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nord_871_3
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Affects of Nephrogenic Systemic Fibrosis
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NSF was first reported in the medical literature in 2000. The first case was noted in 1997. Researchers believe that the perceived safety and increased availability of gadolinium-based contrast dyes contributed to the rise of NSF since 1997. NSF affects men and women in equal numbers. The exact incidence or prevalence of the disorder is not known, although cases have been identified all over the world, typically in developed countries. More than 375 cases have been identified by the NSF Registry. The disorder can affect children, adults or the elderly. It is most common in the middle-aged and no known ethnic or racial predilection exists. Confirmed cases of NSF have only occurred in individuals with kidney disease who have been exposed to gadolinium-based contrast agents. Researchers believe that the increased awareness of the disorder and subsequent precaution or avoidance of using gadolinium-based contrast agents in individuals with decreased kidney function will lead to a decrease in the number of cases of NSF. Since identification of gadolinium as a potential trigger, European and American medical agencies have banned the use of certain GBCAs in individuals with renal disease. According to the International NSF Registry, there have been very few new cases of NSF since this ban went into effect.
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Affects of Nephrogenic Systemic Fibrosis. NSF was first reported in the medical literature in 2000. The first case was noted in 1997. Researchers believe that the perceived safety and increased availability of gadolinium-based contrast dyes contributed to the rise of NSF since 1997. NSF affects men and women in equal numbers. The exact incidence or prevalence of the disorder is not known, although cases have been identified all over the world, typically in developed countries. More than 375 cases have been identified by the NSF Registry. The disorder can affect children, adults or the elderly. It is most common in the middle-aged and no known ethnic or racial predilection exists. Confirmed cases of NSF have only occurred in individuals with kidney disease who have been exposed to gadolinium-based contrast agents. Researchers believe that the increased awareness of the disorder and subsequent precaution or avoidance of using gadolinium-based contrast agents in individuals with decreased kidney function will lead to a decrease in the number of cases of NSF. Since identification of gadolinium as a potential trigger, European and American medical agencies have banned the use of certain GBCAs in individuals with renal disease. According to the International NSF Registry, there have been very few new cases of NSF since this ban went into effect.
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Nephrogenic Systemic Fibrosis
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nord_871_4
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Related disorders of Nephrogenic Systemic Fibrosis
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Symptoms of the following disorders can be similar to those of NSF. Scleroderma is a rare connective tissue disorder characterized by abnormally increased production and accumulation of collagen, the body's major structural protein, in skin and other organs of the body. There are systemic and localized forms of scleroderma. Systemic scleroderma is characterized by hardening (induration) and thickening of the skin and abnormal degenerative changes and formation of fibrous tissue (fibrosis) in certain organs of the body including the lungs, heart, kidneys, and GI tract. Associated symptoms, which may vary widely from case to case, may include abnormal discoloration of and pain affecting the fingers and toes upon exposure to cold temperatures (Raynaud's phenomenon); abnormal tightness, thickening, “waxiness,” and loss of elasticity of the skin; shortness of breath; difficulty swallowing; muscle weakness; joint pain; heart abnormalities including irregular heart beats (palpitations); kidney (renal) abnormalities; and/or other symptoms and findings. In individuals with localized scleroderma, involvement is restricted to the skin, tissue under the skin (subcutaneous tissue), and, in some cases, underlying muscle and bone. Linear scleroderma is a localized form of scleroderma that may involve only certain areas of the body, such as an arm, a leg, or a portion of the face. It is characterized by multiple lesions of the skin, abnormally increased or decreased skin pigmentation (hyper- or hypopigmentation), and associated atrophy of the skin, subcutaneous tissue, muscle, and bone. Although the exact cause of scleroderma is unknown, researchers suggest that the disorder represents an abnormal autoimmune response. (For further information, choose “scleroderma” as your search term in the Rare Disease Database.) Scleromyxedema is a rare skin disorder characterized by widespread reddish papules and abnormally thickened and hardened skin. The range of motion of affected areas such as the face, fingers and arms and legs is often decreased. In scleromyxedema, the pharynx and the upper airways may become involved causing serious breathing (respiratory) complications. Other organ systems including the lungs and the heart may also be affected. Joint pain affecting multiple joints (polyarthritis) may also occur. The disorder primarily affects middle-aged adults. The cause of scleromyxedema is unknown. Eosinophilic fasciitis is a rare disorder characterized by inflammation of the tough band of fibrous tissue beneath the skin (fascia). The arms and legs are most often affected. Inflammation is caused by the abnormal accumulation of certain white blood cells including eosinophils in the fascia. Eosinophilic fasciitis eventually causes the skin to swell and slowly thicken and harden (induration). The disorder most commonly affects middle-aged adults. The exact cause of eosinophilic fasciitis is unknown. Some researchers believe that eosinophilic fasciitis is a variant of scleroderma (systemic sclerosis), an autoimmune connective tissue disorder characterized by hardening of the skin. (For more information on this disorder, choose “eosinophilic fasciitis” as your search term in the Rare Disease Database.)
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Related disorders of Nephrogenic Systemic Fibrosis. Symptoms of the following disorders can be similar to those of NSF. Scleroderma is a rare connective tissue disorder characterized by abnormally increased production and accumulation of collagen, the body's major structural protein, in skin and other organs of the body. There are systemic and localized forms of scleroderma. Systemic scleroderma is characterized by hardening (induration) and thickening of the skin and abnormal degenerative changes and formation of fibrous tissue (fibrosis) in certain organs of the body including the lungs, heart, kidneys, and GI tract. Associated symptoms, which may vary widely from case to case, may include abnormal discoloration of and pain affecting the fingers and toes upon exposure to cold temperatures (Raynaud's phenomenon); abnormal tightness, thickening, “waxiness,” and loss of elasticity of the skin; shortness of breath; difficulty swallowing; muscle weakness; joint pain; heart abnormalities including irregular heart beats (palpitations); kidney (renal) abnormalities; and/or other symptoms and findings. In individuals with localized scleroderma, involvement is restricted to the skin, tissue under the skin (subcutaneous tissue), and, in some cases, underlying muscle and bone. Linear scleroderma is a localized form of scleroderma that may involve only certain areas of the body, such as an arm, a leg, or a portion of the face. It is characterized by multiple lesions of the skin, abnormally increased or decreased skin pigmentation (hyper- or hypopigmentation), and associated atrophy of the skin, subcutaneous tissue, muscle, and bone. Although the exact cause of scleroderma is unknown, researchers suggest that the disorder represents an abnormal autoimmune response. (For further information, choose “scleroderma” as your search term in the Rare Disease Database.) Scleromyxedema is a rare skin disorder characterized by widespread reddish papules and abnormally thickened and hardened skin. The range of motion of affected areas such as the face, fingers and arms and legs is often decreased. In scleromyxedema, the pharynx and the upper airways may become involved causing serious breathing (respiratory) complications. Other organ systems including the lungs and the heart may also be affected. Joint pain affecting multiple joints (polyarthritis) may also occur. The disorder primarily affects middle-aged adults. The cause of scleromyxedema is unknown. Eosinophilic fasciitis is a rare disorder characterized by inflammation of the tough band of fibrous tissue beneath the skin (fascia). The arms and legs are most often affected. Inflammation is caused by the abnormal accumulation of certain white blood cells including eosinophils in the fascia. Eosinophilic fasciitis eventually causes the skin to swell and slowly thicken and harden (induration). The disorder most commonly affects middle-aged adults. The exact cause of eosinophilic fasciitis is unknown. Some researchers believe that eosinophilic fasciitis is a variant of scleroderma (systemic sclerosis), an autoimmune connective tissue disorder characterized by hardening of the skin. (For more information on this disorder, choose “eosinophilic fasciitis” as your search term in the Rare Disease Database.)
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Nephrogenic Systemic Fibrosis
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nord_871_5
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Diagnosis of Nephrogenic Systemic Fibrosis
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Diagnostic criteria for NSF have been recently developed. A diagnosis of NSF is usually made based upon a detailed patient history, a thorough clinical examination and identification of characteristic findings. Surgical removal and microscopic study of a small sample of affected skin tissue (skin biopsy) is required to verify the diagnosis. Additional tests may be performed to exclude several other disorders that can resemble NSF.
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Diagnosis of Nephrogenic Systemic Fibrosis. Diagnostic criteria for NSF have been recently developed. A diagnosis of NSF is usually made based upon a detailed patient history, a thorough clinical examination and identification of characteristic findings. Surgical removal and microscopic study of a small sample of affected skin tissue (skin biopsy) is required to verify the diagnosis. Additional tests may be performed to exclude several other disorders that can resemble NSF.
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Nephrogenic Systemic Fibrosis
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nord_871_6
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Therapies of Nephrogenic Systemic Fibrosis
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TreatmentThere is no specific, consistently effective therapy available for individuals with NSF. Improvement in kidney function, either spontaneously after acute kidney injury or post-transplantation, appears to slow, or stop the progression of NSF. In some cases with improvement in kidney function, a gradual reversal of the disease process may occur over time.A wide variety of different therapies have been tried in individuals with NSF with varying results. These therapies are detailed in the investigational therapies section below.Because NSF can damage and restrict the joints, early physical therapy and medications for pain control may have a role in the treatment of affected individuals.Individuals maintained on chronic hemodialysis and peritoneal dialysis have a significantly higher risk of developing NSF compared with individuals with advanced chronic kidney disease who have not yet started dialysis. Patients with acute kidney injury who have not been dialyzed within the 2 days preceding a GBCA injection may have a very high risk for NSF. Whether hemodialysis has value in preventing NSF post-exposure is unknown. Immediate hemodialysis within 2 hours of GBCA injection in patients on hemodialysis, peritoneal dialysis or those with severe acute kidney injury is recommended based on theoretical and observational data.
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Therapies of Nephrogenic Systemic Fibrosis. TreatmentThere is no specific, consistently effective therapy available for individuals with NSF. Improvement in kidney function, either spontaneously after acute kidney injury or post-transplantation, appears to slow, or stop the progression of NSF. In some cases with improvement in kidney function, a gradual reversal of the disease process may occur over time.A wide variety of different therapies have been tried in individuals with NSF with varying results. These therapies are detailed in the investigational therapies section below.Because NSF can damage and restrict the joints, early physical therapy and medications for pain control may have a role in the treatment of affected individuals.Individuals maintained on chronic hemodialysis and peritoneal dialysis have a significantly higher risk of developing NSF compared with individuals with advanced chronic kidney disease who have not yet started dialysis. Patients with acute kidney injury who have not been dialyzed within the 2 days preceding a GBCA injection may have a very high risk for NSF. Whether hemodialysis has value in preventing NSF post-exposure is unknown. Immediate hemodialysis within 2 hours of GBCA injection in patients on hemodialysis, peritoneal dialysis or those with severe acute kidney injury is recommended based on theoretical and observational data.
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Nephrogenic Systemic Fibrosis
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nord_872_0
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Overview of Neu Laxova Syndrome
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Neu-Laxova syndrome (NLS) is a rare genetic disorder that is inherited as an autosomal recessive trait. The syndrome is characterized by severe growth delays before birth (intrauterine growth retardation); low birth weight and length; and distinctive abnormalities of the head and facial (craniofacial) region. These may include marked smallness of the head (microcephaly), sloping of the forehead, widely spaced eyes (ocular hypertelorism), and other malformations, resulting in a distinctive facial appearance. NLS is also typically characterized by abnormal accumulations of fluid in tissues throughout the body (generalized edema); permanent flexion and immobilization of multiple joints (flexion contractures); other limb malformations; and/or abnormalities of the brain, skin, genitals, kidneys, and/or heart.
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Overview of Neu Laxova Syndrome. Neu-Laxova syndrome (NLS) is a rare genetic disorder that is inherited as an autosomal recessive trait. The syndrome is characterized by severe growth delays before birth (intrauterine growth retardation); low birth weight and length; and distinctive abnormalities of the head and facial (craniofacial) region. These may include marked smallness of the head (microcephaly), sloping of the forehead, widely spaced eyes (ocular hypertelorism), and other malformations, resulting in a distinctive facial appearance. NLS is also typically characterized by abnormal accumulations of fluid in tissues throughout the body (generalized edema); permanent flexion and immobilization of multiple joints (flexion contractures); other limb malformations; and/or abnormalities of the brain, skin, genitals, kidneys, and/or heart.
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Neu Laxova Syndrome
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nord_872_1
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Symptoms of Neu Laxova Syndrome
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NLS is associated with distinctive abnormalities before birth. These may include severely delayed growth (intrauterine growth retardation); excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus during pregnancy (polyhydramnios); abnormally reduced fetal movements; a short umbilical cord; and an abnormally small placenta. (The placenta is the organ within the uterus that joins the blood supplies of the mother and the developing fetus.) In addition, in some cases, the umbilical cord may have only two blood vessels. (The umbilical cord, which is the flexible structure that connects the fetus with the placenta, normally has two umbilical arteries as well as a larger umbilical vein.)Newborns with NLS typically have an abnormally low birth weight and length as well as marked smallness of the head (microcephaly). Additional malformations of the head and facial (craniofacial) area are also usually present, resulting in a characteristic appearance. Such abnormalities include a sloping forehead; a flattened nose with a broad nasal bridge; full cheeks; and a small, underdeveloped jaw (micrognathia). Affected newborns may also have large, low-set, malformed (dysplastic) ears; a round, gaping mouth with thick lips; a short neck; and widely set, unusually prominent eyes. In addition, the eyelids are underdeveloped (hypoplastic) and turned outward (ectropion), causing them to appear absent. Additional eye (ocular) abnormalities may also be present, such as unusually small eyes (microphthalmia) and loss of transparency of the lenses of the eyes (cataracts). Some affected newborns may also have incomplete closure of the roof of the mouth (cleft palate) and a vertical groove in the upper lip (cleft lip).NLS is also associated with musculoskeletal abnormalities, including permanent flexion and immobilization of major joints (flexion contractures), such as the elbows, wrists, hips, knees, and ankles, with skin webbing across certain immobilized joints (e.g., elbows and knees). In addition, the arms and legs are unusually short, and the hands and feet may be swollen. Affected newborns may also have overlapping fingers; webbed or fused fingers and toes (syndactyly); and a deformity in which the feet appear shaped like the rocker of a rocking chair (rocker-bottom feet). In addition, there may be “underossification” of bones in the hands and feet and other abnormalities of bone formation. (Ossification refers to the conversion of fibrous tissue or cartilage into bone.) The disorder is also typically characterized by an abnormal accumulation of fluid in tissues throughout the body (generalized edema). In addition, some infants may have abnormal (i.e., myxomatous) proliferation of connective tissue or excessive fatty deposits beneath the outermost layer of skin (epidermis), with degeneration (atrophy) of surrounding muscles. Less commonly, edema may not be present or may be restricted to the scalp. Some affected infants may also have yellowish, dry, scaling (“ichthyotic”) skin.NLS may also be associated with malformations of the brain. In many cases, there is incomplete development of the folds (gyri) of the outer region of the brain (cerebral cortex), causing the brain's surface to appear unusually smooth (agyria). Additional malformations may include absence of the thick band of nerve fibers that connects the two hemispheres of the brain (agenesis of the corpus callosum) or underdevelopment (hypoplasia) of the cerebellum, which is the region of the brain that plays an essential role in coordinating voluntary movements and maintaining proper posture. In addition, in some instances, there may be cystic malformation of the fourth cavity (ventricle) of the brain (Dandy-Walker malformation) and associated hydrocephalus. Hydrocephalus is a condition in which there is impaired flow or absorption of the fluid that circulates through the ventricles of the brain and the spinal canal [cerebrospinal fluid (CSF)], potentially leading to increasing fluid pressure in the brain, a rapid increase in head size, or other associated findings. In some cases, NLS may also be associated with additional abnormalities of the brain and spinal cord (central nervous system).Some affected newborns may also have additional physical abnormalities, such as underdevelopment of the genitals; absence of one of the kidneys (unilateral renal agenesis) or other renal defects; underdevelopment of the lungs (pulmonary hypoplasia); or structural abnormalities of the heart (congenital heart defects). Congenital cardiac malformations may include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects); persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus); or a heart defect in which the aortic and pulmonary arteries are in one another's normal positions (transposition of the great arteries). Infants with NLS may be stillborn or develop life-threatening complications shortly after birth.
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Symptoms of Neu Laxova Syndrome. NLS is associated with distinctive abnormalities before birth. These may include severely delayed growth (intrauterine growth retardation); excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus during pregnancy (polyhydramnios); abnormally reduced fetal movements; a short umbilical cord; and an abnormally small placenta. (The placenta is the organ within the uterus that joins the blood supplies of the mother and the developing fetus.) In addition, in some cases, the umbilical cord may have only two blood vessels. (The umbilical cord, which is the flexible structure that connects the fetus with the placenta, normally has two umbilical arteries as well as a larger umbilical vein.)Newborns with NLS typically have an abnormally low birth weight and length as well as marked smallness of the head (microcephaly). Additional malformations of the head and facial (craniofacial) area are also usually present, resulting in a characteristic appearance. Such abnormalities include a sloping forehead; a flattened nose with a broad nasal bridge; full cheeks; and a small, underdeveloped jaw (micrognathia). Affected newborns may also have large, low-set, malformed (dysplastic) ears; a round, gaping mouth with thick lips; a short neck; and widely set, unusually prominent eyes. In addition, the eyelids are underdeveloped (hypoplastic) and turned outward (ectropion), causing them to appear absent. Additional eye (ocular) abnormalities may also be present, such as unusually small eyes (microphthalmia) and loss of transparency of the lenses of the eyes (cataracts). Some affected newborns may also have incomplete closure of the roof of the mouth (cleft palate) and a vertical groove in the upper lip (cleft lip).NLS is also associated with musculoskeletal abnormalities, including permanent flexion and immobilization of major joints (flexion contractures), such as the elbows, wrists, hips, knees, and ankles, with skin webbing across certain immobilized joints (e.g., elbows and knees). In addition, the arms and legs are unusually short, and the hands and feet may be swollen. Affected newborns may also have overlapping fingers; webbed or fused fingers and toes (syndactyly); and a deformity in which the feet appear shaped like the rocker of a rocking chair (rocker-bottom feet). In addition, there may be “underossification” of bones in the hands and feet and other abnormalities of bone formation. (Ossification refers to the conversion of fibrous tissue or cartilage into bone.) The disorder is also typically characterized by an abnormal accumulation of fluid in tissues throughout the body (generalized edema). In addition, some infants may have abnormal (i.e., myxomatous) proliferation of connective tissue or excessive fatty deposits beneath the outermost layer of skin (epidermis), with degeneration (atrophy) of surrounding muscles. Less commonly, edema may not be present or may be restricted to the scalp. Some affected infants may also have yellowish, dry, scaling (“ichthyotic”) skin.NLS may also be associated with malformations of the brain. In many cases, there is incomplete development of the folds (gyri) of the outer region of the brain (cerebral cortex), causing the brain's surface to appear unusually smooth (agyria). Additional malformations may include absence of the thick band of nerve fibers that connects the two hemispheres of the brain (agenesis of the corpus callosum) or underdevelopment (hypoplasia) of the cerebellum, which is the region of the brain that plays an essential role in coordinating voluntary movements and maintaining proper posture. In addition, in some instances, there may be cystic malformation of the fourth cavity (ventricle) of the brain (Dandy-Walker malformation) and associated hydrocephalus. Hydrocephalus is a condition in which there is impaired flow or absorption of the fluid that circulates through the ventricles of the brain and the spinal canal [cerebrospinal fluid (CSF)], potentially leading to increasing fluid pressure in the brain, a rapid increase in head size, or other associated findings. In some cases, NLS may also be associated with additional abnormalities of the brain and spinal cord (central nervous system).Some affected newborns may also have additional physical abnormalities, such as underdevelopment of the genitals; absence of one of the kidneys (unilateral renal agenesis) or other renal defects; underdevelopment of the lungs (pulmonary hypoplasia); or structural abnormalities of the heart (congenital heart defects). Congenital cardiac malformations may include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects); persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus); or a heart defect in which the aortic and pulmonary arteries are in one another's normal positions (transposition of the great arteries). Infants with NLS may be stillborn or develop life-threatening complications shortly after birth.
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Neu Laxova Syndrome
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nord_872_2
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Causes of Neu Laxova Syndrome
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NLS is transmitted as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. The parents of several individuals with NLS have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease.A few cases have also been reported in which NLS has appeared to occur randomly for unknown reasons (sporadically). There has been one reported case of NLS that has occurred for no apparent reason (sporadically). Several cases of this disorder have been associated with “blood” related parents.
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Causes of Neu Laxova Syndrome. NLS is transmitted as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy. The parents of several individuals with NLS have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for development of the disease.A few cases have also been reported in which NLS has appeared to occur randomly for unknown reasons (sporadically). There has been one reported case of NLS that has occurred for no apparent reason (sporadically). Several cases of this disorder have been associated with “blood” related parents.
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Neu Laxova Syndrome
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nord_872_3
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Affects of Neu Laxova Syndrome
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NLS appears to affect males and females in relatively equal numbers. Since the disorder was originally described in three siblings in 1971 (Neu, RL) as well as three siblings in another family in 1972 (Laxova, R), over 30 additional cases have been reported. Investigators suggest that the disorder may have a higher frequency in Pakistanis than in other geographic or ethnic populations.
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Affects of Neu Laxova Syndrome. NLS appears to affect males and females in relatively equal numbers. Since the disorder was originally described in three siblings in 1971 (Neu, RL) as well as three siblings in another family in 1972 (Laxova, R), over 30 additional cases have been reported. Investigators suggest that the disorder may have a higher frequency in Pakistanis than in other geographic or ethnic populations.
