occur and can result in vomiting and sensitivity to light (photophobia). Some individuals have dental problems including underdevelopment (hypoplasia) of the enamel of the teeth, discoloration of the enamel, and enamel that may chip easily. Affected individuals may also have endocrine abnormalities. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Affected individuals may experience decreased production of hormones made by the pituitary gland (hypopituitarism) or hormones made from the thyroid gland (hypothyroidism). Hypothyroidism may be present at birth or may be acquired during infancy or childhood and is characterized by poor growth (growth deficiency). Other signs of hypothyroidism can include weakness, fatigue, cold intolerance, and weight gain. Hypopituitarism is characterized by underdevelopment of the ovaries in females and the testes in males (hypogonadotropic hypogonadism) and late-onset adrenal insufficiency, in which the adrenal gland does not produce enough of the hormone cortisol. This can cause unintended weight loss, muscle weakness, fatigue, and low blood pressure. Some individuals may develop hearing loss. This may be because of a hemangioma forming in the auditory canal or affecting the auditory nerve. They are two main types of hearing loss: conductive and sensorineural. Conductive hearing loss is when there is a failure of sound to be conducted from the outer ear to the middle ear. Sensorineural hearing loss is when there is an impaired ability of the nerves of the ear to transmit sensory input from the inner ear to the brain. Mixed hearing loss is a combination of both. There are additional abnormalities that have been reported in individuals with PHACE syndrome. These additional abnormalities include Tetralogy of Fallot, ectopia cordis, and patent foreman ovale; arteriovenous malformations or arteriovenous fistula; malformations in the development of the outer layer of the cerebrum (abnormal cortical development); and the presence of thyroid tissue outside of its normal location (ectopic thyroid). For more information on these conditions, choose the specific condition name as your search term in the Rare Disease Database, or visit the organizations listed in the Resources section of this report.
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Causes of PHACE Syndrome
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The exact cause of PHACE syndrome is unknown. It appears to occur randomly (sporadically) for no known reason. There have not been reports of the disorder occurring in multiple members of the same family. Some researchers believe that the disorder results from an unknown postzygotic somatic mosaic mutation. A somatic mutation is a change in a gene that occurs in any cell of the body except the sex cells, namely the sperm and the egg. In PHACE syndrome, the affected gene(s) is unknown. A somatic mutation usually occurs in the body in a mosaic pattern, which means that some cells will have a normal copy of the gene and some cells will have an altered copy of the gene. This may be referred to as having two distinct cell lines in the body. The variability in symptoms and severity would be due, in part, to the ratio of healthy cells to altered cells. Some researchers believe that a somatic mutation in PHACE syndrome may affect a gene vital to health and function of neural crest cells. These cells form very early during embryonic development and give rise to most of the bone and cartilage underlying the face. Somatic mutations are not inherited and are not passed on to children. Researchers have also hypothesized that PHACE syndrome may be due to a de novo gene mutation. A de novo mutation is a new genetic change occurring for the first time in a family member due to a mutation in an egg or sperm from a parent or a mutation that occurs later, after the egg is fertilized. PHACE syndrome may be a multifactorial disorder, which means that the disorder develops through the interaction of several genetic and environmental factors. Researchers are trying to determine the specific, underlying factors that play a role in the development of the disorder.
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Causes of PHACE Syndrome. The exact cause of PHACE syndrome is unknown. It appears to occur randomly (sporadically) for no known reason. There have not been reports of the disorder occurring in multiple members of the same family. Some researchers believe that the disorder results from an unknown postzygotic somatic mosaic mutation. A somatic mutation is a change in a gene that occurs in any cell of the body except the sex cells, namely the sperm and the egg. In PHACE syndrome, the affected gene(s) is unknown. A somatic mutation usually occurs in the body in a mosaic pattern, which means that some cells will have a normal copy of the gene and some cells will have an altered copy of the gene. This may be referred to as having two distinct cell lines in the body. The variability in symptoms and severity would be due, in part, to the ratio of healthy cells to altered cells. Some researchers believe that a somatic mutation in PHACE syndrome may affect a gene vital to health and function of neural crest cells. These cells form very early during embryonic development and give rise to most of the bone and cartilage underlying the face. Somatic mutations are not inherited and are not passed on to children. Researchers have also hypothesized that PHACE syndrome may be due to a de novo gene mutation. A de novo mutation is a new genetic change occurring for the first time in a family member due to a mutation in an egg or sperm from a parent or a mutation that occurs later, after the egg is fertilized. PHACE syndrome may be a multifactorial disorder, which means that the disorder develops through the interaction of several genetic and environmental factors. Researchers are trying to determine the specific, underlying factors that play a role in the development of the disorder.
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Affects of PHACE Syndrome
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PHACE syndrome affects more females than it does males, although researchers are not exactly sure why this is the case. It has been described affecting many different ethnic groups. The exact incidence or prevalence of the disorder is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
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Affects of PHACE Syndrome. PHACE syndrome affects more females than it does males, although researchers are not exactly sure why this is the case. It has been described affecting many different ethnic groups. The exact incidence or prevalence of the disorder is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
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Related disorders of PHACE Syndrome
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Symptoms of the following disorders can be similar to those of PHACE syndrome. Comparisons may be useful for a differential diagnosis.Sturge-Weber syndrome (SWS) is a rare disorder characterized by the association of a facial birthmark called a port-wine stain, neurological abnormalities, and eye abnormalities such as glaucoma. SWS can be thought of as a spectrum of disease in which individuals may have abnormalities affecting all three of these systems (i.e. brain, skin and eyes), or only two, or only one (isolated brain involvement). Consequently, the specific symptoms and severity of the disorder can vary dramatically from one person to another. Symptoms are usually present at birth (congenital), yet the disorder is not inherited and does not run in families. Some symptoms may not develop until adulthood. SWS is caused by a somatic mutation in the GNAQ gene. This mutation occurs randomly (sporadically) for no known reason. (For more information on this disorder, choose “Sturge Weber” as your search term in the Rare Disease Database.)LUMBAR syndrome is a rare disorder in which one or multiple hemangiomas forms over the lower body. These hemangiomas occur along with additional abnormalities. Hemangiomas can break open and become extremely painful. LUMBAR is an acronym that stands for: (L)ower segmental hemangioma; (U)rogenital defects, which are defects affecting the urinary tract and genitals, and (U)lceration; (M)yelopathy, which is a defect of the spinal cord; (B)ony deformities; (A)rterial and anorectal defects, such as imperforate anus, fistula formation, and deviated gluteal cleft; and (R)enal (kidney) abnormalities. As with PHACE syndrome, the specific symptoms that occur and the severity of the disorder can vary greatly from one person to another. The exact cause of this disorder is unknown.
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Related disorders of PHACE Syndrome. Symptoms of the following disorders can be similar to those of PHACE syndrome. Comparisons may be useful for a differential diagnosis.Sturge-Weber syndrome (SWS) is a rare disorder characterized by the association of a facial birthmark called a port-wine stain, neurological abnormalities, and eye abnormalities such as glaucoma. SWS can be thought of as a spectrum of disease in which individuals may have abnormalities affecting all three of these systems (i.e. brain, skin and eyes), or only two, or only one (isolated brain involvement). Consequently, the specific symptoms and severity of the disorder can vary dramatically from one person to another. Symptoms are usually present at birth (congenital), yet the disorder is not inherited and does not run in families. Some symptoms may not develop until adulthood. SWS is caused by a somatic mutation in the GNAQ gene. This mutation occurs randomly (sporadically) for no known reason. (For more information on this disorder, choose “Sturge Weber” as your search term in the Rare Disease Database.)LUMBAR syndrome is a rare disorder in which one or multiple hemangiomas forms over the lower body. These hemangiomas occur along with additional abnormalities. Hemangiomas can break open and become extremely painful. LUMBAR is an acronym that stands for: (L)ower segmental hemangioma; (U)rogenital defects, which are defects affecting the urinary tract and genitals, and (U)lceration; (M)yelopathy, which is a defect of the spinal cord; (B)ony deformities; (A)rterial and anorectal defects, such as imperforate anus, fistula formation, and deviated gluteal cleft; and (R)enal (kidney) abnormalities. As with PHACE syndrome, the specific symptoms that occur and the severity of the disorder can vary greatly from one person to another. The exact cause of this disorder is unknown.
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PHACE Syndrome
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Diagnosis of PHACE Syndrome
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A diagnosis of PHACE syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. There are consensus-based diagnostic criteria that have been established by medical experts for PHACE syndrome. These were first published in 2009 (Garzon et al.) and updated in 2016 (Metry et al.). These diagnostic guidelines break down the symptoms of PHACE syndrome into major and minor criteria. A diagnosis is based on the presence of a hemangioma of the head or scalp that is greater than 5 centimeters in diameter (about 2 inches) that occurs along with one major or two minor criteria or the presence of a hemangioma of the neck, upper trunk or trunk and proximal upper extremity plus two major criteria. Clinical Testing and Workup
Affected individuals will also undergo periodic screening to detect potential signs and symptoms associated with this disorder. However, medical institutions and physicians may differ on how often screening tests are necessary. Specialized imaging techniques may be used to screen for potential signs associated with the disorder. These tests include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and echocardiogram. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the head and neck region can detect structural abnormalities of the brain associated with PHACE syndrome. An MRA uses the same equipment used for an MRI in order to evaluate the health and function of blood vessels. In some instances, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. An echocardiogram is a test that uses reflected sound waves to create images of the heart, and can reveal structural heart defects associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with PHACE syndrome.
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Diagnosis of PHACE Syndrome. A diagnosis of PHACE syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. There are consensus-based diagnostic criteria that have been established by medical experts for PHACE syndrome. These were first published in 2009 (Garzon et al.) and updated in 2016 (Metry et al.). These diagnostic guidelines break down the symptoms of PHACE syndrome into major and minor criteria. A diagnosis is based on the presence of a hemangioma of the head or scalp that is greater than 5 centimeters in diameter (about 2 inches) that occurs along with one major or two minor criteria or the presence of a hemangioma of the neck, upper trunk or trunk and proximal upper extremity plus two major criteria. Clinical Testing and Workup
Affected individuals will also undergo periodic screening to detect potential signs and symptoms associated with this disorder. However, medical institutions and physicians may differ on how often screening tests are necessary. Specialized imaging techniques may be used to screen for potential signs associated with the disorder. These tests include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and echocardiogram. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the head and neck region can detect structural abnormalities of the brain associated with PHACE syndrome. An MRA uses the same equipment used for an MRI in order to evaluate the health and function of blood vessels. In some instances, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. An echocardiogram is a test that uses reflected sound waves to create images of the heart, and can reveal structural heart defects associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with PHACE syndrome.
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PHACE Syndrome
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Therapies of PHACE Syndrome
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Treatment
The treatment of PHACE syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; specialists in diagnosing and treating skin disorders (dermatologists); specialists in diagnosing and treating eye disorders (ophthalmologists); specialists in diagnosing and treating heart or blood vessel disorders in children (pediatric cardiologists); specialists in diagnosing and treating disorders of the endocrine system (endocrinologists); specialists in diagnosing and treating disorders of the brain and central nervous system (neurologists and neurosurgeons); specialists in diagnosing and treating disorders of the ear, nose, and throat (otolaryngologists); dental specialists; speech pathologists; psychiatrists; and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with PHACE syndrome. Surgery may be necessary to treat some of the complications of PHACE syndrome including hemangiomas, certain heart defects, and blood vessel abnormalities. Hearing aids or restorative hearing surgery may be necessary to treat hearing loss.
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Therapies of PHACE Syndrome. Treatment
The treatment of PHACE syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; specialists in diagnosing and treating skin disorders (dermatologists); specialists in diagnosing and treating eye disorders (ophthalmologists); specialists in diagnosing and treating heart or blood vessel disorders in children (pediatric cardiologists); specialists in diagnosing and treating disorders of the endocrine system (endocrinologists); specialists in diagnosing and treating disorders of the brain and central nervous system (neurologists and neurosurgeons); specialists in diagnosing and treating disorders of the ear, nose, and throat (otolaryngologists); dental specialists; speech pathologists; psychiatrists; and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with PHACE syndrome. Surgery may be necessary to treat some of the complications of PHACE syndrome including hemangiomas, certain heart defects, and blood vessel abnormalities. Hearing aids or restorative hearing surgery may be necessary to treat hearing loss.
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PHACE Syndrome
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Overview of Phelan-McDermid Syndrome
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Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing (pathogenic) variant of the SHANK3 gene.The genetic change that causes PMS can occur sporadically (de novo) or be inherited from a parent (20%) who carries a related genetic change. Because the genetic change varies in terms of the size of the deleted segment of chromosome 22 or the specific pathogenic variant of SHANK3, the signs and symptoms of PMS are variable as well and can cause a wide range of medical, intellectual and behavioral challenges. Although the range and severity of symptoms may vary, PMS is generally characterized by neonatal hypotonia (low muscle tone in the newborn), intellectual disability of varying degrees, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. Other common characteristics are behavioral issues including autism spectrum disorder or autistic-like traits, decreased perception of pain, motor delays, sleep disorders and seizures. Individuals with PMS may also present with gastrointestinal, renal and cardiac problems. There is currently no cure or treatment specifically for PMS, but many of the symptoms are managed by therapies and/or medications and researchers are working diligently to improve the understanding and knowledge of PMS and to find drugs and therapies that can improve the lives of people affected by PMS.Current research indicates that the inability of the single functioning copy of the SHANK3 gene to produce sufficient SHANK3 protein for normal functioning (haploinsufficiency) may be responsible for most of the neurologic symptoms (developmental and speech delay, hypotonia, seizures) associated with PMS.
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Overview of Phelan-McDermid Syndrome. Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing (pathogenic) variant of the SHANK3 gene.The genetic change that causes PMS can occur sporadically (de novo) or be inherited from a parent (20%) who carries a related genetic change. Because the genetic change varies in terms of the size of the deleted segment of chromosome 22 or the specific pathogenic variant of SHANK3, the signs and symptoms of PMS are variable as well and can cause a wide range of medical, intellectual and behavioral challenges. Although the range and severity of symptoms may vary, PMS is generally characterized by neonatal hypotonia (low muscle tone in the newborn), intellectual disability of varying degrees, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. Other common characteristics are behavioral issues including autism spectrum disorder or autistic-like traits, decreased perception of pain, motor delays, sleep disorders and seizures. Individuals with PMS may also present with gastrointestinal, renal and cardiac problems. There is currently no cure or treatment specifically for PMS, but many of the symptoms are managed by therapies and/or medications and researchers are working diligently to improve the understanding and knowledge of PMS and to find drugs and therapies that can improve the lives of people affected by PMS.Current research indicates that the inability of the single functioning copy of the SHANK3 gene to produce sufficient SHANK3 protein for normal functioning (haploinsufficiency) may be responsible for most of the neurologic symptoms (developmental and speech delay, hypotonia, seizures) associated with PMS.
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Phelan-McDermid Syndrome
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Symptoms of Phelan-McDermid Syndrome
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Most infants with PMS exhibit normal growth before birth (intrauterine growth) with normal growth after birth (postnatally). The first physical sign associated with PMS is neonatal hypotonia (low muscle tone) which is often accompanied by feeding difficulties, weak cry and poor head control. Children also experience a significant delay in reaching early developmental milestones, such as rolling over, sitting, crawling and walking; this delay is likely associated with low muscle tone. These are often the first noticeable symptoms that prompt families to start their diagnostic journey.As children grow, additional symptoms develop. People with PMS typically have moderate to severe developmental and intellectual impairment, absent or severely delayed speech and about 75% have been diagnosed with an autism spectrum disorder or autistic traits. “Autistic-like” behavior includes tactile defensiveness, anxiety in social situations, avoidance of eye contact and self-stimulatory behavior. Individuals also exhibit obsessive chewing of non-food items. Sleep disorders are commonly reported, as are difficulties with toilet training, and problems with swallowing and eating. About 40% of people develop seizures which can range from mild to severe.Many parents report that their child does not seem to feel pain as most people do, but instead has a very low perception of pain. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain due to constipation, reflux and other medical conditions that require treatment, or physical injuries. People with PMS also seem to perspire less than others and are at risk of overheating. It is very important that caregivers monitor carefully for injuries and overheating. Precautions must be taken to shield the individual from direct sunlight, avoid dehydration, use sunblock or sunscreen and wear protective clothing.The facial features associated with PMS include long head shape (dolichocephaly), large/prominent ears, full brow, deep-set eyes, long eyelashes, full or puffy eyelids, droopy eyelids (ptosis), flat midface, full or puffy cheeks, wide nasal bridge, bulbous nose and pointed chin. Other features include underdeveloped (dysplastic) toenails during infancy and early childhood and relatively large, fleshy hands.Up to 40% of individuals with PMS have kidney abnormalities, including multi-cystic kidneys, one non-functioning (under-developed or dysplastic) kidney, collection of fluid in the kidney (hydronephrosis) and backward flow of urine into the ureter and eventually the kidney (vesicoureteral reflux). All individuals diagnosed with PMS should have a renal ultrasound performed to check for kidney defects since many of these defects can be asymptomatic but may pose serious health risks that require intervention.Gastrointestinal issues have been reported in several individuals with PMS, including gastroesophageal reflux (30% of cases), cyclic vomiting (25%), liver dysfunction and/or steatosis, constipation and diarrhea. Management of patients with gastrointestinal issues such as vomiting or diarrhea should prioritize the prevention of dehydration.Over 15% of individuals with PMS have arachnoid cysts (fluid-filled sacs on the surface of the brain) compared to about 1% of the general population. While small arachnoid cysts may remain without symptoms (asymptomatic), larger cysts may cause increased intracranial pressure resulting in irritability, incessant crying bouts, severe headaches, cyclic vomiting and seizures. Brain imaging with magnetic resonance imaging (MRI) and computed tomography (CT scan) are indicated if an arachnoid cyst is suspected based on symptoms of increased intracranial pressure.Lymphedema (accumulation of fluid in the arms and legs) and cellulitis (inflammation of subcutaneous tissue due to infection) may develop during the teenage and early adult years. Lymphedema can be treated by elevation, exercise, compression bandages and sequential pneumatic compression to move the fluid from the affected limb.Neuropsychiatric illnesses including bipolar disorder, anxiety, depression, catatonia, psychosis, temporary loss of skills or long-term regression of skillsets occur in a subset of individuals with PMS. The exact percentage of people with PMS that experience these issues is not yet known. These problems often arise at the onset of puberty or early adulthood. Medical treatment guidelines devised by PMS medical experts continue to be refined in this area.
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Symptoms of Phelan-McDermid Syndrome. Most infants with PMS exhibit normal growth before birth (intrauterine growth) with normal growth after birth (postnatally). The first physical sign associated with PMS is neonatal hypotonia (low muscle tone) which is often accompanied by feeding difficulties, weak cry and poor head control. Children also experience a significant delay in reaching early developmental milestones, such as rolling over, sitting, crawling and walking; this delay is likely associated with low muscle tone. These are often the first noticeable symptoms that prompt families to start their diagnostic journey.As children grow, additional symptoms develop. People with PMS typically have moderate to severe developmental and intellectual impairment, absent or severely delayed speech and about 75% have been diagnosed with an autism spectrum disorder or autistic traits. “Autistic-like” behavior includes tactile defensiveness, anxiety in social situations, avoidance of eye contact and self-stimulatory behavior. Individuals also exhibit obsessive chewing of non-food items. Sleep disorders are commonly reported, as are difficulties with toilet training, and problems with swallowing and eating. About 40% of people develop seizures which can range from mild to severe.Many parents report that their child does not seem to feel pain as most people do, but instead has a very low perception of pain. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain due to constipation, reflux and other medical conditions that require treatment, or physical injuries. People with PMS also seem to perspire less than others and are at risk of overheating. It is very important that caregivers monitor carefully for injuries and overheating. Precautions must be taken to shield the individual from direct sunlight, avoid dehydration, use sunblock or sunscreen and wear protective clothing.The facial features associated with PMS include long head shape (dolichocephaly), large/prominent ears, full brow, deep-set eyes, long eyelashes, full or puffy eyelids, droopy eyelids (ptosis), flat midface, full or puffy cheeks, wide nasal bridge, bulbous nose and pointed chin. Other features include underdeveloped (dysplastic) toenails during infancy and early childhood and relatively large, fleshy hands.Up to 40% of individuals with PMS have kidney abnormalities, including multi-cystic kidneys, one non-functioning (under-developed or dysplastic) kidney, collection of fluid in the kidney (hydronephrosis) and backward flow of urine into the ureter and eventually the kidney (vesicoureteral reflux). All individuals diagnosed with PMS should have a renal ultrasound performed to check for kidney defects since many of these defects can be asymptomatic but may pose serious health risks that require intervention.Gastrointestinal issues have been reported in several individuals with PMS, including gastroesophageal reflux (30% of cases), cyclic vomiting (25%), liver dysfunction and/or steatosis, constipation and diarrhea. Management of patients with gastrointestinal issues such as vomiting or diarrhea should prioritize the prevention of dehydration.Over 15% of individuals with PMS have arachnoid cysts (fluid-filled sacs on the surface of the brain) compared to about 1% of the general population. While small arachnoid cysts may remain without symptoms (asymptomatic), larger cysts may cause increased intracranial pressure resulting in irritability, incessant crying bouts, severe headaches, cyclic vomiting and seizures. Brain imaging with magnetic resonance imaging (MRI) and computed tomography (CT scan) are indicated if an arachnoid cyst is suspected based on symptoms of increased intracranial pressure.Lymphedema (accumulation of fluid in the arms and legs) and cellulitis (inflammation of subcutaneous tissue due to infection) may develop during the teenage and early adult years. Lymphedema can be treated by elevation, exercise, compression bandages and sequential pneumatic compression to move the fluid from the affected limb.Neuropsychiatric illnesses including bipolar disorder, anxiety, depression, catatonia, psychosis, temporary loss of skills or long-term regression of skillsets occur in a subset of individuals with PMS. The exact percentage of people with PMS that experience these issues is not yet known. These problems often arise at the onset of puberty or early adulthood. Medical treatment guidelines devised by PMS medical experts continue to be refined in this area.