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Neu Laxova Syndrome
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nord_872_4
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Related disorders of Neu Laxova Syndrome
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Symptoms of the following disorders may be similar to those of NLS. Comparisons may be useful for a differential diagnosis:Cerebro-oculo-facio-skeletal (COFS) syndrome is a rare genetic disorder that is sometimes referred to as Pena-Shokeir syndrome type II. Some researchers suggest that NLS and COFS syndrome may represent the same disease entity. (Other investigators have indicated that COFS syndrome and another condition known as Bowen Hutterite syndrome may be the same disorder. [For information on Bowen Hutterite syndrome, please see the description below.]) COFS syndrome is characterized by severe, progressive growth delays after birth (postnatal growth deficiency); characteristic craniofacial malformations, resulting in a distinctive facial appearance; eye (ocular) abnormalities; musculoskeletal defects; and malformations and progressive degenerative changes of the brain and spinal cord (central nervous system). Infants with COFS syndrome fail to gain weight as expected and experience little growth despite an apparently sufficient intake of calories (failure to thrive). Distinctive craniofacial malformations include an unusually small head (microcephaly); a prominent nose and high nasal bridge; an overhanging upper lip; a small mouth, underdeveloped jaw (micrognathia), and receding chin; and large, low-set ears. Most affected infants also have narrow eyelid folds (palpebral fissures), unusually small eyes (microphthalmia), loss of transparency of the lenses of the eyes (cataracts), and/or other ocular abnormalities. Characteristic musculoskeletal defects include permanent flexion of certain fingers (camptodactyly) and particular joints of the arms and legs (flexion contractures); abnormal front-to-back and/or sideways curvature of the spine (kyphosis and/or scoliosis); rocker-bottom feet; characteristic defects of the hips and pelvis; and/or other abnormalities. In addition, central nervous system (CNS) abnormalities are usually present including severe intellectual disability; certain malformations of the brain (e.g., cerebellar hypoplasia, hypoplasia or agenesis of the corpus callosum); and progressive degeneration of myelin (demyelination), a fatty, protective substance around certain nerve fibers that enables the effective transmission of nerve signals. Infants and children with the disorder are also prone to repeated respiratory infections and may experience increasing difficulties breathing (respiratory distress). COFS syndrome is thought to be inherited as an autosomal recessive trait. (For further information, choose “Cerebro-oculo-facio-skeletal” or “COFS” as your search term in the Rare Disease Database.)Bowen Hutterite syndrome is a rare genetic disorder that has primarily occurred in individuals of Hutterite descent. The disorder is characterized by growth delays before birth (intrauterine growth retardation); failure to grow and gain weight at the expected rate (failure to thrive) during infancy; distinctive craniofacial abnormalities, such as an abnormally small head (microcephaly), a prominent nose, and a small, underdeveloped jaw (micrognathia); and other physical abnormalities. These may include restricted joint movements, abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, rocker-bottom feet, and/or undescended testes (cryptorchidism) in affected males. Some affected infants may also have kidney (renal), brain, and/or other malformations. Bowen Hutterite syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Bowen Hutterite” as your search term in the Rare Disease Database.)Fetal akinesia sequence, also known as Pena-Shokeir syndrome type I, is characterized by growth deficiency before birth (intrauterine growth retardation); severely underdeveloped lungs (pulmonary hypoplasia) and difficulties breathing (respiratory distress) at birth; permanent flexion and immobilization of several joints; and characteristic craniofacial malformations. Many researchers suggest that fetal akinesia sequence does not represent a particular syndrome or distinct disease entity, but rather the occurrence of characteristic symptoms and physical findings (typical phenotype) due to abnormally decreased movement during fetal development (fetal hypokinesia or akinesia) and muscle weakness from many different underlying causes. Infants with fetal akinesia sequence typically have moderate joint contractures of the wrists, elbows, hips, knees, and ankles; skin webbing across certain immobilized joints; permanent flexion (camptodactyly) and abnormal deviation of certain fingers toward the “pinky” side of the hand (ulnar deviation); malformations of the feet (e.g., clubfeet [talipes equinovarus] or rocker-bottom feet); and/or other musculoskeletal abnormalities. Characteristic craniofacial malformations may include a high nasal bridge with a depressed nasal tip; widely spaced eyes (ocular hypertelorism); low-set, malformed ears; an abnormally small, retracted jaw (microretrognathia); and/or incomplete closure of the roof of the mouth (cleft palate). Affected infants may also have additional abnormalities including an unusually short and/or webbed neck, malformations of the genital and urinary (genitourinary) tracts, heart defects, and/or other malformations. Researchers suggest that fetal akinesia sequence may result from many different underlying neurological (neurogenic) or muscular (myopathic) disorders and/or other factors. (For further information on this disorder, choose “fetal akinesia” or “Pena Shokeir” as your search term in the Rare Disease Database.)Restrictive dermopathy is a rare genetic disorder that is inherited as an autosomal recessive trait. The disorder is associated with severe growth delays before birth; excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus (polyhydramnios); a short umbilical cord; and abnormally reduced movements during fetal development. In addition, affected newborns typically have rigid, tense, adherent skin; underdeveloped lungs (pulmonary hypoplasia); permanently flexed, immobilized joints (contractures); rocker-bottom feet; and other skeletal abnormalities. Newborns also have characteristic craniofacial malformations, such as widely spaced eyes (ocular hypertelorism); outwardly turned eyelids (ectropion); a small, pinched nose; a small, open mouth; and an underdeveloped jaw (micrognathia). Affected infants may be stillborn or develop life-threatening complications shortly after birth.Multiple pterygium syndrome is a rare genetic disorder characterized by abnormal growth delays (growth retardation), webbing of the skin (pterygium) in several areas of the body, permanent flexion of certain joints (contractures), skeletal abnormalities, and craniofacial malformations. Affected individuals typically have webbing of the neck (pterygium colli), of the fingers (syndactyly), under the arms (axillae), in the crook of the elbows (antecubital fossae), and behind the knees (popliteal fossae); multiple joint contractures; permanent flexion of certain fingers and toes (camptodactyly); and foot deformities, such as rocker-bottom feet. Individuals with the disorder may also have abnormal front-to-back and sideways curvature of the spine (kyphoscoliosis) and other malformations of bones of the spinal column (vertebrae); abnormalities of the ribs; dislocation of the hips; and/or other skeletal malformations. Craniofacial defects may include an abnormally small jaw (micrognathia), drooping of the upper eyelids (ptosis), downwardly slanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes' inner corners (epicanthal folds), and low-set ears. In addition, genital and/or other abnormalities may be present. In most cases, the disorder appears to occur randomly for unknown reasons (sporadically). (For more information on this disorder, choose “multiple pterygium” as your search term in the Rare Disease Database.) There are also several rare autosomal recessive forms of multiple pterygium syndrome that may be characterized by decreased fetal movements (fetal hypokinesia or akinesia), multiple joint contractures, and skin webbing across joints. Additional features may include permanent flexion of certain fingers (camptodactyly); abnormal cystic growths consisting of widened (dilated) lymph vessels beneath the skin in the neck area (cystic hygroma); and/or abnormal accumulation of fluid in tissues throughout the body and in body cavities (fetal hydrops), such as around the lungs (pleural effusion), around the heart (pericardial effusion), and/or in the abdominal cavity (ascites). Affected individuals may also have an underdeveloped jaw (micrognathia), an unusually flat nose, an abnormal groove in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), and/or other craniofacial malformations; abnormally crowded, thin ribs; and underdevelopment (hyoplasia) of the heart and lungs. Life-threatening complications may occur during fetal development.Trisomy 18 syndrome is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in some (mosaicism) or all cells of the body. Depending on the specific location of the duplicated (trisomic) portion of chromosome 18–as well as the percentage of cells containing the abnormality–symptoms and findings may be extremely variable from case to case. However, before birth, abnormalities often include weak fetal activity, a small placenta, and excessive fluid in the membranous sac surrounding the developing fetus (polyhydramnios). After birth, characteristic findings include growth deficiency, feeding and breathing difficulties, developmental delays, intellectual disability, and, in affected males, undescended testes (cryptorchidism). Individuals with Trisomy 18 syndrome may also have distinctive craniofacial malformations, such as a small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent back region of the head (occiput); a small mouth (microstomia) and an underdeveloped jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and/or an upturned nose. Affected infants may also have narrow eyelid folds (palpebral fissures), widely spaced eyes (ocular hypertelorism), and drooping of the upper eyelids (ptosis). Malformations of the hands and feet are also often present, including overlapped, flexed fingers; webbing of certain toes (syndactyly); and a deformity in which the heels are turned inward and the soles are flexed (clubfeet [talipes equinovarus]). Infants with Trisomy 18 syndrome may also have a small pelvis with limited movements of the hips, a short breastbone (sternum), kidney malformations, and structural heart defects that are present at birth. Such cardiac defects may include an abnormal opening in the partition dividing the lower chambers of the heart (ventricular septal defect) or persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus). (For further information on this disorder, choose “trisomy 18” as your search term in the Rare Disease Database.)There are a number of other disorders that may be characterized by abnormally decreased movement during fetal development; growth delays; multiple joint contractures; skin webbing; craniofacial, central nervous system, cardiac, or renal malformations; and/or other abnormalities similar to those potentially associated with NLS. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Neu Laxova Syndrome. Symptoms of the following disorders may be similar to those of NLS. Comparisons may be useful for a differential diagnosis:Cerebro-oculo-facio-skeletal (COFS) syndrome is a rare genetic disorder that is sometimes referred to as Pena-Shokeir syndrome type II. Some researchers suggest that NLS and COFS syndrome may represent the same disease entity. (Other investigators have indicated that COFS syndrome and another condition known as Bowen Hutterite syndrome may be the same disorder. [For information on Bowen Hutterite syndrome, please see the description below.]) COFS syndrome is characterized by severe, progressive growth delays after birth (postnatal growth deficiency); characteristic craniofacial malformations, resulting in a distinctive facial appearance; eye (ocular) abnormalities; musculoskeletal defects; and malformations and progressive degenerative changes of the brain and spinal cord (central nervous system). Infants with COFS syndrome fail to gain weight as expected and experience little growth despite an apparently sufficient intake of calories (failure to thrive). Distinctive craniofacial malformations include an unusually small head (microcephaly); a prominent nose and high nasal bridge; an overhanging upper lip; a small mouth, underdeveloped jaw (micrognathia), and receding chin; and large, low-set ears. Most affected infants also have narrow eyelid folds (palpebral fissures), unusually small eyes (microphthalmia), loss of transparency of the lenses of the eyes (cataracts), and/or other ocular abnormalities. Characteristic musculoskeletal defects include permanent flexion of certain fingers (camptodactyly) and particular joints of the arms and legs (flexion contractures); abnormal front-to-back and/or sideways curvature of the spine (kyphosis and/or scoliosis); rocker-bottom feet; characteristic defects of the hips and pelvis; and/or other abnormalities. In addition, central nervous system (CNS) abnormalities are usually present including severe intellectual disability; certain malformations of the brain (e.g., cerebellar hypoplasia, hypoplasia or agenesis of the corpus callosum); and progressive degeneration of myelin (demyelination), a fatty, protective substance around certain nerve fibers that enables the effective transmission of nerve signals. Infants and children with the disorder are also prone to repeated respiratory infections and may experience increasing difficulties breathing (respiratory distress). COFS syndrome is thought to be inherited as an autosomal recessive trait. (For further information, choose “Cerebro-oculo-facio-skeletal” or “COFS” as your search term in the Rare Disease Database.)Bowen Hutterite syndrome is a rare genetic disorder that has primarily occurred in individuals of Hutterite descent. The disorder is characterized by growth delays before birth (intrauterine growth retardation); failure to grow and gain weight at the expected rate (failure to thrive) during infancy; distinctive craniofacial abnormalities, such as an abnormally small head (microcephaly), a prominent nose, and a small, underdeveloped jaw (micrognathia); and other physical abnormalities. These may include restricted joint movements, abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, rocker-bottom feet, and/or undescended testes (cryptorchidism) in affected males. Some affected infants may also have kidney (renal), brain, and/or other malformations. Bowen Hutterite syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Bowen Hutterite” as your search term in the Rare Disease Database.)Fetal akinesia sequence, also known as Pena-Shokeir syndrome type I, is characterized by growth deficiency before birth (intrauterine growth retardation); severely underdeveloped lungs (pulmonary hypoplasia) and difficulties breathing (respiratory distress) at birth; permanent flexion and immobilization of several joints; and characteristic craniofacial malformations. Many researchers suggest that fetal akinesia sequence does not represent a particular syndrome or distinct disease entity, but rather the occurrence of characteristic symptoms and physical findings (typical phenotype) due to abnormally decreased movement during fetal development (fetal hypokinesia or akinesia) and muscle weakness from many different underlying causes. Infants with fetal akinesia sequence typically have moderate joint contractures of the wrists, elbows, hips, knees, and ankles; skin webbing across certain immobilized joints; permanent flexion (camptodactyly) and abnormal deviation of certain fingers toward the “pinky” side of the hand (ulnar deviation); malformations of the feet (e.g., clubfeet [talipes equinovarus] or rocker-bottom feet); and/or other musculoskeletal abnormalities. Characteristic craniofacial malformations may include a high nasal bridge with a depressed nasal tip; widely spaced eyes (ocular hypertelorism); low-set, malformed ears; an abnormally small, retracted jaw (microretrognathia); and/or incomplete closure of the roof of the mouth (cleft palate). Affected infants may also have additional abnormalities including an unusually short and/or webbed neck, malformations of the genital and urinary (genitourinary) tracts, heart defects, and/or other malformations. Researchers suggest that fetal akinesia sequence may result from many different underlying neurological (neurogenic) or muscular (myopathic) disorders and/or other factors. (For further information on this disorder, choose “fetal akinesia” or “Pena Shokeir” as your search term in the Rare Disease Database.)Restrictive dermopathy is a rare genetic disorder that is inherited as an autosomal recessive trait. The disorder is associated with severe growth delays before birth; excessive fluid in the thin-walled membrane (amniotic sac) surrounding the fetus (polyhydramnios); a short umbilical cord; and abnormally reduced movements during fetal development. In addition, affected newborns typically have rigid, tense, adherent skin; underdeveloped lungs (pulmonary hypoplasia); permanently flexed, immobilized joints (contractures); rocker-bottom feet; and other skeletal abnormalities. Newborns also have characteristic craniofacial malformations, such as widely spaced eyes (ocular hypertelorism); outwardly turned eyelids (ectropion); a small, pinched nose; a small, open mouth; and an underdeveloped jaw (micrognathia). Affected infants may be stillborn or develop life-threatening complications shortly after birth.Multiple pterygium syndrome is a rare genetic disorder characterized by abnormal growth delays (growth retardation), webbing of the skin (pterygium) in several areas of the body, permanent flexion of certain joints (contractures), skeletal abnormalities, and craniofacial malformations. Affected individuals typically have webbing of the neck (pterygium colli), of the fingers (syndactyly), under the arms (axillae), in the crook of the elbows (antecubital fossae), and behind the knees (popliteal fossae); multiple joint contractures; permanent flexion of certain fingers and toes (camptodactyly); and foot deformities, such as rocker-bottom feet. Individuals with the disorder may also have abnormal front-to-back and sideways curvature of the spine (kyphoscoliosis) and other malformations of bones of the spinal column (vertebrae); abnormalities of the ribs; dislocation of the hips; and/or other skeletal malformations. Craniofacial defects may include an abnormally small jaw (micrognathia), drooping of the upper eyelids (ptosis), downwardly slanting eyelid folds (palpebral fissures), vertical skin folds that may cover the eyes' inner corners (epicanthal folds), and low-set ears. In addition, genital and/or other abnormalities may be present. In most cases, the disorder appears to occur randomly for unknown reasons (sporadically). (For more information on this disorder, choose “multiple pterygium” as your search term in the Rare Disease Database.) There are also several rare autosomal recessive forms of multiple pterygium syndrome that may be characterized by decreased fetal movements (fetal hypokinesia or akinesia), multiple joint contractures, and skin webbing across joints. Additional features may include permanent flexion of certain fingers (camptodactyly); abnormal cystic growths consisting of widened (dilated) lymph vessels beneath the skin in the neck area (cystic hygroma); and/or abnormal accumulation of fluid in tissues throughout the body and in body cavities (fetal hydrops), such as around the lungs (pleural effusion), around the heart (pericardial effusion), and/or in the abdominal cavity (ascites). Affected individuals may also have an underdeveloped jaw (micrognathia), an unusually flat nose, an abnormal groove in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), and/or other craniofacial malformations; abnormally crowded, thin ribs; and underdevelopment (hyoplasia) of the heart and lungs. Life-threatening complications may occur during fetal development.Trisomy 18 syndrome is a rare chromosomal disorder in which all or a critical region of chromosome 18 appears three times (trisomy) rather than twice in some (mosaicism) or all cells of the body. Depending on the specific location of the duplicated (trisomic) portion of chromosome 18–as well as the percentage of cells containing the abnormality–symptoms and findings may be extremely variable from case to case. However, before birth, abnormalities often include weak fetal activity, a small placenta, and excessive fluid in the membranous sac surrounding the developing fetus (polyhydramnios). After birth, characteristic findings include growth deficiency, feeding and breathing difficulties, developmental delays, intellectual disability, and, in affected males, undescended testes (cryptorchidism). Individuals with Trisomy 18 syndrome may also have distinctive craniofacial malformations, such as a small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent back region of the head (occiput); a small mouth (microstomia) and an underdeveloped jaw (micrognathia); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and/or an upturned nose. Affected infants may also have narrow eyelid folds (palpebral fissures), widely spaced eyes (ocular hypertelorism), and drooping of the upper eyelids (ptosis). Malformations of the hands and feet are also often present, including overlapped, flexed fingers; webbing of certain toes (syndactyly); and a deformity in which the heels are turned inward and the soles are flexed (clubfeet [talipes equinovarus]). Infants with Trisomy 18 syndrome may also have a small pelvis with limited movements of the hips, a short breastbone (sternum), kidney malformations, and structural heart defects that are present at birth. Such cardiac defects may include an abnormal opening in the partition dividing the lower chambers of the heart (ventricular septal defect) or persistence of the fetal opening between the two major arteries (aorta, pulmonary artery) emerging from the heart (patent ductus arteriosus). (For further information on this disorder, choose “trisomy 18” as your search term in the Rare Disease Database.)There are a number of other disorders that may be characterized by abnormally decreased movement during fetal development; growth delays; multiple joint contractures; skin webbing; craniofacial, central nervous system, cardiac, or renal malformations; and/or other abnormalities similar to those potentially associated with NLS. (For more information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Neu Laxova Syndrome
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Diagnosis of Neu Laxova Syndrome
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A diagnosis of NLS may be suggested before birth (prenatally) based upon specialized testing, such as repeated fetal ultrasonography. During fetal ultrasonography, sound waves are used to create an image of the developing fetus. Such testing may reveal characteristic findings that suggest NLS, such as weak fetal activity, restricted limb movement, excessive fluid in the membranous sac surrounding the developing fetus (polyhydramnios), a small placenta, and intrauterine growth retardation. Additional findings seen on ultrasound that may suggest NLS include an abnormally small head, receding forehead, prominent eyes, joint contractures, and/or generalized edema.The diagnosis of NLS may also be made or confirmed after birth (postnatally) based upon a thorough clinical evaluation and characteristic physical findings. Specialized testing may also be conducted to detect certain conditions that may potentially be associated with the disorder (e.g., congenital heart defects).
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Diagnosis of Neu Laxova Syndrome. A diagnosis of NLS may be suggested before birth (prenatally) based upon specialized testing, such as repeated fetal ultrasonography. During fetal ultrasonography, sound waves are used to create an image of the developing fetus. Such testing may reveal characteristic findings that suggest NLS, such as weak fetal activity, restricted limb movement, excessive fluid in the membranous sac surrounding the developing fetus (polyhydramnios), a small placenta, and intrauterine growth retardation. Additional findings seen on ultrasound that may suggest NLS include an abnormally small head, receding forehead, prominent eyes, joint contractures, and/or generalized edema.The diagnosis of NLS may also be made or confirmed after birth (postnatally) based upon a thorough clinical evaluation and characteristic physical findings. Specialized testing may also be conducted to detect certain conditions that may potentially be associated with the disorder (e.g., congenital heart defects).
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Neu Laxova Syndrome
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Therapies of Neu Laxova Syndrome
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TreatmentThe treatment of NLS is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who diagnose and treat neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); and/or other health care professionals.Specific therapies for the treatment of NLS are symptomatic and supportive. In addition, genetic counseling will be of benefit for affected families.
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Therapies of Neu Laxova Syndrome. TreatmentThe treatment of NLS is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; physicians who diagnose and treat neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); and/or other health care professionals.Specific therapies for the treatment of NLS are symptomatic and supportive. In addition, genetic counseling will be of benefit for affected families.
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Neu Laxova Syndrome
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Overview of Neuroacanthocytosis
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Neuroacanthocytosis is a general term for a group of rare progressive disorders characterized by the association of misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. Chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands, is the most common movement disorder associated with neuroacanthocytosis. Additional symptoms often develop including progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. The onset, severity and specific physical findings vary depending upon the specific type of neuroacanthocytosis present. Neuroacanthocytosis syndromes typically progress to cause serious, disabling and sometimes life-threatening complications (and are usually fatal). These disorders are inherited although the mode of transmission can vary. There is disagreement in the medical literature about what disorders should be classified as forms of neuroacanthocytosis. Four distinct disorders are usually classified as the “core” neuroacanthocytosis syndromes – chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration (PKAN). Some medical sources also include abetalipoproteinemia and hypobetalipoproteinemia types I and II as forms of neuroacanthocytosis. This report concentrates only on the four “core” disorders of neuroacanthocytosis. NORD has a separate report on abetalipoproteinemia.
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Overview of Neuroacanthocytosis. Neuroacanthocytosis is a general term for a group of rare progressive disorders characterized by the association of misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. Chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, feet and hands, is the most common movement disorder associated with neuroacanthocytosis. Additional symptoms often develop including progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. The onset, severity and specific physical findings vary depending upon the specific type of neuroacanthocytosis present. Neuroacanthocytosis syndromes typically progress to cause serious, disabling and sometimes life-threatening complications (and are usually fatal). These disorders are inherited although the mode of transmission can vary. There is disagreement in the medical literature about what disorders should be classified as forms of neuroacanthocytosis. Four distinct disorders are usually classified as the “core” neuroacanthocytosis syndromes – chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration (PKAN). Some medical sources also include abetalipoproteinemia and hypobetalipoproteinemia types I and II as forms of neuroacanthocytosis. This report concentrates only on the four “core” disorders of neuroacanthocytosis. NORD has a separate report on abetalipoproteinemia.