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Phelan-McDermid Syndrome
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Causes of Phelan-McDermid Syndrome
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PMS is caused by the deletion or disruption of the segment of the long arm (q) of chromosome 22 that is identified as 22q13. Chromosomes are found in the nucleus of all body cells. They carry the genetic information for the growth and development of each individual. Pairs of human chromosomes include the autosomes, numbered from 1 to 22, and the sex chromosomes, X and Y. Females have two X chromosomes while males have one X and one Y chromosome. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into numbered bands. Therefore, “chromosome 22q13” refers to band 13 on the long arm (q) of chromosome 22.Most cases of PMS are due to a spontaneous (de novo) break in the long arm of chromosome 22 that occurs for unknown reasons (sporadic). The segment of chromosome 22 beyond (distal to) the break is lost (deleted). In such cases, called simple deletions, the disorder is not inherited from the parents. That is, the parents have normal chromosomes but the break in chromosome 22 has occurred as a new chromosomal variant in the egg or in the sperm cell that contributes to the formation of the embryo. As in many other distal deletion syndromes, the deletion of 22q13 is more likely to occur on the chromosome 22 that is inherited from the father (in the sperm cell) than the chromosome 22 inherited from the mother (in the egg cell).Because the deletion of chromosome 22 typically occurs on the distal portion of the long arm of the chromosome that is away from the centromere, it is often referred to as a “terminal” deletion. In this sense, “terminal” refers to the end of the chromosome. It is important that families and healthcare providers understand that in this context “terminal” refers to the distal portion of the chromosome and does not imply that the PMS is a “terminal” or lethal (life-threatening) condition.About 20% of deletions of 22q13 are due to unbalanced translocations. A translocation is an unusual arrangement of chromosomes, where pieces of genetic material from chromosomes may be switched, added or lost to other chromosomes. Translocations may be balanced (switched without loss of function of genes) or unbalanced (switched in a way that causes loss or addition of genes) and may be inherited or may occur as a new event (de novo). Translocations typically occur when breaks occur on two different chromosomes and the segments distal to the breakpoints trade places. For example, consider a translocation between the short arm (p) of chromosome 2 and the long arm (q) of chromosome 22. One break occurs in 2p, and a second break occurs in 22q. The segment distal to the breakpoint on 2p trades places with the segment distal to the breakpoint on 22q. Such a translocation is called “balanced” because the correct amount of genetic material is present although its position has been altered. Balanced translocations are usually harmless to the carrier. However, a parent with a balanced rearrangement is at risk of transmitting an unbalanced translocation to a child. Chromosomal (cytogenetic) testing, or karyotyping, and fluorescence in situ hybridization (FISH) can be used to determine whether a parent has a balanced translocation and is at risk of passing an unbalanced translocation to his or her offspring. Chromosomal microarray (CMA) detects the presence or absence of genetic material; therefore, it would not be effective in detecting a balanced chromosome translocation because there is no loss or gain of material. (See Diagnosis)Unbalanced translocations may also occur de novo, or as a new event, when both parents have normal chromosomes. Even though neither parent carries a balanced translocation, a segment of chromosome 22 may switch places with a segment from another chromosome (example: chromosome 2) during the formation of the germ cell (egg or sperm). If the mature egg or sperm carries the translocated chromosome 22 but a normal copy of chromosome 2, an unbalanced translocation results. The embryo will be missing a piece of chromosome 22 but will have an extra copy of a segment of chromosome 2. The loss of 22q13 leads to PMS. The extra piece of chromosome 2 may also be associated with unusual features. Although chromosome 2 was used in this example, a translocation can occur between chromosome 22 and any of the other autosomes (chromosomes 1 to 22), or the sex chromosomes (X and Y). About half of the unbalanced translocations in PMS are inherited while the other half occur de novo. An unbalanced translocation can be inferred by CMA when there is a deletion of chromosome 22 and a gain of a distal segment from a second chromosome. Unbalanced translocations can also be detected by karyotyping if the involved segments are visible at the resolution of the microscope.Ring 22 is another structural chromosome change that can result in PMS. Chromosome 22 breaks at both ends (i.e., the ends of the long arm [22q] and the short arm [22p]) and the distal segments are lost (deleted). The “new” chromosomal ends then join, forming a circular structure, or ring. About 14-33% of individuals with PMS carry a ring 22, although this is likely to be an underestimate because not all individuals with ring 22 report their diagnosis as PMS and not everyone who has been diagnosed with PMS by chromosomal microarray (CMA) has a follow-up chromosome studies to determine if a ring chromosome is present (see “Diagnosis”). The formation of the ring is usually accompanied by a similar loss of genetic material as seen in cases of 22q13 deletion, and the symptoms observed to date appear to be consistent between the two conditions. However, due to the instability of the ring chromosome during cell division (mitosis), one of the daughter cells may receive only one copy of chromosome 22, a condition called monosomy 22. Individuals with ring 22 are at risk of developing neurofibromatosis type 2 (NF2), a condition associated with non-cancerous tumors of the nervous system. This risk arises from a “two-hit” sequence. The first hit is the loss of the ring 22 in cells in the nervous system. If one of these cells undergoes a second hit – a pathogenic variant in the NF2 gene – neurofibromatosis type 2 can result. Parents, caregivers, and healthcare professionals must be aware of this risk. It is imperative chromosome analysis (karyotyping) is performed in follow-up whenever a deletion of 22q13 is diagnosed by CMA. CMA can detect the deletion of 22q but cannot rule out the presence of a ring 22. The risk of NF2 is not related to a pathogenic variant of the NF2 gene or deletion of the NF2 locus. It results from the presence of a ring chromosome 22 and parents must be aware of this risk so their child can be monitored appropriately. (See Chromosome 22 Ring https://rarediseases.org/rare-diseases/chromosome-22-ring/)
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Causes of Phelan-McDermid Syndrome. PMS is caused by the deletion or disruption of the segment of the long arm (q) of chromosome 22 that is identified as 22q13. Chromosomes are found in the nucleus of all body cells. They carry the genetic information for the growth and development of each individual. Pairs of human chromosomes include the autosomes, numbered from 1 to 22, and the sex chromosomes, X and Y. Females have two X chromosomes while males have one X and one Y chromosome. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into numbered bands. Therefore, “chromosome 22q13” refers to band 13 on the long arm (q) of chromosome 22.Most cases of PMS are due to a spontaneous (de novo) break in the long arm of chromosome 22 that occurs for unknown reasons (sporadic). The segment of chromosome 22 beyond (distal to) the break is lost (deleted). In such cases, called simple deletions, the disorder is not inherited from the parents. That is, the parents have normal chromosomes but the break in chromosome 22 has occurred as a new chromosomal variant in the egg or in the sperm cell that contributes to the formation of the embryo. As in many other distal deletion syndromes, the deletion of 22q13 is more likely to occur on the chromosome 22 that is inherited from the father (in the sperm cell) than the chromosome 22 inherited from the mother (in the egg cell).Because the deletion of chromosome 22 typically occurs on the distal portion of the long arm of the chromosome that is away from the centromere, it is often referred to as a “terminal” deletion. In this sense, “terminal” refers to the end of the chromosome. It is important that families and healthcare providers understand that in this context “terminal” refers to the distal portion of the chromosome and does not imply that the PMS is a “terminal” or lethal (life-threatening) condition.About 20% of deletions of 22q13 are due to unbalanced translocations. A translocation is an unusual arrangement of chromosomes, where pieces of genetic material from chromosomes may be switched, added or lost to other chromosomes. Translocations may be balanced (switched without loss of function of genes) or unbalanced (switched in a way that causes loss or addition of genes) and may be inherited or may occur as a new event (de novo). Translocations typically occur when breaks occur on two different chromosomes and the segments distal to the breakpoints trade places. For example, consider a translocation between the short arm (p) of chromosome 2 and the long arm (q) of chromosome 22. One break occurs in 2p, and a second break occurs in 22q. The segment distal to the breakpoint on 2p trades places with the segment distal to the breakpoint on 22q. Such a translocation is called “balanced” because the correct amount of genetic material is present although its position has been altered. Balanced translocations are usually harmless to the carrier. However, a parent with a balanced rearrangement is at risk of transmitting an unbalanced translocation to a child. Chromosomal (cytogenetic) testing, or karyotyping, and fluorescence in situ hybridization (FISH) can be used to determine whether a parent has a balanced translocation and is at risk of passing an unbalanced translocation to his or her offspring. Chromosomal microarray (CMA) detects the presence or absence of genetic material; therefore, it would not be effective in detecting a balanced chromosome translocation because there is no loss or gain of material. (See Diagnosis)Unbalanced translocations may also occur de novo, or as a new event, when both parents have normal chromosomes. Even though neither parent carries a balanced translocation, a segment of chromosome 22 may switch places with a segment from another chromosome (example: chromosome 2) during the formation of the germ cell (egg or sperm). If the mature egg or sperm carries the translocated chromosome 22 but a normal copy of chromosome 2, an unbalanced translocation results. The embryo will be missing a piece of chromosome 22 but will have an extra copy of a segment of chromosome 2. The loss of 22q13 leads to PMS. The extra piece of chromosome 2 may also be associated with unusual features. Although chromosome 2 was used in this example, a translocation can occur between chromosome 22 and any of the other autosomes (chromosomes 1 to 22), or the sex chromosomes (X and Y). About half of the unbalanced translocations in PMS are inherited while the other half occur de novo. An unbalanced translocation can be inferred by CMA when there is a deletion of chromosome 22 and a gain of a distal segment from a second chromosome. Unbalanced translocations can also be detected by karyotyping if the involved segments are visible at the resolution of the microscope.Ring 22 is another structural chromosome change that can result in PMS. Chromosome 22 breaks at both ends (i.e., the ends of the long arm [22q] and the short arm [22p]) and the distal segments are lost (deleted). The “new” chromosomal ends then join, forming a circular structure, or ring. About 14-33% of individuals with PMS carry a ring 22, although this is likely to be an underestimate because not all individuals with ring 22 report their diagnosis as PMS and not everyone who has been diagnosed with PMS by chromosomal microarray (CMA) has a follow-up chromosome studies to determine if a ring chromosome is present (see “Diagnosis”). The formation of the ring is usually accompanied by a similar loss of genetic material as seen in cases of 22q13 deletion, and the symptoms observed to date appear to be consistent between the two conditions. However, due to the instability of the ring chromosome during cell division (mitosis), one of the daughter cells may receive only one copy of chromosome 22, a condition called monosomy 22. Individuals with ring 22 are at risk of developing neurofibromatosis type 2 (NF2), a condition associated with non-cancerous tumors of the nervous system. This risk arises from a “two-hit” sequence. The first hit is the loss of the ring 22 in cells in the nervous system. If one of these cells undergoes a second hit – a pathogenic variant in the NF2 gene – neurofibromatosis type 2 can result. Parents, caregivers, and healthcare professionals must be aware of this risk. It is imperative chromosome analysis (karyotyping) is performed in follow-up whenever a deletion of 22q13 is diagnosed by CMA. CMA can detect the deletion of 22q but cannot rule out the presence of a ring 22. The risk of NF2 is not related to a pathogenic variant of the NF2 gene or deletion of the NF2 locus. It results from the presence of a ring chromosome 22 and parents must be aware of this risk so their child can be monitored appropriately. (See Chromosome 22 Ring https://rarediseases.org/rare-diseases/chromosome-22-ring/)
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Phelan-McDermid Syndrome
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Affects of Phelan-McDermid Syndrome
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Deletion of 22q13 was initially described in the medical literature in 1985. Since that time, increased understanding through scientific research, advances in genetic testing and advocacy have led to approximately 3,000 members in the Phelan-McDermid Syndrome Foundation as of 2022. Males and females are equally likely to be affected. Based on limited statistical analysis, the occurrence rate has been estimated to fall in the range of 2.5-10 per million births, although this is likely to be a gross underestimate. Due to the subtle appearance of the deletion of chromosome 22 and the relatively mild physical features of affected individuals, diagnosis of PMS is often difficult. Prior to the advent of CMA testing, over 30% of individuals with this deletion required two or more chromosome studies before the deletion was detected. It is likely that there are many older individuals who had “normal” chromosome studies at an earlier age but who actually carry this subtle chromosome abnormality or pathogenic variant of SHANK3. Unless these individuals are studied by CMA testing or NGS, their diagnosis will remain a mystery.
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Affects of Phelan-McDermid Syndrome. Deletion of 22q13 was initially described in the medical literature in 1985. Since that time, increased understanding through scientific research, advances in genetic testing and advocacy have led to approximately 3,000 members in the Phelan-McDermid Syndrome Foundation as of 2022. Males and females are equally likely to be affected. Based on limited statistical analysis, the occurrence rate has been estimated to fall in the range of 2.5-10 per million births, although this is likely to be a gross underestimate. Due to the subtle appearance of the deletion of chromosome 22 and the relatively mild physical features of affected individuals, diagnosis of PMS is often difficult. Prior to the advent of CMA testing, over 30% of individuals with this deletion required two or more chromosome studies before the deletion was detected. It is likely that there are many older individuals who had “normal” chromosome studies at an earlier age but who actually carry this subtle chromosome abnormality or pathogenic variant of SHANK3. Unless these individuals are studied by CMA testing or NGS, their diagnosis will remain a mystery.
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Related disorders of Phelan-McDermid Syndrome
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Autism spectrum disorders (ASD) refer to a wide range of conditions characterized by impaired social interaction and communication. Individuals with ASD may or may not have intellectual disability (ID). Genetic testing for ASD often consists of a CMA and/or a targeted gene panel that includes SHANK3. This testing will distinguish most cases of PMS from non-syndromic autism.Cerebral palsy (CP) defines a group of neurological disorders that affect muscle tone, body movements and coordination. The symptoms of CP vary and, in some cases, there are features that are similar to PMS. These include intellectual disability, seizures and impaired speech. At least 2 genes (FBXO31 and RHOB) have been implicated in the causation of CP.
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Related disorders of Phelan-McDermid Syndrome. Autism spectrum disorders (ASD) refer to a wide range of conditions characterized by impaired social interaction and communication. Individuals with ASD may or may not have intellectual disability (ID). Genetic testing for ASD often consists of a CMA and/or a targeted gene panel that includes SHANK3. This testing will distinguish most cases of PMS from non-syndromic autism.Cerebral palsy (CP) defines a group of neurological disorders that affect muscle tone, body movements and coordination. The symptoms of CP vary and, in some cases, there are features that are similar to PMS. These include intellectual disability, seizures and impaired speech. At least 2 genes (FBXO31 and RHOB) have been implicated in the causation of CP.
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Phelan-McDermid Syndrome
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Diagnosis of Phelan-McDermid Syndrome
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The diagnosis of PMS is based on genetic testing for the identification of a deletion or disruption of the chromosome region 22q13. The first tier of genetic testing for individuals with intellectual disability or developmental delay includes chromosomal microarray analysis (CMA) and next generation sequencing (NGS).Chromosomal microarray analysis (CMA): The test involves providing a small amount of blood. Deletions of 22q13 are reliably detected by CMA because this test detects copy number variations (CNVs), including chromosomal deletions and duplications, across the entire genome. Deletions within the 22q13 region, which commonly impact the SHANK3 gene, are consistent with a diagnosis of PMS.If a deletion of 22q13 is detected through microarray, additional steps should be undertaken to determine if the individual has a ring configuration of chromosome 22, in which the ends of the chromosome stick together at deletion breakpoints. A chromosome analysis will show the structure of the chromosomes (karyotype) and should be performed to determine if the individual has ring 22. Ring 22 carries an added risk of neurofibromatosis type 2 (NF2), a disorder linked with the development of noncancerous tumors in the nervous system.If the CMA shows a terminal deletion of chromosome 22q and a terminal duplication in another chromosome, the individual may have an unbalanced translocation, and fluorescence in situ hybridization (FISH) and/or karyotype studies to visualize the chromosome are warranted. Unbalanced translocations may arise from parental balanced rearrangements. Although 80% of PMS cases occur spontaneously at birth (de novo), inheritance of a parental genetic alteration can occur in about 20% of those affected. Parents who carry a balanced rearrangement, although healthy, have an increased risk of having another affected child and should undergo metaphase FISH and/or karyotype testing.Next-Generation sequencing (NGS): If chromosomal microarray analysis (CMA) has been done but a pathogenic deletion is not identified, the next step is NGS. NGS detects genetic spelling errors, called variants, in a genetic sequence by essentially “reading” the genome. NGS can include sequencing of protein-coding genes, sequencing of the whole genome or targeted sequencing of specific genes. Some variants detected with sequencing are benign (do not cause disease). Some variants have uncertain effects (variants of unknown significance). Other variants are known to cause disease (pathogenic variants).Pathogenic variants of the SHANK3 gene are associated with PMS. If a likely pathogenic variant of SHANK3 is detected, the parents should also undergo NGS to determine if one of the parents carries the same variant. If the variant is present in a healthy parent, it is unlikely to be pathogenic. Indeed, pathogenic variants in SHANK3 are de novo in most people with PMS (they are present in the child and absent in the parents). Data on the medical consequence of SHANK3 variants continue to accrue with time, especially as NGS is more widely used. It is recommended practice for genetic experts to regularly check the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar//) and other variant databases for updates connecting variants to pathogenicity.In terms of prenatal testing, there are no characteristic structural abnormalities that would lead to the diagnosis of deletion 22q13 by an ultrasound exam before birth.Nonetheless, some renal abnormalities have been detected in fetuses that were found after birth to have PMS. In some children, the diagnosis of PMS can be determined before birth by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. CMA, FISH or karyotype studies performed on this fluid or tissue sample may indicate a partial monosomy, or deletion, of chromosome 22q.PMS can also be diagnosed and/or confirmed postnatally by a thorough clinical evaluation, characteristic physical findings and laboratory studies. The first tier of testing should include a chromosomal microarray (CMA). If additional testing is required to determine if a ring is present, chromosome analysis may be requested. If parental studies are needed, the ordering physician will determine which test will provide the best information for accurate genetic counseling.
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Diagnosis of Phelan-McDermid Syndrome. The diagnosis of PMS is based on genetic testing for the identification of a deletion or disruption of the chromosome region 22q13. The first tier of genetic testing for individuals with intellectual disability or developmental delay includes chromosomal microarray analysis (CMA) and next generation sequencing (NGS).Chromosomal microarray analysis (CMA): The test involves providing a small amount of blood. Deletions of 22q13 are reliably detected by CMA because this test detects copy number variations (CNVs), including chromosomal deletions and duplications, across the entire genome. Deletions within the 22q13 region, which commonly impact the SHANK3 gene, are consistent with a diagnosis of PMS.If a deletion of 22q13 is detected through microarray, additional steps should be undertaken to determine if the individual has a ring configuration of chromosome 22, in which the ends of the chromosome stick together at deletion breakpoints. A chromosome analysis will show the structure of the chromosomes (karyotype) and should be performed to determine if the individual has ring 22. Ring 22 carries an added risk of neurofibromatosis type 2 (NF2), a disorder linked with the development of noncancerous tumors in the nervous system.If the CMA shows a terminal deletion of chromosome 22q and a terminal duplication in another chromosome, the individual may have an unbalanced translocation, and fluorescence in situ hybridization (FISH) and/or karyotype studies to visualize the chromosome are warranted. Unbalanced translocations may arise from parental balanced rearrangements. Although 80% of PMS cases occur spontaneously at birth (de novo), inheritance of a parental genetic alteration can occur in about 20% of those affected. Parents who carry a balanced rearrangement, although healthy, have an increased risk of having another affected child and should undergo metaphase FISH and/or karyotype testing.Next-Generation sequencing (NGS): If chromosomal microarray analysis (CMA) has been done but a pathogenic deletion is not identified, the next step is NGS. NGS detects genetic spelling errors, called variants, in a genetic sequence by essentially “reading” the genome. NGS can include sequencing of protein-coding genes, sequencing of the whole genome or targeted sequencing of specific genes. Some variants detected with sequencing are benign (do not cause disease). Some variants have uncertain effects (variants of unknown significance). Other variants are known to cause disease (pathogenic variants).Pathogenic variants of the SHANK3 gene are associated with PMS. If a likely pathogenic variant of SHANK3 is detected, the parents should also undergo NGS to determine if one of the parents carries the same variant. If the variant is present in a healthy parent, it is unlikely to be pathogenic. Indeed, pathogenic variants in SHANK3 are de novo in most people with PMS (they are present in the child and absent in the parents). Data on the medical consequence of SHANK3 variants continue to accrue with time, especially as NGS is more widely used. It is recommended practice for genetic experts to regularly check the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar//) and other variant databases for updates connecting variants to pathogenicity.In terms of prenatal testing, there are no characteristic structural abnormalities that would lead to the diagnosis of deletion 22q13 by an ultrasound exam before birth.Nonetheless, some renal abnormalities have been detected in fetuses that were found after birth to have PMS. In some children, the diagnosis of PMS can be determined before birth by specialized tests such as amniocentesis and/or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. CMA, FISH or karyotype studies performed on this fluid or tissue sample may indicate a partial monosomy, or deletion, of chromosome 22q.PMS can also be diagnosed and/or confirmed postnatally by a thorough clinical evaluation, characteristic physical findings and laboratory studies. The first tier of testing should include a chromosomal microarray (CMA). If additional testing is required to determine if a ring is present, chromosome analysis may be requested. If parental studies are needed, the ordering physician will determine which test will provide the best information for accurate genetic counseling.
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Phelan-McDermid Syndrome
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Therapies of Phelan-McDermid Syndrome
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TreatmentThe treatment for PMS addresses the specific symptoms of each individual and typically requires the coordinated efforts of a team of specialists that may include several of the following: pediatricians, neurologists, nephrologists, gastroenterologists, immunologists, orthopedists, physical or occupational therapists and speech/language pathologists. Cardiac abnormalities are not typical of PMS, but if present will require assessment and appropriate management. In some people, treatment may include surgical repair of certain malformations. The surgical procedures will depend on the severity of the anatomical abnormalities and their associated symptoms.No known treatments have been successful at targeting the underlying cause of Phelan-McDermid syndrome. Instead, treatments are based on symptom management and monitoring organ function. Some frequently used treatment approaches in PMS include but are not limited to: occupational therapy, physical therapy, behavioral therapy (especially if autism spectrum disorder is indicated), anticonvulsants and benzodiazepines for those with seizures and myoclonus, anti-psychotics/electroconvulsive therapy/alpha agonists/stimulants for psychiatric and attention disorders, melatonin and other treatments for sleep disturbances and fluids and anti-nausea medications for gastrointestinal distress. Individuals with PMS may have some or a subset of the symptoms for which these treatments are indicated, and treatment is highly specialized.
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Therapies of Phelan-McDermid Syndrome. TreatmentThe treatment for PMS addresses the specific symptoms of each individual and typically requires the coordinated efforts of a team of specialists that may include several of the following: pediatricians, neurologists, nephrologists, gastroenterologists, immunologists, orthopedists, physical or occupational therapists and speech/language pathologists. Cardiac abnormalities are not typical of PMS, but if present will require assessment and appropriate management. In some people, treatment may include surgical repair of certain malformations. The surgical procedures will depend on the severity of the anatomical abnormalities and their associated symptoms.No known treatments have been successful at targeting the underlying cause of Phelan-McDermid syndrome. Instead, treatments are based on symptom management and monitoring organ function. Some frequently used treatment approaches in PMS include but are not limited to: occupational therapy, physical therapy, behavioral therapy (especially if autism spectrum disorder is indicated), anticonvulsants and benzodiazepines for those with seizures and myoclonus, anti-psychotics/electroconvulsive therapy/alpha agonists/stimulants for psychiatric and attention disorders, melatonin and other treatments for sleep disturbances and fluids and anti-nausea medications for gastrointestinal distress. Individuals with PMS may have some or a subset of the symptoms for which these treatments are indicated, and treatment is highly specialized.
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Overview of Phenylketonuria
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Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life via routine newborn screening. PKU is characterized by absence or deficiency of an enzyme called phenylalanine hydroxylase (PAH), responsible for processing the amino acid phenylalanine. Amino acids are the chemical building blocks of proteins, and are essential for proper growth and development. With normal PAH activity, phenylalanine is converted to another amino acid, tyrosine. However, when PAH is absent or deficient, phenylalanine accumulates and is toxic to the brain. Without treatment, most people with PKU would develop severe intellectual disability. To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life.
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Overview of Phenylketonuria. Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life via routine newborn screening. PKU is characterized by absence or deficiency of an enzyme called phenylalanine hydroxylase (PAH), responsible for processing the amino acid phenylalanine. Amino acids are the chemical building blocks of proteins, and are essential for proper growth and development. With normal PAH activity, phenylalanine is converted to another amino acid, tyrosine. However, when PAH is absent or deficient, phenylalanine accumulates and is toxic to the brain. Without treatment, most people with PKU would develop severe intellectual disability. To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life.
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Phenylketonuria
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Symptoms of Phenylketonuria
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Infants with PKU typically appear normal at birth. With early screening and dietary treatment, affected individuals may never show symptoms of PKU. However, untreated newborns not diagnosed in the first days of life may be weak and feed poorly. Other symptoms may include vomiting, irritability, and/or a red skin rash with small pimples. Developmental delay may be obvious at several months of age. The average IQ of untreated children is usually less than 50. Intellectual disability in PKU is a direct result of elevated levels of phenylalanine in the brain which causes the destruction of the fatty covering (myelin) of individual nerve fibers. It can also cause depression by reducing brain levels of dopamine and serotonin (neurotransmitters).Untreated infants with PKU tend to have unusually light eye, skin, and hair color due to high phenylalanine levels interfering with production of melanin, a substance that causes pigmentation. They may also have a musty or “mousy” body odor caused by phenyl acetic acid in the urine or sweat.Neurological symptoms are present in some untreated patients with PKU, including seizures, abnormal muscle movements, tight muscles, increased reflexes, involuntary movements, or tremor.Untreated females with PKU who become pregnant are at high risk for having a miscarriage or problems with fetal growth (intrauterine growth retardation). Children of women with untreated PKU may have an abnormally small head (microcephaly), congenital heart disease, developmental abnormalities, or facial abnormalities. There is a strong relationship between the severity of these symptoms and high levels of phenylalanine in the mother. As a result, all women with PKU who have stopped treatment should resume treatment before conception and continue on it throughout pregnancy, managed by a metabolic geneticist and dietician.
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Symptoms of Phenylketonuria. Infants with PKU typically appear normal at birth. With early screening and dietary treatment, affected individuals may never show symptoms of PKU. However, untreated newborns not diagnosed in the first days of life may be weak and feed poorly. Other symptoms may include vomiting, irritability, and/or a red skin rash with small pimples. Developmental delay may be obvious at several months of age. The average IQ of untreated children is usually less than 50. Intellectual disability in PKU is a direct result of elevated levels of phenylalanine in the brain which causes the destruction of the fatty covering (myelin) of individual nerve fibers. It can also cause depression by reducing brain levels of dopamine and serotonin (neurotransmitters).Untreated infants with PKU tend to have unusually light eye, skin, and hair color due to high phenylalanine levels interfering with production of melanin, a substance that causes pigmentation. They may also have a musty or “mousy” body odor caused by phenyl acetic acid in the urine or sweat.Neurological symptoms are present in some untreated patients with PKU, including seizures, abnormal muscle movements, tight muscles, increased reflexes, involuntary movements, or tremor.Untreated females with PKU who become pregnant are at high risk for having a miscarriage or problems with fetal growth (intrauterine growth retardation). Children of women with untreated PKU may have an abnormally small head (microcephaly), congenital heart disease, developmental abnormalities, or facial abnormalities. There is a strong relationship between the severity of these symptoms and high levels of phenylalanine in the mother. As a result, all women with PKU who have stopped treatment should resume treatment before conception and continue on it throughout pregnancy, managed by a metabolic geneticist and dietician.
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Phenylketonuria
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Causes of Phenylketonuria
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PKU is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene copy and one abnormal gene copy, they will be a carrier for the condition, but will not have symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk is the same for males and females.More than 300 different changes (mutations) in the PKU gene have been identified. Because the different mutations result in varying degrees of PAH enzyme activity, and therefore varying degrees of phenylalanine elevation in blood, the diet of each child must be adjusted to the individual’s specific phenylalanine tolerance.
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Causes of Phenylketonuria. PKU is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene copy and one abnormal gene copy, they will be a carrier for the condition, but will not have symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk is the same for males and females.More than 300 different changes (mutations) in the PKU gene have been identified. Because the different mutations result in varying degrees of PAH enzyme activity, and therefore varying degrees of phenylalanine elevation in blood, the diet of each child must be adjusted to the individual’s specific phenylalanine tolerance.
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Affects of Phenylketonuria
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The reported incidence of PKU from newborn screening programs ranges from one in 13,500 to 19,000 newborns in the United States. PKU affects people from most ethnic backgrounds, although it is rare in Americans of African descent and Jews of Ashkenazi ancestry.
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Affects of Phenylketonuria. The reported incidence of PKU from newborn screening programs ranges from one in 13,500 to 19,000 newborns in the United States. PKU affects people from most ethnic backgrounds, although it is rare in Americans of African descent and Jews of Ashkenazi ancestry.
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Phenylketonuria
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Related disorders of Phenylketonuria
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Related disorders of Phenylketonuria.
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Phenylketonuria
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Diagnosis of Phenylketonuria
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Diagnosis of Phenylketonuria.
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Therapies of Phenylketonuria
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TreatmentThe goal of treatment for PKU is to keep plasma phenylalanine levels within 120-360 umol/L (2-6 mg/dL). This is generally achieved through carefully planned and monitored diet. Limiting the child’s intake of phenylalanine must be done cautiously because it is an essential amino acid. A carefully maintained diet can prevent intellectual disability as well as neurological, behavioral, and dermatological problems. Treatment must be started at a very young age or some degree of intellectual disability may be expected. However, even some late-treated children have done quite well. Studies have repeatedly demonstrated that children with PKU who are treated with a low phenylalanine diet before the age of three months do well, with an IQ in the normal range.If people with PKU stop controlling their dietary intake of phenylalanine, neurological changes usually occur. IQs may decline. Other problems that may appear and become severe once dietary regulation is stopped include difficulties in school, behavioral problems, mood changes, poor visual-motor coordination, poor memory, poor problem-solving skills, fatigue, tremors, poor concentration, and depression.After years of controversy, there now is nearly universal acceptance among clinicians that the diet needs to be continued indefinitely, and that adults with PKU who stopped the diet in childhood or beyond should return to the diet. Many young adults have restarted the diet and found improvement in mental clarity as a result of lowered blood phenylalanine levels.Because phenylalanine occurs in practically all natural proteins, it is impossible to adequately restrict the diet using natural foods alone without compromising health. For this reason, special phenylalanine-free food preparations are helpful. Foods high in protein, such as meat, milk, fish and cheese are typically not allowed on the diet. Naturally low protein foods such as fruits, vegetables, and some cereals are allowed in limited quantities.In 2007, Kuvan (sapropterin hydrochloride) was approved by the U.S. Food and Drug Administration (FDA) to treat PKU. Kuvan is an oral pharmaceutical formulation of BH4, the natural cofactor for the PAH enzyme, which stimulates activity of the residual PAH enzyme to metabolize phenylalanine into tyrosine. Kuvan is to be used in conjunction with a phenylalanine restricted diet. Kuvan is manufactured by BioMarin Pharmaceutical Inc.In 2018, Palynziq (pegvaliase-pqpz) was approved by the FDA for adults with PKU. Palynziq is an injectable enzyme therapy for patients who have uncontrolled blood phenylalanine concentrations on current treatment. Palynziq is manufactured by BioMarin Pharmaceutical Inc.
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Therapies of Phenylketonuria. TreatmentThe goal of treatment for PKU is to keep plasma phenylalanine levels within 120-360 umol/L (2-6 mg/dL). This is generally achieved through carefully planned and monitored diet. Limiting the child’s intake of phenylalanine must be done cautiously because it is an essential amino acid. A carefully maintained diet can prevent intellectual disability as well as neurological, behavioral, and dermatological problems. Treatment must be started at a very young age or some degree of intellectual disability may be expected. However, even some late-treated children have done quite well. Studies have repeatedly demonstrated that children with PKU who are treated with a low phenylalanine diet before the age of three months do well, with an IQ in the normal range.If people with PKU stop controlling their dietary intake of phenylalanine, neurological changes usually occur. IQs may decline. Other problems that may appear and become severe once dietary regulation is stopped include difficulties in school, behavioral problems, mood changes, poor visual-motor coordination, poor memory, poor problem-solving skills, fatigue, tremors, poor concentration, and depression.After years of controversy, there now is nearly universal acceptance among clinicians that the diet needs to be continued indefinitely, and that adults with PKU who stopped the diet in childhood or beyond should return to the diet. Many young adults have restarted the diet and found improvement in mental clarity as a result of lowered blood phenylalanine levels.Because phenylalanine occurs in practically all natural proteins, it is impossible to adequately restrict the diet using natural foods alone without compromising health. For this reason, special phenylalanine-free food preparations are helpful. Foods high in protein, such as meat, milk, fish and cheese are typically not allowed on the diet. Naturally low protein foods such as fruits, vegetables, and some cereals are allowed in limited quantities.In 2007, Kuvan (sapropterin hydrochloride) was approved by the U.S. Food and Drug Administration (FDA) to treat PKU. Kuvan is an oral pharmaceutical formulation of BH4, the natural cofactor for the PAH enzyme, which stimulates activity of the residual PAH enzyme to metabolize phenylalanine into tyrosine. Kuvan is to be used in conjunction with a phenylalanine restricted diet. Kuvan is manufactured by BioMarin Pharmaceutical Inc.In 2018, Palynziq (pegvaliase-pqpz) was approved by the FDA for adults with PKU. Palynziq is an injectable enzyme therapy for patients who have uncontrolled blood phenylalanine concentrations on current treatment. Palynziq is manufactured by BioMarin Pharmaceutical Inc.
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Phenylketonuria
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Overview of Pheochromocytoma/Paraganglioma
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Pheochromocytoma is a rare type of tumor that arises in adrenal glands, specifically from certain cells known as chromaffin cells in the center of the adrenal gland called the adrenal medulla. These cells secrete hormones epinephrine and norepinephrine, and the pheochromocytoma continuously overproduces them. Pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. Paragangliomas are similar tumors which form in the paraganglia (nerve bundles) throughout the body. Under the microscope, pheochromocytoma and paraganglioma are the same. They are named differently largely just based on the location. For all pheochromocytoma/paraganglioma, approximately 80-85% occur in the adrenal medulla. Approximately 15-20% occur outside of this area in the chest, heart, abdomen, pelvis, bladder, and/or neck or base of the skull. The paraganglioma from the head and neck, and sometimes other locations, are silent meaning they do not produce high epinephrine or norepinephrine. Symptoms associated with secreting pheochromocytomas/paragangliomas include high blood pressure (hypertension), headaches, excessive sweating and/or heart palpitations. In most patients, pheochromocytomas/paragangliomas occur randomly for unknown reasons (sporadically). In approximately 35% of cases, pheochromocytomas may be inherited in an autosomal dominant pattern. Some inherited cases may occur as part of another disorder such as multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis type 1 or hereditary paraganglioma-pheochromocytoma syndromes or as familial isolated pheochromocytoma. Most pheochromocytomas/paragangliomas can be treated via targeted surgery.
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Overview of Pheochromocytoma/Paraganglioma. Pheochromocytoma is a rare type of tumor that arises in adrenal glands, specifically from certain cells known as chromaffin cells in the center of the adrenal gland called the adrenal medulla. These cells secrete hormones epinephrine and norepinephrine, and the pheochromocytoma continuously overproduces them. Pheochromocytomas originate in one of the two adrenal glands located above the kidneys in the back of the upper abdomen. Paragangliomas are similar tumors which form in the paraganglia (nerve bundles) throughout the body. Under the microscope, pheochromocytoma and paraganglioma are the same. They are named differently largely just based on the location. For all pheochromocytoma/paraganglioma, approximately 80-85% occur in the adrenal medulla. Approximately 15-20% occur outside of this area in the chest, heart, abdomen, pelvis, bladder, and/or neck or base of the skull. The paraganglioma from the head and neck, and sometimes other locations, are silent meaning they do not produce high epinephrine or norepinephrine. Symptoms associated with secreting pheochromocytomas/paragangliomas include high blood pressure (hypertension), headaches, excessive sweating and/or heart palpitations. In most patients, pheochromocytomas/paragangliomas occur randomly for unknown reasons (sporadically). In approximately 35% of cases, pheochromocytomas may be inherited in an autosomal dominant pattern. Some inherited cases may occur as part of another disorder such as multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis type 1 or hereditary paraganglioma-pheochromocytoma syndromes or as familial isolated pheochromocytoma. Most pheochromocytomas/paragangliomas can be treated via targeted surgery.
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Symptoms of Pheochromocytoma/Paraganglioma
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Some people with a pheochromocytoma/paraganglioma may not develop symptoms (asymptomatic). High blood pressure (hypertension) is the most common finding associated with pheochromocytomas. High blood pressure may be always present or may come and go. Affected individuals may experience chronic episodes of high blood pressure often resulting in headaches, irregular heartbeats (palpitations) and profuse sweating (diaphoresis). The frequency of these episodes varies anywhere from several times a day to a couple of times a month.Symptoms associated with pheochromocytomas/paragangliomas occur because of the release of certain hormones known as catecholamines (e.g., norepinephrine and epinephrine). The release of excessive catecholamines results in high blood pressure and other characteristic symptoms of pheochromocytoma.Additional symptoms that occur less frequently may include pain in the chest or abdomen, nausea, vomiting, diarrhea, constipation, pale skin (pallor), weakness and weight loss. Attacks of anxiety or apprehension may also occur. Some individuals experience an extreme drop in blood pressure upon standing suddenly, sometimes resulting in dizziness (orthostatic hypotension). Some individuals with a pheochromocytoma/paraganglioma may have difficulties in the breakdown (metabolism) of carbohydrates and can develop diabetes.If left untreated, pheochromocytomas/paragangliomas may progress to cause serious, life-threatening complications including heart muscle disease (cardiomyopathy), bleeding in the brain (cerebral hemorrhaging) or the accumulation of fluid in the lungs (pulmonary edema). Some individuals with pheochromocytoma/paraganglioma may be at risk of developing a stroke or heart attack (myocardial infarction).Approximately 15% of pheochromocytomas/paragangliomas may be cancer-causing (metastatic, meaning spread to other locations in the body). Extra-adrenal paragangliomas are more likely to be metastatic than adrenal pheochromocytomas. Metastatic pheochromocytomas/paragangliomas can spread (metastasize) to various areas of the body including the lymph nodes, liver, lungs and bones.
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Symptoms of Pheochromocytoma/Paraganglioma. Some people with a pheochromocytoma/paraganglioma may not develop symptoms (asymptomatic). High blood pressure (hypertension) is the most common finding associated with pheochromocytomas. High blood pressure may be always present or may come and go. Affected individuals may experience chronic episodes of high blood pressure often resulting in headaches, irregular heartbeats (palpitations) and profuse sweating (diaphoresis). The frequency of these episodes varies anywhere from several times a day to a couple of times a month.Symptoms associated with pheochromocytomas/paragangliomas occur because of the release of certain hormones known as catecholamines (e.g., norepinephrine and epinephrine). The release of excessive catecholamines results in high blood pressure and other characteristic symptoms of pheochromocytoma.Additional symptoms that occur less frequently may include pain in the chest or abdomen, nausea, vomiting, diarrhea, constipation, pale skin (pallor), weakness and weight loss. Attacks of anxiety or apprehension may also occur. Some individuals experience an extreme drop in blood pressure upon standing suddenly, sometimes resulting in dizziness (orthostatic hypotension). Some individuals with a pheochromocytoma/paraganglioma may have difficulties in the breakdown (metabolism) of carbohydrates and can develop diabetes.If left untreated, pheochromocytomas/paragangliomas may progress to cause serious, life-threatening complications including heart muscle disease (cardiomyopathy), bleeding in the brain (cerebral hemorrhaging) or the accumulation of fluid in the lungs (pulmonary edema). Some individuals with pheochromocytoma/paraganglioma may be at risk of developing a stroke or heart attack (myocardial infarction).Approximately 15% of pheochromocytomas/paragangliomas may be cancer-causing (metastatic, meaning spread to other locations in the body). Extra-adrenal paragangliomas are more likely to be metastatic than adrenal pheochromocytomas. Metastatic pheochromocytomas/paragangliomas can spread (metastasize) to various areas of the body including the lymph nodes, liver, lungs and bones.
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Pheochromocytoma/Paraganglioma
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Causes of Pheochromocytoma/Paraganglioma
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In most cases, the exact cause of pheochromocytoma/paraganglioma is unknown. Most cases occur randomly, for unknown reasons (sporadically).Approximately 35% of cases of pheochromocytomas result from genetic disruptions or changes (mutations) to certain genes. These mutations are inherited in an autosomal dominant pattern. Autosomal dominant genetic disorders occur when only a single copy of an altered gene is necessary for the appearance of the disease. The altered gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Some cases of pheochromocytoma/paraganglioma occur as part of a genetic syndrome. Disorders in which pheochromocytomas/paragangliomas may be a secondary finding include multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis type 1, hereditary paraganglioma-pheochromocytoma syndromes and isolated familial pheochromocytoma.Individuals with isolated, nonsyndromic pheochromocytoma/paraganglioma still may have a genetic predisposition or cause to developing the tumor. A person who is genetically predisposed to a disorder carries a mutated gene for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances. Some people with the genetic predisposition may never have a trigger and may never develop a tumor. Some of these cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation) which does not come from either parent but now can be passed on to their children.Pheochromocytomas/paragangliomas may be caused by mutations of one of at least ten different genes: the RET gene, which is also associated with multiple endocrine neoplasia type 2; the VHL gene, which is also associated with von Hippel-Lindau syndrome; the neurofibromatosis (NF1) gene, associated with neurofibromatosis type 1; the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which are associated with the hereditary paraganglioma-pheochromocytoma syndromes; the TMEM127 gene; and the MAX gene.
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Causes of Pheochromocytoma/Paraganglioma. In most cases, the exact cause of pheochromocytoma/paraganglioma is unknown. Most cases occur randomly, for unknown reasons (sporadically).Approximately 35% of cases of pheochromocytomas result from genetic disruptions or changes (mutations) to certain genes. These mutations are inherited in an autosomal dominant pattern. Autosomal dominant genetic disorders occur when only a single copy of an altered gene is necessary for the appearance of the disease. The altered gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the altered gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Some cases of pheochromocytoma/paraganglioma occur as part of a genetic syndrome. Disorders in which pheochromocytomas/paragangliomas may be a secondary finding include multiple endocrine neoplasia types 2a and 2b, von Hippel-Lindau syndrome, neurofibromatosis type 1, hereditary paraganglioma-pheochromocytoma syndromes and isolated familial pheochromocytoma.Individuals with isolated, nonsyndromic pheochromocytoma/paraganglioma still may have a genetic predisposition or cause to developing the tumor. A person who is genetically predisposed to a disorder carries a mutated gene for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances. Some people with the genetic predisposition may never have a trigger and may never develop a tumor. Some of these cases may occur randomly as the result of a spontaneous genetic change (i.e., new mutation) which does not come from either parent but now can be passed on to their children.Pheochromocytomas/paragangliomas may be caused by mutations of one of at least ten different genes: the RET gene, which is also associated with multiple endocrine neoplasia type 2; the VHL gene, which is also associated with von Hippel-Lindau syndrome; the neurofibromatosis (NF1) gene, associated with neurofibromatosis type 1; the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which are associated with the hereditary paraganglioma-pheochromocytoma syndromes; the TMEM127 gene; and the MAX gene.
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Pheochromocytoma/Paraganglioma
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Affects of Pheochromocytoma/Paraganglioma
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Pheochromocytomas/paragangliomas affect males and females in equal numbers and may affect individuals of any age. These tumors occur most often in individuals between 30 and 50 years of age. At the present time, it is thought that approximately 10% of cases occur in children.Pheochromocytomas/paragangliomas are rare tumors, occurring in less than 1 percent of all individuals with high blood pressure. The true incidence of pheochromocytomas is unknown. Many individuals with pheochromocytomas go undiagnosed during their lifetime. Approximately 85% of pheochromocytomas/paragangliomas are non-cancerous.
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Affects of Pheochromocytoma/Paraganglioma. Pheochromocytomas/paragangliomas affect males and females in equal numbers and may affect individuals of any age. These tumors occur most often in individuals between 30 and 50 years of age. At the present time, it is thought that approximately 10% of cases occur in children.Pheochromocytomas/paragangliomas are rare tumors, occurring in less than 1 percent of all individuals with high blood pressure. The true incidence of pheochromocytomas is unknown. Many individuals with pheochromocytomas go undiagnosed during their lifetime. Approximately 85% of pheochromocytomas/paragangliomas are non-cancerous.
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Pheochromocytoma/Paraganglioma
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Related disorders of Pheochromocytoma/Paraganglioma
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Because the main symptom of pheochromocytoma/paraganglioma is high blood pressure, it shares the symptoms of many other diseases that cause high blood pressure like neurogenic hypertension. Comparisons may be useful for a differential diagnosis. Thyrotoxicosis, hypoglycemia, anxiety or panic attacks, hyperthyroidism, adrenal medullary hyperplasia, familial dysautonomia, and intracranial lesions may also have similar symptoms. Various tumors including neuroblastomas, ganglioneuroblastomas and ganglioneuromas may mimic pheochromocytomas/paragangliomas. Symptoms associated with pheochromocytoma/paraganglioma, such as high blood pressure, may be induced by the use of certain medications. These medications are non-steroidal anti-inflammatory drugs like ibuprofen and naproxen, cough and cold medicine, and migraine medications. Withdrawal of the medication used to treat high blood pressure, clonidine, may cause similar symptoms.
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Related disorders of Pheochromocytoma/Paraganglioma. Because the main symptom of pheochromocytoma/paraganglioma is high blood pressure, it shares the symptoms of many other diseases that cause high blood pressure like neurogenic hypertension. Comparisons may be useful for a differential diagnosis. Thyrotoxicosis, hypoglycemia, anxiety or panic attacks, hyperthyroidism, adrenal medullary hyperplasia, familial dysautonomia, and intracranial lesions may also have similar symptoms. Various tumors including neuroblastomas, ganglioneuroblastomas and ganglioneuromas may mimic pheochromocytomas/paragangliomas. Symptoms associated with pheochromocytoma/paraganglioma, such as high blood pressure, may be induced by the use of certain medications. These medications are non-steroidal anti-inflammatory drugs like ibuprofen and naproxen, cough and cold medicine, and migraine medications. Withdrawal of the medication used to treat high blood pressure, clonidine, may cause similar symptoms.