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Neuroacanthocytosis
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Symptoms of Neuroacanthocytosis
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The symptoms and severity of neuroacanthocytosis can vary from one person to another, even among individuals with the same subtype or among individuals within the same family. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The age of onset and progression of these disorders also varies. Chorea-acanthocytosis and McLeod syndrome progress slowly over many years or decades during adulthood. In many cases, PKAN presents in childhood and rapidly progresses within 10 years. These disorders can all potentially progress to cause life-threatening complications.All of these disorders share certain findings including abnormal involuntary movements, cognitive deterioration and acanthocytosis. The most common movement disorder associated with neuroacanthocytosis is chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, arms and legs.Although the neuroacanthocytosis syndromes are marked by the association of acanthocytosis and movement disorders, acanthocytosis does not occur in all cases (variable finding). Specifically, acanthocytosis refers to the presence of abnormally-shaped red blood cells called acanthocytes. Red blood cells are formed in the bone marrow and released into the bloodstream where they travel throughout the body delivering oxygen to tissue. Normally, red blood cells have a life span of approximately 120 days before they are removed by the spleen. Acanthocytes are abnormal red blood cells that have thorny or spiny projections of varying lengths protruding from the surface of the cell. They are also known as “spur” cells. Most adults normally have a small percentage of these unique red blood cells. When individuals have abnormally high levels of acanthocytes, it often indicates the presence of an underlying disorder. Specific symptoms that occur in association with acanthocytosis are related to the underlying cause of the condition.Acanthocytosis occurs most often with chorea-acanthocytosis and McLeod syndrome. It is seen less frequently in individuals with Huntington's disease-like 2 or PKAN.CHOREA-ACANTHOCYTOSISChorea affecting the arms and legs is the most common finding of chorea-acanthocytosis. Affected individuals may exhibit abnormal movements of the arms and legs, shoulder shrugs and pelvic thrusts. The abnormal movements of the arms and legs are often compared to dancing or piano playing. These movements may also cause an abnormal manner of walking (gait) characterized by lurching and involuntary knee flexion. In most cases, chorea begins in adulthood and is slowly progressive. In some cases, chorea-acanthocytosis can eventually progress so that individuals require a wheelchair or become bedridden.In addition to chorea, individuals with chorea-acanthocytosis also exhibit dystonia. Dystonia is a general term for a group of neurological conditions characterized by involuntary muscle contractions that force certain part(s) of the body into abnormal, movements and positions (postures). Dystonia affecting the mouth and face is common in chorea-acanthocytosis.Dystonia and chorea affecting the muscles of the face and tongue can cause a variety of symptoms. These symptoms may be referred to as orofacial and lingual dyskinesia and include protrusion of the tongue, grimacing, and abnormal jaw movements. Chronic teeth grinding, involuntary belching, drooling and spitting have also been reported. Many individuals will habitually bite the lip and tongue, potentially causing mutilation. Some affected individuals may eventually develop difficulty swallowing (dysphagia). The various orofacial and lingual dyskinesias can cause significant feeding problems and unintended weight loss. Difficulties with speech and communication, usually due to problems with the muscles that enable speech (dysarthria), are also common findings. Vocal tics such as grunting or involuntary speaking can also occur. Slurred speech is common and eventually chorea-acanthocytosis can progress to limit speech to grunting or whispering. In some cases, affected individuals may eventually become mute.Less often, individuals with chorea-acanthocytosis develop parkinsonism, which is characterized by symptoms that resemble Parkinson's disease including slow, stiff movements, tremors and low speech.Other typical findings are nerve damage (peripheral neuropathy), resulting in absence of reflexes (areflexia) and sensory loss. Progressive wasting of muscle tissue (amyotrophy) and muscle weakness are often seen as well. Occasionally these are the first features to develop, and suggest a primary nerve or muscle disease. Seizures are seen in about 50 percent of people with this condition and can be a presenting sign.A wide variety of personality or behavioral changes may occur in individuals with chorea-acanthocytosis including apathy, irritability, hyperactivity, depression, slowness of thought and emotional instability. Anxiety, paranoia, disinhibition, aggression, and self-neglect have also occurred. Some affected individuals develop obsessive-compulsive disorders such as chronic hair pulling (trichotillomania). Eventually, chorea-acanthocytosis may cause progressive memory loss and deterioration of intellectual abilities (dementia).In the past, chorea-acanthocytosis was also known as Levine-Critchley syndrome. The family reported by Dr. Critchley has been genetically confirmed to have chorea-acanthocytosis, however, it is not known what the diagnosis was of the family reported by Dr. Levine, thus this term is imprecise. Sometimes, the term neuroacanthocytosis is used specifically to refer to chorea-acanthocytosis.MCLEOD SYNDROMEMcLeod syndrome is a rare multisystem disorder characterized by various abnormalities, especially those affecting the central nervous system. The specific symptoms can vary greatly from one person to another. The disorder predominantly affects males, although in rare cases females have developed some symptoms of the disorder.Affected individuals may experience chorea, especially affecting the arms and legs but also affecting the trunk, face and neck. Chorea is slowly progressive and can eventually affect the ability to walk. Unlike chorea-acanthocytosis, lip and tongue biting are not typically seen in McLeod syndrome. Dystonia and parkinsonism are also far less common in McLeod syndrome than in chorea-acanthocytosis.Affected males may also have muscle weakness, muscle degeneration, and absence of deep tendon reflexes usually due to nerve damage. In some cases, seizures may occur and can be the presenting sign of the disorder.Cognitive impairment has also been reported in approximately 50 percent of cases. Cognitive impairment can cause memory loss as well as difficulties learning or processing new information. Cognitive impairment can affect a person's ability to manage everyday tasks and activities. The severity of cognitive impairment in McLeod syndrome can vary greatly even among members of the same family. It can range from slight problems with memory to dementia.Psychiatric problems may occur in McLeod syndrome including apathy, disinhibition, irritability, anxiety, distractibility, and depression. Some affected individuals may develop obsessive-compulsive disorder. In some families, psychiatric problems may predominate (as oppose to movement abnormalities).Affected individuals may also develop heart (cardiac) problems including abnormal electrical activity in the heart (arrhythmia) and dilated cardiomyopathy. Dilated cardiomyopathy is characterized by abnormal enlargement or widening (dilatation) of one or ventricles which results in a weakening of the heart's pumping action, causing a limited ability to circulate blood to the lungs and the rest of the body which may result in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Additional symptoms may occur in McLeod syndrome including an enlarged liver and spleen (hepatosplenomegaly).A characteristic finding associated with McLeod syndrome is absent expression of the Kx red blood cell antigen and weak expression of Kell blood group antigens. Antigens are substances that cause immune system to produce antibodies. The Kx antigen is normally found on the surface of erythrocytes (red blood cells). These characteristic findings are referred to as the McLeod blood group phenotype. Because of abnormalities affecting these antigens, individuals with McLeod syndrome may be susceptible to adverse reactions to blood transfusions with incompatible blood. The exact role these antigens play in the development of McLeod syndrome is not fully understood.HUNTINGTON'S DISEASE-LIKE 2Huntington's disease-like 2 (HDL-2) is an autosomal dominant disorder remarkably like Huntington's disease but characterized by a trinucleotide repeat expansion in a different gene. Onset typically occurs in the third-fourth decade, with involuntary movements and abnormalities of voluntary movements, as well as dementia.Specific symptoms may include a variety of movement disorders including dystonia and chorea Affected individuals may also develop excessive or exaggerated response of certain reflexes (hyperreflexia), extreme slowness of voluntary movements (bradykinesia) and difficulty with speech and communication. Cognitive impairment is typical and can eventually progress to cause dementia.Behavioral and psychiatric problems may also occur in Huntington's disease-like 2 including depression, anxiety, irritability, and apathy. Some affected individuals may experience delusions or hallucinations.PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION (PKAN)PKAN is a form of neurodegeneration with brain iron accumulation (NBIA). It is the largest subgroup of NBIA observed so far. The common feature among affected individuals is iron accumulation in the brain, along with a progressive movement disorder. Individuals can remain stable for long periods of time and then undergo intervals of rapid deterioration.Common features include dystonia, an abnormality in muscle tone, muscular rigidity, and sudden involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs. These features can result in clumsiness, gait (walking) problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina (retinopathy), resulting in progressive night blindness and loss of peripheral (side) vision. In general, symptoms are progressive and become worse over time.Atypical cases develop after the age of 20 and are characterized by dystonia, rigidity and gait abnormalities. The progression of the atypical cases is slower than in younger children and retinopathy does not occur. Speech abnormalities including dysarthria are common. Personality changes and progressive cognitive decline are also seen.
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Symptoms of Neuroacanthocytosis. The symptoms and severity of neuroacanthocytosis can vary from one person to another, even among individuals with the same subtype or among individuals within the same family. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The age of onset and progression of these disorders also varies. Chorea-acanthocytosis and McLeod syndrome progress slowly over many years or decades during adulthood. In many cases, PKAN presents in childhood and rapidly progresses within 10 years. These disorders can all potentially progress to cause life-threatening complications.All of these disorders share certain findings including abnormal involuntary movements, cognitive deterioration and acanthocytosis. The most common movement disorder associated with neuroacanthocytosis is chorea, which is characterized by rapid, involuntary, purposeless movements, especially of the face, arms and legs.Although the neuroacanthocytosis syndromes are marked by the association of acanthocytosis and movement disorders, acanthocytosis does not occur in all cases (variable finding). Specifically, acanthocytosis refers to the presence of abnormally-shaped red blood cells called acanthocytes. Red blood cells are formed in the bone marrow and released into the bloodstream where they travel throughout the body delivering oxygen to tissue. Normally, red blood cells have a life span of approximately 120 days before they are removed by the spleen. Acanthocytes are abnormal red blood cells that have thorny or spiny projections of varying lengths protruding from the surface of the cell. They are also known as “spur” cells. Most adults normally have a small percentage of these unique red blood cells. When individuals have abnormally high levels of acanthocytes, it often indicates the presence of an underlying disorder. Specific symptoms that occur in association with acanthocytosis are related to the underlying cause of the condition.Acanthocytosis occurs most often with chorea-acanthocytosis and McLeod syndrome. It is seen less frequently in individuals with Huntington's disease-like 2 or PKAN.CHOREA-ACANTHOCYTOSISChorea affecting the arms and legs is the most common finding of chorea-acanthocytosis. Affected individuals may exhibit abnormal movements of the arms and legs, shoulder shrugs and pelvic thrusts. The abnormal movements of the arms and legs are often compared to dancing or piano playing. These movements may also cause an abnormal manner of walking (gait) characterized by lurching and involuntary knee flexion. In most cases, chorea begins in adulthood and is slowly progressive. In some cases, chorea-acanthocytosis can eventually progress so that individuals require a wheelchair or become bedridden.In addition to chorea, individuals with chorea-acanthocytosis also exhibit dystonia. Dystonia is a general term for a group of neurological conditions characterized by involuntary muscle contractions that force certain part(s) of the body into abnormal, movements and positions (postures). Dystonia affecting the mouth and face is common in chorea-acanthocytosis.Dystonia and chorea affecting the muscles of the face and tongue can cause a variety of symptoms. These symptoms may be referred to as orofacial and lingual dyskinesia and include protrusion of the tongue, grimacing, and abnormal jaw movements. Chronic teeth grinding, involuntary belching, drooling and spitting have also been reported. Many individuals will habitually bite the lip and tongue, potentially causing mutilation. Some affected individuals may eventually develop difficulty swallowing (dysphagia). The various orofacial and lingual dyskinesias can cause significant feeding problems and unintended weight loss. Difficulties with speech and communication, usually due to problems with the muscles that enable speech (dysarthria), are also common findings. Vocal tics such as grunting or involuntary speaking can also occur. Slurred speech is common and eventually chorea-acanthocytosis can progress to limit speech to grunting or whispering. In some cases, affected individuals may eventually become mute.Less often, individuals with chorea-acanthocytosis develop parkinsonism, which is characterized by symptoms that resemble Parkinson's disease including slow, stiff movements, tremors and low speech.Other typical findings are nerve damage (peripheral neuropathy), resulting in absence of reflexes (areflexia) and sensory loss. Progressive wasting of muscle tissue (amyotrophy) and muscle weakness are often seen as well. Occasionally these are the first features to develop, and suggest a primary nerve or muscle disease. Seizures are seen in about 50 percent of people with this condition and can be a presenting sign.A wide variety of personality or behavioral changes may occur in individuals with chorea-acanthocytosis including apathy, irritability, hyperactivity, depression, slowness of thought and emotional instability. Anxiety, paranoia, disinhibition, aggression, and self-neglect have also occurred. Some affected individuals develop obsessive-compulsive disorders such as chronic hair pulling (trichotillomania). Eventually, chorea-acanthocytosis may cause progressive memory loss and deterioration of intellectual abilities (dementia).In the past, chorea-acanthocytosis was also known as Levine-Critchley syndrome. The family reported by Dr. Critchley has been genetically confirmed to have chorea-acanthocytosis, however, it is not known what the diagnosis was of the family reported by Dr. Levine, thus this term is imprecise. Sometimes, the term neuroacanthocytosis is used specifically to refer to chorea-acanthocytosis.MCLEOD SYNDROMEMcLeod syndrome is a rare multisystem disorder characterized by various abnormalities, especially those affecting the central nervous system. The specific symptoms can vary greatly from one person to another. The disorder predominantly affects males, although in rare cases females have developed some symptoms of the disorder.Affected individuals may experience chorea, especially affecting the arms and legs but also affecting the trunk, face and neck. Chorea is slowly progressive and can eventually affect the ability to walk. Unlike chorea-acanthocytosis, lip and tongue biting are not typically seen in McLeod syndrome. Dystonia and parkinsonism are also far less common in McLeod syndrome than in chorea-acanthocytosis.Affected males may also have muscle weakness, muscle degeneration, and absence of deep tendon reflexes usually due to nerve damage. In some cases, seizures may occur and can be the presenting sign of the disorder.Cognitive impairment has also been reported in approximately 50 percent of cases. Cognitive impairment can cause memory loss as well as difficulties learning or processing new information. Cognitive impairment can affect a person's ability to manage everyday tasks and activities. The severity of cognitive impairment in McLeod syndrome can vary greatly even among members of the same family. It can range from slight problems with memory to dementia.Psychiatric problems may occur in McLeod syndrome including apathy, disinhibition, irritability, anxiety, distractibility, and depression. Some affected individuals may develop obsessive-compulsive disorder. In some families, psychiatric problems may predominate (as oppose to movement abnormalities).Affected individuals may also develop heart (cardiac) problems including abnormal electrical activity in the heart (arrhythmia) and dilated cardiomyopathy. Dilated cardiomyopathy is characterized by abnormal enlargement or widening (dilatation) of one or ventricles which results in a weakening of the heart's pumping action, causing a limited ability to circulate blood to the lungs and the rest of the body which may result in fluid buildup in the heart, lung and various body tissues (congestive heart failure).Additional symptoms may occur in McLeod syndrome including an enlarged liver and spleen (hepatosplenomegaly).A characteristic finding associated with McLeod syndrome is absent expression of the Kx red blood cell antigen and weak expression of Kell blood group antigens. Antigens are substances that cause immune system to produce antibodies. The Kx antigen is normally found on the surface of erythrocytes (red blood cells). These characteristic findings are referred to as the McLeod blood group phenotype. Because of abnormalities affecting these antigens, individuals with McLeod syndrome may be susceptible to adverse reactions to blood transfusions with incompatible blood. The exact role these antigens play in the development of McLeod syndrome is not fully understood.HUNTINGTON'S DISEASE-LIKE 2Huntington's disease-like 2 (HDL-2) is an autosomal dominant disorder remarkably like Huntington's disease but characterized by a trinucleotide repeat expansion in a different gene. Onset typically occurs in the third-fourth decade, with involuntary movements and abnormalities of voluntary movements, as well as dementia.Specific symptoms may include a variety of movement disorders including dystonia and chorea Affected individuals may also develop excessive or exaggerated response of certain reflexes (hyperreflexia), extreme slowness of voluntary movements (bradykinesia) and difficulty with speech and communication. Cognitive impairment is typical and can eventually progress to cause dementia.Behavioral and psychiatric problems may also occur in Huntington's disease-like 2 including depression, anxiety, irritability, and apathy. Some affected individuals may experience delusions or hallucinations.PANTOTHENATE KINASE-ASSOCIATED NEURODEGENERATION (PKAN)PKAN is a form of neurodegeneration with brain iron accumulation (NBIA). It is the largest subgroup of NBIA observed so far. The common feature among affected individuals is iron accumulation in the brain, along with a progressive movement disorder. Individuals can remain stable for long periods of time and then undergo intervals of rapid deterioration.Common features include dystonia, an abnormality in muscle tone, muscular rigidity, and sudden involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs. These features can result in clumsiness, gait (walking) problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina (retinopathy), resulting in progressive night blindness and loss of peripheral (side) vision. In general, symptoms are progressive and become worse over time.Atypical cases develop after the age of 20 and are characterized by dystonia, rigidity and gait abnormalities. The progression of the atypical cases is slower than in younger children and retinopathy does not occur. Speech abnormalities including dysarthria are common. Personality changes and progressive cognitive decline are also seen.
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Causes of Neuroacanthocytosis
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The four core disorders under the umbrella term neuroacanthocytosis are genetic disorders. They are caused by mutations in specific genes. The mode of inheritance and age of onset varies.Chorea-acanthocytosis and PKAN are inherited as autosomal recessive traits. 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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.Huntington's disease-like 2 is inherited as an autosomal dominant trait. 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 percent for each pregnancy regardless of the sex of the resulting child.McLeod syndrome is inherited as an X-linked recessive trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their 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. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son.Chorea-acanthocytosis is caused by mutations of the VPS13A gene located on the long arm (q) of chromosome 9 (9q21). 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 9q21” refers to band 21 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The VPS13A gene contains instructions for creating (encoding) a protein known as chorein. The exact role and function of chorein is not fully understood, but it may be involved in transporting cellular proteins.McLeod syndrome is caused by mutations of the XK gene located on the X chromosome. The XK gene encodes the XK protein, which bears (expresses) the Kx red blood cell antigen. The exact function of the XK protein is not fully understood. This protein is believed to play a role in transport and possibly may assist substances to move into and out of cells. The XK protein is found in the brain, muscle and heart and on the surface of red blood cells.Huntington's disease-like 2 is caused by mutations of the junctophilin 3 (JPH3) gene located on the long arm (q) of chromosome 16 (16q24.3). The JPH3 gene encodes the protein JPH3, which is believed to play a role in certain membrane structures and in regulating calcium.PKAN is caused by mutations of the pantothenate kinase 2 gene (PANK2) located on the short arm (p) on chromosome 20 (20p13-p12.3). The PANK2 gene encodes the PANK2 protein, which is active in the nerve cells in the brain.Most individuals with a neuroacanthocytosis syndrome have progression degeneration of an area deep within the brain known as the basal ganglia, which is a cluster of nerve cells located near the base of the brain that processes information involved in involuntary movements, coordination and cognition. The exact roles that these proteins play in the development of neuroacanthocytosis syndromes are unknown. Nor is it known whether they are related in any way. Researchers are investigating how the missing or nonfunctioning proteins result in or contribute to damage in the brain that ultimately causes the symptoms of these disorders.
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Causes of Neuroacanthocytosis. The four core disorders under the umbrella term neuroacanthocytosis are genetic disorders. They are caused by mutations in specific genes. The mode of inheritance and age of onset varies.Chorea-acanthocytosis and PKAN are inherited as autosomal recessive traits. 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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.Huntington's disease-like 2 is inherited as an autosomal dominant trait. 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 percent for each pregnancy regardless of the sex of the resulting child.McLeod syndrome is inherited as an X-linked recessive trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their 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. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son.Chorea-acanthocytosis is caused by mutations of the VPS13A gene located on the long arm (q) of chromosome 9 (9q21). 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 9q21” refers to band 21 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The VPS13A gene contains instructions for creating (encoding) a protein known as chorein. The exact role and function of chorein is not fully understood, but it may be involved in transporting cellular proteins.McLeod syndrome is caused by mutations of the XK gene located on the X chromosome. The XK gene encodes the XK protein, which bears (expresses) the Kx red blood cell antigen. The exact function of the XK protein is not fully understood. This protein is believed to play a role in transport and possibly may assist substances to move into and out of cells. The XK protein is found in the brain, muscle and heart and on the surface of red blood cells.Huntington's disease-like 2 is caused by mutations of the junctophilin 3 (JPH3) gene located on the long arm (q) of chromosome 16 (16q24.3). The JPH3 gene encodes the protein JPH3, which is believed to play a role in certain membrane structures and in regulating calcium.PKAN is caused by mutations of the pantothenate kinase 2 gene (PANK2) located on the short arm (p) on chromosome 20 (20p13-p12.3). The PANK2 gene encodes the PANK2 protein, which is active in the nerve cells in the brain.Most individuals with a neuroacanthocytosis syndrome have progression degeneration of an area deep within the brain known as the basal ganglia, which is a cluster of nerve cells located near the base of the brain that processes information involved in involuntary movements, coordination and cognition. The exact roles that these proteins play in the development of neuroacanthocytosis syndromes are unknown. Nor is it known whether they are related in any way. Researchers are investigating how the missing or nonfunctioning proteins result in or contribute to damage in the brain that ultimately causes the symptoms of these disorders.
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Affects of Neuroacanthocytosis
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Chorea-acanthocytosis most often affects individuals between the ages of 20 and 40, although in rare cases, it can develop in individuals younger than 20 and older than 50. McLeod syndrome typically develops in males between the ages of 40-60. PKAN most often affects children under the age of 10, although in atypical cases onset is often after the age of 20. The age of onset of Huntington's disease-like 2 is variable. The disorder has been reported only in a few families, all of whom are of African descent. Chorea-acanthocytosis, PKAN and Huntington's disease-like 2 affect males and females in equal numbers. McLeod syndrome predominantly affects males, although in rare cases females have developed some symptoms of the disorder.The exact incidence of neuroacanthocytosis is unknown. These disorders may go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population.
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Affects of Neuroacanthocytosis. Chorea-acanthocytosis most often affects individuals between the ages of 20 and 40, although in rare cases, it can develop in individuals younger than 20 and older than 50. McLeod syndrome typically develops in males between the ages of 40-60. PKAN most often affects children under the age of 10, although in atypical cases onset is often after the age of 20. The age of onset of Huntington's disease-like 2 is variable. The disorder has been reported only in a few families, all of whom are of African descent. Chorea-acanthocytosis, PKAN and Huntington's disease-like 2 affect males and females in equal numbers. McLeod syndrome predominantly affects males, although in rare cases females have developed some symptoms of the disorder.The exact incidence of neuroacanthocytosis is unknown. These disorders may go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population.