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Pheochromocytoma/Paraganglioma
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Diagnosis of Pheochromocytoma/Paraganglioma
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A diagnosis of pheochromocytoma/paraganglioma may be suspected based upon a detailed patient history (including previous pheochromocytoma/paraganglioma cases in the family), a thorough clinical evaluation, and identification of characteristic findings (paroxysmal attacks, hypertension unresponsive to normal treatment, etc.). Blood and/or urine analysis can confirm a diagnosis of secreting pheochromocytoma/paraganglioma by detecting elevated levels of catecholamines or their metabolites in the urine and blood (plasma). Metabolites are the byproducts of catecholamines that are produced when the body breaks down (metabolizes) catecholamines. Imaging techniques such as computed tomography (CT scan) and magnetic resonance imaging (MRI) are often performed to determine the specific location and size of a pheochromocytoma/paraganglioma. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. MRI is the imaging technique of choice for pregnant women that are suspected of having a pheochromocytoma/paraganglioma.Lobenguane I 123 injection (AdreView) and gallium 68 dotatate are molecular imaging agents for the detection of rare neuroendocrine tumors in children and adults, and are approved by the U.S. Food and Drug Administration (FDA) for diagnosis. These are often used when metastatic disease (spread through the body) is suspected.
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Diagnosis of Pheochromocytoma/Paraganglioma. A diagnosis of pheochromocytoma/paraganglioma may be suspected based upon a detailed patient history (including previous pheochromocytoma/paraganglioma cases in the family), a thorough clinical evaluation, and identification of characteristic findings (paroxysmal attacks, hypertension unresponsive to normal treatment, etc.). Blood and/or urine analysis can confirm a diagnosis of secreting pheochromocytoma/paraganglioma by detecting elevated levels of catecholamines or their metabolites in the urine and blood (plasma). Metabolites are the byproducts of catecholamines that are produced when the body breaks down (metabolizes) catecholamines. Imaging techniques such as computed tomography (CT scan) and magnetic resonance imaging (MRI) are often performed to determine the specific location and size of a pheochromocytoma/paraganglioma. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues. MRI is the imaging technique of choice for pregnant women that are suspected of having a pheochromocytoma/paraganglioma.Lobenguane I 123 injection (AdreView) and gallium 68 dotatate are molecular imaging agents for the detection of rare neuroendocrine tumors in children and adults, and are approved by the U.S. Food and Drug Administration (FDA) for diagnosis. These are often used when metastatic disease (spread through the body) is suspected.
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Pheochromocytoma/Paraganglioma
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Therapies of Pheochromocytoma/Paraganglioma
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TreatmentThe diagnosis and therapeutic management of pheochromocytoma/paraganglioma may require the coordinated efforts of a team of medical professionals, such as specialists who diagnose and treat endocrine disorders (endocrinologists); physicians who specialize in the diagnosis and treatment of cancer (medical oncologists); specialists in the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors: tumor size; tumor location; whether the tumor is localized or spread (metastasized); the presence or absence of certain symptoms; an individual's age and general health; and/or additional elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Surgery is the main form of treatment for pheochromocytoma/paraganglioma. Approximately 80-85% of pheochromocytomas are successfully removed by surgery. Surgical removal of one or both adrenal glands (adrenalectomy) or another location in case of extra-adrenal paragangliomas, may be performed. The most common surgical procedure for treating adrenal pheochromocytoma is laparoscopic adrenalectomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. In patients in whom both adrenals are removed, a small amount of the adrenal external layer (or adrenal cortex) can be left behind to preserve normal glucocorticoid production of the adrenal (called cortical sparing surgery). This may reduce later complications caused by glucocorticoid deficiency in patients that need removal of both adrenals.Before surgery, affected individuals need to be treated with alpha-adrenergic blockers and possibly beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as doxazosin and prazosin are used to control high blood pressure (hypertension). In some patients, beta-adrenergic blockers such as propranolol or metoprolol can be added to treat arrhythmias fast heart rates (tachycardia).Surgery may be used to treat cases of metastatic pheochromocytoma/paraganglioma. Radiation therapy, in which radiation is used to target and destroy cancer cells and certain combinations of anticancer drugs (chemotherapy), may also be used to treat individuals with metastatic or unresectable pheochromocytoma/paraganglioma. In cases where surgery cannot remove all affect tissue, periodic reduction of metastasized tissue (debulking) may be beneficial. Individuals in whom surgery does not remove all affect tissue may need to be on medications to control high blood pressure.In 2018, the FDA approved Iobenguane I 131 (brand name: Azedra) for the treatment of patients 12 years and older with a pheochromocytoma/paraganglioma that cannot be surgically removed, has spread beyond the original tumor site and requires systemic anticancer therapy. Genetic counseling is recommended for all individuals who have pheochromocytoma/paraganglioma and their families. Other treatment is symptomatic and supportive.
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Therapies of Pheochromocytoma/Paraganglioma. TreatmentThe diagnosis and therapeutic management of pheochromocytoma/paraganglioma may require the coordinated efforts of a team of medical professionals, such as specialists who diagnose and treat endocrine disorders (endocrinologists); physicians who specialize in the diagnosis and treatment of cancer (medical oncologists); specialists in the use of radiation to treat cancers (radiation oncologists); oncology nurses; surgeons; dietitians; and/or other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors: tumor size; tumor location; whether the tumor is localized or spread (metastasized); the presence or absence of certain symptoms; an individual's age and general health; and/or additional elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of the case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Surgery is the main form of treatment for pheochromocytoma/paraganglioma. Approximately 80-85% of pheochromocytomas are successfully removed by surgery. Surgical removal of one or both adrenal glands (adrenalectomy) or another location in case of extra-adrenal paragangliomas, may be performed. The most common surgical procedure for treating adrenal pheochromocytoma is laparoscopic adrenalectomy. During this procedure, a small incision is made in the abdomen, a small tube is inserted (laparoscope) through the incision, and the tumor is removed. In patients in whom both adrenals are removed, a small amount of the adrenal external layer (or adrenal cortex) can be left behind to preserve normal glucocorticoid production of the adrenal (called cortical sparing surgery). This may reduce later complications caused by glucocorticoid deficiency in patients that need removal of both adrenals.Before surgery, affected individuals need to be treated with alpha-adrenergic blockers and possibly beta-adrenergic blockers to minimize the effects of adrenal hormones. Alpha-adrenergic blockers such as doxazosin and prazosin are used to control high blood pressure (hypertension). In some patients, beta-adrenergic blockers such as propranolol or metoprolol can be added to treat arrhythmias fast heart rates (tachycardia).Surgery may be used to treat cases of metastatic pheochromocytoma/paraganglioma. Radiation therapy, in which radiation is used to target and destroy cancer cells and certain combinations of anticancer drugs (chemotherapy), may also be used to treat individuals with metastatic or unresectable pheochromocytoma/paraganglioma. In cases where surgery cannot remove all affect tissue, periodic reduction of metastasized tissue (debulking) may be beneficial. Individuals in whom surgery does not remove all affect tissue may need to be on medications to control high blood pressure.In 2018, the FDA approved Iobenguane I 131 (brand name: Azedra) for the treatment of patients 12 years and older with a pheochromocytoma/paraganglioma that cannot be surgically removed, has spread beyond the original tumor site and requires systemic anticancer therapy. Genetic counseling is recommended for all individuals who have pheochromocytoma/paraganglioma and their families. Other treatment is symptomatic and supportive.
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Pheochromocytoma/Paraganglioma
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Overview of Phosphoglycerate Kinase Deficiency
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Phosphoglycerate kinase deficiency is an extremely rare inherited metabolic disorder characterized by deficiency of the enzyme phosphoglycerate kinase. This enzyme is essential for the breakdown of glycogen, resulting in the release of energy. Symptoms and findings associated with the disorder may include low levels of circulating red blood cells (hemolytic anemia); varying degrees of intellectual disability; rapidly changing emotions (emotional liability); an impaired ability to communicate through and/or to comprehend speech or writing (aphasia); exercise-induced pain, stiffness, or cramps; enlargement of the spleen (splenomegaly); and/or paralysis of one side of the body (hemiplegia). In most cases, phosphoglycerate kinase deficiency is inherited as an X-linked genetic trait. In such cases, the disorder is fully expressed in males only; however, some females who carry one copy of the disease gene (heterozygotes) may have hemolytic anemia.
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Overview of Phosphoglycerate Kinase Deficiency. Phosphoglycerate kinase deficiency is an extremely rare inherited metabolic disorder characterized by deficiency of the enzyme phosphoglycerate kinase. This enzyme is essential for the breakdown of glycogen, resulting in the release of energy. Symptoms and findings associated with the disorder may include low levels of circulating red blood cells (hemolytic anemia); varying degrees of intellectual disability; rapidly changing emotions (emotional liability); an impaired ability to communicate through and/or to comprehend speech or writing (aphasia); exercise-induced pain, stiffness, or cramps; enlargement of the spleen (splenomegaly); and/or paralysis of one side of the body (hemiplegia). In most cases, phosphoglycerate kinase deficiency is inherited as an X-linked genetic trait. In such cases, the disorder is fully expressed in males only; however, some females who carry one copy of the disease gene (heterozygotes) may have hemolytic anemia.
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Phosphoglycerate Kinase Deficiency
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Symptoms of Phosphoglycerate Kinase Deficiency
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The three main features of phosphoglycerate kinase deficiency are hemolytic anemia, intellectual disability, and muscle problems (myopathy). An individual with the disorder may be affected by one or more of these features, but it is unusual for one person to exhibit all three signs.Individuals with childhood PGK deficiency have some degree of intellectual disability with delayed language acquisition. Some have epilepsy and strokes.Most adult patients are moderately affected, and heterozygous females may show only mild hemolytic anemia with no myopathy or intellectual disability.Myopathy with exercise-induced stiffness, cramps, and muscle pain is seen in adolescents and young adult males. The cramps are often severe and may incapacitate the individual for hours. Myoglobinuria is often seen in severe episodes.
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Symptoms of Phosphoglycerate Kinase Deficiency. The three main features of phosphoglycerate kinase deficiency are hemolytic anemia, intellectual disability, and muscle problems (myopathy). An individual with the disorder may be affected by one or more of these features, but it is unusual for one person to exhibit all three signs.Individuals with childhood PGK deficiency have some degree of intellectual disability with delayed language acquisition. Some have epilepsy and strokes.Most adult patients are moderately affected, and heterozygous females may show only mild hemolytic anemia with no myopathy or intellectual disability.Myopathy with exercise-induced stiffness, cramps, and muscle pain is seen in adolescents and young adult males. The cramps are often severe and may incapacitate the individual for hours. Myoglobinuria is often seen in severe episodes.
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Phosphoglycerate Kinase Deficiency
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Causes of Phosphoglycerate Kinase Deficiency
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PGK is considered to be an inborn error of metabolism that is inherited in an X-linked manner. The gene responsible is located on the X chromosome (Xq13).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq13” refers to band 13 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Phosphoglycerate Kinase Deficiency. PGK is considered to be an inborn error of metabolism that is inherited in an X-linked manner. The gene responsible is located on the X chromosome (Xq13).Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq13” refers to band 13 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Phosphoglycerate Kinase Deficiency
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Affects of Phosphoglycerate Kinase Deficiency
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Phosphoglycerate kinase deficiency is a very rare disorder that is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygous carriers) may exhibit some symptoms associated with the disorder (i.e., hemolytic anemia). The disorder can be diagnosed at birth when enzymatic testing is done. More than 30 cases of PGK deficiency have been written up in the medical literature. It is thought that there are people with the disease who do not receive a diagnosis.
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Affects of Phosphoglycerate Kinase Deficiency. Phosphoglycerate kinase deficiency is a very rare disorder that is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygous carriers) may exhibit some symptoms associated with the disorder (i.e., hemolytic anemia). The disorder can be diagnosed at birth when enzymatic testing is done. More than 30 cases of PGK deficiency have been written up in the medical literature. It is thought that there are people with the disease who do not receive a diagnosis.
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Phosphoglycerate Kinase Deficiency
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Related disorders of Phosphoglycerate Kinase Deficiency
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Symptoms of the following disorders can be similar to those of phosphoglycerate kinase deficiency. Comparisons may be useful for a differential diagnosis:Warm antibody hemolytic anemia is an autoimmune disorder characterized by the premature destruction of red blood cells by the body's natural defenses against invading organisms (antibodies). The severity of the anemia is determined by the amount of time the red blood cells survive. (For more information on this disorder, choose “Warm Antibody, Hemolytic Anemia” as your search term in the Rare Disease Database.)Acquired autoimmune hemolytic anemia is an autoimmune disorder characterized by the premature destruction of red blood cells. It occurs in individuals who previously had a normal red blood cell system. The disorder commonly occurs as the result of, or in conjunction with some other medical condition. (For more information on this disorder, choose “Acquired Autoimmune Hemolytic Anemia” as your search term in the Rare Disease Database.)Sideroblastic anemia is a blood disorder characterized by an impaired ability of the bone marrow to produce normal red blood cells. It is characterized by general weakness, fatigue and difficulty breathing. (For more information on this disorder, choose “Sideroblastic Anemia” as your search term in the Rare Disease Database.)Aplastic anemia is characterized by bone marrow failure. The disorder may occur for unknown reasons (idiopathic) or it may be the result of a toxic reaction to radiation, certain drugs, or chemicals. The patient may first become aware of the disease by the progressive onset of weakness, fatigue, and lassitude. (For more information on this disorder, choose “Aplastic Anemia” as your search term in the Rare Disease Database.)One case of myopathy and juvenile parkinsonism has been described in the literature.
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Related disorders of Phosphoglycerate Kinase Deficiency. Symptoms of the following disorders can be similar to those of phosphoglycerate kinase deficiency. Comparisons may be useful for a differential diagnosis:Warm antibody hemolytic anemia is an autoimmune disorder characterized by the premature destruction of red blood cells by the body's natural defenses against invading organisms (antibodies). The severity of the anemia is determined by the amount of time the red blood cells survive. (For more information on this disorder, choose “Warm Antibody, Hemolytic Anemia” as your search term in the Rare Disease Database.)Acquired autoimmune hemolytic anemia is an autoimmune disorder characterized by the premature destruction of red blood cells. It occurs in individuals who previously had a normal red blood cell system. The disorder commonly occurs as the result of, or in conjunction with some other medical condition. (For more information on this disorder, choose “Acquired Autoimmune Hemolytic Anemia” as your search term in the Rare Disease Database.)Sideroblastic anemia is a blood disorder characterized by an impaired ability of the bone marrow to produce normal red blood cells. It is characterized by general weakness, fatigue and difficulty breathing. (For more information on this disorder, choose “Sideroblastic Anemia” as your search term in the Rare Disease Database.)Aplastic anemia is characterized by bone marrow failure. The disorder may occur for unknown reasons (idiopathic) or it may be the result of a toxic reaction to radiation, certain drugs, or chemicals. The patient may first become aware of the disease by the progressive onset of weakness, fatigue, and lassitude. (For more information on this disorder, choose “Aplastic Anemia” as your search term in the Rare Disease Database.)One case of myopathy and juvenile parkinsonism has been described in the literature.
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Phosphoglycerate Kinase Deficiency
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Diagnosis of Phosphoglycerate Kinase Deficiency
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The diagnosis is made on the basis of a thorough physical examination and confirmed by the results of laboratory tests.
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Diagnosis of Phosphoglycerate Kinase Deficiency. The diagnosis is made on the basis of a thorough physical examination and confirmed by the results of laboratory tests.
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Phosphoglycerate Kinase Deficiency
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Therapies of Phosphoglycerate Kinase Deficiency
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TreatmentTreatment of phosphoglycerate kinase deficiency may consist of iron supplements and blood transfusions when needed. The avoidance of strenuous exercise when evidence that muscle breakdown has taken place is very important and special care is needed during neurologic crisis to avoid life-threatening situations. Bone marrow transplantation may be an option in cases with severe neurological deterioration.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Therapies of Phosphoglycerate Kinase Deficiency. TreatmentTreatment of phosphoglycerate kinase deficiency may consist of iron supplements and blood transfusions when needed. The avoidance of strenuous exercise when evidence that muscle breakdown has taken place is very important and special care is needed during neurologic crisis to avoid life-threatening situations. Bone marrow transplantation may be an option in cases with severe neurological deterioration.Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.
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Phosphoglycerate Kinase Deficiency
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Overview of Pierre Robin Sequence
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SummaryPierre Robin sequence (PRS) is characterized by a small lower jaw (micrognathia) and displacement of the tongue toward the back of the oral cavity (glossoptosis). Some infants also have an abnormal opening in the roof of the mouth (cleft palate). PRS is believed to be caused by multiple contributing factors, which lead to a series of physical changes within the oral cavity. The current belief is that the lower jaw does not grow enough, which leads to the tongue being displaced toward the back of the throat. Given the oral cavity’s limited size, the tongue also gets pushed upward, where it interferes with the natural closure of the developing palate. These changes occur during pregnancy, leading to craniofacial abnormalities that are typically detected at birth. Additionally, the altered anatomy of the oral cavity makes breathing difficult, which can range in severity from mild disturbance to life-threatening respiratory distress. Since food must pass through the altered oral cavity to get into the gastrointestinal tract, feeding difficulties are also common. The features of PRS can be present as an isolated sequence or as part of a genetic syndrome. Individuals with isolated PRS most commonly have mutations near the SOX9 gene.IntroductionPRS is a condition with several clinical features: a small lower jaw (micrognathia), displacement of the tongue toward the back of the oral cavity (glossoptosis) and, often but not always, an opening in the roof of the mouth (cleft palate). PRS was named after Dr. Pierre Robin, a French dental surgeon who first observed its features during the early 20th century. While the precise cause is not fully clear, the current belief is that multiple contributing factors lead to sequential physical changes within the oral cavity, which ultimately leads to airway obstruction. For this reason, breathing problems are common manifestations of PRS. Feeding problems are also common, since the oral cavity also serves as a conduit to the gastrointestinal tract.
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Overview of Pierre Robin Sequence. SummaryPierre Robin sequence (PRS) is characterized by a small lower jaw (micrognathia) and displacement of the tongue toward the back of the oral cavity (glossoptosis). Some infants also have an abnormal opening in the roof of the mouth (cleft palate). PRS is believed to be caused by multiple contributing factors, which lead to a series of physical changes within the oral cavity. The current belief is that the lower jaw does not grow enough, which leads to the tongue being displaced toward the back of the throat. Given the oral cavity’s limited size, the tongue also gets pushed upward, where it interferes with the natural closure of the developing palate. These changes occur during pregnancy, leading to craniofacial abnormalities that are typically detected at birth. Additionally, the altered anatomy of the oral cavity makes breathing difficult, which can range in severity from mild disturbance to life-threatening respiratory distress. Since food must pass through the altered oral cavity to get into the gastrointestinal tract, feeding difficulties are also common. The features of PRS can be present as an isolated sequence or as part of a genetic syndrome. Individuals with isolated PRS most commonly have mutations near the SOX9 gene.IntroductionPRS is a condition with several clinical features: a small lower jaw (micrognathia), displacement of the tongue toward the back of the oral cavity (glossoptosis) and, often but not always, an opening in the roof of the mouth (cleft palate). PRS was named after Dr. Pierre Robin, a French dental surgeon who first observed its features during the early 20th century. While the precise cause is not fully clear, the current belief is that multiple contributing factors lead to sequential physical changes within the oral cavity, which ultimately leads to airway obstruction. For this reason, breathing problems are common manifestations of PRS. Feeding problems are also common, since the oral cavity also serves as a conduit to the gastrointestinal tract.
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Pierre Robin Sequence
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Symptoms of Pierre Robin Sequence
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PRS involves physical changes during development that lead to altered oral cavity anatomy. Since air and food both pass through the mouth and down the throat, breathing and feeding problems are common.In PRS, the lower jaw (mandible) characteristically has an altered shape and position. Typically, it has a reduced length and is located toward the back (microretrognathia). In turn, these changes in the mandible can influence the tongue’s positioning toward the back of the mouth (a ‘retruded’ tongue). Anatomic anomalies of PRS also frequently include a U-shaped cleft palate, which affects the dynamics of breathing and speech development.Specifically, the displacement of the tongue toward the back (posterior) of the mouth predisposes it to fall toward the throat. This may obstruct the airway and cause difficulty breathing. This can vary in severity, ranging from mild disturbance to life-threatening respiratory distress. Airway obstruction can also occur during the night, in the case of a related condition called ‘obstructive sleep apnea’. This is a sleep disorder characterized by breathing that temporarily stops and restarts because of periodic blockage of the airways.Since food traveling toward the gastrointestinal tract also passes through the mouth and throat, feeding difficulties can also arise due to abnormal oral cavity anatomy. Depending on the severity, this can lead to issues like choking (aspiration) or gaining less weight gain than expected (which doctors refer to as ‘failure to thrive’). There is also a higher prevalence of acid (gastroesophageal) reflux in children with PRS. Other possible manifestations of PRS include cardiovascular and lung conditions, such as heart murmurs, high blood pressure in the arteries of the lungs (pulmonary hypertension), and narrowing of the opening between the lung artery and the right ventricle of the heart (pulmonary stenosis). Anomalies of the musculoskeletal system, including those in the arms, legs, feet, and vertebral column, are also common. Inflammation of the middle ear (otitis media) usually accompanied by repeat ear infections occurs in about 80% of patients, and eye (ocular) defects are noted in about 10% to 30% of patients. Teeth present at birth (natal teeth) are another frequent finding.
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Symptoms of Pierre Robin Sequence. PRS involves physical changes during development that lead to altered oral cavity anatomy. Since air and food both pass through the mouth and down the throat, breathing and feeding problems are common.In PRS, the lower jaw (mandible) characteristically has an altered shape and position. Typically, it has a reduced length and is located toward the back (microretrognathia). In turn, these changes in the mandible can influence the tongue’s positioning toward the back of the mouth (a ‘retruded’ tongue). Anatomic anomalies of PRS also frequently include a U-shaped cleft palate, which affects the dynamics of breathing and speech development.Specifically, the displacement of the tongue toward the back (posterior) of the mouth predisposes it to fall toward the throat. This may obstruct the airway and cause difficulty breathing. This can vary in severity, ranging from mild disturbance to life-threatening respiratory distress. Airway obstruction can also occur during the night, in the case of a related condition called ‘obstructive sleep apnea’. This is a sleep disorder characterized by breathing that temporarily stops and restarts because of periodic blockage of the airways.Since food traveling toward the gastrointestinal tract also passes through the mouth and throat, feeding difficulties can also arise due to abnormal oral cavity anatomy. Depending on the severity, this can lead to issues like choking (aspiration) or gaining less weight gain than expected (which doctors refer to as ‘failure to thrive’). There is also a higher prevalence of acid (gastroesophageal) reflux in children with PRS. Other possible manifestations of PRS include cardiovascular and lung conditions, such as heart murmurs, high blood pressure in the arteries of the lungs (pulmonary hypertension), and narrowing of the opening between the lung artery and the right ventricle of the heart (pulmonary stenosis). Anomalies of the musculoskeletal system, including those in the arms, legs, feet, and vertebral column, are also common. Inflammation of the middle ear (otitis media) usually accompanied by repeat ear infections occurs in about 80% of patients, and eye (ocular) defects are noted in about 10% to 30% of patients. Teeth present at birth (natal teeth) are another frequent finding.