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Related disorders of Neuroacanthocytosis
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Symptoms of the following disorders can be similar to those of neuroacanthocytosis. Comparisons may be useful for a differential diagnosis.Huntington's disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington's disease is transmitted as an autosomal dominant trait. The disease results from changes (mutations) of a gene known as “huntingtin” located on the short arm (p) of chromosome 4 (4p16.3). In those with the disorder, the huntingtin gene contains errors in the coded “building blocks” (nucleotide bases) that make up the gene's instructions. The gene contains abnormally long repeats of coded instructions consisting of the basic chemicals cytosine, adenine, and guanine (CAG trinucleotide repeat expansion). The length of the expanded repeats may affect the age at symptom onset. The specific symptoms and physical features associated with Huntington's disease result from degeneration of nerve cells (neurons) within certain areas of the brain (e.g., basal ganglia, cerebral cortex). (For more information on this disorder, choose “Huntington's” as your search term in the Rare Disease Database.)Abetalipoproteinemia is a rare inherited disorder of fat metabolism. Abnormalities in fat metabolism result in malabsorption of dietary fat and various essential vitamins. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking, and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision, a condition known as retinitis pigmentosa. Abetalipoproteinemia is inherited as an autosomal recessive trait. (For more information on this disorder, choose “abetalipoproteinemia” as your search term in the Rare Disease Database.)Several other very rare genetic disorders can cause neurodegeneration with brain iron accumulation as in PKAN. For more information on this disorder, choose “NBIA” as your search term in the Rare Disease Database.There are a variety of additional disorders that have signs and symptoms similar to those seen in neuroacanthocytosis syndromes. These disorders include MELAS syndrome, Wilson disease, benign hereditary chorea, tardive dyskinesia, Parkinson's disease and dentatorubral pallidolusyian atrophy. (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 Neuroacanthocytosis. Symptoms of the following disorders can be similar to those of neuroacanthocytosis. Comparisons may be useful for a differential diagnosis.Huntington's disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements. Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness, agitation, and other symptoms and findings. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments. Huntington's disease is transmitted as an autosomal dominant trait. The disease results from changes (mutations) of a gene known as “huntingtin” located on the short arm (p) of chromosome 4 (4p16.3). In those with the disorder, the huntingtin gene contains errors in the coded “building blocks” (nucleotide bases) that make up the gene's instructions. The gene contains abnormally long repeats of coded instructions consisting of the basic chemicals cytosine, adenine, and guanine (CAG trinucleotide repeat expansion). The length of the expanded repeats may affect the age at symptom onset. The specific symptoms and physical features associated with Huntington's disease result from degeneration of nerve cells (neurons) within certain areas of the brain (e.g., basal ganglia, cerebral cortex). (For more information on this disorder, choose “Huntington's” as your search term in the Rare Disease Database.)Abetalipoproteinemia is a rare inherited disorder of fat metabolism. Abnormalities in fat metabolism result in malabsorption of dietary fat and various essential vitamins. Affected individuals experience progressive neurological deterioration, muscle weakness, difficulty walking, and blood abnormalities including a condition in which the red blood cells are malformed (acanthocytosis) resulting in low levels of circulating red blood cells (anemia). Affected individuals may also develop degeneration of the retina of the eyes potentially resulting in loss of vision, a condition known as retinitis pigmentosa. Abetalipoproteinemia is inherited as an autosomal recessive trait. (For more information on this disorder, choose “abetalipoproteinemia” as your search term in the Rare Disease Database.)Several other very rare genetic disorders can cause neurodegeneration with brain iron accumulation as in PKAN. For more information on this disorder, choose “NBIA” as your search term in the Rare Disease Database.There are a variety of additional disorders that have signs and symptoms similar to those seen in neuroacanthocytosis syndromes. These disorders include MELAS syndrome, Wilson disease, benign hereditary chorea, tardive dyskinesia, Parkinson's disease and dentatorubral pallidolusyian atrophy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Neuroacanthocytosis
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A diagnosis of neuroacanthocytosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal the presence of acanthocytes in the blood, although their absence does not exclude a diagnosis of neuroacanthocytosis. Imaging techniques may aid in obtaining a diagnosis and include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. CT scanning or an MRI may reveal characteristic changes in the brain in individuals with neuroacanthocytosis.Additional tests may be performed to help confirm a diagnosis of neuroacanthocytosis including measuring serum creatine kinase (which is often elevated in chorea-acanthocytosis and McLeod syndrome) and electromyography, a test that can determine the health of muscles and nerves and can detect nerve dysfunction.An electroencephalogram (EEG), a test which measures the electrical activity of the brain, may show changes in brain function over time that are indicative of neurodegeneration. An electrocardiogram (ECG) is a test that measures the electrical activity of the heart and may be performed to detect cardiomyopathy or other heart abnormalities.A blood test is available at present on a research basis to detect chorein in the blood in order to confirm the diagnosis of chorea-acanthocytosis.Blood tests can also be used for Kell blood typing in order to confirm or rule out McLeod syndrome. Blood tests can reveal absent expression of the Kx erythrocyte antigen and reduced expression of Kell blood group antigens that characterizes McLeod syndrome.A diagnosis of a neuroacanthocytosis syndrome can be confirmed by molecular genetic testing that identifies the characteristic gene mutation associated with a particular disorder.
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Diagnosis of Neuroacanthocytosis. A diagnosis of neuroacanthocytosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal the presence of acanthocytes in the blood, although their absence does not exclude a diagnosis of neuroacanthocytosis. Imaging techniques may aid in obtaining a diagnosis and include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. CT scanning or an MRI may reveal characteristic changes in the brain in individuals with neuroacanthocytosis.Additional tests may be performed to help confirm a diagnosis of neuroacanthocytosis including measuring serum creatine kinase (which is often elevated in chorea-acanthocytosis and McLeod syndrome) and electromyography, a test that can determine the health of muscles and nerves and can detect nerve dysfunction.An electroencephalogram (EEG), a test which measures the electrical activity of the brain, may show changes in brain function over time that are indicative of neurodegeneration. An electrocardiogram (ECG) is a test that measures the electrical activity of the heart and may be performed to detect cardiomyopathy or other heart abnormalities.A blood test is available at present on a research basis to detect chorein in the blood in order to confirm the diagnosis of chorea-acanthocytosis.Blood tests can also be used for Kell blood typing in order to confirm or rule out McLeod syndrome. Blood tests can reveal absent expression of the Kx erythrocyte antigen and reduced expression of Kell blood group antigens that characterizes McLeod syndrome.A diagnosis of a neuroacanthocytosis syndrome can be confirmed by molecular genetic testing that identifies the characteristic gene mutation associated with a particular disorder.
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Therapies of Neuroacanthocytosis
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TreatmentThere is no curative treatment for neuroacanthocytosis. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, psychiatrists, surgeons, cardiologists, speech pathologists, social workers and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Certain antipsychotic medications known as dopamine-receptor blocking drugs may be used to treat both psychiatric symptoms and chorea associated with neuroacanthocytosis. These drugs include haloperidol, tiapride, clozapine, quetiapine and tetrabenazine. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Dopamine is critical for the proper function of certain processes of the brain especially those that control movement.Additional antipsychotic medications as well as antidepressants and sedatives may be used to treat some individuals with neuroacanthocytosis. Psychiatric symptoms are treated with conventional therapies as symptoms become apparent.Anti-seizure medications (anti-convulsants) such as phenytoin, clobazam, valproate and levetiracetam may be used to treat the seizures sometimes associated with neuroacanthocytosis. Anti-seizure medications can also be of benefit in treating psychiatric symptoms. Certain anti-seizure medications such as carbamazepine and lamotrigine can worsen involuntary movements and should be avoided.Botulinum toxin has been used to treat dystonia associated with neuroacanthocytosis. The botulinum toxin is injected directly into the muscle(s) to relax the muscle and reduce or eliminate spasms. The therapeutic effects of the injections may not become obvious before five to 10 days. Injections with botulinum toxin may be very helpful in relieving dystonic muscle spasms. Injections usually need to be repeated after three to four months when symptoms return.Because of feeding difficulties in some cases, affected individuals should be monitored for nutritional status. Nutritional support and supplementation may be necessary and, in some cases, the insertion of a feeding tube may be necessary. In addition to nutritional support, a feeding tube may be necessary to help prevent aspiration.Additional therapies that may be used to treat individuals with neuroacanthocytosis include speech therapy, physical therapy and occupational therapy all of which should be individualized. Certain mechanical devices may be of benefit such as braces or wheelchairs. A mouth guard or bite plate may be beneficial for individuals with chronic teeth grinding or lip biting. Computer-assisted speech devices may be necessary in some cases.Cardiac abnormalities most often associated with McLeod syndrome are treated through conventional means based upon clinical ECG findings.Individuals with McLeod syndrome may be susceptible to adverse reactions from blood transfusions with incompatible blood. Physicians recommend that affected individuals should store or bank their own blood in case of the need for a transfusion arises.A surgical procedure sometimes used to treat individuals with neuroacanthocytosis is deep brain stimulation, in which an electrode is placed into the portion of the brain that controls certain movements. A thin wire that passes under the skin is connected to a small battery pack that is placed under the skin near the collarbone. The electrode is used to send electrical impulses (stimulate) to the brain and interrupt aberrant nerve signals that contribute to movement disorders such as chorea or dystonia. A recent publication describing all patients with chorea-acanthocytosis who had undergone deep brain stimulation suggests that overall it is beneficial. Further information is required to determine whether people with the other forms of neuroacanthocytosis can also benefit.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Neuroacanthocytosis. TreatmentThere is no curative treatment for neuroacanthocytosis. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, psychiatrists, surgeons, cardiologists, speech pathologists, social workers and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Certain antipsychotic medications known as dopamine-receptor blocking drugs may be used to treat both psychiatric symptoms and chorea associated with neuroacanthocytosis. These drugs include haloperidol, tiapride, clozapine, quetiapine and tetrabenazine. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Dopamine is critical for the proper function of certain processes of the brain especially those that control movement.Additional antipsychotic medications as well as antidepressants and sedatives may be used to treat some individuals with neuroacanthocytosis. Psychiatric symptoms are treated with conventional therapies as symptoms become apparent.Anti-seizure medications (anti-convulsants) such as phenytoin, clobazam, valproate and levetiracetam may be used to treat the seizures sometimes associated with neuroacanthocytosis. Anti-seizure medications can also be of benefit in treating psychiatric symptoms. Certain anti-seizure medications such as carbamazepine and lamotrigine can worsen involuntary movements and should be avoided.Botulinum toxin has been used to treat dystonia associated with neuroacanthocytosis. The botulinum toxin is injected directly into the muscle(s) to relax the muscle and reduce or eliminate spasms. The therapeutic effects of the injections may not become obvious before five to 10 days. Injections with botulinum toxin may be very helpful in relieving dystonic muscle spasms. Injections usually need to be repeated after three to four months when symptoms return.Because of feeding difficulties in some cases, affected individuals should be monitored for nutritional status. Nutritional support and supplementation may be necessary and, in some cases, the insertion of a feeding tube may be necessary. In addition to nutritional support, a feeding tube may be necessary to help prevent aspiration.Additional therapies that may be used to treat individuals with neuroacanthocytosis include speech therapy, physical therapy and occupational therapy all of which should be individualized. Certain mechanical devices may be of benefit such as braces or wheelchairs. A mouth guard or bite plate may be beneficial for individuals with chronic teeth grinding or lip biting. Computer-assisted speech devices may be necessary in some cases.Cardiac abnormalities most often associated with McLeod syndrome are treated through conventional means based upon clinical ECG findings.Individuals with McLeod syndrome may be susceptible to adverse reactions from blood transfusions with incompatible blood. Physicians recommend that affected individuals should store or bank their own blood in case of the need for a transfusion arises.A surgical procedure sometimes used to treat individuals with neuroacanthocytosis is deep brain stimulation, in which an electrode is placed into the portion of the brain that controls certain movements. A thin wire that passes under the skin is connected to a small battery pack that is placed under the skin near the collarbone. The electrode is used to send electrical impulses (stimulate) to the brain and interrupt aberrant nerve signals that contribute to movement disorders such as chorea or dystonia. A recent publication describing all patients with chorea-acanthocytosis who had undergone deep brain stimulation suggests that overall it is beneficial. Further information is required to determine whether people with the other forms of neuroacanthocytosis can also benefit.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Neuroacanthocytosis
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nord_874_0
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Overview of Neurofibromatosis 1
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SummaryNeurofibromatosis 1 (NF1), historically called von Recklinghausen's disease, is a genetic disorder characterized by increased risk of developing noncancerous (benign) and cancerous (malignant) tumors, as well as various other physical and neurological manifestations. The most prevalent manifestations of the disease are multiple tumors of nerves and skin (neurofibromas), as well as areas of abnormal skin color (pigmentation). The abnormal skin color typically includes pale tan or light brown discolorations (cafe-au-lait spots), freckling in atypical locations such as under the arms (axillary region) or in the groin (inguinal region). Such abnormalities of skin pigmentation are often evident by one year of age and tend to increase in size and number through childhood.At birth or early childhood, affected individuals may have relatively large, benign tumors that consist of bundles of nerves and other tissue (plexiform neurofibromas). It is estimated that up to 50% of patients with NF1 may have at least one plexiform neurofibroma. Individuals with NF1 may also develop benign nodules on the colored regions of the eyes (Lisch nodules), or tumors in the nerves of the visual pathway (optic pathway gliomas). More rarely, affected individuals may develop certain malignant (cancerous) tumors. For instance, the risk of breast cancer is significantly increased in women with NF1 compared to the general population, especially during the age range of 30-40 years old. Patients also carry 8-13% lifetime risk of developing a tumor known as malignant peripheral nerve sheath tumor (MPNST), often occurring due to cancerous transformation of a pre-existing benign plexiform neurofibroma. Gastrointestinal stromal tumor (GIST) is a tumor arising from the small intestine that may be either benign or malignant. Pheochromocytoma, which is a tumor on the adrenal gland, may increase blood pressure and pulse. Gliomas, tumors arising within the brain, may occur during childhood (especially in the vision pathway, known as optic pathway gliomas), or later in adulthood. NF1 may also be characterized by an unusually large head size (macrocephaly) and relatively short stature. Additional abnormalities may also be present, such as episodes of uncontrolled electrical activity in the brain (seizures); learning disabilities and attention deficits; speech difficulties; abnormally increased activity (hyperactivity); and skeletal malformations, including progressive curvature of the spine (scoliosis), bowing of the lower legs (pseudoarthrosis), and improper development of certain bones. There is also an increased risk of vascular abnormalities with NF1, including a narrowing of the arteries to the kidneys (renal artery stenosis), which may cause early high blood pressure or aneurysms. Certain types of strokes may be more common with NF1. Associated symptoms and findings may vary greatly in range and severity from person to person, even within the same family. Learning disabilities appear in more than 50% of children with NF1.NF1 is caused by changes (pathogenic variants) in a gene called NF1, which is found on chromosome 17. This gene regulates the production of a protein known as neurofibromin, which is thought to function as a tumor suppressor. In about 50 percent of individuals with NF1, the disorder results from spontaneous (sporadic) changes in the NF1 gene that occur for unknown reasons. These individuals do not inherit NF1 from their parents, but rather they are the first in their family with the disorder. In other patients, NF1 is inherited in an autosomal dominant pattern, which means that each child of an affected parent carries a 50% risk of inheriting the disease. NF1 does not skip generations.
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Overview of Neurofibromatosis 1. SummaryNeurofibromatosis 1 (NF1), historically called von Recklinghausen's disease, is a genetic disorder characterized by increased risk of developing noncancerous (benign) and cancerous (malignant) tumors, as well as various other physical and neurological manifestations. The most prevalent manifestations of the disease are multiple tumors of nerves and skin (neurofibromas), as well as areas of abnormal skin color (pigmentation). The abnormal skin color typically includes pale tan or light brown discolorations (cafe-au-lait spots), freckling in atypical locations such as under the arms (axillary region) or in the groin (inguinal region). Such abnormalities of skin pigmentation are often evident by one year of age and tend to increase in size and number through childhood.At birth or early childhood, affected individuals may have relatively large, benign tumors that consist of bundles of nerves and other tissue (plexiform neurofibromas). It is estimated that up to 50% of patients with NF1 may have at least one plexiform neurofibroma. Individuals with NF1 may also develop benign nodules on the colored regions of the eyes (Lisch nodules), or tumors in the nerves of the visual pathway (optic pathway gliomas). More rarely, affected individuals may develop certain malignant (cancerous) tumors. For instance, the risk of breast cancer is significantly increased in women with NF1 compared to the general population, especially during the age range of 30-40 years old. Patients also carry 8-13% lifetime risk of developing a tumor known as malignant peripheral nerve sheath tumor (MPNST), often occurring due to cancerous transformation of a pre-existing benign plexiform neurofibroma. Gastrointestinal stromal tumor (GIST) is a tumor arising from the small intestine that may be either benign or malignant. Pheochromocytoma, which is a tumor on the adrenal gland, may increase blood pressure and pulse. Gliomas, tumors arising within the brain, may occur during childhood (especially in the vision pathway, known as optic pathway gliomas), or later in adulthood. NF1 may also be characterized by an unusually large head size (macrocephaly) and relatively short stature. Additional abnormalities may also be present, such as episodes of uncontrolled electrical activity in the brain (seizures); learning disabilities and attention deficits; speech difficulties; abnormally increased activity (hyperactivity); and skeletal malformations, including progressive curvature of the spine (scoliosis), bowing of the lower legs (pseudoarthrosis), and improper development of certain bones. There is also an increased risk of vascular abnormalities with NF1, including a narrowing of the arteries to the kidneys (renal artery stenosis), which may cause early high blood pressure or aneurysms. Certain types of strokes may be more common with NF1. Associated symptoms and findings may vary greatly in range and severity from person to person, even within the same family. Learning disabilities appear in more than 50% of children with NF1.NF1 is caused by changes (pathogenic variants) in a gene called NF1, which is found on chromosome 17. This gene regulates the production of a protein known as neurofibromin, which is thought to function as a tumor suppressor. In about 50 percent of individuals with NF1, the disorder results from spontaneous (sporadic) changes in the NF1 gene that occur for unknown reasons. These individuals do not inherit NF1 from their parents, but rather they are the first in their family with the disorder. In other patients, NF1 is inherited in an autosomal dominant pattern, which means that each child of an affected parent carries a 50% risk of inheriting the disease. NF1 does not skip generations.
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Neurofibromatosis 1
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nord_874_1
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Symptoms of Neurofibromatosis 1
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The diagnostic criteria for NF1 were updated by international consensus in 2021. Based on the new criteria, an individual who does not have a parent diagnosed with NF1 will meet clinical diagnostic criteria for NF1 if they demonstrate at least two of the following: (1) Six or more café-au-lait spots of at least 5 millimeters [mm] in size (before puberty) or 15 mm in size (after puberty)(2) Freckling in the underarms (axillary) or groin (inguinal) regions(3) Two or more neurofibromas of any type, or one plexiform neurofibroma(4) Optic pathway glioma(5) Two or more abnormal clumps of pigment on the colored portion of the eye (Lisch nodules) or two or more abnormalities in the back of the eye (choroidal abnormalities) seen with special imaging of the eye(6) Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or a bowing of the tibia bone in the leg or other long bones (pseudoarthrosis)(7) A pathogenic variant in the NF1 gene in normal tissue (such as blood, saliva) meeting certain technical criteria.Notably, for individuals born to a parent with NF1 (meeting diagnostic criteria above), only one of the above criteria must also be met to reach the diagnosis of NF1.Symptoms of NF1 usually begin during childhood, and a definite diagnosis can often be made by three years of age or younger, depending on the circumstance. The disorder is progressive across the lifetime. In some cases, NF1 symptoms have been described to worsen during puberty, pregnancy or when hormonal changes occur, though this correlation remains incompletely understood. The range and severity of NF1 symptoms varies greatly among affected individuals – even within the same family, and the rate of progression of this disorder is not predictable. However, a majority of patients (approximately 60%) are described as having a “mild” form of the condition.Often the first sign of NF1 is the appearance of multiple brown spots on the skin (café-au-lait macules) or freckling in the underarm (axillary) or groin (inguinal) regions, which may occur as early as birth or infancy. Lisch nodules may also be present early in life, and are highly suggestive of an NF1 diagnosis, as they occur in approximately 97% of affected individuals.Multiple noncancerous (benign) tumors (neurofibromas) develop in NF1 along the linings of the nerves (sheath) under the skin or in deeper areas of the body. Neurofibromas may form in any organ in the body. Skin (cutaneous) neurofibromas, under the skin (subcutaneous) neurofibromas or more diffuse neurofibromas (plexiform neurofibromas) may cause disfigurement. Occasionally, tumors may develop in the brain, on the nerves exiting the brain and/or on the spinal cord. The total number of neurofibromas in an adult may range from a few to hundreds or even thousands, and the number of these tumors tends to increase with age. Pain may occur from an affected peripheral nerve, or as a result of regional mass effect on adjacent structures. In 8-15% of affected individuals, neurofibromas may transform to become cancerous (malignant peripheral nerve sheath tumors), which are associated with pain, rapid tumor growth or new neurological symptoms, and require urgent evaluation and treatment.Approximately 15% of people with NF1 develop brain tumors (gliomas), which most commonly develop during childhood. These frequently develop on in the visual structures of the brain (optic pathway gliomas) and may affect vision, cause premature onset of puberty (precocious puberty) or increased head size (macrocephaly). Additionally, a variety of other tumors may develop in patients with NF1, including gastrointestinal stromal tumors (GIST). In women with NF1, there is a 4 to 11-fold increased risk of developing breast cancer compared to the general population before age 50, though this risk is the highest between 30 and 40 years old. Further, even after diagnosis of breast cancer on one side, there is a high risk of developing a second breast cancer in the opposite (contralateral) breast. Orthopedic problems may develop with NF1, including curvature of the spine (scoliosis), abnormal cranial bone growth (sphenoid wing dysplasia) or a condition characterized by bowing and fracturing of weight-bearing long bones (pseudoarthrosis). Additionally, disorders of bone density (osteopenia and osteoporosis) are more common in people with NF1 than in the general population. The process by which these conditions develop is not fully understood, but has been associated with decreased activated vitamin D levels, increased parathyroid hormone levels, and increased markers of bone breakdown. People with NF1 tend to be below average in height, below average in muscle strength and above average in head size for age.High blood pressure (hypertension) is seen with greater frequency in the NF1 population than the general population. While the cause for this is not certain, some cases may not directly relate to NF1, but rather to associated changes in the blood vessels leading to the kidneys (renal artery stenosis). More rarely, patients with NF1 are at risk of developing tumors of the adrenal gland (pheochromocytoma), which may cause severely elevated blood pressure without treatment.Sexual development may be delayed or may occur early (precocious puberty) in individuals with NF1. (For more information on this disorder, choose “precocious puberty” as your search term in the Rare Disease Database.) In addition, over 50% of individuals with NF1 experience learning disabilities such as attention deficit hyperactivity disorder (ADHD). Seizures may also occur. Other symptoms include headache, numbness and/or weakness.In the localized form of NF1, known as segmental neurofibromatosis, abnormal pigmentation and/or tumors may be limited to one area of the body, and there may be an overall milder manifestation of the disease.