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Causes of Pierre Robin Sequence
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At present, the exact cause of PRS is unknown. The most widely held view is that multiple contributing factors lead to a sequence of physical changes within the oral cavity. These changes are thought to occur in a series of steps, rather than as isolated events. Specifically, it is believed that failure of the lower jaw to fully develop early in gestation causes the tongue to be positioned toward the back and high up in the mouth cavity, which, in turn, prevents palate closure. PRS as a condition can occur by itself (‘isolated PRS’) or as a feature in multiple anomaly disorders (‘syndromic PRS’). When PRS occurs on its own, DNA near a gene called SOX9 is the most commonly affected region. The SOX9 gene allows for the production of the SOX9 protein, which plays a critical role in skeletal development. In affected individuals, there are often mutations in regions of DNA that positively modulate SOX9’s activity (enhancers). When these areas are damaged, the SOX9 gene’s activity is reduced, which leads to less normal SOX9 protein being produced. This is believed to play a role in the craniofacial abnormalities characteristically associated with PRS. At present, most cases of isolated PRS are believed to arise sporadically, or through new (de novo) genetic changes, rather than being inherited from one generation to the next. In the rarer familial cases of isolated PRS, research has favored an autosomal dominant mode of inheritance. Syndromic PRS is inherited following the same genetic pattern as the condition that it is associated with, meaning that this may vary depending on the syndrome.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Pierre Robin Sequence. At present, the exact cause of PRS is unknown. The most widely held view is that multiple contributing factors lead to a sequence of physical changes within the oral cavity. These changes are thought to occur in a series of steps, rather than as isolated events. Specifically, it is believed that failure of the lower jaw to fully develop early in gestation causes the tongue to be positioned toward the back and high up in the mouth cavity, which, in turn, prevents palate closure. PRS as a condition can occur by itself (‘isolated PRS’) or as a feature in multiple anomaly disorders (‘syndromic PRS’). When PRS occurs on its own, DNA near a gene called SOX9 is the most commonly affected region. The SOX9 gene allows for the production of the SOX9 protein, which plays a critical role in skeletal development. In affected individuals, there are often mutations in regions of DNA that positively modulate SOX9’s activity (enhancers). When these areas are damaged, the SOX9 gene’s activity is reduced, which leads to less normal SOX9 protein being produced. This is believed to play a role in the craniofacial abnormalities characteristically associated with PRS. At present, most cases of isolated PRS are believed to arise sporadically, or through new (de novo) genetic changes, rather than being inherited from one generation to the next. In the rarer familial cases of isolated PRS, research has favored an autosomal dominant mode of inheritance. Syndromic PRS is inherited following the same genetic pattern as the condition that it is associated with, meaning that this may vary depending on the syndrome.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Pierre Robin Sequence
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PRS affects males and females in equal numbers, with an estimated prevalence of about 1 in 8,500-14,000 individuals.
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Affects of Pierre Robin Sequence. PRS affects males and females in equal numbers, with an estimated prevalence of about 1 in 8,500-14,000 individuals.
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Related disorders of Pierre Robin Sequence
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Symptoms of the following disorders can be similar to, or may be associated with, PRS. Comparisons may be useful for a differential diagnosis.Stickler syndrome is a rare connective tissue disorder that most often affects the eyes, ears, skeleton, and joints. Signs and symptoms may include: nearsightedness (myopia), a detached retina (separation of the retina of the eye from the layers of the eyeball that support it), hearing loss, a characteristic facial appearance with mid-facial flatness, and joint pain. Affected individuals may also have features of PRS, specifically an unusually small lower jaw (micrognathia), displacement of the tongue toward the back of the oral cavity (glossoptosis) and an abnormal opening in the roof of the mouth (cleft palate). (For more information on this disorder, choose “Stickler” as your search term in the Rare Disease Database.)Chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome) is a disorder caused by a small piece of chromosome 22 missing. 22q11.2DS is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences. The symptoms of this condition are extremely variable, even among members of the same family. (For more information on this disorder, choose “chromosome 22q11.2 deletion” as your search term in the Rare Disease Database.)Treacher Collins syndrome is a rare genetic disorder characterized by distinctive abnormalities of the head and face, notably severe micrognathia. Associated manifestations include malformation of the eyes, anomalies of the ear that may lead to hearing loss, and more. (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)Other related syndromes and conditions include: chromosome 11, partial trisomy 11q; trisomy 18 syndrome; cerebro-costo-mandibular syndrome; Catel Manzke syndrome; campomelic dysplasia; Moebius syndrome; and CHARGE syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Pierre Robin Sequence. Symptoms of the following disorders can be similar to, or may be associated with, PRS. Comparisons may be useful for a differential diagnosis.Stickler syndrome is a rare connective tissue disorder that most often affects the eyes, ears, skeleton, and joints. Signs and symptoms may include: nearsightedness (myopia), a detached retina (separation of the retina of the eye from the layers of the eyeball that support it), hearing loss, a characteristic facial appearance with mid-facial flatness, and joint pain. Affected individuals may also have features of PRS, specifically an unusually small lower jaw (micrognathia), displacement of the tongue toward the back of the oral cavity (glossoptosis) and an abnormal opening in the roof of the mouth (cleft palate). (For more information on this disorder, choose “Stickler” as your search term in the Rare Disease Database.)Chromosome 22q11.2 deletion syndrome (velocardiofacial syndrome) is a disorder caused by a small piece of chromosome 22 missing. 22q11.2DS is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences. The symptoms of this condition are extremely variable, even among members of the same family. (For more information on this disorder, choose “chromosome 22q11.2 deletion” as your search term in the Rare Disease Database.)Treacher Collins syndrome is a rare genetic disorder characterized by distinctive abnormalities of the head and face, notably severe micrognathia. Associated manifestations include malformation of the eyes, anomalies of the ear that may lead to hearing loss, and more. (For more information on this disorder, choose “Treacher Collins” as your search term in the Rare Disease Database.)Other related syndromes and conditions include: chromosome 11, partial trisomy 11q; trisomy 18 syndrome; cerebro-costo-mandibular syndrome; Catel Manzke syndrome; campomelic dysplasia; Moebius syndrome; and CHARGE syndrome. NORD has individual reports on many of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Pierre Robin Sequence
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PRS can be detected while the fetus is still in the womb. Trained medical personnel may visualize characteristic features of PRS using ultrasound imaging. If not diagnosed previously, craniofacial abnormalities are typically detected at birth on physical exam. Infants with severe airway obstruction may present with respiratory distress at birth, and may require medical intervention. There is no one standard test that is routinely used to diagnose isolated PRS, though molecular genetic testing can be used to identify DNA changes involving the SOX9 gene.If syndromic PRS is suspected, consultation with a geneticist is highly recommended. This healthcare professional may carry out a laboratory workup in support of the suspected condition.
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Diagnosis of Pierre Robin Sequence. PRS can be detected while the fetus is still in the womb. Trained medical personnel may visualize characteristic features of PRS using ultrasound imaging. If not diagnosed previously, craniofacial abnormalities are typically detected at birth on physical exam. Infants with severe airway obstruction may present with respiratory distress at birth, and may require medical intervention. There is no one standard test that is routinely used to diagnose isolated PRS, though molecular genetic testing can be used to identify DNA changes involving the SOX9 gene.If syndromic PRS is suspected, consultation with a geneticist is highly recommended. This healthcare professional may carry out a laboratory workup in support of the suspected condition.
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Therapies of Pierre Robin Sequence
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Treatment
Treatment of PRS is multifaceted and individualized, with surgery being performed only to solve the functional problems that a patient may have. Surgical treatments may be indicated for PRS patients with more severe clinical conditions, often those associated with airway impairment.Infants with PRS should be observed closely for breathing difficulties. Placing the child on his or her stomach (prone position), rather than on his or her back, can help prevent the tongue from falling back toward the throat. If this does not solve the problem of airway obstruction, small tube-like instruments such as a ‘nasopharyngeal airway’ may be inserted into the nose to keep the airways open. If airway obstruction is even more severe, a tube may be inserted in the infant's throat in hospital (intubation) or, rarely, a surgical opening may be made into the trachea through the neck (tracheostomy) to assist the infant in breathing.To close the cleft palate, surgery is typically performed between 12 and 18 months of age. Doctors may postpone the corrective surgery, however, to allow the opening in the palate to close on its own as natural growth occurs. Surgery to improve the appearance of the jaw is rarely necessary because the small lower jaw seen at birth most often grows to a more normal size by 18 months of age.
To address feeding-related difficulties, a variety of specially adapted bottles and nipples may be used. If feeding problems are unresolved and severe, a feeding tube may be needed temporarily in order to assist with proper weight gain. Symptomatic and supportive treatment may be provided using a multidisciplinary team approach, in order to best meet the needs of the affected individual. If speech is impaired, the child should participate in speech therapy or be monitored by a speech pathologist. Ear, nose, and throat doctors (otolaryngologists) and audiologists can provide follow-up on ear- and hearing-related issues. Surgically placed drainage tubes may be recommended if ear infections are recurrent. A combination of orthodontists, maxillofacial surgeons, and dentists may work together to monitor the oral cavity, for example by looking to avoid crowding of the teeth and to ensure proper tooth alignment. Ophthalmology may be consulted to monitor for ocular abnormalities. Genetic counseling may be of benefit for patients and their families.
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Therapies of Pierre Robin Sequence. Treatment
Treatment of PRS is multifaceted and individualized, with surgery being performed only to solve the functional problems that a patient may have. Surgical treatments may be indicated for PRS patients with more severe clinical conditions, often those associated with airway impairment.Infants with PRS should be observed closely for breathing difficulties. Placing the child on his or her stomach (prone position), rather than on his or her back, can help prevent the tongue from falling back toward the throat. If this does not solve the problem of airway obstruction, small tube-like instruments such as a ‘nasopharyngeal airway’ may be inserted into the nose to keep the airways open. If airway obstruction is even more severe, a tube may be inserted in the infant's throat in hospital (intubation) or, rarely, a surgical opening may be made into the trachea through the neck (tracheostomy) to assist the infant in breathing.To close the cleft palate, surgery is typically performed between 12 and 18 months of age. Doctors may postpone the corrective surgery, however, to allow the opening in the palate to close on its own as natural growth occurs. Surgery to improve the appearance of the jaw is rarely necessary because the small lower jaw seen at birth most often grows to a more normal size by 18 months of age.
To address feeding-related difficulties, a variety of specially adapted bottles and nipples may be used. If feeding problems are unresolved and severe, a feeding tube may be needed temporarily in order to assist with proper weight gain. Symptomatic and supportive treatment may be provided using a multidisciplinary team approach, in order to best meet the needs of the affected individual. If speech is impaired, the child should participate in speech therapy or be monitored by a speech pathologist. Ear, nose, and throat doctors (otolaryngologists) and audiologists can provide follow-up on ear- and hearing-related issues. Surgically placed drainage tubes may be recommended if ear infections are recurrent. A combination of orthodontists, maxillofacial surgeons, and dentists may work together to monitor the oral cavity, for example by looking to avoid crowding of the teeth and to ensure proper tooth alignment. Ophthalmology may be consulted to monitor for ocular abnormalities. Genetic counseling may be of benefit for patients and their families.
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Overview of PIK3CA-Related Overgrowth Spectrum
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SummaryPIK3CA-related overgrowth spectrum (PROS) includes a group of genetic disorders that leads to overgrowth of various body parts due to changes (mutations) in the gene PIK3CA. This gene is involved in making a protein that helps regulate cell growth, division and survival. A broad array of disorders falls within this spectrum, with some overlap of symptoms between the different disorders. Syndromes within the spectrum may also overlap genetically, meaning they may share specific PIK3CA gene mutations in cells in the areas of the body that are affected. Since PIK3CA mutations in these disorders are not present in all cells, only certain areas of the body are overgrown, ranging from isolated digits to whole limbs, trunk, or brain. Different tissues may be involved individually or in combination such as fat, muscle, bone, nerve, brain and blood vessels. Genetic mutations that cause these disorders are not passed down from parent to child but instead result from changes to genes during development in the womb. Symptoms associated with these disorders can be present at birth (congenital) or appear later in early childhood. Overgrowth may stop in childhood or continue into adulthood.
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Overview of PIK3CA-Related Overgrowth Spectrum. SummaryPIK3CA-related overgrowth spectrum (PROS) includes a group of genetic disorders that leads to overgrowth of various body parts due to changes (mutations) in the gene PIK3CA. This gene is involved in making a protein that helps regulate cell growth, division and survival. A broad array of disorders falls within this spectrum, with some overlap of symptoms between the different disorders. Syndromes within the spectrum may also overlap genetically, meaning they may share specific PIK3CA gene mutations in cells in the areas of the body that are affected. Since PIK3CA mutations in these disorders are not present in all cells, only certain areas of the body are overgrown, ranging from isolated digits to whole limbs, trunk, or brain. Different tissues may be involved individually or in combination such as fat, muscle, bone, nerve, brain and blood vessels. Genetic mutations that cause these disorders are not passed down from parent to child but instead result from changes to genes during development in the womb. Symptoms associated with these disorders can be present at birth (congenital) or appear later in early childhood. Overgrowth may stop in childhood or continue into adulthood.
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Symptoms of PIK3CA-Related Overgrowth Spectrum
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Different subtypes within PROS include: CLAPO syndrome, CLOVES syndrome, DCMO, DMEG, FAH/FAO/HHML, FAVA, FIL, HMEG, Klippel-Trenaunay syndrome (KTS), LON, macrodactyly, MCAP and muscular hemihyperplasia (HH). Symptoms vary widely and depend on which part of the body overgrows, ranging from intellectual disability, seizures and autism when the brain is involved to blood clots when blood vessels are affected. Some PROS syndromes affect a wider range of body systems while others are more limited in which parts of the body overgrow.CLAPO SyndromeCLAPO is an acronym for the multiple features that can co-occur in this syndrome: capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of face and limbs and partial or generalized overgrowth involving one or more body segments. This syndrome was first described in 2008. Features that distinguish CLAPO from other PROS syndromes with similar signs, like MCAP syndrome, are the presence of capillary malformations on the lower lip and the absence of neurological symptoms since CLAPO does not affect the brain. Capillary malformations in MCAP are most frequently found on or above the upper lip instead. Overgrowth in CLAPO may be difficult to detect and what may appear as overgrowth of fatty tissue may be asymmetry between body parts due to vascular changes.CLOVES SyndromeCLOVES syndrome is a rare disorder first described as a distinct syndrome in 2007. It is characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for Congenital Lipomatous (fatty) Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies. It can affect soft tissue, blood vessels, bone and internal organs, and symptoms can range from mild to severe. This syndrome has many potential symptoms, but these are among the most common ones:1. Lipomatous overgrowth where soft fatty masses are present at birth on the trunk (back, flanks, axilla, abdomen or buttocks). These overgrowths can appear on one or both sides of the body.2. Vascular malformations may be found overlying these masses or elsewhere on the body, most often as a red-pinkish birthmark called a capillary malformation (also known as a port-wine stain). Other skin abnormalities in this syndrome include moles, prominent veins and epidermal nevi (slightly raised often rough areas of skin with light brownish color).3. Patients with CLOVES are more susceptible to blood clots, including pulmonary embolism (clots in the lungs), due to abnormal malformed veins (usually residual embryonic dilated veins) in the chest and upper and lower extremities. Abnormal veins may also cause localized pain and inflammation.4. Swellings of lymph fluid, known as lymphatic malformations, can also occur within the fatty masses or elsewhere in body (abdomen, chest, extremities).5. Overgrowth of one or more extremities (arms and legs) is common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap deformity) and uneven size of extremities (length and/or girth discrepancy) are common. This can also occur in the face and head when those areas are involved.6. Spinal anomalies include scoliosis (curving of the spine), fatty masses pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band). Rarely, patients may suffer from arteriovenous malformations around the area of the spinal cord, which can be quite aggressive and difficult to treat.7. The size of the kidneys may be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome so screening with serial ultrasound examinations during childhood is recommended.Additional findings can occur in CLOVES syndrome including bleeding from abnormal vessels in the skin, gastrointestinal tract (the stomach and intestines) and/or the genitourinary tract (urinary bladder and urethra). (For more information on this disorder, choose “CLOVES Syndrome” as your search term in the Rare Disease Database).Diffuse Capillary Malformation with Overgrowth (DCMO)DCMO patients have multiple and/or extensive capillary malformations associated with facial asymmetry, limb overgrowth and hand or foot deformities. These capillary malformations form a blotchy network of birthmarks that may lighten over the first several months and are typically lighter than birthmarks in KTS. Capillary malformations in DCMO extend beyond just one body region. They may be present on the abdomen but never on the back. Limb overgrowth in DCMO does not progress, so vascular complications are not expected to occur.Dysplastic Megalencephaly (DMEG)Dysplastic megalencephaly, or bilateral hemimegalencephaly, causes overgrowth of both hemispheres of the brain, leading to abnormal development. Symptoms include seizures that don't respond well to medications, severe neurological impairment, abnormal muscle tone and developmental delays in motor, language and cognitive skills. DMEG may also be associated with cardiac failure during fetal development.Fibroadipose Hyperplasia (FAH)/Fibroadipose Overgrowth (FAO)First reported in 2012 as a PIK3CA-related condition, this overgrowth syndrome affects connective tissues (including fat, skin, ligaments, tendons and blood). Body parts that may enlarge are the trunk, an individual limb, or fingers and toes. Fat, bone, and muscle may overgrow, but most commonly, overgrowth is seen in fatty tissue below the skin and around the abdomen. Although extra fingers or toes may be present at birth, overgrowth in fibroadipose hyperplasia is not usually apparent at birth and tends to progress over time. Functional limitations with completing everyday tasks may occur due to anatomical differences between body parts and limited movement of enlarged body parts.Hemihyperplasia Multiple Lipomatosis (HHML) SyndromeWhen the overgrowth is more diffuse it may present as hemihyperplasia multiple lipomatosis (HHML) syndrome, a rare disorder characterized by the development of multiple benign fatty tumors (lipomas) and the abnormal enlargement of one side or structure of the body (hemihyperplasia). Hemihyperplasia may present as asymmetry between just one limb as compared to the other side, or between one half of the body and the other. Hemihyperplasia may be mildly progressive as the result of asymmetric (more rapid) growth on the affected side.Fibro-Adipose Vascular Anomaly (FAVA)FAVA is a rare mass of blood vessels and fatty tissue that develops within a muscle. It normally leads to overgrowth of a single limb, most commonly in the lower extremities about 90% of the time but may also form in the upper extremities and the trunk. It tends to cause pain as its most prominent symptom, but may present as reduced mobility, swelling, or visible veins. Diagnosis with FAVA may be delayed into late childhood or even adulthood. FAVA is three times more common in females than males. As of 2020, there were only 20 patients with FAVA reported in the medical literature.Facial Infiltrating Lipomatosis (FIL)Facial infiltrating lipomatosis (FIL) results in overgrowth in areas of the face due to invasion by mature fat cells (lipocytes). One side of the face becomes swollen and enlarged over time due to enlargement of bones and soft tissues. Other features may include early development of teeth, enlarged teeth (macrodontia), tongue enlargement on the affected side and nerve tumors (neuromas) in areas around the tongue and lips.Hemimegalencephaly (HME)Hemimegalencephaly (HME) is a rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the other. The structure of the brain on the affected side may be markedly abnormal or show only subtle changes. In either case, because of this size and structural difference, the enlarged brain tissue causes frequent seizures, often associated with cognitive or behavioral disabilities. Seizures in association with HME often begin in early infant life, including infantile spasms. Hemimegalencephaly may occur as an isolated or sporadic brain malformation, or it may be associated with other neurodevelopmental syndromes; it has been observed in some patients with CLOVES syndrome when the face/head are involved. Thus, when detected, HME should prompt a search for other syndromic diagnoses.Anti-seizure medications are not typically effective in controlling seizures in HME and surgery is often recommended to control the seizures. If the affected side is surgically removed (anatomic hemispherectomy) or disconnected from the other brain structures (functional hemispherectomy) early in life, the remaining side of the brain may gradually take over the functions normally performed by the affected side.Any combination of altered mental status, seizures, enlarged head and /or colored birthmark should prompt consideration of HME. In general, the presence of HME is definitively diagnosed by brain MRI. With the evolution of more widespread fetal imaging including ultrasound and MRI, many HME cases are detected prenatally. (For more information on this disorder, choose “Hemimegalencephaly” as your search term in the Rare Disease Database).Klippel-Trenaunay Syndrome (KTS)Originally described in the early 1900s according to a set of symptoms, many but not all patients with KTS have since been found to have PIK3CA gene mutations. KTS is present at birth and is characterized by a triad of cutaneous capillary malformation (port-wine stain) and abnormal veins in association with limb overgrowth, and patients often show lymphatic malformations as well. KTS occurs typically in one lower limb and may extend into the pelvis. KTS affects males and females equally. There is some overlap with symptoms of CLOVES syndrome depending on the extent of involvement. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database).Lipomatosis of Nerve (LON)Lipomatosis of nerve occurs when nerve bundles enlarge from overgrown fat that impacts nerve function. LON may be associated with bone or soft tissue overgrowth in areas served by but at somewhat of a distance from the affected portion of the nerve. This means LON may occur with other overgrowth conditions like macrodactyly or muscular hemihyperplasia. Overgrowth progresses slowly so patients usually do not present with symptoms until childhood or young adulthood and symptoms are usually of a neurological dysfunction. LON most often affects the median nerve that controls the forearm and hand so patients can present with carpal tunnel syndrome. Other nerves more frequently affected are the ulnar and plantar nerves serving the arm and feet, respectively. LON affects males and females equally.MacrodactylyMacrodactyly refers to abnormally large fingers or toes present at birth due to overgrowth of bones and soft tissue. It can occur as a feature of other PROS syndromes or in isolation. Macrodactyly occurs more often in the hands than feet but can affect both in one individual. It may also affect one or more digits and may occur on one or both sides of the body. Growth of the enlarged digits may occur at the same or at a much faster rate than unaffected digits and growth rates can vary across time in the affected individual. Webbed fingers and toes, known as syndactyly, may co-occur in patients with macrodactyly. Other accompanying symptoms in macrodactyly include stiffness, reduced mobility, swelling and rarely, pain. PIK3CA gene mutations are a primary cause of isolated macrodactyly.Megalencephaly-Capillary Malformation (MCAP) SyndromeMegalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation (M-CM), is a complex disorder that usually presents at birth and involves many organ systems, including the brain; skin; blood vessels; connective tissue and others. Some patients with this syndrome have mild symptoms while others have more severe ones.Most affected individuals have a disproportionately large head and vascular malformations on the skin, typically light pink vascular markings on the midline face, trunk, and sometimes limbs.Most children with MCAP have an enlarged brain (megalencephaly) and other findings on brain MRI scans with associated neurological problems. One particularly common type of malformation of the brain’s cortex in MCAP is polymicrogyria (PMG), which refers to abnormally small and numerous folds of the cortical surface. The corpus callosum (a midline structure that joins the two cerebral hemispheres) is usually twice as thick as normal. Head overgrowth tends to progress with time, and brain overgrowth within the skull can even lead to brain herniation. Brain overgrowth can interfere with drainage of cerebrospinal fluid, leading to abnormal widening of the ventricles and excessive accumulation of this fluid (hydrocephalus). Chiari malformation may also occur when megalencephaly causes portions of the cerebellum of the brain to become dislodged and compress the brainstem. Symptoms of hydrocephalus and Chiari malformation include headaches, lethargy, breathing abnormalities and recurrent vomiting; when this occurs, neurosurgical intervention is needed urgently.Most infants with this syndrome have some degree of body overgrowth at birth that tends to stabilize or normalize with age, although others may have body growth deficiency later. Body growth may also be uneven between the two halves of the body, ranging from very noticeable to very subtle.Specific skin findings are associated with MCAP syndrome. These light-pink vascular markings, known as capillary malformations, are most commonly at the midline face (on the forehead or above the upper lip) in MCAP, but they can also be found in children who don't have this syndrome. They may fade as children with MCAP get older. MCAP-associated capillary malformations often show a lacy or reticulated pattern (resembling a net or web) called cutis marmorata.Children with MCAP syndrome may also have low blood sugar levels (hypoglycemia). This is from growth hormone deficiency caused by abnormal brain development. (For more information on this disorder, choose “Megalencephaly-Capillary Malformation” as your search term in the Rare Disease Database).Muscular Hemihyperplasia (HH)Formerly known as muscular hemihypertrophy, muscular hemihyperplasia is an overgrowth of muscle tissue on one side of the body and usually present at birth. It can overlap with features of macrodactyly, HHML and FAO.
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Symptoms of PIK3CA-Related Overgrowth Spectrum. Different subtypes within PROS include: CLAPO syndrome, CLOVES syndrome, DCMO, DMEG, FAH/FAO/HHML, FAVA, FIL, HMEG, Klippel-Trenaunay syndrome (KTS), LON, macrodactyly, MCAP and muscular hemihyperplasia (HH). Symptoms vary widely and depend on which part of the body overgrows, ranging from intellectual disability, seizures and autism when the brain is involved to blood clots when blood vessels are affected. Some PROS syndromes affect a wider range of body systems while others are more limited in which parts of the body overgrow.CLAPO SyndromeCLAPO is an acronym for the multiple features that can co-occur in this syndrome: capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of face and limbs and partial or generalized overgrowth involving one or more body segments. This syndrome was first described in 2008. Features that distinguish CLAPO from other PROS syndromes with similar signs, like MCAP syndrome, are the presence of capillary malformations on the lower lip and the absence of neurological symptoms since CLAPO does not affect the brain. Capillary malformations in MCAP are most frequently found on or above the upper lip instead. Overgrowth in CLAPO may be difficult to detect and what may appear as overgrowth of fatty tissue may be asymmetry between body parts due to vascular changes.CLOVES SyndromeCLOVES syndrome is a rare disorder first described as a distinct syndrome in 2007. It is characterized by tissue overgrowth and complex vascular anomalies. CLOVES stands for Congenital Lipomatous (fatty) Overgrowth, Vascular malformations, Epidermal nevi and Scoliosis/Skeletal/Spinal anomalies. It can affect soft tissue, blood vessels, bone and internal organs, and symptoms can range from mild to severe. This syndrome has many potential symptoms, but these are among the most common ones:1. Lipomatous overgrowth where soft fatty masses are present at birth on the trunk (back, flanks, axilla, abdomen or buttocks). These overgrowths can appear on one or both sides of the body.2. Vascular malformations may be found overlying these masses or elsewhere on the body, most often as a red-pinkish birthmark called a capillary malformation (also known as a port-wine stain). Other skin abnormalities in this syndrome include moles, prominent veins and epidermal nevi (slightly raised often rough areas of skin with light brownish color).3. Patients with CLOVES are more susceptible to blood clots, including pulmonary embolism (clots in the lungs), due to abnormal malformed veins (usually residual embryonic dilated veins) in the chest and upper and lower extremities. Abnormal veins may also cause localized pain and inflammation.4. Swellings of lymph fluid, known as lymphatic malformations, can also occur within the fatty masses or elsewhere in body (abdomen, chest, extremities).5. Overgrowth of one or more extremities (arms and legs) is common. Large wide hands or feet, large fingers or toes, wide space between digits (sandal gap deformity) and uneven size of extremities (length and/or girth discrepancy) are common. This can also occur in the face and head when those areas are involved.6. Spinal anomalies include scoliosis (curving of the spine), fatty masses pushing on the spinal cord and tethered cord (spinal cord fixed by abnormal band). Rarely, patients may suffer from arteriovenous malformations around the area of the spinal cord, which can be quite aggressive and difficult to treat.7. The size of the kidneys may be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome so screening with serial ultrasound examinations during childhood is recommended.Additional findings can occur in CLOVES syndrome including bleeding from abnormal vessels in the skin, gastrointestinal tract (the stomach and intestines) and/or the genitourinary tract (urinary bladder and urethra). (For more information on this disorder, choose “CLOVES Syndrome” as your search term in the Rare Disease Database).Diffuse Capillary Malformation with Overgrowth (DCMO)DCMO patients have multiple and/or extensive capillary malformations associated with facial asymmetry, limb overgrowth and hand or foot deformities. These capillary malformations form a blotchy network of birthmarks that may lighten over the first several months and are typically lighter than birthmarks in KTS. Capillary malformations in DCMO extend beyond just one body region. They may be present on the abdomen but never on the back. Limb overgrowth in DCMO does not progress, so vascular complications are not expected to occur.Dysplastic Megalencephaly (DMEG)Dysplastic megalencephaly, or bilateral hemimegalencephaly, causes overgrowth of both hemispheres of the brain, leading to abnormal development. Symptoms include seizures that don't respond well to medications, severe neurological impairment, abnormal muscle tone and developmental delays in motor, language and cognitive skills. DMEG may also be associated with cardiac failure during fetal development.Fibroadipose Hyperplasia (FAH)/Fibroadipose Overgrowth (FAO)First reported in 2012 as a PIK3CA-related condition, this overgrowth syndrome affects connective tissues (including fat, skin, ligaments, tendons and blood). Body parts that may enlarge are the trunk, an individual limb, or fingers and toes. Fat, bone, and muscle may overgrow, but most commonly, overgrowth is seen in fatty tissue below the skin and around the abdomen. Although extra fingers or toes may be present at birth, overgrowth in fibroadipose hyperplasia is not usually apparent at birth and tends to progress over time. Functional limitations with completing everyday tasks may occur due to anatomical differences between body parts and limited movement of enlarged body parts.Hemihyperplasia Multiple Lipomatosis (HHML) SyndromeWhen the overgrowth is more diffuse it may present as hemihyperplasia multiple lipomatosis (HHML) syndrome, a rare disorder characterized by the development of multiple benign fatty tumors (lipomas) and the abnormal enlargement of one side or structure of the body (hemihyperplasia). Hemihyperplasia may present as asymmetry between just one limb as compared to the other side, or between one half of the body and the other. Hemihyperplasia may be mildly progressive as the result of asymmetric (more rapid) growth on the affected side.Fibro-Adipose Vascular Anomaly (FAVA)FAVA is a rare mass of blood vessels and fatty tissue that develops within a muscle. It normally leads to overgrowth of a single limb, most commonly in the lower extremities about 90% of the time but may also form in the upper extremities and the trunk. It tends to cause pain as its most prominent symptom, but may present as reduced mobility, swelling, or visible veins. Diagnosis with FAVA may be delayed into late childhood or even adulthood. FAVA is three times more common in females than males. As of 2020, there were only 20 patients with FAVA reported in the medical literature.Facial Infiltrating Lipomatosis (FIL)Facial infiltrating lipomatosis (FIL) results in overgrowth in areas of the face due to invasion by mature fat cells (lipocytes). One side of the face becomes swollen and enlarged over time due to enlargement of bones and soft tissues. Other features may include early development of teeth, enlarged teeth (macrodontia), tongue enlargement on the affected side and nerve tumors (neuromas) in areas around the tongue and lips.Hemimegalencephaly (HME)Hemimegalencephaly (HME) is a rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the other. The structure of the brain on the affected side may be markedly abnormal or show only subtle changes. In either case, because of this size and structural difference, the enlarged brain tissue causes frequent seizures, often associated with cognitive or behavioral disabilities. Seizures in association with HME often begin in early infant life, including infantile spasms. Hemimegalencephaly may occur as an isolated or sporadic brain malformation, or it may be associated with other neurodevelopmental syndromes; it has been observed in some patients with CLOVES syndrome when the face/head are involved. Thus, when detected, HME should prompt a search for other syndromic diagnoses.Anti-seizure medications are not typically effective in controlling seizures in HME and surgery is often recommended to control the seizures. If the affected side is surgically removed (anatomic hemispherectomy) or disconnected from the other brain structures (functional hemispherectomy) early in life, the remaining side of the brain may gradually take over the functions normally performed by the affected side.Any combination of altered mental status, seizures, enlarged head and /or colored birthmark should prompt consideration of HME. In general, the presence of HME is definitively diagnosed by brain MRI. With the evolution of more widespread fetal imaging including ultrasound and MRI, many HME cases are detected prenatally. (For more information on this disorder, choose “Hemimegalencephaly” as your search term in the Rare Disease Database).Klippel-Trenaunay Syndrome (KTS)Originally described in the early 1900s according to a set of symptoms, many but not all patients with KTS have since been found to have PIK3CA gene mutations. KTS is present at birth and is characterized by a triad of cutaneous capillary malformation (port-wine stain) and abnormal veins in association with limb overgrowth, and patients often show lymphatic malformations as well. KTS occurs typically in one lower limb and may extend into the pelvis. KTS affects males and females equally. There is some overlap with symptoms of CLOVES syndrome depending on the extent of involvement. (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database).Lipomatosis of Nerve (LON)Lipomatosis of nerve occurs when nerve bundles enlarge from overgrown fat that impacts nerve function. LON may be associated with bone or soft tissue overgrowth in areas served by but at somewhat of a distance from the affected portion of the nerve. This means LON may occur with other overgrowth conditions like macrodactyly or muscular hemihyperplasia. Overgrowth progresses slowly so patients usually do not present with symptoms until childhood or young adulthood and symptoms are usually of a neurological dysfunction. LON most often affects the median nerve that controls the forearm and hand so patients can present with carpal tunnel syndrome. Other nerves more frequently affected are the ulnar and plantar nerves serving the arm and feet, respectively. LON affects males and females equally.MacrodactylyMacrodactyly refers to abnormally large fingers or toes present at birth due to overgrowth of bones and soft tissue. It can occur as a feature of other PROS syndromes or in isolation. Macrodactyly occurs more often in the hands than feet but can affect both in one individual. It may also affect one or more digits and may occur on one or both sides of the body. Growth of the enlarged digits may occur at the same or at a much faster rate than unaffected digits and growth rates can vary across time in the affected individual. Webbed fingers and toes, known as syndactyly, may co-occur in patients with macrodactyly. Other accompanying symptoms in macrodactyly include stiffness, reduced mobility, swelling and rarely, pain. PIK3CA gene mutations are a primary cause of isolated macrodactyly.Megalencephaly-Capillary Malformation (MCAP) SyndromeMegalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation (M-CM), is a complex disorder that usually presents at birth and involves many organ systems, including the brain; skin; blood vessels; connective tissue and others. Some patients with this syndrome have mild symptoms while others have more severe ones.Most affected individuals have a disproportionately large head and vascular malformations on the skin, typically light pink vascular markings on the midline face, trunk, and sometimes limbs.Most children with MCAP have an enlarged brain (megalencephaly) and other findings on brain MRI scans with associated neurological problems. One particularly common type of malformation of the brain’s cortex in MCAP is polymicrogyria (PMG), which refers to abnormally small and numerous folds of the cortical surface. The corpus callosum (a midline structure that joins the two cerebral hemispheres) is usually twice as thick as normal. Head overgrowth tends to progress with time, and brain overgrowth within the skull can even lead to brain herniation. Brain overgrowth can interfere with drainage of cerebrospinal fluid, leading to abnormal widening of the ventricles and excessive accumulation of this fluid (hydrocephalus). Chiari malformation may also occur when megalencephaly causes portions of the cerebellum of the brain to become dislodged and compress the brainstem. Symptoms of hydrocephalus and Chiari malformation include headaches, lethargy, breathing abnormalities and recurrent vomiting; when this occurs, neurosurgical intervention is needed urgently.Most infants with this syndrome have some degree of body overgrowth at birth that tends to stabilize or normalize with age, although others may have body growth deficiency later. Body growth may also be uneven between the two halves of the body, ranging from very noticeable to very subtle.Specific skin findings are associated with MCAP syndrome. These light-pink vascular markings, known as capillary malformations, are most commonly at the midline face (on the forehead or above the upper lip) in MCAP, but they can also be found in children who don't have this syndrome. They may fade as children with MCAP get older. MCAP-associated capillary malformations often show a lacy or reticulated pattern (resembling a net or web) called cutis marmorata.Children with MCAP syndrome may also have low blood sugar levels (hypoglycemia). This is from growth hormone deficiency caused by abnormal brain development. (For more information on this disorder, choose “Megalencephaly-Capillary Malformation” as your search term in the Rare Disease Database).Muscular Hemihyperplasia (HH)Formerly known as muscular hemihypertrophy, muscular hemihyperplasia is an overgrowth of muscle tissue on one side of the body and usually present at birth. It can overlap with features of macrodactyly, HHML and FAO.
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Causes of PIK3CA-Related Overgrowth Spectrum
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PROS is caused by somatic mutations in the PIK3CA gene. There are a variety of activating mutations of the PIK3CA gene associated with each syndrome with some genetic overlap between the different syndromes. During prenatal development, mutations known as somatic and germline mutations can occur. Germline mutations are genetic changes in sperm or egg cells (germ cells) that are passed down during conception to affect offspring. Somatic mutations are genetic changes in any body cell other than germ cells and, therefore, cannot be passed down to offspring. Somatic mutations can occur during prenatal development and any time during the lifespan.In the case of PROS, these somatic mutations occur during prenatal development and are said to be somatic mosaic mutations. Mosaic refers to these mutations being present in only certain body cells that affect only certain areas of the body rather than in all body (somatic) cells, which is why overgrowth appears in only certain body regions or asymmetrically.The PIK3CA gene provides instructions for making the protein known as p110α, and mutations in this gene result in an abnormally active PI3K enzyme. With this increase in activity, affected cells grow and divide more than they should, leading to abnormal bone, soft tissue and blood vessel growth. PIK3CA mutations may also cause overgrowth by influencing the effects of growth factors and hormones on nearby and distant cells.Since 2004, mutations in the PIK3CA gene have been found in certain cancers of the lower GI tract, the ovaries, breasts, brain and liver. Currently, most patients with PROS do not appear to be at a significantly higher risk for cancer. The only cancer reported in PROS to date has been Wilms tumor, the most common pediatric kidney cancer in very young children.
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Causes of PIK3CA-Related Overgrowth Spectrum. PROS is caused by somatic mutations in the PIK3CA gene. There are a variety of activating mutations of the PIK3CA gene associated with each syndrome with some genetic overlap between the different syndromes. During prenatal development, mutations known as somatic and germline mutations can occur. Germline mutations are genetic changes in sperm or egg cells (germ cells) that are passed down during conception to affect offspring. Somatic mutations are genetic changes in any body cell other than germ cells and, therefore, cannot be passed down to offspring. Somatic mutations can occur during prenatal development and any time during the lifespan.In the case of PROS, these somatic mutations occur during prenatal development and are said to be somatic mosaic mutations. Mosaic refers to these mutations being present in only certain body cells that affect only certain areas of the body rather than in all body (somatic) cells, which is why overgrowth appears in only certain body regions or asymmetrically.The PIK3CA gene provides instructions for making the protein known as p110α, and mutations in this gene result in an abnormally active PI3K enzyme. With this increase in activity, affected cells grow and divide more than they should, leading to abnormal bone, soft tissue and blood vessel growth. PIK3CA mutations may also cause overgrowth by influencing the effects of growth factors and hormones on nearby and distant cells.Since 2004, mutations in the PIK3CA gene have been found in certain cancers of the lower GI tract, the ovaries, breasts, brain and liver. Currently, most patients with PROS do not appear to be at a significantly higher risk for cancer. The only cancer reported in PROS to date has been Wilms tumor, the most common pediatric kidney cancer in very young children.
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Affects of PIK3CA-Related Overgrowth Spectrum
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Because PROS includes several different syndromes, the exact incidence and prevalence rates are not known. These syndromes are typically diagnosed at birth or in early childhood. Many syndromes such as MCAP, CLOVES and KTS affect males and females in equal numbers.
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Affects of PIK3CA-Related Overgrowth Spectrum. Because PROS includes several different syndromes, the exact incidence and prevalence rates are not known. These syndromes are typically diagnosed at birth or in early childhood. Many syndromes such as MCAP, CLOVES and KTS affect males and females in equal numbers.
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Related disorders of PIK3CA-Related Overgrowth Spectrum
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Proteus syndrome is a rare disorder characterized by asymmetric, patchy overgrowth of various tissues of the body. The cause of the disorder is a mosaic variant in a gene called AKT1 instead of PIK3CA as in PROS. (For more information on this disorder, choose “Proteus Syndrome” as your search term in the Rare Disease Database).The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN tumor suppressor gene in egg or sperm cells (germline). These disorders are characterized by multiple tumor-like malformations (hamartomas) that can affect various areas of the body, with vascular malformations identified in up to 1/3 of patients.Neurofibromatosis 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. It is characterized by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas), areas of abnormal skin color (pigmentation) and in some patients, neurological deficits and intellectual disabilities. Epidermal nevus syndromes (ENSs) are a group of rare complex disorders characterized by the presence of skin lesions known as epidermal nevi associated with additional extra-cutaneous abnormalities, most often affecting the brain, eye and skeletal system. Epidermal nevi are overgrowths of structures and tissue of the epidermis, the outermost layer of the skin. Isolated epidermal nevi can also be associated with PIK3CA mutations when the mutation is limited to skin cells (epidermis) rather than in multiple cell types when found in PROS. (For more information on any of the related disorders mentioned above, use the search box of the Rare Disease Database).
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Related disorders of PIK3CA-Related Overgrowth Spectrum. Proteus syndrome is a rare disorder characterized by asymmetric, patchy overgrowth of various tissues of the body. The cause of the disorder is a mosaic variant in a gene called AKT1 instead of PIK3CA as in PROS. (For more information on this disorder, choose “Proteus Syndrome” as your search term in the Rare Disease Database).The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN tumor suppressor gene in egg or sperm cells (germline). These disorders are characterized by multiple tumor-like malformations (hamartomas) that can affect various areas of the body, with vascular malformations identified in up to 1/3 of patients.Neurofibromatosis 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. It is characterized by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas), areas of abnormal skin color (pigmentation) and in some patients, neurological deficits and intellectual disabilities. Epidermal nevus syndromes (ENSs) are a group of rare complex disorders characterized by the presence of skin lesions known as epidermal nevi associated with additional extra-cutaneous abnormalities, most often affecting the brain, eye and skeletal system. Epidermal nevi are overgrowths of structures and tissue of the epidermis, the outermost layer of the skin. Isolated epidermal nevi can also be associated with PIK3CA mutations when the mutation is limited to skin cells (epidermis) rather than in multiple cell types when found in PROS. (For more information on any of the related disorders mentioned above, use the search box of the Rare Disease Database).
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Diagnosis of PIK3CA-Related Overgrowth Spectrum
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Diagnosis of PROS is based on genetic testing for PIK3CA genetic variants. Testing for somatic conditions includes biopsy of tissue affected by overgrowth. Detection of a PIK3CA mutation in biopsied tissue may be difficult because these mutations are detected at widely varying levels in affected cells and tissues.For MCAP, however, diagnostic testing may be done with blood and saliva samples because the PIK3CA mutations in this syndrome may be found in more cells.A combination of clinical features that help doctors suspect PROS and order PIK3CA genetic testing include: • overgrowth symptoms either at birth or during early childhood
• tissue overgrowth that is patchy and irregular
• overgrowth in fat, muscle, nerve or skeletal tissue
• vascular malformations in capillaries, veins, arteries or lymphatic vessels
• epidermal nevus
• congenital neurological disorders
Symptoms may present in isolation or with two or more of the above features.For patients with megalencephaly and neurological symptoms, brain imaging techniques are part of the diagnostic workup and are frequently used for monitoring structural changes. Vascular anomalies are detected with imaging studies, usually MRI of the affected regions with contrast to show vascular details. Prenatal ultrasound may reveal some features of these conditions.
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Diagnosis of PIK3CA-Related Overgrowth Spectrum. Diagnosis of PROS is based on genetic testing for PIK3CA genetic variants. Testing for somatic conditions includes biopsy of tissue affected by overgrowth. Detection of a PIK3CA mutation in biopsied tissue may be difficult because these mutations are detected at widely varying levels in affected cells and tissues.For MCAP, however, diagnostic testing may be done with blood and saliva samples because the PIK3CA mutations in this syndrome may be found in more cells.A combination of clinical features that help doctors suspect PROS and order PIK3CA genetic testing include: • overgrowth symptoms either at birth or during early childhood
• tissue overgrowth that is patchy and irregular
• overgrowth in fat, muscle, nerve or skeletal tissue
• vascular malformations in capillaries, veins, arteries or lymphatic vessels
• epidermal nevus
• congenital neurological disorders
Symptoms may present in isolation or with two or more of the above features.For patients with megalencephaly and neurological symptoms, brain imaging techniques are part of the diagnostic workup and are frequently used for monitoring structural changes. Vascular anomalies are detected with imaging studies, usually MRI of the affected regions with contrast to show vascular details. Prenatal ultrasound may reveal some features of these conditions.
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Therapies of PIK3CA-Related Overgrowth Spectrum
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Treatment depends on symptoms present for each syndrome and, for those patients with multiple features, requires collaboration between an interdisciplinary team of physicians and specialists.Diagnosis of PROS disorders with involvement below the skin typically requires imaging. This is most often MRI for soft tissue and vasculature, but may include x-rays to follow changes in bones, or ultrasounds for organ surveillance.Extensive or involved lesions are usually treated with drugs designed to slow down or turn off the hyperactivity of the PI3K enzyme and the PI3K/Akt/mTOR pathway. Several different medicines have been used, and alpelisib was approved in 2022 by the U.S. Food and Drug Administration (FDA) as a treatment for severe cases of PROS in adults and children two years of age or older.Laser ablation may be used to treat vascular anomalies in the skin. In more severe cases, surgical removal of a skin vascular malformation followed by a skin graft may be helpful. For deeper malformations, sclerotherapy (for venous or lymphatic malformations) or embolization (for arterial lesions) may be performed as single therapy or in conjunction with/prior to surgery. For patients with abnormal embryonic veins at high risk of clot, veins are often ablated prior to surgery if possible. Anticoagulation therapy is often used around large surgeries to prevent clotting and risk of embolism in the perioperative period.For bulky tissue overgrowth of limbs, digits or soft tissues, surgical removal or debulking may be an option but can be complicated by vascular changes in these tissues. Abnormal tissue can also regrow, requiring repeated surgical interventions during a lifetime.Orthopedic measures such as surgical closure of the growth plate (epiphysiodesis) at joints, most commonly the knee, may equalize leg length. This can also be performed in digits (fingers or toes) with overgrowth. Shoe lifts on the shorter leg’s foot can also correct unequal leg length until timing is appropriate for epiphysiodesis in order to prevent scoliosis (spine curvature) that might occur otherwise.Megalencephaly usually warrants referral to a neurosurgeon, especially if hydrocephalus or Chiari malformation occurs. Hydrocephalus is treated with shunt placement to drain excess cerebrospinal fluid; brain overgrowth with threated herniation may also be treated with laminectomy for decompression. In patients with hemimegalencephaly, seizures are often poorly controlled with medication, so surgery to separate the hemispheres is usually undertaken. The connection between the two hemispheres may be severed while leaving the abnormal hemisphere within the skull (hemispherotomy) or the abnormal hemisphere may be removed altogether (hemispherectomy).Treatment with physical, occupational and speech therapies along with special education services may be beneficial depending on motor and intellectual disabilities present.Imaging studies should also be used to monitor for tumor development since Wilms tumor has been reported in patients with PROS. Ultrasound monitoring is recommended every 3-4 months until age 7 years.