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Symptoms of Neurofibromatosis 1. The diagnostic criteria for NF1 were updated by international consensus in 2021. Based on the new criteria, an individual who does not have a parent diagnosed with NF1 will meet clinical diagnostic criteria for NF1 if they demonstrate at least two of the following: (1) Six or more café-au-lait spots of at least 5 millimeters [mm] in size (before puberty) or 15 mm in size (after puberty)(2) Freckling in the underarms (axillary) or groin (inguinal) regions(3) Two or more neurofibromas of any type, or one plexiform neurofibroma(4) Optic pathway glioma(5) Two or more abnormal clumps of pigment on the colored portion of the eye (Lisch nodules) or two or more abnormalities in the back of the eye (choroidal abnormalities) seen with special imaging of the eye(6) Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or a bowing of the tibia bone in the leg or other long bones (pseudoarthrosis)(7) A pathogenic variant in the NF1 gene in normal tissue (such as blood, saliva) meeting certain technical criteria.Notably, for individuals born to a parent with NF1 (meeting diagnostic criteria above), only one of the above criteria must also be met to reach the diagnosis of NF1.Symptoms of NF1 usually begin during childhood, and a definite diagnosis can often be made by three years of age or younger, depending on the circumstance. The disorder is progressive across the lifetime. In some cases, NF1 symptoms have been described to worsen during puberty, pregnancy or when hormonal changes occur, though this correlation remains incompletely understood. The range and severity of NF1 symptoms varies greatly among affected individuals – even within the same family, and the rate of progression of this disorder is not predictable. However, a majority of patients (approximately 60%) are described as having a “mild” form of the condition.Often the first sign of NF1 is the appearance of multiple brown spots on the skin (café-au-lait macules) or freckling in the underarm (axillary) or groin (inguinal) regions, which may occur as early as birth or infancy. Lisch nodules may also be present early in life, and are highly suggestive of an NF1 diagnosis, as they occur in approximately 97% of affected individuals.Multiple noncancerous (benign) tumors (neurofibromas) develop in NF1 along the linings of the nerves (sheath) under the skin or in deeper areas of the body. Neurofibromas may form in any organ in the body. Skin (cutaneous) neurofibromas, under the skin (subcutaneous) neurofibromas or more diffuse neurofibromas (plexiform neurofibromas) may cause disfigurement. Occasionally, tumors may develop in the brain, on the nerves exiting the brain and/or on the spinal cord. The total number of neurofibromas in an adult may range from a few to hundreds or even thousands, and the number of these tumors tends to increase with age. Pain may occur from an affected peripheral nerve, or as a result of regional mass effect on adjacent structures. In 8-15% of affected individuals, neurofibromas may transform to become cancerous (malignant peripheral nerve sheath tumors), which are associated with pain, rapid tumor growth or new neurological symptoms, and require urgent evaluation and treatment.Approximately 15% of people with NF1 develop brain tumors (gliomas), which most commonly develop during childhood. These frequently develop on in the visual structures of the brain (optic pathway gliomas) and may affect vision, cause premature onset of puberty (precocious puberty) or increased head size (macrocephaly). Additionally, a variety of other tumors may develop in patients with NF1, including gastrointestinal stromal tumors (GIST). In women with NF1, there is a 4 to 11-fold increased risk of developing breast cancer compared to the general population before age 50, though this risk is the highest between 30 and 40 years old. Further, even after diagnosis of breast cancer on one side, there is a high risk of developing a second breast cancer in the opposite (contralateral) breast. Orthopedic problems may develop with NF1, including curvature of the spine (scoliosis), abnormal cranial bone growth (sphenoid wing dysplasia) or a condition characterized by bowing and fracturing of weight-bearing long bones (pseudoarthrosis). Additionally, disorders of bone density (osteopenia and osteoporosis) are more common in people with NF1 than in the general population. The process by which these conditions develop is not fully understood, but has been associated with decreased activated vitamin D levels, increased parathyroid hormone levels, and increased markers of bone breakdown. People with NF1 tend to be below average in height, below average in muscle strength and above average in head size for age.High blood pressure (hypertension) is seen with greater frequency in the NF1 population than the general population. While the cause for this is not certain, some cases may not directly relate to NF1, but rather to associated changes in the blood vessels leading to the kidneys (renal artery stenosis). More rarely, patients with NF1 are at risk of developing tumors of the adrenal gland (pheochromocytoma), which may cause severely elevated blood pressure without treatment.Sexual development may be delayed or may occur early (precocious puberty) in individuals with NF1. (For more information on this disorder, choose “precocious puberty” as your search term in the Rare Disease Database.) In addition, over 50% of individuals with NF1 experience learning disabilities such as attention deficit hyperactivity disorder (ADHD). Seizures may also occur. Other symptoms include headache, numbness and/or weakness.In the localized form of NF1, known as segmental neurofibromatosis, abnormal pigmentation and/or tumors may be limited to one area of the body, and there may be an overall milder manifestation of the disease.
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Neurofibromatosis 1
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nord_874_2
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Causes of Neurofibromatosis 1
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In about 50% of individuals with NF1, the disorder is inherited from a parent. Only one parent need be affected to cause a child to have NF1 (autosomal dominant inheritance). NF1 does not skip generations. Sporadic or random pathogenic variants in the gene responsible for NF1 account for the remaining 50% of cases and occur when a child has NF1 but neither parent does. The NF1 gene regulates (encodes for) the production of neurofibromin, a protein that functions to prevent the development of tumors (tumor suppressor). Mutations (pathogenic variants) in the NF1 gene lead to the production of a nonfunctional version of neurofibromin or decreased expression of neurofibromin, thereby dysregulating cellular growth and division. Whereas there are two functional copies of every gene in the human body, and only one copy of the NF1 gene is mutated in all tissues due to its autosomal dominant nature, a second mutation event is necessary in a given cell to completely lose neurofibromin’s tumor suppressor activity and cause a tumor in that region.Many different pathogenic variants of the NF1 gene have been identified in individuals with the disorder. In general, there is little correlation between a particular pathogenic variant and particular disease manifestations or severity, as evidenced by the wide disease variation within families that have the same NF1 gene change. It is hypothesized that disease variability relates to variability in other genes (modifier genes) and to environmental factors. A more localized form of NF1 (segmental NF1) is caused by a genetic change in the NF1 gene that is not inherited, but rather occurs sporadically during embryo development (somatic mutation). Only a portion of the cells in the body have the disease-causing NF1 pathogenic variant (genetic mosaicism), so signs and symptoms of segmental NF1 may appear in only a portion of the body or may be overall reduced in severity and distribution. The NF1 pathogenic variant responsible for a segmental NF1 case may be inherited by offspring and cause full NF1; the risk of this transmission is not well understood, and likely depends on the distribution of mutated cells in the parent.
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Causes of Neurofibromatosis 1. In about 50% of individuals with NF1, the disorder is inherited from a parent. Only one parent need be affected to cause a child to have NF1 (autosomal dominant inheritance). NF1 does not skip generations. Sporadic or random pathogenic variants in the gene responsible for NF1 account for the remaining 50% of cases and occur when a child has NF1 but neither parent does. The NF1 gene regulates (encodes for) the production of neurofibromin, a protein that functions to prevent the development of tumors (tumor suppressor). Mutations (pathogenic variants) in the NF1 gene lead to the production of a nonfunctional version of neurofibromin or decreased expression of neurofibromin, thereby dysregulating cellular growth and division. Whereas there are two functional copies of every gene in the human body, and only one copy of the NF1 gene is mutated in all tissues due to its autosomal dominant nature, a second mutation event is necessary in a given cell to completely lose neurofibromin’s tumor suppressor activity and cause a tumor in that region.Many different pathogenic variants of the NF1 gene have been identified in individuals with the disorder. In general, there is little correlation between a particular pathogenic variant and particular disease manifestations or severity, as evidenced by the wide disease variation within families that have the same NF1 gene change. It is hypothesized that disease variability relates to variability in other genes (modifier genes) and to environmental factors. A more localized form of NF1 (segmental NF1) is caused by a genetic change in the NF1 gene that is not inherited, but rather occurs sporadically during embryo development (somatic mutation). Only a portion of the cells in the body have the disease-causing NF1 pathogenic variant (genetic mosaicism), so signs and symptoms of segmental NF1 may appear in only a portion of the body or may be overall reduced in severity and distribution. The NF1 pathogenic variant responsible for a segmental NF1 case may be inherited by offspring and cause full NF1; the risk of this transmission is not well understood, and likely depends on the distribution of mutated cells in the parent.
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Neurofibromatosis 1
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nord_874_3
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Affects of Neurofibromatosis 1
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NF1 is a rare disorder that affects males and females in equal numbers. NF1 affects all races and ethnic groups equally and is estimated to occur in 1 in 2,500 to 3,000 births.
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Affects of Neurofibromatosis 1. NF1 is a rare disorder that affects males and females in equal numbers. NF1 affects all races and ethnic groups equally and is estimated to occur in 1 in 2,500 to 3,000 births.
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Neurofibromatosis 1
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nord_874_4
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Related disorders of Neurofibromatosis 1
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Symptoms of the following disorders may be similar to those of NF1. Comparisons may be useful for a differential diagnosis:NF2-related schwannomatosis (NF2) is a rare disorder that is genetically distinct from NF1. NF2 is characterized by noncancerous (benign) tumors on both auditory nerves (vestibular schwannomas) and in other areas of the body. Other tumors of the central nervous system may develop including meningiomas and/or ependymomas. Individuals with NF2 do not typically have cafe-au-lait macules or abnormal skin freckling. Other symptoms of NF2 may include problems with balance, buzzing or ringing in the ears (tinnitus), progressive hearing loss or facial weakness. (For more information on this disorder, choose “NF2” as your search term in the Rare Disease Database.)McCune-Albright syndrome is a multi-system disorder characterized by abnormal fibrous tissue development (dysplasia) in one or more bones. Any bone of the body may be affected. Symptoms include increasing pain, bone fractures and limited mobility. Shortening of the limbs and other skeletal deformities may occur. Abnormally early puberty and brown (cafe-au-lait) spots on the skin are also characteristic of this disease. Other symptoms may include an overactive thyroid gland (hyperthyroidism), other hormone abnormalities and a variety of bone and soft tissue tumors. (For more information on this disorder, choose “McCune-Albright” as your search term in the Rare Disease Database.)Proteus syndrome is a rare disorder characterized by overgrowth of various tissues of the body. The cause of the disorder is a mosaic pathogenic variant in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), lung disease and certain skin lesions. In some people, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database.)Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign tumors called hamartomas in various organ systems of the body. The hamartomas can grow to be relatively large, and can damage an affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely. Patients may also develop brain tumors known as subependymal giant cell astrocytomas (SEGAs). Tuberous sclerosis results from pathogenic variants in a gene or genes that may occur spontaneously or can be inherited in an autosomal dominant pattern. Most cases represent new (sporadic or de novo) gene changes, with no family history of the disease. Pathogenic variants of at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Noonan syndrome is a genetic disorder that is typically evident at birth and characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. Associated abnormalities can include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic features of the head and facial area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart defects and additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder caused by pathogenic variants in more than eight genes. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Neurofibromatosis-Noonan syndrome is characterized by the occurrence of NF1 in association with manifestations of Noonan syndrome. Associated symptoms and findings may include multiple benign tumors of the nerves and skin, short stature, webbing of the neck (pterygium colli), muscle weakness and/or learning disabilities. Affected individuals may also have certain craniofacial abnormalities associated with Noonan syndrome including drooping of the upper eyelids (ptosis), low-set ears and/or unusually prominent folds between the nose and the lips (nasolabial folds). In addition, congenital heart defects often seen in Noonan syndrome may be present, such as obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis) and/or an abnormal opening in the fibrous partition (septum) between the upper chambers (atria) of the heart (atrial septal defect). It is unclear whether neurofibromatosis-Noonan syndrome is a rare variant of NF1, is due to the occurrence of multiple pathogenic variants in the same individual, is a rare variant of Noonan syndrome or represents a new disease entity.Legius syndrome is characterized by café-au-lait macules, axillary freckling, macrocephaly and facial features resembling those of Noonan syndrome. These individuals may meet the diagnostic criteria for NF1; however, they typically do not have Lisch nodules, neurofibromas or tumors of the central nervous system. Due to the similarity of symptoms with NF1, molecular testing may be necessary to confirm or establish the diagnosis.Phakomatoses is a term that refers to several disorders characterized by benign skin lesions and neurological disorders, which includes neurofibromatosis.Neurocutaneous disorder refers to several disorders affecting the skin and the nervous system and includes neurofibromatosis as the most common condition.Piebald trait is defined by areas of skin pigmentation, depigmentation and/or hyperpigmentation. Some individuals with this condition may meet the diagnostic criteria for NF1.
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Related disorders of Neurofibromatosis 1. Symptoms of the following disorders may be similar to those of NF1. Comparisons may be useful for a differential diagnosis:NF2-related schwannomatosis (NF2) is a rare disorder that is genetically distinct from NF1. NF2 is characterized by noncancerous (benign) tumors on both auditory nerves (vestibular schwannomas) and in other areas of the body. Other tumors of the central nervous system may develop including meningiomas and/or ependymomas. Individuals with NF2 do not typically have cafe-au-lait macules or abnormal skin freckling. Other symptoms of NF2 may include problems with balance, buzzing or ringing in the ears (tinnitus), progressive hearing loss or facial weakness. (For more information on this disorder, choose “NF2” as your search term in the Rare Disease Database.)McCune-Albright syndrome is a multi-system disorder characterized by abnormal fibrous tissue development (dysplasia) in one or more bones. Any bone of the body may be affected. Symptoms include increasing pain, bone fractures and limited mobility. Shortening of the limbs and other skeletal deformities may occur. Abnormally early puberty and brown (cafe-au-lait) spots on the skin are also characteristic of this disease. Other symptoms may include an overactive thyroid gland (hyperthyroidism), other hormone abnormalities and a variety of bone and soft tissue tumors. (For more information on this disorder, choose “McCune-Albright” as your search term in the Rare Disease Database.)Proteus syndrome is a rare disorder characterized by overgrowth of various tissues of the body. The cause of the disorder is a mosaic pathogenic variant in a gene called AKT1. Disproportionate, asymmetric overgrowth occurs in a mosaic pattern (i.e., a random “patchy” pattern of affected and unaffected areas). Affected individuals may experience a wide variety of complications that may include progressive skeletal malformations, benign and malignant tumors, malformations of blood vessels (vascular malformations), lung disease and certain skin lesions. In some people, life-threatening conditions relating to abnormal blood clotting may develop including deep vein thrombosis and pulmonary embolism. (For more information on this disorder, choose “Proteus” as your search term in the Rare Disease Database.)Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign tumors called hamartomas in various organ systems of the body. The hamartomas can grow to be relatively large, and can damage an affected organ system. The number, size, and specific location of these abnormal growths in individuals with tuberous sclerosis can vary widely and consequently the severity of the disorder can vary widely. Patients may also develop brain tumors known as subependymal giant cell astrocytomas (SEGAs). Tuberous sclerosis results from pathogenic variants in a gene or genes that may occur spontaneously or can be inherited in an autosomal dominant pattern. Most cases represent new (sporadic or de novo) gene changes, with no family history of the disease. Pathogenic variants of at least two different genes are known to cause tuberous sclerosis, the TSC1 gene or the TSC2 gene. (For more information on this disorder, choose “tuberous sclerosis” as your search term in the Rare Disease Database.)Noonan syndrome is a genetic disorder that is typically evident at birth and characterized by a wide spectrum of symptoms and physical features that vary greatly in range and severity. Associated abnormalities can include a distinctive facial appearance; a broad or webbed neck; a low posterior hairline; a typical chest deformity and short stature. Characteristic features of the head and facial area may include widely set eyes (ocular hypertelorism); skin folds that may cover the eyes’ inner corners (epicanthal folds); drooping of the upper eyelids (ptosis); a small jaw (micrognathia); a depressed nasal root; a short nose with broad base; and low-set, posteriorly rotated ears (pinnae). Distinctive skeletal malformations are also typically present, such as abnormalities of the breastbone (sternum), curvature of the spine (kyphosis and/or scoliosis), and outward deviation of the elbows (cubitus valgus). Many infants with Noonan syndrome also have heart defects and additional abnormalities may include malformations of certain blood and lymph vessels, blood clotting and platelet deficiencies, learning difficulties or mild intellectual disability, failure of the testes to descend into the scrotum (cryptorchidism) by the first year of life in affected males and/or other symptoms and findings. Noonan syndrome is an autosomal dominant genetic disorder caused by pathogenic variants in more than eight genes. (For more information on this disorder, choose “Noonan” as your search term in the Rare Disease Database.)Neurofibromatosis-Noonan syndrome is characterized by the occurrence of NF1 in association with manifestations of Noonan syndrome. Associated symptoms and findings may include multiple benign tumors of the nerves and skin, short stature, webbing of the neck (pterygium colli), muscle weakness and/or learning disabilities. Affected individuals may also have certain craniofacial abnormalities associated with Noonan syndrome including drooping of the upper eyelids (ptosis), low-set ears and/or unusually prominent folds between the nose and the lips (nasolabial folds). In addition, congenital heart defects often seen in Noonan syndrome may be present, such as obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (pulmonary stenosis) and/or an abnormal opening in the fibrous partition (septum) between the upper chambers (atria) of the heart (atrial septal defect). It is unclear whether neurofibromatosis-Noonan syndrome is a rare variant of NF1, is due to the occurrence of multiple pathogenic variants in the same individual, is a rare variant of Noonan syndrome or represents a new disease entity.Legius syndrome is characterized by café-au-lait macules, axillary freckling, macrocephaly and facial features resembling those of Noonan syndrome. These individuals may meet the diagnostic criteria for NF1; however, they typically do not have Lisch nodules, neurofibromas or tumors of the central nervous system. Due to the similarity of symptoms with NF1, molecular testing may be necessary to confirm or establish the diagnosis.Phakomatoses is a term that refers to several disorders characterized by benign skin lesions and neurological disorders, which includes neurofibromatosis.Neurocutaneous disorder refers to several disorders affecting the skin and the nervous system and includes neurofibromatosis as the most common condition.Piebald trait is defined by areas of skin pigmentation, depigmentation and/or hyperpigmentation. Some individuals with this condition may meet the diagnostic criteria for NF1.
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Neurofibromatosis 1
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Diagnosis of Neurofibromatosis 1
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The diagnosis of NF1 is usually made during the first decade of life, based on characteristic skin freckling, cafe-au-lait spots, optic glioma and/or pseudoarthrosis. NF1 should be suspected if any one of the criteria are present and diagnosed if the following are met: • For an individual who does not have a parent diagnosed with NF1, two or more of the items listed below are required for a diagnosis of NF1. For individuals born to a parent with NF1, only one finding in the below list is required to meet diagnostic criteria for NF1• Six or more café-au-lait spots of at least 5 millimeters [mm] in size (before puberty) or 15 mm in size (after puberty)• Freckling in the underarms (axillary) or groin (inguinal) regions• Two or more neurofibromas of any type, or one plexiform neurofibroma• A tumor of the visual structures of the brain or eye nerves (optic pathway glioma)• Two or more abnormal clumps of pigment on the colored portion of the eye (Lisch nodules) or two or more abnormalities in the back of the eye (choroidal abnormalities) seen with special imaging of the eye• Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or a bowing of the tibia bone in the leg or other long bones (pseudoarthrosis)• A pathogenic variant in the NF1 gene in normal tissue (such as blood, saliva) with an allele fraction of 50% (meaning half of the copies of NF1 in the body are impacted by the pathogenic variant)Diagnosis of NF1 is usually based on clinical findings, although increasingly genetic testing is used to support the evaluation and/or for family planning purposes. Some of the skin findings (i.e., café-au-lait spots) are not always easily visible and may require use of an ultraviolet light (Wood’s lamp) to identify.
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Diagnosis of Neurofibromatosis 1. The diagnosis of NF1 is usually made during the first decade of life, based on characteristic skin freckling, cafe-au-lait spots, optic glioma and/or pseudoarthrosis. NF1 should be suspected if any one of the criteria are present and diagnosed if the following are met: • For an individual who does not have a parent diagnosed with NF1, two or more of the items listed below are required for a diagnosis of NF1. For individuals born to a parent with NF1, only one finding in the below list is required to meet diagnostic criteria for NF1• Six or more café-au-lait spots of at least 5 millimeters [mm] in size (before puberty) or 15 mm in size (after puberty)• Freckling in the underarms (axillary) or groin (inguinal) regions• Two or more neurofibromas of any type, or one plexiform neurofibroma• A tumor of the visual structures of the brain or eye nerves (optic pathway glioma)• Two or more abnormal clumps of pigment on the colored portion of the eye (Lisch nodules) or two or more abnormalities in the back of the eye (choroidal abnormalities) seen with special imaging of the eye• Certain abnormalities of bone development in the head (sphenoid wing dysplasia) or a bowing of the tibia bone in the leg or other long bones (pseudoarthrosis)• A pathogenic variant in the NF1 gene in normal tissue (such as blood, saliva) with an allele fraction of 50% (meaning half of the copies of NF1 in the body are impacted by the pathogenic variant)Diagnosis of NF1 is usually based on clinical findings, although increasingly genetic testing is used to support the evaluation and/or for family planning purposes. Some of the skin findings (i.e., café-au-lait spots) are not always easily visible and may require use of an ultraviolet light (Wood’s lamp) to identify.
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Neurofibromatosis 1
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Therapies of Neurofibromatosis 1
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TreatmentFor cutaneous, subcutaneous, and deep neurofibromas, surveillance is often the preferred strategy due to the benign nature of the lesions. If treatment is required, patients may undergo surgery to remove particularly troublesome or disfiguring tumors, depending on their size and location. Laser or electrocautery treatment may also be an option for smaller skin neurofibromas. Radiation therapy, chemotherapy or both treatments may be used by some clinicians to treat NF1-associated tumors, though their role is less clear as the risks are often considered to outweigh the benefits in such cases. Clinical trials are ongoing to better understand these options.For plexiform neurofibromas, complete surgical removal is generally not possible due to the diffuse nature of the lesions. In April 2020, Koselugo (selumetinib) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of NF1-associated plexiform neurofibromas that are disfiguring or inoperable in children 2 years and older. This drug is a kinase inhibitor, meaning it functions by blocking a key enzyme that promotes cellular growth, and according to published data this medication results in shrinking plexiform tumors in up to 70% of patients. Physical therapy may be beneficial for some people, based on difficulties arising from tumors or bone abnormalities. A variety of orthopedic devices may help to improve mobility in some patients. Other treatment is symptomatic and supportive. For example, in patients who develop scoliosis, a brace may be necessary to prevent progression.Regular monitoring is important for managing the disease. Annual physical exams are recommended for all patients, in addition to blood pressure screening and frequent eye exams. Children with NF1 are recommended to have annual ophthalmologic exams, as well as regular checks of head circumference and developmental assessments. Advanced imaging (MRI, PET, or PET/CT) may be advised to monitor internal tumors depending on location and symptoms. Whole-body MRI is under investigation as a tool for monitoring of internal tumors. Annual breast cancer screening (either by mammography or breast MRI) is recommended to begin at age 30 for females with NF1. Further monitoring of specific system abnormalities may be necessary. Patients should consult an appropriate specialist if they have abnormalities of the central nervous system, skeletal system, cardiovascular system or eyes.Genetic counseling is recommended for people with NF1 and their families. For clinical facilities that treat people with neurofibromatosis, please refer to the Organizations section of this report.
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Therapies of Neurofibromatosis 1. TreatmentFor cutaneous, subcutaneous, and deep neurofibromas, surveillance is often the preferred strategy due to the benign nature of the lesions. If treatment is required, patients may undergo surgery to remove particularly troublesome or disfiguring tumors, depending on their size and location. Laser or electrocautery treatment may also be an option for smaller skin neurofibromas. Radiation therapy, chemotherapy or both treatments may be used by some clinicians to treat NF1-associated tumors, though their role is less clear as the risks are often considered to outweigh the benefits in such cases. Clinical trials are ongoing to better understand these options.For plexiform neurofibromas, complete surgical removal is generally not possible due to the diffuse nature of the lesions. In April 2020, Koselugo (selumetinib) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of NF1-associated plexiform neurofibromas that are disfiguring or inoperable in children 2 years and older. This drug is a kinase inhibitor, meaning it functions by blocking a key enzyme that promotes cellular growth, and according to published data this medication results in shrinking plexiform tumors in up to 70% of patients. Physical therapy may be beneficial for some people, based on difficulties arising from tumors or bone abnormalities. A variety of orthopedic devices may help to improve mobility in some patients. Other treatment is symptomatic and supportive. For example, in patients who develop scoliosis, a brace may be necessary to prevent progression.Regular monitoring is important for managing the disease. Annual physical exams are recommended for all patients, in addition to blood pressure screening and frequent eye exams. Children with NF1 are recommended to have annual ophthalmologic exams, as well as regular checks of head circumference and developmental assessments. Advanced imaging (MRI, PET, or PET/CT) may be advised to monitor internal tumors depending on location and symptoms. Whole-body MRI is under investigation as a tool for monitoring of internal tumors. Annual breast cancer screening (either by mammography or breast MRI) is recommended to begin at age 30 for females with NF1. Further monitoring of specific system abnormalities may be necessary. Patients should consult an appropriate specialist if they have abnormalities of the central nervous system, skeletal system, cardiovascular system or eyes.Genetic counseling is recommended for people with NF1 and their families. For clinical facilities that treat people with neurofibromatosis, please refer to the Organizations section of this report.
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Overview of Neuroleptic Malignant Syndrome
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Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group of antipsychotic drugs or major tranquilizers (neuroleptics). These drugs are commonly prescribed for the treatment of schizophrenia and other neurological, mental, or emotional disorders. Several of the more commonly prescribed neuroleptics include thioridazine, haloperidol, chlorpromazine, fluphenazine and perphenazine.The syndrome is characterized by high fever, stiffness of the muscles, altered mental status (paranoid behavior), and autonomic dysfunction. Autonomic dysfunction alludes to defective operations of the components of the involuntary (autonomic) nervous system, leading to wide swings of blood pressure, excessive sweating and excessive secretion of saliva.A genetic basis for the disorder is suspected but not proven. It does appear to be clear that a defect in the receptors to dopamine (dopamine D2 receptor antagonism) is an important contributor to the cause of neuroleptic malignant syndrome.
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Overview of Neuroleptic Malignant Syndrome. Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group of antipsychotic drugs or major tranquilizers (neuroleptics). These drugs are commonly prescribed for the treatment of schizophrenia and other neurological, mental, or emotional disorders. Several of the more commonly prescribed neuroleptics include thioridazine, haloperidol, chlorpromazine, fluphenazine and perphenazine.The syndrome is characterized by high fever, stiffness of the muscles, altered mental status (paranoid behavior), and autonomic dysfunction. Autonomic dysfunction alludes to defective operations of the components of the involuntary (autonomic) nervous system, leading to wide swings of blood pressure, excessive sweating and excessive secretion of saliva.A genetic basis for the disorder is suspected but not proven. It does appear to be clear that a defect in the receptors to dopamine (dopamine D2 receptor antagonism) is an important contributor to the cause of neuroleptic malignant syndrome.
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Neuroleptic Malignant Syndrome
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Symptoms of Neuroleptic Malignant Syndrome
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Symptoms of neuroleptic malignant syndrome usually include very high fever (102 to 104 degrees F), irregular pulse, accelerated heartbeat (tachycardia), increased rate of respiration (tachypnea), muscle rigidity, altered mental status, autonomic nervous system dysfunction resulting in high or low blood pressure, profuse perspiration, and excessive sweating.Other symptoms may include liver or kidney failure, abnormally high potassium levels (hyperkalemia), major destruction of skeletal muscle tissue (rhabdo-myolysis) or blood clots in veins and arteries.
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Symptoms of Neuroleptic Malignant Syndrome. Symptoms of neuroleptic malignant syndrome usually include very high fever (102 to 104 degrees F), irregular pulse, accelerated heartbeat (tachycardia), increased rate of respiration (tachypnea), muscle rigidity, altered mental status, autonomic nervous system dysfunction resulting in high or low blood pressure, profuse perspiration, and excessive sweating.Other symptoms may include liver or kidney failure, abnormally high potassium levels (hyperkalemia), major destruction of skeletal muscle tissue (rhabdo-myolysis) or blood clots in veins and arteries.
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Neuroleptic Malignant Syndrome
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Causes of Neuroleptic Malignant Syndrome
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Neuroleptic malignant syndrome comes about, most likely, as a result of “dopamine D2 receptor antagonism”. Dopamine is a chemical substance (neurotransmitter) found in the brain and elsewhere in the central nervous system that acts to convey messages from one cell to another. In some way, the use of a particular drug blocks the receptor in the brain cell for dopamine.When the dopamine receptors in the hypothalamus or another bundle of nerve fibers (nigrostriatal pathways) and/or the spinal cord are blocked, increased muscle rigidity is the result. The interference with the dopamine receptors in the hypothalamus is also probably responsible for high body temperature, as well as the swings in blood pressure.Some clinicians believe that neuroleptic malignant syndrome may be related to malignant hyperthermia, a genetic disorder characterized by an abnormal reaction to anesthesia drugs. (See related disorders section for more information about malignant hyperthermia.)
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Causes of Neuroleptic Malignant Syndrome. Neuroleptic malignant syndrome comes about, most likely, as a result of “dopamine D2 receptor antagonism”. Dopamine is a chemical substance (neurotransmitter) found in the brain and elsewhere in the central nervous system that acts to convey messages from one cell to another. In some way, the use of a particular drug blocks the receptor in the brain cell for dopamine.When the dopamine receptors in the hypothalamus or another bundle of nerve fibers (nigrostriatal pathways) and/or the spinal cord are blocked, increased muscle rigidity is the result. The interference with the dopamine receptors in the hypothalamus is also probably responsible for high body temperature, as well as the swings in blood pressure.Some clinicians believe that neuroleptic malignant syndrome may be related to malignant hyperthermia, a genetic disorder characterized by an abnormal reaction to anesthesia drugs. (See related disorders section for more information about malignant hyperthermia.)
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Affects of Neuroleptic Malignant Syndrome
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Neuroleptic malignant syndrome may affect any person taking neuroleptic drugs. Men appear to be at higher risk than women. Some clinicians believe that the stronger neuroleptic medications are more likely to precipitate an attack of NMS.Although two-thirds of cases are thought to occur within the first week of start of treatment, the syndrome may begin at any time during treatment.Recurrence of an attack of NMS is not uncommon. The risk of recurrence is closely related to the time elapsed between the end of the original episode of neuroleptic malignant syndrome and the beginning of renewed administration of an antipsychotic drug. If the waiting period is two weeks or less, about 63% will have a recurrence. If the waiting period is more than two weeks, the percentage of patients experiencing a relapse drops to about 30.
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Affects of Neuroleptic Malignant Syndrome. Neuroleptic malignant syndrome may affect any person taking neuroleptic drugs. Men appear to be at higher risk than women. Some clinicians believe that the stronger neuroleptic medications are more likely to precipitate an attack of NMS.Although two-thirds of cases are thought to occur within the first week of start of treatment, the syndrome may begin at any time during treatment.Recurrence of an attack of NMS is not uncommon. The risk of recurrence is closely related to the time elapsed between the end of the original episode of neuroleptic malignant syndrome and the beginning of renewed administration of an antipsychotic drug. If the waiting period is two weeks or less, about 63% will have a recurrence. If the waiting period is more than two weeks, the percentage of patients experiencing a relapse drops to about 30.
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Neuroleptic Malignant Syndrome
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Related disorders of Neuroleptic Malignant Syndrome
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Symptoms of the following disorders can be similar to those of neuroleptic malignant syndrome. Comparisons may be useful for a differential diagnosis:Anaphylaxis is an abnormally severe allergic reaction to a substance. Major symptoms may include severe itching, hives, flushing, swelling, vomiting, diarrhea, difficulty breathing and unconsciousness. High fever is not a symptom of this disorder. (For more information on this disorder, choose “Anaphylaxis” as your search term in the Rare Disease Database.)Lethal catatonia is a condition similar to NMS and not infrequently confused with it. A detailed history may indicate that the patient has endured catatonic states while not on neuroleptic medications. If so, the chances are that the presenting syndrome is NMS. A lethal catatonia patient will respond to the administration of neuroleptics. It is, however, almost impossible to predict whether the patient's symptoms will worsen or improve. Patients with lethal catatonia almost invariably endure a period of agitation and excitement prior to the catatonia. This is in contrast to the patient with NMS in which the first symptom is usually muscular rigidity.Heat stroke is a very serious condition characterized by an abrupt and rapid increase in body temperature that may reach as high as 104 to 106 degrees F. Heat stroke usually results from exposure to an extremely hot environment. The skin may become hot, flushed and dry. Rapid loss of fluids may result in the inability to sweat. Sweating is necessary to cool the body. There may also be an increase in pulse rate and respiration. The affected individual may become disoriented and eventually experience convulsions or slip into unconsciousness. Measures such as wrapping the individual in cold, wet sheets should be taken immediately to lower body temperature. An individual suffering from heat stroke should be hospitalized as quickly as possible. (For more information on this disorder, choose “Hyperthermia” as your search term in the Rare Disease Database.)Malignant hyperthermia is a genetic disorder characterized by an abnormal response to muscle relaxants and general anesthesia drugs. Symptoms of Malignant Hyperthermia are apparent only after the patient has been placed under general anesthesia. Along with rapidly elevating body temperature that may rise as high as 110 degrees, muscle rigidity and/or muscle twitching occurs. The patient may also exhibit a very rapid and irregular heartbeat, abnormally low blood pressure, sickly sweet breath, headache, nausea and vomiting. It is not known whether neuroleptic malignant hyperthermia is a variant form of Malignant Hyperthermia, but some researchers have suggested that these disorders may be related. (For more information on this disorder, choose “Malignant Hyperthermia” as your search term in the Rare Disease Database.)The serotonin syndrome mimics neuroleptic malignant hyperthermia. If the use of selective serotonin reuptake inhibitors (SSRIs) results in symptoms such as altered mental state, autonomic dysfunction (see above), and neuromuscular defects, then the condition is likely to be serotonin syndrome. Since SSRIs are being used in increasing amounts, it is not unreasonable to expect that the incidence of serotonin syndrome will increase as well. The serotonin syndrome may be distinguished from NMS in most cases by a detailed history in which any changes in medication and/or dosages are clarified. In addition, serotonin syndrome usually is not accompanied by severe muscle rigidity.The following disorder may be associated with the extended use of neuroleptic drugs. It is not necessary for a differential diagnosis:Tardive dyskinesia is a disorder that results from the long-term use of neuroleptic drugs and is characterized by involuntary and abnormal movements of the jaw, lips and tongue. Typical symptoms include grimacing, sticking out the tongue, and sucking or fishlike movements of the mouth. A high percentage of schizophrenic people who have spent long periods of time in mental hospitals taking neuroleptic drugs have a high risk of developing tardive dyskinesia. (For more information on this disorder, choose “tardive dyskinesia” for your search term in the Rare Disease Database.)
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Related disorders of Neuroleptic Malignant Syndrome. Symptoms of the following disorders can be similar to those of neuroleptic malignant syndrome. Comparisons may be useful for a differential diagnosis:Anaphylaxis is an abnormally severe allergic reaction to a substance. Major symptoms may include severe itching, hives, flushing, swelling, vomiting, diarrhea, difficulty breathing and unconsciousness. High fever is not a symptom of this disorder. (For more information on this disorder, choose “Anaphylaxis” as your search term in the Rare Disease Database.)Lethal catatonia is a condition similar to NMS and not infrequently confused with it. A detailed history may indicate that the patient has endured catatonic states while not on neuroleptic medications. If so, the chances are that the presenting syndrome is NMS. A lethal catatonia patient will respond to the administration of neuroleptics. It is, however, almost impossible to predict whether the patient's symptoms will worsen or improve. Patients with lethal catatonia almost invariably endure a period of agitation and excitement prior to the catatonia. This is in contrast to the patient with NMS in which the first symptom is usually muscular rigidity.Heat stroke is a very serious condition characterized by an abrupt and rapid increase in body temperature that may reach as high as 104 to 106 degrees F. Heat stroke usually results from exposure to an extremely hot environment. The skin may become hot, flushed and dry. Rapid loss of fluids may result in the inability to sweat. Sweating is necessary to cool the body. There may also be an increase in pulse rate and respiration. The affected individual may become disoriented and eventually experience convulsions or slip into unconsciousness. Measures such as wrapping the individual in cold, wet sheets should be taken immediately to lower body temperature. An individual suffering from heat stroke should be hospitalized as quickly as possible. (For more information on this disorder, choose “Hyperthermia” as your search term in the Rare Disease Database.)Malignant hyperthermia is a genetic disorder characterized by an abnormal response to muscle relaxants and general anesthesia drugs. Symptoms of Malignant Hyperthermia are apparent only after the patient has been placed under general anesthesia. Along with rapidly elevating body temperature that may rise as high as 110 degrees, muscle rigidity and/or muscle twitching occurs. The patient may also exhibit a very rapid and irregular heartbeat, abnormally low blood pressure, sickly sweet breath, headache, nausea and vomiting. It is not known whether neuroleptic malignant hyperthermia is a variant form of Malignant Hyperthermia, but some researchers have suggested that these disorders may be related. (For more information on this disorder, choose “Malignant Hyperthermia” as your search term in the Rare Disease Database.)The serotonin syndrome mimics neuroleptic malignant hyperthermia. If the use of selective serotonin reuptake inhibitors (SSRIs) results in symptoms such as altered mental state, autonomic dysfunction (see above), and neuromuscular defects, then the condition is likely to be serotonin syndrome. Since SSRIs are being used in increasing amounts, it is not unreasonable to expect that the incidence of serotonin syndrome will increase as well. The serotonin syndrome may be distinguished from NMS in most cases by a detailed history in which any changes in medication and/or dosages are clarified. In addition, serotonin syndrome usually is not accompanied by severe muscle rigidity.The following disorder may be associated with the extended use of neuroleptic drugs. It is not necessary for a differential diagnosis:Tardive dyskinesia is a disorder that results from the long-term use of neuroleptic drugs and is characterized by involuntary and abnormal movements of the jaw, lips and tongue. Typical symptoms include grimacing, sticking out the tongue, and sucking or fishlike movements of the mouth. A high percentage of schizophrenic people who have spent long periods of time in mental hospitals taking neuroleptic drugs have a high risk of developing tardive dyskinesia. (For more information on this disorder, choose “tardive dyskinesia” for your search term in the Rare Disease Database.)
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Neuroleptic Malignant Syndrome
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Diagnosis of Neuroleptic Malignant Syndrome
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The diagnosis of neuroleptic malignant syndrome is based on the presence of characteristics that include treatment with neuroleptic drugs within the past 1-4 weeks. high body temperature (greater than 38 degrees centigrade); muscle rigidity; and at least five of the following:Change in mental statusRapid heart beat (tachycardia)Low or high blood pressure (hypo- or hypertension)Excessive sweating (diaphoresis)Excessive saliva production (sialorrhea)TremorIncontinenceIncreased creatine phosphokinase, or increased urinary myoglobinIncreased number of white blood cells (leukocytosis)Increased concentrations of metabolic acids in blood and urineExclusion of other drug-induced psychiatric or systemic illness.
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Diagnosis of Neuroleptic Malignant Syndrome. The diagnosis of neuroleptic malignant syndrome is based on the presence of characteristics that include treatment with neuroleptic drugs within the past 1-4 weeks. high body temperature (greater than 38 degrees centigrade); muscle rigidity; and at least five of the following:Change in mental statusRapid heart beat (tachycardia)Low or high blood pressure (hypo- or hypertension)Excessive sweating (diaphoresis)Excessive saliva production (sialorrhea)TremorIncontinenceIncreased creatine phosphokinase, or increased urinary myoglobinIncreased number of white blood cells (leukocytosis)Increased concentrations of metabolic acids in blood and urineExclusion of other drug-induced psychiatric or systemic illness.
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Therapies of Neuroleptic Malignant Syndrome
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TreatmentTreatment of neuroleptic malignant syndrome consists of withdrawal ofneuroleptic medications under a doctor's supervision, immediate measures to restore appropriate water and nutrient levels, and steps to lower the individual's body temperature. Medications prescribed as treatment may include skeletal muscle relaxants, such as dantrolene; stimulators of dopamine production and activity, such as bromocriptine; and/or continuous perfusion of central nervous system depressants, such as diazepam.Complications that may result from neuroleptic malignant syndrome, such as kidney (renal) insufficiency, deficiency of oxygen reaching the tissues (hypoxia), and/or decreased alkalinity of the blood and tissues (acidosis) can be extremely serious and must be treated immediately. Once patients have recovered from neuroleptic malignant syndrome, about 87% will be able to tolerate an antipsychotic at some point in the future. Physicians usually switch to a different antipsychotic class and to an atypical antipsychotic. Such patients must be carefully monitored since recurrences of neuroleptic malignant syndrome are not infrequent.Electroconvulsive treatments have been prescribed for patients with neuroleptic malignant syndrome with varied results.
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Therapies of Neuroleptic Malignant Syndrome. TreatmentTreatment of neuroleptic malignant syndrome consists of withdrawal ofneuroleptic medications under a doctor's supervision, immediate measures to restore appropriate water and nutrient levels, and steps to lower the individual's body temperature. Medications prescribed as treatment may include skeletal muscle relaxants, such as dantrolene; stimulators of dopamine production and activity, such as bromocriptine; and/or continuous perfusion of central nervous system depressants, such as diazepam.Complications that may result from neuroleptic malignant syndrome, such as kidney (renal) insufficiency, deficiency of oxygen reaching the tissues (hypoxia), and/or decreased alkalinity of the blood and tissues (acidosis) can be extremely serious and must be treated immediately. Once patients have recovered from neuroleptic malignant syndrome, about 87% will be able to tolerate an antipsychotic at some point in the future. Physicians usually switch to a different antipsychotic class and to an atypical antipsychotic. Such patients must be carefully monitored since recurrences of neuroleptic malignant syndrome are not infrequent.Electroconvulsive treatments have been prescribed for patients with neuroleptic malignant syndrome with varied results.
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Neuroleptic Malignant Syndrome
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Overview of Neuromyelitis Optica Spectrum Disorder
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Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is a chronic disorder of the brain and spinal cord dominated by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). Classically, it was felt to be a monophasic illness, consisting of episodes of inflammation of one or both optic nerves and the spinal cord over a short period of time (days or weeks) but, after the initial episode, no recurrence. It is now recognized that most patients satisfying current criteria for NMOSD experience repeated attacks separated by periods of remission. The interval between attacks may be weeks, months or years. In its early stages, NMOSD may be confused with multiple sclerosis (MS).
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Overview of Neuromyelitis Optica Spectrum Disorder. Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is a chronic disorder of the brain and spinal cord dominated by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). Classically, it was felt to be a monophasic illness, consisting of episodes of inflammation of one or both optic nerves and the spinal cord over a short period of time (days or weeks) but, after the initial episode, no recurrence. It is now recognized that most patients satisfying current criteria for NMOSD experience repeated attacks separated by periods of remission. The interval between attacks may be weeks, months or years. In its early stages, NMOSD may be confused with multiple sclerosis (MS).
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Neuromyelitis Optica Spectrum Disorder
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Symptoms of Neuromyelitis Optica Spectrum Disorder
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The characteristic symptoms of NMOSD are either optic neuritis or myelitis; either may occur as the first symptom. Optic neuritis is inflammation, of the optic nerve (optic neuritis) leading to pain inside the eye which rapidly is followed by loss of clear vision (acuity). Usually, only one eye is affected (unilateral) although both eyes may be involved simultaneously (bilateral). NMOSD may or may not be preceded by a prodromal upper respiratory infection.The other cardinal syndrome is inflammation of the spinal cord, a condition known as transverse myelitis because the symptoms tend to affect some, and often all motor, sensory and autonomic functions (bladder and bowel) below a certain level on the body, although, not infrequently, symptoms may be confined to one side of the body. Affected individuals may experience pain in the spine or limbs, and mild to severe paralysis (paraparesis to paraplegia) of the lower limbs, and loss of bowel and bladder control. Deep tendon reflexes may be exaggerated, or may be diminished or absent initially and later become exaggerated. A variable degree of sensory loss may occur. Affected individuals may also have a stiff neck, back or limb pain, and/or headaches. This syndrome may be indistinguishable from other cases of “idiopathic” transverse myelitis.Early in the course of the disease, it may be difficult to distinguish between NMOSD and multiple sclerosis because both may cause optic neuritis and myelitis as symptoms. However, the optic neuritis and myelitis tend to be more severe in NMOSD; the brain MRI is more commonly normal, and the spinal fluid analysis does not usually show oligoclonal bands in NMOSD, which are features that help distinguish it from MS.In most cases of NMOSD, the initial symptoms of vision loss or paralysis improve with standard treatment with high dose corticosteroids, and partial recovery of vision, motor, sensory, or bladder function occurs. However, in recurring cases, NMOSD frequently causes significant permanent disturbances of vision and/or spinal cord function leading to blindness or impaired mobility.NMOSD includes limited versions of neuromyelitis associated with positive test for aquaporin-4 autoantibodies and NMOSD brain syndromes associated with positive test for aquaporin-4 autoantibodies (AQP4-IgG), as well as similar clinical conditions where AQP4-IgG is not detected, but rigorous criteria distinguish them from multiple sclerosis and other conditions that may mimic NMOSD (see below for differential diagnosis). An international panel established diagnostic criteria for NMOSD in 2015.Some patients with NMOSD have only recurrent myelitis or only recurrent optic neuritis. When patients have antibodies to aquaporin-4 with just these manifestations, most investigators would argue that they should be treated as having NMOSD. Brain lesions may occur in patients with NMOSD, typically, but not always, in later phases of the disease. Intractable vomiting or hiccups is now a generally accepted specific syndrome of this condition and is the result of inflammation in the dorsal medulla of the brainstem and may be the initial symptom of NMOSD. Brainstem and hypothalamic syndromes are particularly common, but inflammation of the forebrain may also occur, often associated with prominent brain swelling (edema). Clinicians suspecting this disorder must have a strong index of suspicion for this condition especially in patients with a history of severe myelitis or optic neuritis.NMOSD can also be associated with systemic or brain autoimmune diseases, and this may lead to diagnostic confusion (e.g. “lupus myelitis” is most often NMOSD coexisting with systemic lupus erythematosus).