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Therapies of PIK3CA-Related Overgrowth Spectrum. Treatment depends on symptoms present for each syndrome and, for those patients with multiple features, requires collaboration between an interdisciplinary team of physicians and specialists.Diagnosis of PROS disorders with involvement below the skin typically requires imaging. This is most often MRI for soft tissue and vasculature, but may include x-rays to follow changes in bones, or ultrasounds for organ surveillance.Extensive or involved lesions are usually treated with drugs designed to slow down or turn off the hyperactivity of the PI3K enzyme and the PI3K/Akt/mTOR pathway. Several different medicines have been used, and alpelisib was approved in 2022 by the U.S. Food and Drug Administration (FDA) as a treatment for severe cases of PROS in adults and children two years of age or older.Laser ablation may be used to treat vascular anomalies in the skin. In more severe cases, surgical removal of a skin vascular malformation followed by a skin graft may be helpful. For deeper malformations, sclerotherapy (for venous or lymphatic malformations) or embolization (for arterial lesions) may be performed as single therapy or in conjunction with/prior to surgery. For patients with abnormal embryonic veins at high risk of clot, veins are often ablated prior to surgery if possible. Anticoagulation therapy is often used around large surgeries to prevent clotting and risk of embolism in the perioperative period.For bulky tissue overgrowth of limbs, digits or soft tissues, surgical removal or debulking may be an option but can be complicated by vascular changes in these tissues. Abnormal tissue can also regrow, requiring repeated surgical interventions during a lifetime.Orthopedic measures such as surgical closure of the growth plate (epiphysiodesis) at joints, most commonly the knee, may equalize leg length. This can also be performed in digits (fingers or toes) with overgrowth. Shoe lifts on the shorter leg’s foot can also correct unequal leg length until timing is appropriate for epiphysiodesis in order to prevent scoliosis (spine curvature) that might occur otherwise.Megalencephaly usually warrants referral to a neurosurgeon, especially if hydrocephalus or Chiari malformation occurs. Hydrocephalus is treated with shunt placement to drain excess cerebrospinal fluid; brain overgrowth with threated herniation may also be treated with laminectomy for decompression. In patients with hemimegalencephaly, seizures are often poorly controlled with medication, so surgery to separate the hemispheres is usually undertaken. The connection between the two hemispheres may be severed while leaving the abnormal hemisphere within the skull (hemispherotomy) or the abnormal hemisphere may be removed altogether (hemispherectomy).Treatment with physical, occupational and speech therapies along with special education services may be beneficial depending on motor and intellectual disabilities present.Imaging studies should also be used to monitor for tumor development since Wilms tumor has been reported in patients with PROS. Ultrasound monitoring is recommended every 3-4 months until age 7 years.
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Overview of Pinta
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Pinta is a rare infectious tropical disease affecting the skin that is caused by the bacterium Treponema carateum, which is transmitted by direct, nonsexual contact. Pinta progresses through three distinct stages, which are characterized by various skin lesions and discoloration. Other organ systems are not affected. Exposed areas of the skin such as the face and extremities are most often affected.Pinta is classified as a treponematosis, which is an infectious disease caused by a treponema. Treponemas are a genus of spiral-shaped bacteria (spirochetes). Treponemas caused several infectious diseases including pinta, yaws, and syphilis.
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Overview of Pinta. Pinta is a rare infectious tropical disease affecting the skin that is caused by the bacterium Treponema carateum, which is transmitted by direct, nonsexual contact. Pinta progresses through three distinct stages, which are characterized by various skin lesions and discoloration. Other organ systems are not affected. Exposed areas of the skin such as the face and extremities are most often affected.Pinta is classified as a treponematosis, which is an infectious disease caused by a treponema. Treponemas are a genus of spiral-shaped bacteria (spirochetes). Treponemas caused several infectious diseases including pinta, yaws, and syphilis.
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Symptoms of Pinta
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The symptoms and progression of pinta may vary among affected individuals. Pinta usually progresses in three separate stages: an early phase with initial lesions; an intermediate phase with widespread (disseminated) lesions; and a late phase. The incubation period may range from seven to 21 days. The skin is the only organ involved in pinta.In most cases, the initial lesions (primary) are small, reddish (erythematous) spots (papules) that occur most often on exposed areas of the arms and legs. The face, neck, chest and abdomen may also be affected. Papules are often itchy (pruritic) and may spread combining to form large plaques. In some cases, nearby lymph nodes may be inflamed (lymphadenitis). One month to one year after the development of initial lesions, affected individuals may develop secondary skin eruptions called pintids. Pintids are small scaly, reddish lesions that normally affect the same sites as primary lesions. They may be dry and crusted (psoriatic pintids).Anywhere from three months to a year, secondary lesions and, in some cases, primary lesions may slowly change color from red to brown or slate blue. These lesions may eventually lose their color (depigmentation) becoming white, leaving the skin with a mottled appearance. Pintids may recur for up to 10 years. The late phase of pinta occurs approximately two to five years after the development of initial lesions and is characterized by white or colorless (achromatic) lesions. During this phase, affected individuals may also develop unusually dry, thickened skin on the soles of the feet and palms of the hands (hyperkeratosis). Eventually, affected individuals may develop dry, wrinkled thin (atrophic) skin in certain areas.
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Symptoms of Pinta. The symptoms and progression of pinta may vary among affected individuals. Pinta usually progresses in three separate stages: an early phase with initial lesions; an intermediate phase with widespread (disseminated) lesions; and a late phase. The incubation period may range from seven to 21 days. The skin is the only organ involved in pinta.In most cases, the initial lesions (primary) are small, reddish (erythematous) spots (papules) that occur most often on exposed areas of the arms and legs. The face, neck, chest and abdomen may also be affected. Papules are often itchy (pruritic) and may spread combining to form large plaques. In some cases, nearby lymph nodes may be inflamed (lymphadenitis). One month to one year after the development of initial lesions, affected individuals may develop secondary skin eruptions called pintids. Pintids are small scaly, reddish lesions that normally affect the same sites as primary lesions. They may be dry and crusted (psoriatic pintids).Anywhere from three months to a year, secondary lesions and, in some cases, primary lesions may slowly change color from red to brown or slate blue. These lesions may eventually lose their color (depigmentation) becoming white, leaving the skin with a mottled appearance. Pintids may recur for up to 10 years. The late phase of pinta occurs approximately two to five years after the development of initial lesions and is characterized by white or colorless (achromatic) lesions. During this phase, affected individuals may also develop unusually dry, thickened skin on the soles of the feet and palms of the hands (hyperkeratosis). Eventually, affected individuals may develop dry, wrinkled thin (atrophic) skin in certain areas.
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Causes of Pinta
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Pinta is an infectious tropical disease caused by the spiral-shaped bacterium (spirochete) known as Treponema carateum.
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Causes of Pinta. Pinta is an infectious tropical disease caused by the spiral-shaped bacterium (spirochete) known as Treponema carateum.
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Affects of Pinta
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Pinta affects males and females in equal numbers. Most cases are children or adolescents from endemic areas of the world. It is most common in remote rural tropical areas such as the southern portion of Mexico, Central America and Columbia. It occurs with lower incidence rates in various Caribbean Islands. In recent years, only a few hundred cases of pinta have been reported in the medical literature each year. Pinta does not occur in the United States unless affected individuals have visited endemic areas. The prevalence of pinta declined greatly following a mass treatment campaign with penicillin by the World Health Organzation (WHO) in the 1950s and 60s. The current incidence of pinta is unknown.
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Affects of Pinta. Pinta affects males and females in equal numbers. Most cases are children or adolescents from endemic areas of the world. It is most common in remote rural tropical areas such as the southern portion of Mexico, Central America and Columbia. It occurs with lower incidence rates in various Caribbean Islands. In recent years, only a few hundred cases of pinta have been reported in the medical literature each year. Pinta does not occur in the United States unless affected individuals have visited endemic areas. The prevalence of pinta declined greatly following a mass treatment campaign with penicillin by the World Health Organzation (WHO) in the 1950s and 60s. The current incidence of pinta is unknown.
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Related disorders of Pinta
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Symptoms of the following disorders can be similar to those of pinta. Comparisons may be useful for a differential diagnosis: Yaws is an infectious tropical disease caused by the spirochete (spiral shaped) bacterium known as Treponema pertenue. The disease presents in three stages of which the first and second are easily treated. The third, however, may involve complex changes to the bones in many parts of the body. The first stage is characterized by the appearance of small, painless bumps on the skin that group together and grow until they resemble a strawberry. The skin may break open, forming an ulcer. The second stage (usually starting several weeks or months after the first) presents with a crispy, crunchy rash that may cover arms, legs, buttocks and/or face. If the bottoms of the feet are involved, walking is painful and the stage is known as “crab yaws.” Stage 3 yaws involves the long bones, joints, and/or skin. Yaws is very common in tropical areas of the world but rare in the United States. It is not a sexually transmitted disease. (For more information on this disorder, choose “yaws” as your search term in the Rare Disease Database.) Bejel, also known as endemic syphilis, is an infectious disease that is rare in the United States, but common in certain parts of the world. It is characterized by lesions of the skin and bones and is caused by a bacterium known as Treponema pallidum II. The infection is very similar to syphilis but is not sexually transmitted. Children with Bejel have patchy ulcerations on mucous membranes particularly in or near the mouth. Eventually, the legs, arms, and trunk may become affected. Bone infection occurs later in the disease. (For more information on this disorder, choose “Bejel” as your search term in the Rare Disease Database.)Acquired syphilis is a chronic infectious disease caused by the bacteria Treponema pallidum. It is transmitted by direct contact with an infected individual, usually through sexual intercourse. When left untreated, the symptoms of syphilis progress (i.e., primary, secondary, and latent stages). Eventually any tissue or organ in the body may be affected. Early symptoms include lesions (chancres) of the skin, anus, vagina, or the moist surfaces of the mouth. The symptoms may remain dormant for years. (For more information on this disorder, choose “Syphilis” as your search term in the Rare Disease Database.)Vitiligo is a dermatological condition characterized by the appearance of white patches of skin on (depigementation) different parts of the body as a result of the destruction of the cells that make pigment (melanocytes). This may vary from one or two white spots on the skin to large areas of depigmentation. The affected areas most often appear on the face, neck, hands, abdomen and thighs although they can occur on all parts of the skin. Vitiligo is not contagious. It seems to occur more often among people who have certain autoimmune diseases. For some people, although not for everyone, the depigmentation is progressive. (For more information on this disorder, choose “vitiligo” as your search term in the Rare Disease Database.)
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Related disorders of Pinta. Symptoms of the following disorders can be similar to those of pinta. Comparisons may be useful for a differential diagnosis: Yaws is an infectious tropical disease caused by the spirochete (spiral shaped) bacterium known as Treponema pertenue. The disease presents in three stages of which the first and second are easily treated. The third, however, may involve complex changes to the bones in many parts of the body. The first stage is characterized by the appearance of small, painless bumps on the skin that group together and grow until they resemble a strawberry. The skin may break open, forming an ulcer. The second stage (usually starting several weeks or months after the first) presents with a crispy, crunchy rash that may cover arms, legs, buttocks and/or face. If the bottoms of the feet are involved, walking is painful and the stage is known as “crab yaws.” Stage 3 yaws involves the long bones, joints, and/or skin. Yaws is very common in tropical areas of the world but rare in the United States. It is not a sexually transmitted disease. (For more information on this disorder, choose “yaws” as your search term in the Rare Disease Database.) Bejel, also known as endemic syphilis, is an infectious disease that is rare in the United States, but common in certain parts of the world. It is characterized by lesions of the skin and bones and is caused by a bacterium known as Treponema pallidum II. The infection is very similar to syphilis but is not sexually transmitted. Children with Bejel have patchy ulcerations on mucous membranes particularly in or near the mouth. Eventually, the legs, arms, and trunk may become affected. Bone infection occurs later in the disease. (For more information on this disorder, choose “Bejel” as your search term in the Rare Disease Database.)Acquired syphilis is a chronic infectious disease caused by the bacteria Treponema pallidum. It is transmitted by direct contact with an infected individual, usually through sexual intercourse. When left untreated, the symptoms of syphilis progress (i.e., primary, secondary, and latent stages). Eventually any tissue or organ in the body may be affected. Early symptoms include lesions (chancres) of the skin, anus, vagina, or the moist surfaces of the mouth. The symptoms may remain dormant for years. (For more information on this disorder, choose “Syphilis” as your search term in the Rare Disease Database.)Vitiligo is a dermatological condition characterized by the appearance of white patches of skin on (depigementation) different parts of the body as a result of the destruction of the cells that make pigment (melanocytes). This may vary from one or two white spots on the skin to large areas of depigmentation. The affected areas most often appear on the face, neck, hands, abdomen and thighs although they can occur on all parts of the skin. Vitiligo is not contagious. It seems to occur more often among people who have certain autoimmune diseases. For some people, although not for everyone, the depigmentation is progressive. (For more information on this disorder, choose “vitiligo” as your search term in the Rare Disease Database.)
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Diagnosis of Pinta
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A diagnosis of pinta is suspected based upon a detailed patient history (e.g., recent travel to endemic area), a thorough clinical evaluation, identification of characteristic symptoms, and a variety of tests. These tests may include the microscopic examination of tissue samples (darkfield examination) from the skin lesions of affected individuals. Other blood tests (e.g., VDRL and Treponemal antibody absorption test [FTA-ABS]) usually become positive only after the secondary skin lesions appear.
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Diagnosis of Pinta. A diagnosis of pinta is suspected based upon a detailed patient history (e.g., recent travel to endemic area), a thorough clinical evaluation, identification of characteristic symptoms, and a variety of tests. These tests may include the microscopic examination of tissue samples (darkfield examination) from the skin lesions of affected individuals. Other blood tests (e.g., VDRL and Treponemal antibody absorption test [FTA-ABS]) usually become positive only after the secondary skin lesions appear.
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Therapies of Pinta
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TreatmentThe treatment for pinta includes antimicrobial drugs. The drug of choice is benzathine penicillin G. A single large dose of this antibiotic usually heals the skin lesions and eliminates the organism. Primary and secondary lesions often heal within six to 12 months; late phase lesions take more time to resolve. Individuals who are allergic to penicillin may be treated with tetracycline or erythromycin.Drug therapy may also be used to prevent the disease in family members and others who are in frequent contact with affected individuals.
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Therapies of Pinta. TreatmentThe treatment for pinta includes antimicrobial drugs. The drug of choice is benzathine penicillin G. A single large dose of this antibiotic usually heals the skin lesions and eliminates the organism. Primary and secondary lesions often heal within six to 12 months; late phase lesions take more time to resolve. Individuals who are allergic to penicillin may be treated with tetracycline or erythromycin.Drug therapy may also be used to prevent the disease in family members and others who are in frequent contact with affected individuals.
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Overview of Pitt-Hopkins Syndrome
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SummaryPitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder. Affected children have distinctive facial features and experience intellectual disability, delays in reaching developmental milestones, impaired ability to speak, and can have recurrent seizures, and breathing pattern abnormalities. Additional symptoms that can occur include poor coordination (ataxia), repetitive nonfunctional hand movements, constipation, sleep disturbances, and severe nearsightedness (myopia). Behavioral abnormalities are common, although children are often described as social and having happy dispositions. Some affected children meet the criteria for an autism spectrum disorder. The specific signs and symptoms of the disorder and their severity can vary from one affected individual to another. Pitt-Hopkins syndrome is caused by a change (mutation) in the TCF4 gene. This mutation occurs spontaneously and in almost all instances, does not run in a family. The disorder was first described in the medical literature in 1978 and the causative gene was discovered in 2008.
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Overview of Pitt-Hopkins Syndrome. SummaryPitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder. Affected children have distinctive facial features and experience intellectual disability, delays in reaching developmental milestones, impaired ability to speak, and can have recurrent seizures, and breathing pattern abnormalities. Additional symptoms that can occur include poor coordination (ataxia), repetitive nonfunctional hand movements, constipation, sleep disturbances, and severe nearsightedness (myopia). Behavioral abnormalities are common, although children are often described as social and having happy dispositions. Some affected children meet the criteria for an autism spectrum disorder. The specific signs and symptoms of the disorder and their severity can vary from one affected individual to another. Pitt-Hopkins syndrome is caused by a change (mutation) in the TCF4 gene. This mutation occurs spontaneously and in almost all instances, does not run in a family. The disorder was first described in the medical literature in 1978 and the causative gene was discovered in 2008.
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Symptoms of Pitt-Hopkins Syndrome
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With the publication of an increasing number of case series we are developing a better picture of associated symptoms and prognosis of individuals with Pitt-Hopkins syndrome. However, much about the disorder is not fully understood. It is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Infants with Pitt-Hopkins syndrome may have diminished muscle tone (hypotonia) and appear abnormally “floppy.” Hypotonia can affect feeding and impact motor skills such as walking. Feeding difficulties may occur in infancy but tend to resolve once the child ages. They may be described as very quiet and sleep excessively. Some infants may exhibit an abnormally small head circumference (postnatal microcephaly). Affected infants and children experience delays in reaching developmental milestones, including sitting up or holding one’s head up. They are usually significantly delays in learning to walk. Some children will only be able to walk with assistance while others may be unable to walk. Most children benefit from bracing to stabilize loose ankles. Children who can walk may have an unsteady manner of walking with a wide gait. They may exhibit a lack of coordination (ataxia) and be clumsy. Speech is significantly delayed. Some children develop the ability to speak a few words, but many children are unable to speak. Most children have better receptive language skills, which means that they can understand more information spoken to them than they are able to speak themselves. These children can benefit from assistive communication devices including picture boards and tablet based speaking devices. Many are able to learn and communication to a degree with sign language.Most affected children have moderate to severe intellectual disability. However, speech and motor abnormalities make it difficult to determine a child’s true mental capacity. Advances in technology and new therapies have enabled affected children to achieve more than originally believed and some physicians and parents believe that there is a broader range of intellectual capability than is generally reported in the medical literature. Infants and children typically have distinctive facial features. These features include an abnormally wide mouth with a full lower lip; widely-spaced teeth; flared nostrils; a broad bridge of the nose; a sharp, downturned nasal tip; mildly cup-shaped ears; and deep-set eyes that slant slightly upward with a prominent supraorbital ridge. They may have a protruding upper lip that is curved twice (Cupid’s bow), full cheeks and the lower part of the face and chin may be prominent. These distinctive facial features may become more pronounced or noticeable with age. Children with Pitt-Hopkins syndrome can have irregular or abnormal breathing patterns. They may experience recurrent episodes where they breathe very fast (hyperventilation), often followed by episodes where they struggle to breath or momentarily stop breathing (apnea crises). Apnea can cause cyanosis, a condition in which there is abnormal bluish discoloration to the skin due to lack of oxygen. Breathing irregularities may be triggered by stress, strong emotions, or fatigue. Breathing problems usually do not occur during sleep. The age of onset of breathing abnormalities can vary and has ranged from anywhere from 7 months to 7 years. Affected children are described as sociable and having a happy disposition, frequently laughing and smiling. Laughter may occur spontaneously or at inappropriate times. However, some children may be quiet or withdrawn into their own world (self-absorption) and have difficulties engaging socially. Episodes of aggression or shouting or agitation, often in response to unexpected changes in routine occur as well. Additional behavioral issues are common and can include hyperactivity, anxiety, self-injury, and shyness. Children with Pitt-Hopkins syndrome also exhibit stereotypic hand movements, which include hand clapping, hand flapping, flicking hands, hand washing, fingers crossing, and frequent hand-to-mouth movements. Head shaking, head banging, body rocking, teeth grinding (bruxism) and hair pulling may also be seen. Children may repeatedly and repetitively play with a toy, and may show a fascination with one specific part of a toy. Seizures can occur in just under half of individuals and usually begin in childhood, but sometimes are present from birth or develop as late as the teen-age years. Most children experience constipation, which can be severe. Gastroesophageal reflux has been reported in less than half of affected individuals. Most individuals have a high pain threshold.Additional symptoms can include excessive drooling (especially when younger), severe nearsightedness (myopia), crossed eyes (strabismus), and abnormal curving of the lens of the eye (astigmatism). Abnormal curving of the spine (scoliosis) has occurred in a small number of individuals. Approximately one third of affected males experience failure of one or both testicles to descend into the scrotum (cryptorchidism). Some minor abnormalities of the hands may be seen including broad fingertips, tapered fingers, curved pinkies (clinodactyly), a single crease across the palm, and prominent pads on the fingertips and toes (persistent fetal pads). There is often an extra crease or absent on the thumb and rare individuals are unable to bend the thumb due to an absent tendon. They often have redness and swelling of the skin at the base of their nails and can have blunting of the normal angle at the baes of the nail (clubbing). They often have overriding toes. Hands and feet may be cold or bluish in appearance due to cyanosis.
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Symptoms of Pitt-Hopkins Syndrome. With the publication of an increasing number of case series we are developing a better picture of associated symptoms and prognosis of individuals with Pitt-Hopkins syndrome. However, much about the disorder is not fully understood. It is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.Infants with Pitt-Hopkins syndrome may have diminished muscle tone (hypotonia) and appear abnormally “floppy.” Hypotonia can affect feeding and impact motor skills such as walking. Feeding difficulties may occur in infancy but tend to resolve once the child ages. They may be described as very quiet and sleep excessively. Some infants may exhibit an abnormally small head circumference (postnatal microcephaly). Affected infants and children experience delays in reaching developmental milestones, including sitting up or holding one’s head up. They are usually significantly delays in learning to walk. Some children will only be able to walk with assistance while others may be unable to walk. Most children benefit from bracing to stabilize loose ankles. Children who can walk may have an unsteady manner of walking with a wide gait. They may exhibit a lack of coordination (ataxia) and be clumsy. Speech is significantly delayed. Some children develop the ability to speak a few words, but many children are unable to speak. Most children have better receptive language skills, which means that they can understand more information spoken to them than they are able to speak themselves. These children can benefit from assistive communication devices including picture boards and tablet based speaking devices. Many are able to learn and communication to a degree with sign language.Most affected children have moderate to severe intellectual disability. However, speech and motor abnormalities make it difficult to determine a child’s true mental capacity. Advances in technology and new therapies have enabled affected children to achieve more than originally believed and some physicians and parents believe that there is a broader range of intellectual capability than is generally reported in the medical literature. Infants and children typically have distinctive facial features. These features include an abnormally wide mouth with a full lower lip; widely-spaced teeth; flared nostrils; a broad bridge of the nose; a sharp, downturned nasal tip; mildly cup-shaped ears; and deep-set eyes that slant slightly upward with a prominent supraorbital ridge. They may have a protruding upper lip that is curved twice (Cupid’s bow), full cheeks and the lower part of the face and chin may be prominent. These distinctive facial features may become more pronounced or noticeable with age. Children with Pitt-Hopkins syndrome can have irregular or abnormal breathing patterns. They may experience recurrent episodes where they breathe very fast (hyperventilation), often followed by episodes where they struggle to breath or momentarily stop breathing (apnea crises). Apnea can cause cyanosis, a condition in which there is abnormal bluish discoloration to the skin due to lack of oxygen. Breathing irregularities may be triggered by stress, strong emotions, or fatigue. Breathing problems usually do not occur during sleep. The age of onset of breathing abnormalities can vary and has ranged from anywhere from 7 months to 7 years. Affected children are described as sociable and having a happy disposition, frequently laughing and smiling. Laughter may occur spontaneously or at inappropriate times. However, some children may be quiet or withdrawn into their own world (self-absorption) and have difficulties engaging socially. Episodes of aggression or shouting or agitation, often in response to unexpected changes in routine occur as well. Additional behavioral issues are common and can include hyperactivity, anxiety, self-injury, and shyness. Children with Pitt-Hopkins syndrome also exhibit stereotypic hand movements, which include hand clapping, hand flapping, flicking hands, hand washing, fingers crossing, and frequent hand-to-mouth movements. Head shaking, head banging, body rocking, teeth grinding (bruxism) and hair pulling may also be seen. Children may repeatedly and repetitively play with a toy, and may show a fascination with one specific part of a toy. Seizures can occur in just under half of individuals and usually begin in childhood, but sometimes are present from birth or develop as late as the teen-age years. Most children experience constipation, which can be severe. Gastroesophageal reflux has been reported in less than half of affected individuals. Most individuals have a high pain threshold.Additional symptoms can include excessive drooling (especially when younger), severe nearsightedness (myopia), crossed eyes (strabismus), and abnormal curving of the lens of the eye (astigmatism). Abnormal curving of the spine (scoliosis) has occurred in a small number of individuals. Approximately one third of affected males experience failure of one or both testicles to descend into the scrotum (cryptorchidism). Some minor abnormalities of the hands may be seen including broad fingertips, tapered fingers, curved pinkies (clinodactyly), a single crease across the palm, and prominent pads on the fingertips and toes (persistent fetal pads). There is often an extra crease or absent on the thumb and rare individuals are unable to bend the thumb due to an absent tendon. They often have redness and swelling of the skin at the base of their nails and can have blunting of the normal angle at the baes of the nail (clubbing). They often have overriding toes. Hands and feet may be cold or bluish in appearance due to cyanosis.
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Causes of Pitt-Hopkins Syndrome
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Pitt-Hopkins syndrome is caused by an unexpected change (mutation) in the TCF4 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The TCF4 gene creates a protein that is a transcription factor. This protein has an important role in various developmental processes of the body. It is highly expressed early during human development and is found throughout the central nervous system. In cases where a mutation in TCF4 is disease causing, Pitt-Hopkins syndrome almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. If the mutation were to be passed on from an affected individual to a child, in most instance this would occur in an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.There are several instances in which an unaffected parent has more than one child with Pitt-Hopkins syndrome. This extremely rare event occurred because of germline mosaicism. In germline mosaicism, one parent has some reproductive cells (germ cells) in the ovaries or testes that have the TCF4 gene mutation. The other cells in the parent’s body do not have the mutation, so these parents are unaffected but can pass an altered gene to their children. Because of this possibility, we estimate parents of a child with Pitt-Hopkins syndrome have about a 1-2% chance of having another affected child, even if the parents test negative for the mutation in their blood.Investigators have determined that the TCF4 gene is located on the long arm (q) of chromosome 18 (18q21.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 18q21.2” refers to band 21.2 on the long arm of chromosome 18. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Causes of Pitt-Hopkins Syndrome. Pitt-Hopkins syndrome is caused by an unexpected change (mutation) in the TCF4 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The TCF4 gene creates a protein that is a transcription factor. This protein has an important role in various developmental processes of the body. It is highly expressed early during human development and is found throughout the central nervous system. In cases where a mutation in TCF4 is disease causing, Pitt-Hopkins syndrome almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. If the mutation were to be passed on from an affected individual to a child, in most instance this would occur in an autosomal dominant manner. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.There are several instances in which an unaffected parent has more than one child with Pitt-Hopkins syndrome. This extremely rare event occurred because of germline mosaicism. In germline mosaicism, one parent has some reproductive cells (germ cells) in the ovaries or testes that have the TCF4 gene mutation. The other cells in the parent’s body do not have the mutation, so these parents are unaffected but can pass an altered gene to their children. Because of this possibility, we estimate parents of a child with Pitt-Hopkins syndrome have about a 1-2% chance of having another affected child, even if the parents test negative for the mutation in their blood.Investigators have determined that the TCF4 gene is located on the long arm (q) of chromosome 18 (18q21.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 18q21.2” refers to band 21.2 on the long arm of chromosome 18. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Affects of Pitt-Hopkins Syndrome
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Pitt-Hopkins syndrome affects both males and females and can affect individuals of any ethnic or racial background. The exact incidence of the disorder is unknown. Approximately 500 affected individuals have been identified worldwide. Researchers believe that affected individuals often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency the disorder in the general population. Intellectual disability (due to all causes) affects approximately 1%-3% of the general population.
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Affects of Pitt-Hopkins Syndrome. Pitt-Hopkins syndrome affects both males and females and can affect individuals of any ethnic or racial background. The exact incidence of the disorder is unknown. Approximately 500 affected individuals have been identified worldwide. Researchers believe that affected individuals often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency the disorder in the general population. Intellectual disability (due to all causes) affects approximately 1%-3% of the general population.
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Related disorders of Pitt-Hopkins Syndrome
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Symptoms of the following disorders can be similar to those of Pitt-Hopkins syndrome. Comparisons may be useful for a differential diagnosis.Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional common symptoms include seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, absent speech, distinctive facial features and seizures. This disorder is more likely to have congenital anomalies including a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by an abnormality in the ZEB2 gene that is usually the result of a new genetic change (mutation) in the affected person. (For more information on this disorder, choose “Mowat Wilson” as your search term in the Rare Disease Database.)Rett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowing of head growth (acquired microcephaly), Affected children often develop autistic-like behaviors, feeding and swallowing difficulties, growth retardation, and seizures. Similar to Pitt-Hopkins syndrome these individuals can also develop spells of hyperventilation and apnea. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation (see Causes section below). Therefore, two girls of the same age with the same mutation can appear significantly different. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)Some children with changes (mutations) in the CNTNAP2 gene or the NRX1 gene have developed similar symptoms as children who have Pitt-Hopkins syndrome, including absent speech and global developmental delays. These disorders are known as CTNAP2-associated autosomal recessive intellectual disability disorder (or Pitt-Hopkins-Like syndrome 1), and NRX1-associated autosomal recessive intellectual disability disorder (or Pitt-Hopkins-Like syndrome 2). These disorders are extremely rare and affected children do not have the same distinctive facial features as seen in children with Pitt-Hopkins syndrome. They also have abnormal sleep-wake cycles. Additional disorders in which children exhibit intellectual disability, seizures, constipation, breathing abnormalities, stereotypic movements, and distinctive facial features include MECP2 duplication syndrome, alpha thalassemia/intellectual disability syndrome, congenital central hypoventilation syndrome (CCHS), Joubert syndrome, and Partington syndrome (ARX-related intellectual disability disorder). These disorders have characteristics features that can distinguish them from Pitt-Hopkins syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Pitt-Hopkins Syndrome. Symptoms of the following disorders can be similar to those of Pitt-Hopkins syndrome. Comparisons may be useful for a differential diagnosis.Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional common symptoms include seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)Mowat-Wilson syndrome (MWS) is a rare genetic disorder that may be apparent at birth or later in childhood. MWS is characterized by intellectual disability, absent speech, distinctive facial features and seizures. This disorder is more likely to have congenital anomalies including a gastrointestinal disease known as Hirschsprung disease (40-50% of individuals) in which a narrowing of a portion of the colon is present, eye (ophthalmologic) defects, heart (cardiac) defects, kidney (renal) abnormalities, male genital abnormalities and short stature. Some affected individuals may not be recognized until childhood or adulthood, especially when Hirschsprung disease is not present. MWS is caused by an abnormality in the ZEB2 gene that is usually the result of a new genetic change (mutation) in the affected person. (For more information on this disorder, choose “Mowat Wilson” as your search term in the Rare Disease Database.)Rett syndrome is a progressive neurodevelopmental disorder that almost exclusively affects females. Only in rare cases are males affected. Infants with Rett syndrome generally develop normally for about 7 to 18 months after birth. At this point, they lose previously acquired skills (developmental regression) such as purposeful hand movements and the ability to communicate. Additional abnormalities occur including impaired control of voluntary movements (ataxia) and the development of distinctive, uncontrolled hand movements such as hand clapping or rubbing. Some children also have slowing of head growth (acquired microcephaly), Affected children often develop autistic-like behaviors, feeding and swallowing difficulties, growth retardation, and seizures. Similar to Pitt-Hopkins syndrome these individuals can also develop spells of hyperventilation and apnea. Most Rett syndrome cases are caused by identifiable mutations of the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and the process of random X-inactivation (see Causes section below). Therefore, two girls of the same age with the same mutation can appear significantly different. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.)Some children with changes (mutations) in the CNTNAP2 gene or the NRX1 gene have developed similar symptoms as children who have Pitt-Hopkins syndrome, including absent speech and global developmental delays. These disorders are known as CTNAP2-associated autosomal recessive intellectual disability disorder (or Pitt-Hopkins-Like syndrome 1), and NRX1-associated autosomal recessive intellectual disability disorder (or Pitt-Hopkins-Like syndrome 2). These disorders are extremely rare and affected children do not have the same distinctive facial features as seen in children with Pitt-Hopkins syndrome. They also have abnormal sleep-wake cycles. Additional disorders in which children exhibit intellectual disability, seizures, constipation, breathing abnormalities, stereotypic movements, and distinctive facial features include MECP2 duplication syndrome, alpha thalassemia/intellectual disability syndrome, congenital central hypoventilation syndrome (CCHS), Joubert syndrome, and Partington syndrome (ARX-related intellectual disability disorder). These disorders have characteristics features that can distinguish them from Pitt-Hopkins syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Pitt-Hopkins Syndrome
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Diagnosis of Pitt-Hopkins Syndrome
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A diagnosis of Pitt-Hopkins syndrome depends upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic symptoms. There is overlap among symptoms associated with Pitt-Hopkins syndrome and other similar neurological disorders. The lack of major congenital malformations, which are structural or functional abnormalities that are present at birth, supports a diagnosis, which can generally be confirmed by molecular testing demonstrating a specific change (mutation) or deletion involving the TCF4 gene. This gene is often included on gene panels that can be ordered for individuals with features of Pitt-Hopkins/Rett/Angelman syndromes. There are individuals with clinical features that can’t be distinguished from Pitt-Hopkins syndrome for which no mutation in TCF4 can be found, and some individuals with variants in TCF4 with a phenotype differing from Pitt-Hopkins syndrome. Diagnostic criteria have been published based on published cases, but are being redefined as more molecularly confirmed cases have been identified. Clinical Evaluations and Workup
If the diagnosis is suspected by exam and history, molecular testing can be ordered. If the diagnosis is confirmed, investigations for other congenital malformations such a heart or kidney defects are only needed if there is a specific clinical concern, as there is not an increased incidence for these with Pitt-Hopkins syndrome.If seizure activity is seen or suspected – body shaking or staring spells, physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures. An advanced imaging techniques magnetic resonance imaging (MRI) of the brain may also be performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Physicians use an MRI to obtain a detailed image of a major region of the brain called the cerebrum. A variety of nonspecific brain MRI findings have been seen in Pitt-Hopkins syndrome, though many studies are reported as normal.
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Diagnosis of Pitt-Hopkins Syndrome. A diagnosis of Pitt-Hopkins syndrome depends upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic symptoms. There is overlap among symptoms associated with Pitt-Hopkins syndrome and other similar neurological disorders. The lack of major congenital malformations, which are structural or functional abnormalities that are present at birth, supports a diagnosis, which can generally be confirmed by molecular testing demonstrating a specific change (mutation) or deletion involving the TCF4 gene. This gene is often included on gene panels that can be ordered for individuals with features of Pitt-Hopkins/Rett/Angelman syndromes. There are individuals with clinical features that can’t be distinguished from Pitt-Hopkins syndrome for which no mutation in TCF4 can be found, and some individuals with variants in TCF4 with a phenotype differing from Pitt-Hopkins syndrome. Diagnostic criteria have been published based on published cases, but are being redefined as more molecularly confirmed cases have been identified. Clinical Evaluations and Workup
If the diagnosis is suspected by exam and history, molecular testing can be ordered. If the diagnosis is confirmed, investigations for other congenital malformations such a heart or kidney defects are only needed if there is a specific clinical concern, as there is not an increased incidence for these with Pitt-Hopkins syndrome.If seizure activity is seen or suspected – body shaking or staring spells, physicians may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain and may show changes in brain function and help to detect seizures. An advanced imaging techniques magnetic resonance imaging (MRI) of the brain may also be performed. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues, including the brain. Physicians use an MRI to obtain a detailed image of a major region of the brain called the cerebrum. A variety of nonspecific brain MRI findings have been seen in Pitt-Hopkins syndrome, though many studies are reported as normal.
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Pitt-Hopkins Syndrome
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nord_970_6
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Therapies of Pitt-Hopkins Syndrome
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Treatment is directed toward the specific symptoms that are apparent in each individual and generally requires a team of specialists, that can be coordinated by a medical geneticist or your pediatrician. Members of this team may include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), a pulmonologist (a physician who specializes in the diagnosis and treatment of disorders of the lungs and breathing issues), a speech pathologist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. Following an initial diagnosis, it is recommended that a developmental assessment be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. Given the likelihood of severe speech impairment strong consideration should be given to early training with alternative and augmentative communication devices. Children may benefit from treatments used in the treatment of autism spectrum disorder such as applied behavioral analysis (ABA) therapy targeted to the strengths and weaknesses of each child. A developmental pediatrician can help with management of behavioral issues and medication considerations, while more serious aggressive behaviors may be helped by a pediatric psychiatrist. In these individuals who have limited communication, potential medical issues such as severe constipation that might adversely impact behavior should be considered.Constipation is very common with Pitt-Hopkins and usually standard measures such as high fiber diets or laxatives are sufficient. If there is a significant problem with hyperventilation and/or apnea, advice from a pulmonologist should be sought as in some instances medications such as antiepileptic medications or acetazolamide have been helpful. Seizures that may occur are generally well controlled by anticonvulsants that can be individualized by a neurologist. Most individuals with Pitt-Hopkins will benefit from glasses and some may need surgery for crossed eyes that fail to self-correct. Regular ophthalmology exams are recommended.As of April 2018, Pitt-Hopkins syndrome clinics have been established at Massachusetts General Hospital (https://www.massgeneral.org/children/services/treatmentprograms.aspx?id=1849), University of Texas Southwestern's Children's Health (https://www.childrens.com/specialties-services/specialty-centers-and-programs/autism-and-developmental-disabilities/conditions-and-treatments/pitt-hopkins-syndrome), and UCSF Benioff Children's Hospital San Francisco (https://www.ucsf.edu/news/2015/09/131486/ucsf-pediatric-clinic-focused-rare-pitt-hopkins-syndrome-third-its-kind-world). These centers are devoted to the diagnosis and comprehensive treatment of this disorder and to further research to better understand this disorder.
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Therapies of Pitt-Hopkins Syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual and generally requires a team of specialists, that can be coordinated by a medical geneticist or your pediatrician. Members of this team may include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), a pulmonologist (a physician who specializes in the diagnosis and treatment of disorders of the lungs and breathing issues), a speech pathologist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well. Following an initial diagnosis, it is recommended that a developmental assessment be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Periodic reassessments and adjustment of services should be provided with all children. Given the likelihood of severe speech impairment strong consideration should be given to early training with alternative and augmentative communication devices. Children may benefit from treatments used in the treatment of autism spectrum disorder such as applied behavioral analysis (ABA) therapy targeted to the strengths and weaknesses of each child. A developmental pediatrician can help with management of behavioral issues and medication considerations, while more serious aggressive behaviors may be helped by a pediatric psychiatrist. In these individuals who have limited communication, potential medical issues such as severe constipation that might adversely impact behavior should be considered.Constipation is very common with Pitt-Hopkins and usually standard measures such as high fiber diets or laxatives are sufficient. If there is a significant problem with hyperventilation and/or apnea, advice from a pulmonologist should be sought as in some instances medications such as antiepileptic medications or acetazolamide have been helpful. Seizures that may occur are generally well controlled by anticonvulsants that can be individualized by a neurologist. Most individuals with Pitt-Hopkins will benefit from glasses and some may need surgery for crossed eyes that fail to self-correct. Regular ophthalmology exams are recommended.As of April 2018, Pitt-Hopkins syndrome clinics have been established at Massachusetts General Hospital (https://www.massgeneral.org/children/services/treatmentprograms.aspx?id=1849), University of Texas Southwestern's Children's Health (https://www.childrens.com/specialties-services/specialty-centers-and-programs/autism-and-developmental-disabilities/conditions-and-treatments/pitt-hopkins-syndrome), and UCSF Benioff Children's Hospital San Francisco (https://www.ucsf.edu/news/2015/09/131486/ucsf-pediatric-clinic-focused-rare-pitt-hopkins-syndrome-third-its-kind-world). These centers are devoted to the diagnosis and comprehensive treatment of this disorder and to further research to better understand this disorder.
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Pitt-Hopkins Syndrome
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Overview of Pityriasis Rosea
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Pityriasis rosea is a relatively mild skin disorder characterized by a salmon or pink colored, scaly rash. Pityriasis rosea most often affects children and young adults. In many individuals with pityriasis rosea, the characteristic rash develops after vague, nonspecific symptoms that resemble those associated with an upper respiratory infection. The rash is usually located on the back, chest and stomach and resolves on its own within one to three months. Certain treatments may reduce the duration of the rash. Researchers believe that pityriasis rosea is caused by an infectious pathogen, but they have been unable to isolate and identify such a pathogen.
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Overview of Pityriasis Rosea. Pityriasis rosea is a relatively mild skin disorder characterized by a salmon or pink colored, scaly rash. Pityriasis rosea most often affects children and young adults. In many individuals with pityriasis rosea, the characteristic rash develops after vague, nonspecific symptoms that resemble those associated with an upper respiratory infection. The rash is usually located on the back, chest and stomach and resolves on its own within one to three months. Certain treatments may reduce the duration of the rash. Researchers believe that pityriasis rosea is caused by an infectious pathogen, but they have been unable to isolate and identify such a pathogen.
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Pityriasis Rosea
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nord_971_1
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Symptoms of Pityriasis Rosea
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In many cases, the characteristic rash associated with pityriasis rosea is preceded by vague, nonspecific symptoms similar to those seen with a viral upper respiratory infection. Such symptoms can include fever, headache, stuffy nose, sore throat and fatigue. Sometimes there is no history of preceding illness before the rash appears.Initially, affected individuals develop a herald patch, which is a single scaly red patch, usually on the back, chest or stomach. When located on the back the herald patch may go undetected before appearance of the generalized rash. A herald patch is a slightly raised plaque that is usually between 2 to 4 inches large. Often the herald patch is misdiagnosed as ring worm (tinea corporis). Over the next few days or weeks, multiple smaller scaly, pink or red spots will develop. In individuals with darker skin, the rash may be gray, dark brown or black. Although the back, chest and stomach are most commonly affected, the rash may spread to affect the arms, legs and neck. Less often, other areas of the body may become involved. In rare cases, the rash may be isolated (localized) to one specific area of the body. In some people, the rash does not itch; in other people, the rash may be extremely itchy (pruritic).The rash usually lasts one to three months in approximately 80 percent of cases. Pityriasis rosea eventually goes away on its own, even without treatment, and usually does not leave any scars or permanent marks. However, people with darker skin may have residual dark spots at sites of inflammation which can last for many months before resolution.
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Symptoms of Pityriasis Rosea. In many cases, the characteristic rash associated with pityriasis rosea is preceded by vague, nonspecific symptoms similar to those seen with a viral upper respiratory infection. Such symptoms can include fever, headache, stuffy nose, sore throat and fatigue. Sometimes there is no history of preceding illness before the rash appears.Initially, affected individuals develop a herald patch, which is a single scaly red patch, usually on the back, chest or stomach. When located on the back the herald patch may go undetected before appearance of the generalized rash. A herald patch is a slightly raised plaque that is usually between 2 to 4 inches large. Often the herald patch is misdiagnosed as ring worm (tinea corporis). Over the next few days or weeks, multiple smaller scaly, pink or red spots will develop. In individuals with darker skin, the rash may be gray, dark brown or black. Although the back, chest and stomach are most commonly affected, the rash may spread to affect the arms, legs and neck. Less often, other areas of the body may become involved. In rare cases, the rash may be isolated (localized) to one specific area of the body. In some people, the rash does not itch; in other people, the rash may be extremely itchy (pruritic).The rash usually lasts one to three months in approximately 80 percent of cases. Pityriasis rosea eventually goes away on its own, even without treatment, and usually does not leave any scars or permanent marks. However, people with darker skin may have residual dark spots at sites of inflammation which can last for many months before resolution.
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Pityriasis Rosea
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nord_971_2
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Causes of Pityriasis Rosea
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Researchers believe that pityriasis rosea is caused by a viral infection. However, even though the disorder was first described in the medical literature in 1860, no infectious pathogen has ever been identified.Several factors support the theory that pityriasis rosea is caused by a viral infection – most individuals have vague, nonspecific symptoms before the development of the rash (prodromal illness); after the acute phase of infection the disorder does not recur, suggesting that the body builds up an immunity to the infection; and pityriasis rosea has occurred in clusters, suggesting that a viral illness is affecting a community. Although a virus is believed to cause pityriasis rosea, the disorder is not thought to be contagious.Some researchers have theorized that autoimmune factors may play a role in the development of pityriasis rosea. Autoimmunity is when the body’s immune system mistakenly attacks healthy tissue for unknown reasons.
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Causes of Pityriasis Rosea. Researchers believe that pityriasis rosea is caused by a viral infection. However, even though the disorder was first described in the medical literature in 1860, no infectious pathogen has ever been identified.Several factors support the theory that pityriasis rosea is caused by a viral infection – most individuals have vague, nonspecific symptoms before the development of the rash (prodromal illness); after the acute phase of infection the disorder does not recur, suggesting that the body builds up an immunity to the infection; and pityriasis rosea has occurred in clusters, suggesting that a viral illness is affecting a community. Although a virus is believed to cause pityriasis rosea, the disorder is not thought to be contagious.Some researchers have theorized that autoimmune factors may play a role in the development of pityriasis rosea. Autoimmunity is when the body’s immune system mistakenly attacks healthy tissue for unknown reasons.
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Pityriasis Rosea
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