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Symptoms of Neuromyelitis Optica Spectrum Disorder. The characteristic symptoms of NMOSD are either optic neuritis or myelitis; either may occur as the first symptom. Optic neuritis is inflammation, of the optic nerve (optic neuritis) leading to pain inside the eye which rapidly is followed by loss of clear vision (acuity). Usually, only one eye is affected (unilateral) although both eyes may be involved simultaneously (bilateral). NMOSD may or may not be preceded by a prodromal upper respiratory infection.The other cardinal syndrome is inflammation of the spinal cord, a condition known as transverse myelitis because the symptoms tend to affect some, and often all motor, sensory and autonomic functions (bladder and bowel) below a certain level on the body, although, not infrequently, symptoms may be confined to one side of the body. Affected individuals may experience pain in the spine or limbs, and mild to severe paralysis (paraparesis to paraplegia) of the lower limbs, and loss of bowel and bladder control. Deep tendon reflexes may be exaggerated, or may be diminished or absent initially and later become exaggerated. A variable degree of sensory loss may occur. Affected individuals may also have a stiff neck, back or limb pain, and/or headaches. This syndrome may be indistinguishable from other cases of “idiopathic” transverse myelitis.Early in the course of the disease, it may be difficult to distinguish between NMOSD and multiple sclerosis because both may cause optic neuritis and myelitis as symptoms. However, the optic neuritis and myelitis tend to be more severe in NMOSD; the brain MRI is more commonly normal, and the spinal fluid analysis does not usually show oligoclonal bands in NMOSD, which are features that help distinguish it from MS.In most cases of NMOSD, the initial symptoms of vision loss or paralysis improve with standard treatment with high dose corticosteroids, and partial recovery of vision, motor, sensory, or bladder function occurs. However, in recurring cases, NMOSD frequently causes significant permanent disturbances of vision and/or spinal cord function leading to blindness or impaired mobility.NMOSD includes limited versions of neuromyelitis associated with positive test for aquaporin-4 autoantibodies and NMOSD brain syndromes associated with positive test for aquaporin-4 autoantibodies (AQP4-IgG), as well as similar clinical conditions where AQP4-IgG is not detected, but rigorous criteria distinguish them from multiple sclerosis and other conditions that may mimic NMOSD (see below for differential diagnosis). An international panel established diagnostic criteria for NMOSD in 2015.Some patients with NMOSD have only recurrent myelitis or only recurrent optic neuritis. When patients have antibodies to aquaporin-4 with just these manifestations, most investigators would argue that they should be treated as having NMOSD. Brain lesions may occur in patients with NMOSD, typically, but not always, in later phases of the disease. Intractable vomiting or hiccups is now a generally accepted specific syndrome of this condition and is the result of inflammation in the dorsal medulla of the brainstem and may be the initial symptom of NMOSD. Brainstem and hypothalamic syndromes are particularly common, but inflammation of the forebrain may also occur, often associated with prominent brain swelling (edema). Clinicians suspecting this disorder must have a strong index of suspicion for this condition especially in patients with a history of severe myelitis or optic neuritis.NMOSD can also be associated with systemic or brain autoimmune diseases, and this may lead to diagnostic confusion (e.g. “lupus myelitis” is most often NMOSD coexisting with systemic lupus erythematosus).
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Causes of Neuromyelitis Optica Spectrum Disorder
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Greater than 95% of patients with NMOSD report no relatives with the disease, but approximately 3% report having other relatives with the condition. There is a strong association with a personal or family history of autoimmunity, which are present in 50% of cases. NMOSD is regarded as an autoimmune disease though the exact cause for the autoimmunity is unknown.Autoimmune disorders occur when the body’s natural defenses against disease or invading organisms (such as bacteria), for unknown reasons, suddenly begin to attack healthy tissue. These defenses, for reasons not at all understood, attack proteins in the central nervous system, especially aquaporin-4. In some patients with NMOSD, especially those with the non-relapsing variant, antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been discovered. Patients who are seropositive for MOG differ in some respects from those with AQP4-IgG antibodies: they do not have as striking a predilection for women, attacks are less severe and recover better, optic neuritis tends to be associated with more swelling of the optic nerve head and occurs in the anterior optic nerve, whereas myelitis has a somewhat greater predilection for the caudal spinal cord. NMOSD may be immunologically heterogeneous.
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Causes of Neuromyelitis Optica Spectrum Disorder. Greater than 95% of patients with NMOSD report no relatives with the disease, but approximately 3% report having other relatives with the condition. There is a strong association with a personal or family history of autoimmunity, which are present in 50% of cases. NMOSD is regarded as an autoimmune disease though the exact cause for the autoimmunity is unknown.Autoimmune disorders occur when the body’s natural defenses against disease or invading organisms (such as bacteria), for unknown reasons, suddenly begin to attack healthy tissue. These defenses, for reasons not at all understood, attack proteins in the central nervous system, especially aquaporin-4. In some patients with NMOSD, especially those with the non-relapsing variant, antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been discovered. Patients who are seropositive for MOG differ in some respects from those with AQP4-IgG antibodies: they do not have as striking a predilection for women, attacks are less severe and recover better, optic neuritis tends to be associated with more swelling of the optic nerve head and occurs in the anterior optic nerve, whereas myelitis has a somewhat greater predilection for the caudal spinal cord. NMOSD may be immunologically heterogeneous.
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Affects of Neuromyelitis Optica Spectrum Disorder
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NMOSD occurs in individuals of all races. The prevalence of NMOSD is approximately 1-10 per 100,000 individuals and seems to be similar worldwide, although somewhat higher rates have been reported in countries with a higher proportion of individuals of African ancestry. Relative to MS that it mimics, it occurs with greater frequency in individuals of Asian and African descent, but the majority of patients with this illness in Western countries are Caucasian. Individuals of any age may be affected, but typically NMOSD, especially cases seropositive for AQP4-IgG, occur in late middle-aged women. Equal numbers of men and women have the form that does not recur after the initial flurry of attacks, but women, especially those with AQP4-IgG, are four or five times more likely to be affected than men by the recurring (relapsing) form. Children represent may also be affected by this condition; children more commonly develop brain symptoms at onset and seem to have a higher frequency of monophasic presentation than adults.
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Affects of Neuromyelitis Optica Spectrum Disorder. NMOSD occurs in individuals of all races. The prevalence of NMOSD is approximately 1-10 per 100,000 individuals and seems to be similar worldwide, although somewhat higher rates have been reported in countries with a higher proportion of individuals of African ancestry. Relative to MS that it mimics, it occurs with greater frequency in individuals of Asian and African descent, but the majority of patients with this illness in Western countries are Caucasian. Individuals of any age may be affected, but typically NMOSD, especially cases seropositive for AQP4-IgG, occur in late middle-aged women. Equal numbers of men and women have the form that does not recur after the initial flurry of attacks, but women, especially those with AQP4-IgG, are four or five times more likely to be affected than men by the recurring (relapsing) form. Children represent may also be affected by this condition; children more commonly develop brain symptoms at onset and seem to have a higher frequency of monophasic presentation than adults.
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Related disorders of Neuromyelitis Optica Spectrum Disorder
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Symptoms of the following disorders can be similar to those of NMOSD. Comparisons may be useful for a differential diagnosis:Acute disseminated encephalomyelitis (postinfectious encephalitis) is a central nervous system disorder characterized by inflammation of the brain and spinal cord caused by damage to the fatty sheath surrounding the nerves. This can occur spontaneously, but usually follows a viral infection or inoculation such as a bacterial or viral vaccine. Individuals with acute disseminated encephalomyelitis may have MOG-IgG, adding extra confusion.Multiple sclerosis is a chronic disease of the brain and spinal cord (central nervous system) which may be progressive, relapsing and remitting, or stable. The pathology of MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. In these plaques, the fatty sheath surrounding nerves is lost, which prevents proper transmission of nervous system signals and thus result in a variety of neurological symptoms. Most individuals with MS have a near normal life span. Symptoms often include visual difficulties as well as speech impairment, abnormal skin sensations or numbness, gait disturbance, and difficulties with bladder and bowel function. In a small number of cases, selective involvement of the optic nerves and spinal cord may occur in early stages of MS, but in these situations rarely would the spinal cord information extend over long segments of the spinal cord as occurs in NMOSD. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)Systemic lupus erythematosus (also known as lupus) is an inflammatory connective tissue disease that can affect many parts of the body including the joints, skin and internal organs. Lupus is a disease of the body’s immune system, most often striking young women between the ages of fifteen and thirty-five years. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.) Transverse myelitis and optic neuritis have been reported to occur in patients with systemic lupus erythematosus, but recent research demonstrates that a high proportion of such individuals have the NMO-IgG antibody, and likely have coexisting NMOSD.Paraneoplastic disorders are conditions in which patients develop inflammation or cell injury caused by autoimmune reactions to a cancer that leads to production of autoantibodies or cell-mediated autoimmunity. In some paraneoplastic syndromes, particularly those associated with collapsin response mediated protein 5 (CRMP5), optic neuritis and extensive myelitis may occur that may closely simulate NMOSD.Sarcoidosis is a granulomatous disorder that may affect the optic nerves and spinal cord when it affects the central nervous system. This condition frequently presents with pulmonary disease, either symptomatic or asymptomatic, or enlarged lymph nodes, often present on chest xray. Many patients with central nervous system involvement do not have demonstrable sarcoidosis in other organs. Sarcoidosis may result in long inflammatory spinal cord lesions that mimic the myelitis in NMOSD, but symptoms usually develop more insidiously and regress more slowly following corticosteroid treatment.
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Related disorders of Neuromyelitis Optica Spectrum Disorder. Symptoms of the following disorders can be similar to those of NMOSD. Comparisons may be useful for a differential diagnosis:Acute disseminated encephalomyelitis (postinfectious encephalitis) is a central nervous system disorder characterized by inflammation of the brain and spinal cord caused by damage to the fatty sheath surrounding the nerves. This can occur spontaneously, but usually follows a viral infection or inoculation such as a bacterial or viral vaccine. Individuals with acute disseminated encephalomyelitis may have MOG-IgG, adding extra confusion.Multiple sclerosis is a chronic disease of the brain and spinal cord (central nervous system) which may be progressive, relapsing and remitting, or stable. The pathology of MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. In these plaques, the fatty sheath surrounding nerves is lost, which prevents proper transmission of nervous system signals and thus result in a variety of neurological symptoms. Most individuals with MS have a near normal life span. Symptoms often include visual difficulties as well as speech impairment, abnormal skin sensations or numbness, gait disturbance, and difficulties with bladder and bowel function. In a small number of cases, selective involvement of the optic nerves and spinal cord may occur in early stages of MS, but in these situations rarely would the spinal cord information extend over long segments of the spinal cord as occurs in NMOSD. (For more information on this disorder, choose “Multiple Sclerosis” as your search term in the Rare Disease Database.)Systemic lupus erythematosus (also known as lupus) is an inflammatory connective tissue disease that can affect many parts of the body including the joints, skin and internal organs. Lupus is a disease of the body’s immune system, most often striking young women between the ages of fifteen and thirty-five years. (For more information on this disorder, choose “Lupus” as your search term in the Rare Disease Database.) Transverse myelitis and optic neuritis have been reported to occur in patients with systemic lupus erythematosus, but recent research demonstrates that a high proportion of such individuals have the NMO-IgG antibody, and likely have coexisting NMOSD.Paraneoplastic disorders are conditions in which patients develop inflammation or cell injury caused by autoimmune reactions to a cancer that leads to production of autoantibodies or cell-mediated autoimmunity. In some paraneoplastic syndromes, particularly those associated with collapsin response mediated protein 5 (CRMP5), optic neuritis and extensive myelitis may occur that may closely simulate NMOSD.Sarcoidosis is a granulomatous disorder that may affect the optic nerves and spinal cord when it affects the central nervous system. This condition frequently presents with pulmonary disease, either symptomatic or asymptomatic, or enlarged lymph nodes, often present on chest xray. Many patients with central nervous system involvement do not have demonstrable sarcoidosis in other organs. Sarcoidosis may result in long inflammatory spinal cord lesions that mimic the myelitis in NMOSD, but symptoms usually develop more insidiously and regress more slowly following corticosteroid treatment.
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Neuromyelitis Optica Spectrum Disorder
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Diagnosis of Neuromyelitis Optica Spectrum Disorder
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A diagnosis of NMOSD is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. Such tests include blood tests, examination of cerebrospinal fluid (CSF), spinal taps, or x-ray procedures such as magnetic resonance imaging (MRIs) or computed tomography (CT or CAT) scans. A blood test, AQP4-IgG, is highly specific and moderately sensitive for NMOSD. It has been shown that it detects antibodies that are specific for an astrocyte protein, aquaporin-4. This is very helpful to request this test at the first significant suspicion of NMOSD, as it is frequently positive at the time of the very first symptom even before a confident clinical diagnosis is possible. A recently discovered antibody, MOG-IgG, is present in about half of those who do not have AQP4-IgG; while it seems specific for a form of NMOSD, and is rarely seen in typical MS, it also occurs in some patients with recurrent optic neuritis and in some patients with acute disseminated encephalomyelitis; in the latter patients, it is often transient. Successful diagnosis of NMOSD depends on distinguishing it from MS.
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Diagnosis of Neuromyelitis Optica Spectrum Disorder. A diagnosis of NMOSD is made based upon a detailed patient history, a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests. Such tests include blood tests, examination of cerebrospinal fluid (CSF), spinal taps, or x-ray procedures such as magnetic resonance imaging (MRIs) or computed tomography (CT or CAT) scans. A blood test, AQP4-IgG, is highly specific and moderately sensitive for NMOSD. It has been shown that it detects antibodies that are specific for an astrocyte protein, aquaporin-4. This is very helpful to request this test at the first significant suspicion of NMOSD, as it is frequently positive at the time of the very first symptom even before a confident clinical diagnosis is possible. A recently discovered antibody, MOG-IgG, is present in about half of those who do not have AQP4-IgG; while it seems specific for a form of NMOSD, and is rarely seen in typical MS, it also occurs in some patients with recurrent optic neuritis and in some patients with acute disseminated encephalomyelitis; in the latter patients, it is often transient. Successful diagnosis of NMOSD depends on distinguishing it from MS.
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Therapies of Neuromyelitis Optica Spectrum Disorder
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Treatment In 2019, Soliris (eculizumab) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of NMOSD in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. In 2020, Uplizna (inebilizumab-cdon) and Enspryng (satralizumab-mwge) were approved for the treatment of NMOSD in adult patients with the same AQP4 antibody. For acute attacks, the standard treatment is high-dose intravenous corticosteroids, typically methylprednisolone. Plasma exchange may be effective in patients who experience acute severe attacks that do not response to intravenous corticosteroids. This procedure involves removing some blood and mechanically separating the blood cells from the fluid (plasma). Blood cells are then mixed with a replacement solution and returned to the body. For long-term suppression of the disease, a variety of immunosuppressive drugs are regarded by many clinicians as first-line therapy. Corticosteroids, azathioprine, mycophenolate mofetil and rituximab are the treatments most widely prescribed treatments. Typically, azathioprine or mycophenolate mofetil are prescribed along with low doses of corticosteroids. Rituximab has been shown to be helpful in retrospective studies, including in patients who fail first-line immunosuppressive treatments. Immunomodulatory drugs for multiple sclerosis are ineffective, and in the case of interferon beta, there is some evidence that suggest that it may be harmful. Symptom treatment may also involve the use of low doses of carbamazepine to control paroxysmal (sudden) tonic spasms that often occur during attacks of NMOSD and antispasticity agents to treat long term complication of spasticity that frequently develops in those with permanent motor deficits.
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Therapies of Neuromyelitis Optica Spectrum Disorder. Treatment In 2019, Soliris (eculizumab) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of NMOSD in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. In 2020, Uplizna (inebilizumab-cdon) and Enspryng (satralizumab-mwge) were approved for the treatment of NMOSD in adult patients with the same AQP4 antibody. For acute attacks, the standard treatment is high-dose intravenous corticosteroids, typically methylprednisolone. Plasma exchange may be effective in patients who experience acute severe attacks that do not response to intravenous corticosteroids. This procedure involves removing some blood and mechanically separating the blood cells from the fluid (plasma). Blood cells are then mixed with a replacement solution and returned to the body. For long-term suppression of the disease, a variety of immunosuppressive drugs are regarded by many clinicians as first-line therapy. Corticosteroids, azathioprine, mycophenolate mofetil and rituximab are the treatments most widely prescribed treatments. Typically, azathioprine or mycophenolate mofetil are prescribed along with low doses of corticosteroids. Rituximab has been shown to be helpful in retrospective studies, including in patients who fail first-line immunosuppressive treatments. Immunomodulatory drugs for multiple sclerosis are ineffective, and in the case of interferon beta, there is some evidence that suggest that it may be harmful. Symptom treatment may also involve the use of low doses of carbamazepine to control paroxysmal (sudden) tonic spasms that often occur during attacks of NMOSD and antispasticity agents to treat long term complication of spasticity that frequently develops in those with permanent motor deficits.
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Overview of Neuropathic Ocular Pain
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SummaryNeuropathic ocular pain (NOP) refers to a constellation of persistent ocular pain symptoms (i.e., burning, increased sensitivity to light or wind, shooting pains originating in one or both eyes) that may present with or without ocular surface abnormalities.1 In the past, NOP was considered a sub-type dry eye (DE), which is an umbrella term that represents various symptoms (e.g. sensations of dryness, pain, poor or fluctuating vision) and/or signs (e.g. decreased tear production, rapid tear break up, corneal epithelial disruption, ocular surface inflammation, high or unstable tear composition). In recent years, however, there is an understanding that NOP is better represented as an entity on its own.Understanding the epidemiology of NOP is challenging as data regarding symptoms has been buried within the DE literature. Overall, DE symptoms are common in the general population. In the US, a population-based study out of Beaver Dam, Wisconsin found that 14% of individuals between the ages of 48 and 91 years reported symptoms, which included dryness and foreign body sensation.2 A similar frequency was found in Salisbury, Maryland with 15% of the population reporting one or more symptoms (dryness, grittiness, burning, redness, crustiness, eyelids stuck shut) often or all the time.3 These numbers were even higher in Asia, where 34% of participants in a Taiwanese study4 and 28% of participants in an Indonesian study5 reported these same symptoms often or all of the time. Ocular surface abnormalities (e.g. tear film and anatomy) are one cause of ocular symptoms. However, it is well recognized that ocular symptom severity does not correlate well with ocular surface findings6, suggesting that symptoms in many individuals are driven by other factors.One such factor is corneal nerve dysfunction, which may manifest as hyposensitivity (“neurotrophic phenotype”) or hypersensitivity (“neuropathic phenotype”).7 Corneal nerve hyposensitivity often manifests with cornea epithelial cell disruption with minimal ocular symptoms while corneal nerve hypersensitivity often manifests with pain out of proportion to ocular surface findings. In the latter case, ocular pain often persists despite treatment with traditional dry eye treatments.8 A neuropathic origin to ocular pain is suggested in individuals who have a particular set of symptoms (e.g., burning sensation, light or wind sensitivity), risk factors (e.g., pain that started after surgery, migraine, fibromyalgia) and treatment response history (e.g., poor response to therapies aimed at correcting ocular surface abnormalities).9 NOP symptoms can be present in one or both eyes and start spontaneously or after trauma or surgery. NOP can be persistent, agonizing and severely affect quality of life and ability to work. When untreated, persistent symptoms can lead to extreme distress. The severity of symptoms is often not recognized and patients may be seen as drug-seeking or overly anxious by providers. A challenge is that many patients have few physical signs of ocular damage and the underlying cause of symptoms can be overlooked. Thus, there is a need to educate patients, eye care providers and pain specialists on this condition, recognize its effect on patients’ health and functioning and treat patients with empathy and urgency.IntroductionThe cornea has the densest sensory innervation in the body and can be a powerful producer of pain. Ocular surface pain is a frequent cause of visits to eye care providers and pain clinics, with a substantial negative impact on an individuals’ quality of life and mental health. Ocular surface pain can arise from a number of factors including tear film and anatomical abnormalities, environmental exposures and nerve dysfunction of the peripheral and central nerves that connect the cornea and conjunctivae to the brain. Causes of ocular surface pain are typically divided into nociceptive and neuropathic. Nociceptive causes include an unhealthy tear film (e.g., low tear production, rapid tear break up), anatomic abnormalities of the eyelids, conjunctiva and cornea, and environmental insults (e.g., low humidity, air pollution). However, corneal nerves and their central connections may become dysfunctional, leading to ocular surface pain. NOP falls under the umbrella terms of “ocular surface pain”, “ocular pain”, “eye pain” and “oculofacial pain”. NOP is a condition where individuals have ocular surface pain that is generated by nerve dysfunction. While there are no consensus criteria for the diagnosis, new advances in the understanding of clinical presentations and the neurobiology involved in ocular sensation have led to the classification of NOP as a distinct and important disease entity.
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Overview of Neuropathic Ocular Pain. SummaryNeuropathic ocular pain (NOP) refers to a constellation of persistent ocular pain symptoms (i.e., burning, increased sensitivity to light or wind, shooting pains originating in one or both eyes) that may present with or without ocular surface abnormalities.1 In the past, NOP was considered a sub-type dry eye (DE), which is an umbrella term that represents various symptoms (e.g. sensations of dryness, pain, poor or fluctuating vision) and/or signs (e.g. decreased tear production, rapid tear break up, corneal epithelial disruption, ocular surface inflammation, high or unstable tear composition). In recent years, however, there is an understanding that NOP is better represented as an entity on its own.Understanding the epidemiology of NOP is challenging as data regarding symptoms has been buried within the DE literature. Overall, DE symptoms are common in the general population. In the US, a population-based study out of Beaver Dam, Wisconsin found that 14% of individuals between the ages of 48 and 91 years reported symptoms, which included dryness and foreign body sensation.2 A similar frequency was found in Salisbury, Maryland with 15% of the population reporting one or more symptoms (dryness, grittiness, burning, redness, crustiness, eyelids stuck shut) often or all the time.3 These numbers were even higher in Asia, where 34% of participants in a Taiwanese study4 and 28% of participants in an Indonesian study5 reported these same symptoms often or all of the time. Ocular surface abnormalities (e.g. tear film and anatomy) are one cause of ocular symptoms. However, it is well recognized that ocular symptom severity does not correlate well with ocular surface findings6, suggesting that symptoms in many individuals are driven by other factors.One such factor is corneal nerve dysfunction, which may manifest as hyposensitivity (“neurotrophic phenotype”) or hypersensitivity (“neuropathic phenotype”).7 Corneal nerve hyposensitivity often manifests with cornea epithelial cell disruption with minimal ocular symptoms while corneal nerve hypersensitivity often manifests with pain out of proportion to ocular surface findings. In the latter case, ocular pain often persists despite treatment with traditional dry eye treatments.8 A neuropathic origin to ocular pain is suggested in individuals who have a particular set of symptoms (e.g., burning sensation, light or wind sensitivity), risk factors (e.g., pain that started after surgery, migraine, fibromyalgia) and treatment response history (e.g., poor response to therapies aimed at correcting ocular surface abnormalities).9 NOP symptoms can be present in one or both eyes and start spontaneously or after trauma or surgery. NOP can be persistent, agonizing and severely affect quality of life and ability to work. When untreated, persistent symptoms can lead to extreme distress. The severity of symptoms is often not recognized and patients may be seen as drug-seeking or overly anxious by providers. A challenge is that many patients have few physical signs of ocular damage and the underlying cause of symptoms can be overlooked. Thus, there is a need to educate patients, eye care providers and pain specialists on this condition, recognize its effect on patients’ health and functioning and treat patients with empathy and urgency.IntroductionThe cornea has the densest sensory innervation in the body and can be a powerful producer of pain. Ocular surface pain is a frequent cause of visits to eye care providers and pain clinics, with a substantial negative impact on an individuals’ quality of life and mental health. Ocular surface pain can arise from a number of factors including tear film and anatomical abnormalities, environmental exposures and nerve dysfunction of the peripheral and central nerves that connect the cornea and conjunctivae to the brain. Causes of ocular surface pain are typically divided into nociceptive and neuropathic. Nociceptive causes include an unhealthy tear film (e.g., low tear production, rapid tear break up), anatomic abnormalities of the eyelids, conjunctiva and cornea, and environmental insults (e.g., low humidity, air pollution). However, corneal nerves and their central connections may become dysfunctional, leading to ocular surface pain. NOP falls under the umbrella terms of “ocular surface pain”, “ocular pain”, “eye pain” and “oculofacial pain”. NOP is a condition where individuals have ocular surface pain that is generated by nerve dysfunction. While there are no consensus criteria for the diagnosis, new advances in the understanding of clinical presentations and the neurobiology involved in ocular sensation have led to the classification of NOP as a distinct and important disease entity.
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Symptoms of Neuropathic Ocular Pain
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Symptoms of NOP include a host of ocular pain symptoms that have been described as dryness (with minimal or no relief with over-the-counter lubricating drops), burning, shooting, pressure-like pain, foreign body sensation, grittiness, aching, stabbing or cutting sensation and/or throbbing. Pain may occur spontaneously or be evoked by light (e.g., fluorescent room lights, sunlight), wind (e.g., indoor fans, in-clinic “air puff test” for eye pressure) and/or temperature changes (e.g., air conditioning, hair dryers, seasonal variation). One or both eyes may be involved. The onset may be sudden, as is usually the case when there is an identifiable trigger (such as trauma or surgery to the eye) or insidious. While the pain is typically chronic, its severity can range from mild to excruciating.10Symptoms of NOP may be isolated to the eyes, but many individuals experience pain or aching in areas around the eye (e.g., heavy eyelids, pressure around the eyes, aching in the cheek bones, forehead, or temple) or describe pain radiating from the eye to the back of the head.Visible ocular defects are notably absent or out of proportion to ocular surface findings in many cases of NOP. Given the shared and interrelated symptomatic pictures of NOP and dry eye, a thorough ocular surface examination is indicated when either condition is suspected. In general, absent or minimal signs of ocular surface disease (e.g., corneal epithelial disruption, low tear production, rapid tear break-up, anatomical abnormalities, meibomian gland dysfunction) points to NOP as a potential contributor to pain.
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Symptoms of Neuropathic Ocular Pain. Symptoms of NOP include a host of ocular pain symptoms that have been described as dryness (with minimal or no relief with over-the-counter lubricating drops), burning, shooting, pressure-like pain, foreign body sensation, grittiness, aching, stabbing or cutting sensation and/or throbbing. Pain may occur spontaneously or be evoked by light (e.g., fluorescent room lights, sunlight), wind (e.g., indoor fans, in-clinic “air puff test” for eye pressure) and/or temperature changes (e.g., air conditioning, hair dryers, seasonal variation). One or both eyes may be involved. The onset may be sudden, as is usually the case when there is an identifiable trigger (such as trauma or surgery to the eye) or insidious. While the pain is typically chronic, its severity can range from mild to excruciating.10Symptoms of NOP may be isolated to the eyes, but many individuals experience pain or aching in areas around the eye (e.g., heavy eyelids, pressure around the eyes, aching in the cheek bones, forehead, or temple) or describe pain radiating from the eye to the back of the head.Visible ocular defects are notably absent or out of proportion to ocular surface findings in many cases of NOP. Given the shared and interrelated symptomatic pictures of NOP and dry eye, a thorough ocular surface examination is indicated when either condition is suspected. In general, absent or minimal signs of ocular surface disease (e.g., corneal epithelial disruption, low tear production, rapid tear break-up, anatomical abnormalities, meibomian gland dysfunction) points to NOP as a potential contributor to pain.
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Causes of Neuropathic Ocular Pain
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The exact cause of NOP is not fully understood and onset may occur in the presence or absence of a particular trigger. It is suggested that any initial insult to the eye may result in chronic nerve abnormalities in susceptible individuals, manifesting as chronic ocular pain. The initial trigger may be any of the following: Symptoms of NOP often begin soon after an initial trigger but can have a delayed onset. Refractive surgeries (e.g., laser assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK)) have been most closely aligned with NOP although chronic ocular pain can occur after any ocular surgery. NOP can co-exist with ocular surface abnormalities (e.g., tear film, epithelial irregularity, degenerative processes) and these abnormalities may further impact peripheral nerve function. Nevertheless, NOP often occurs in the absence of any identifiable cause and does not require any initial damage to the eye for diagnosis.At a deeper level, NOP is thought to occur due to nerve abnormalities (i.e. sensitization) at the peripheral level (i.e., corneal surface) and/or in central pathways (i.e., trigeminal sensory pathway, thalamus, cerebral cortex). These changes result in over-activation of sensory neurons, experienced as pain with subnormal inputs (hyperalgesia) or abnormal inputs (allodynia).11 In the eye, hyperalgesia is often experienced as sensitivity to wind and allodynia as sensitivity to light. Importantly, nerve changes are dynamic, and there is no timetable for development of abnormalities or improvement in function. Thus, treatments may improve nerve function and pain even years after the onset of symptoms.
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Causes of Neuropathic Ocular Pain. The exact cause of NOP is not fully understood and onset may occur in the presence or absence of a particular trigger. It is suggested that any initial insult to the eye may result in chronic nerve abnormalities in susceptible individuals, manifesting as chronic ocular pain. The initial trigger may be any of the following: Symptoms of NOP often begin soon after an initial trigger but can have a delayed onset. Refractive surgeries (e.g., laser assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK)) have been most closely aligned with NOP although chronic ocular pain can occur after any ocular surgery. NOP can co-exist with ocular surface abnormalities (e.g., tear film, epithelial irregularity, degenerative processes) and these abnormalities may further impact peripheral nerve function. Nevertheless, NOP often occurs in the absence of any identifiable cause and does not require any initial damage to the eye for diagnosis.At a deeper level, NOP is thought to occur due to nerve abnormalities (i.e. sensitization) at the peripheral level (i.e., corneal surface) and/or in central pathways (i.e., trigeminal sensory pathway, thalamus, cerebral cortex). These changes result in over-activation of sensory neurons, experienced as pain with subnormal inputs (hyperalgesia) or abnormal inputs (allodynia).11 In the eye, hyperalgesia is often experienced as sensitivity to wind and allodynia as sensitivity to light. Importantly, nerve changes are dynamic, and there is no timetable for development of abnormalities or improvement in function. Thus, treatments may improve nerve function and pain even years after the onset of symptoms.
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Affects of Neuropathic Ocular Pain
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NOP may affect individuals of any age, sex, ethnicity, or background. NOP often occurs with pain in other areas of the body (e.g., fibromyalgia, chronic joint pain, peripheral neuropathy) and migraine headaches (both with and without ocular aura).12 Many individuals with NOP also have mood disorders (e.g., depression, anxiety), although it is not understood if this is a cause or consequence of disease or if both entities share common underlying factors. Global abnormalities in sensory processing (e.g., glial activation, pre- and post-synaptic upregulation, neuro-inflammation), systemic inflammation and genetic predisposition have all been implicated in the development of chronic pain and are areas of research focus for NOP.
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Affects of Neuropathic Ocular Pain. NOP may affect individuals of any age, sex, ethnicity, or background. NOP often occurs with pain in other areas of the body (e.g., fibromyalgia, chronic joint pain, peripheral neuropathy) and migraine headaches (both with and without ocular aura).12 Many individuals with NOP also have mood disorders (e.g., depression, anxiety), although it is not understood if this is a cause or consequence of disease or if both entities share common underlying factors. Global abnormalities in sensory processing (e.g., glial activation, pre- and post-synaptic upregulation, neuro-inflammation), systemic inflammation and genetic predisposition have all been implicated in the development of chronic pain and are areas of research focus for NOP.
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Related disorders of Neuropathic Ocular Pain
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Many conditions and events (e.g., infection, trauma or surgery, chemical/toxin exposure, allergy, dry eye, other ocular conditions) can irritate the ocular surface and lead to symptoms of ocular pain which can manifest as sensations of dryness, grittiness, itchiness, burning, wind or light sensitivity and more. Thus, all such ocular conditions must be in the differential of NOP and should be evaluated for in the eye clinic. As above, dry eye (DE) in particular is closely associated with NOP as many individuals with NOP have been diagnosed as having DE. DE is an umbrella term that includes ocular symptoms often alongside ocular signs (e.g., low tear production, rapid tear break-up, corneal epithelial disruption manifesting as corneal staining, crusting of the eyelashes, plugging or dropout of meibomian glands). DE is further divided into sub-types. Aqueous tear deficiency (ATD) is defined by reduced tear production and is often accompanied by ocular surface inflammation. ATD is closely related to systemic immune conditions such as Sjögren syndrome and graft-versus-host disease. Evaporative tear deficiency (ETD) is defined by normal tear production and rapid tear break-up time. ETD is closely related to periocular skin diseases such as rosacea. Some view NOP as a subclassification of DE, while others view it as a separate diagnosis. Regardless, given significant overlap in symptoms, a thorough eye examination is warranted, and all other potential contributors to pain should be addressed and treated in any person suspected of NOP to prevent further ocular damage and an exacerbation of symptoms.Referred pain may also present similarly to NOP, as abnormalities in other areas of the face (e.g., temporomandibular joint, dental tissues) can present with ocular pain. In fact, in anecdotal cases, treatment of such abnormalities (e.g. improving denture fit) improved eye pain. As such, a broad differential needs to be considered for eye pain, including disorders outside the eye.
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Related disorders of Neuropathic Ocular Pain. Many conditions and events (e.g., infection, trauma or surgery, chemical/toxin exposure, allergy, dry eye, other ocular conditions) can irritate the ocular surface and lead to symptoms of ocular pain which can manifest as sensations of dryness, grittiness, itchiness, burning, wind or light sensitivity and more. Thus, all such ocular conditions must be in the differential of NOP and should be evaluated for in the eye clinic. As above, dry eye (DE) in particular is closely associated with NOP as many individuals with NOP have been diagnosed as having DE. DE is an umbrella term that includes ocular symptoms often alongside ocular signs (e.g., low tear production, rapid tear break-up, corneal epithelial disruption manifesting as corneal staining, crusting of the eyelashes, plugging or dropout of meibomian glands). DE is further divided into sub-types. Aqueous tear deficiency (ATD) is defined by reduced tear production and is often accompanied by ocular surface inflammation. ATD is closely related to systemic immune conditions such as Sjögren syndrome and graft-versus-host disease. Evaporative tear deficiency (ETD) is defined by normal tear production and rapid tear break-up time. ETD is closely related to periocular skin diseases such as rosacea. Some view NOP as a subclassification of DE, while others view it as a separate diagnosis. Regardless, given significant overlap in symptoms, a thorough eye examination is warranted, and all other potential contributors to pain should be addressed and treated in any person suspected of NOP to prevent further ocular damage and an exacerbation of symptoms.Referred pain may also present similarly to NOP, as abnormalities in other areas of the face (e.g., temporomandibular joint, dental tissues) can present with ocular pain. In fact, in anecdotal cases, treatment of such abnormalities (e.g. improving denture fit) improved eye pain. As such, a broad differential needs to be considered for eye pain, including disorders outside the eye.
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Diagnosis of Neuropathic Ocular Pain
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A thorough history and clinical exam is essential to a diagnosis of NOP. As there are no universal criteria for diagnosis, NOP remains a clinical diagnosis. A combination of history, symptoms, physical examination and imaging findings are used to arrive at a diagnosis of NOP, after excluding other causes of ocular pain. The examination of an individual with suspected NOP begins with a comprehensive history, capturing initial triggers for pain, its time course, alleviating and exacerbating factors and treatment history.It is helpful to assess current symptoms using standardized questionnaires to determine the severity and nature of symptoms, associated factors and functional disability. The modified Neuropathic Pain Symptom Inventory (NPSI-Eye)13 and the Ocular Pain Assessment Survey (OPAS)14 are two validated questionnaires that assess, quantify and characterize pain symptoms. In addition, the OPAS evaluates impact of pain on quality of life. These questionnaires can be used to determine baseline symptoms, guide treatment and monitor for changes over time.One clinical indicator of NOP is disproportionately intense symptoms in the presence of few or minimal signs of ocular surface disease. Thus, an unremarkable ocular surface exam, or persistent/unchanged symptoms after treatment of the ocular surface should raise the possibility that neuropathic mechanisms underlie pain. In particular, topical lubricating drops often provide no or minimal alleviation of ocular symptoms and can even exacerbate symptoms in individuals with NOP.Corneal sensitivity can be examined in clinic with the use of a cotton tip or dental floss. Corneal sensation is measured in all ‘quadrants’ (central, superior, inferior, nasal, temporal) or simply in the center of the cornea. In the clinical arena, sensitivity is often assessed qualitatively using a 0-3 numerical scale (0= no sensation, 1=reduced, 2=normal, and 3=increased). In the research arena, sensitivity can be evaluated using more sophisticated tools, namely the Cochet-Bonnet or Belmonte aesthesiometers. The Cochet-Bonnet utilizes a 6cm nylon microfilament that is slowly brought in contact with the cornea and retracted until sensation is felt. Corneal sensation is quantified on a 0-6 cm scale, with 0 cm representing no sensation and 6 cm full sensation. A limitation of Cochet-Bonnet is that most healthy individuals can detect the sensation at 6 cm, thus limiting the ability to test for hypersensitivity. The Belmonte aesthesiometer is not commercially available. It applies a non-contact air jet to the cornea to generate mechanical (air flow), thermal (hot and cold air pulses), or chemical (varying CO2 concentrations) stimuli. It has a wider testing range and can determine sensation and pain thresholds in each eye. While both decreased and increased corneal sensation can be seen in NOP, individuals with NOP most often report corneal hypersensitivity.Testing the effect of a topical anesthetic on pain can be used to differentiate peripheral versus central sources of pain. Application of a topical anesthetic (such as proparacaine 0.5%) quiets corneal nerve inputs and thus largely eliminates nociceptive and peripheral neuropathic sources of pain. Individuals who experience persistent pain after anesthesia (30 seconds to 2 minutes after placement of anesthesia) are likely to have centrally mediated or non-ocular surface sources of pain. Imaging of the cornea using in vivo confocal microscopy (IVCM) provides an anatomic picture of corneal nerves and inflammatory cells, most often in the central cornea.15 The subbasal nerve plexus, just under the corneal basal epithelium, is commonly imaged although nerves can also be detected in the stroma. Nerve abnormalities have been described in the setting of various DED sub-types, most often decreased nerve density and an increased number of inflammatory cells in individuals with ATD (i.e., decreased tear production) and systemic immune disorders.16 Microneuromas, or abrupt endings of nerve fibers on imaging, have been identified as potential markers of peripheral neuropathic pain17, although this finding has not been replicated by other groups.18
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Diagnosis of Neuropathic Ocular Pain. A thorough history and clinical exam is essential to a diagnosis of NOP. As there are no universal criteria for diagnosis, NOP remains a clinical diagnosis. A combination of history, symptoms, physical examination and imaging findings are used to arrive at a diagnosis of NOP, after excluding other causes of ocular pain. The examination of an individual with suspected NOP begins with a comprehensive history, capturing initial triggers for pain, its time course, alleviating and exacerbating factors and treatment history.It is helpful to assess current symptoms using standardized questionnaires to determine the severity and nature of symptoms, associated factors and functional disability. The modified Neuropathic Pain Symptom Inventory (NPSI-Eye)13 and the Ocular Pain Assessment Survey (OPAS)14 are two validated questionnaires that assess, quantify and characterize pain symptoms. In addition, the OPAS evaluates impact of pain on quality of life. These questionnaires can be used to determine baseline symptoms, guide treatment and monitor for changes over time.One clinical indicator of NOP is disproportionately intense symptoms in the presence of few or minimal signs of ocular surface disease. Thus, an unremarkable ocular surface exam, or persistent/unchanged symptoms after treatment of the ocular surface should raise the possibility that neuropathic mechanisms underlie pain. In particular, topical lubricating drops often provide no or minimal alleviation of ocular symptoms and can even exacerbate symptoms in individuals with NOP.Corneal sensitivity can be examined in clinic with the use of a cotton tip or dental floss. Corneal sensation is measured in all ‘quadrants’ (central, superior, inferior, nasal, temporal) or simply in the center of the cornea. In the clinical arena, sensitivity is often assessed qualitatively using a 0-3 numerical scale (0= no sensation, 1=reduced, 2=normal, and 3=increased). In the research arena, sensitivity can be evaluated using more sophisticated tools, namely the Cochet-Bonnet or Belmonte aesthesiometers. The Cochet-Bonnet utilizes a 6cm nylon microfilament that is slowly brought in contact with the cornea and retracted until sensation is felt. Corneal sensation is quantified on a 0-6 cm scale, with 0 cm representing no sensation and 6 cm full sensation. A limitation of Cochet-Bonnet is that most healthy individuals can detect the sensation at 6 cm, thus limiting the ability to test for hypersensitivity. The Belmonte aesthesiometer is not commercially available. It applies a non-contact air jet to the cornea to generate mechanical (air flow), thermal (hot and cold air pulses), or chemical (varying CO2 concentrations) stimuli. It has a wider testing range and can determine sensation and pain thresholds in each eye. While both decreased and increased corneal sensation can be seen in NOP, individuals with NOP most often report corneal hypersensitivity.Testing the effect of a topical anesthetic on pain can be used to differentiate peripheral versus central sources of pain. Application of a topical anesthetic (such as proparacaine 0.5%) quiets corneal nerve inputs and thus largely eliminates nociceptive and peripheral neuropathic sources of pain. Individuals who experience persistent pain after anesthesia (30 seconds to 2 minutes after placement of anesthesia) are likely to have centrally mediated or non-ocular surface sources of pain. Imaging of the cornea using in vivo confocal microscopy (IVCM) provides an anatomic picture of corneal nerves and inflammatory cells, most often in the central cornea.15 The subbasal nerve plexus, just under the corneal basal epithelium, is commonly imaged although nerves can also be detected in the stroma. Nerve abnormalities have been described in the setting of various DED sub-types, most often decreased nerve density and an increased number of inflammatory cells in individuals with ATD (i.e., decreased tear production) and systemic immune disorders.16 Microneuromas, or abrupt endings of nerve fibers on imaging, have been identified as potential markers of peripheral neuropathic pain17, although this finding has not been replicated by other groups.18
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Therapies of Neuropathic Ocular Pain
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Treatment
The goal of treatment in individuals with NOP is to improve nerve function and further to treat and avoid noxious stimuli that can worsen the neuropathic cascade. As such, following a thorough evaluation, the first step in management is to treat all nociceptive sources of pain, as ongoing nociceptive traffic can lead to peripheral nerve abnormalities. These include therapies such as artificial tears, topical anti-inflammatories (e.g., short term corticosteroids, cyclosporine, lifitegrast), nutritional supplements (e.g., omega-3 supplementation) and antibiotics (e.g. azithromycin). However, if pain persists despite these therapies or in individuals with the appropriate history and clinical findings (i.e. pain out of proportion to ocular surface signs, corneal hypersensitivity, persistent pain after anesthesia), therapies targeting underlying neural pathways should be considered.When starting therapy in an individual with NOP, a realistic understanding of the treatment approach is important. Important features include an understanding that:With these points in mind, within a multimodal approach, pain does improve to some extent in most people with NOP, followed by improvements in the ability work and function.In individuals with a suspected central component to pain, systemic neuromodulators are often used. α2δ-calcium channel blockers are first-line oral options for treating neuropathic pain and are used for eye pain, including gabapentin (initiated at 300 mg daily and titrated to a therapeutic goal of 600-900mg TID, must be adjusted for renal insufficiency) and pregabalin (initiated at 75 mg daily and titrated to 150mg BID).19 Other oral neuromodulators may be used alone or in conjunction with α2δ ligands. These include tricyclic antidepressants (TCAs, e.g., nortriptyline initiated at 10-25 mg and titrated to 50-100mg once daily), and serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., duloxetine initiated at 20 mg and titrated up to 60mg once daily).In individuals with a suspected peripheral component to pain, local therapies can be tried, including blood products.20 After a peripheral blood draw, serum is extracted and diluted for use as autologous serum tears (AST). ASTs contain several growth factors that are beneficial for nerve and epithelial health (e.g. nerve growth factor (NGF), epithelial growth factor (EGF), transforming growth factor-β (TGF-β) and other vitamins. Platelet rich plasma (PRP) is another blood-derived product that provides an even higher concentration of growth factors and cell adhesion molecules than AST and has been used to treat post-LASIK eye pain among other ocular surface conditions.21 Availability of blood products, however, may be limited to academic centers and blood-processing eye banks.There is a strong association between NOP and other neurologic and psychiatric mood disorders, and interdisciplinary treatment is imperative to the delivery of effective holistic care. Individuals with NOP frequently suffer from depression, anxiety, insomnia and post-traumatic stress disorder. Further, neuropathic eye pain often coexists with neuropathic pain elsewhere in the body, manifesting as joint/back pain, fibromyalgia and other chronic pain disorders. These conditions are common and can be functionally debilitating. Individualized and regular support from providers, both medical and mental health, can be instrumental in helping patients cope with these distressing and chronic conditions. Eye care providers should form partnerships with appropriate individuals to facilitate the holistic care of patients. The multidisciplinary team may include a neurologist, pain or headache specialist, acupuncturist, psychologist, psychiatrist and primary care physician, as appropriate. As in other pain conditions, psychotherapy techniques (e.g., cognitive behavioral, desensitization, relaxation and acceptance-based therapies) can be helpful. Restoring patient comfort and function are fundamental goals of treatment which requires the destigmatized management of underlying psychiatric and neurologic conditions with individualized and multitargeted systemic approaches.
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Therapies of Neuropathic Ocular Pain. Treatment
The goal of treatment in individuals with NOP is to improve nerve function and further to treat and avoid noxious stimuli that can worsen the neuropathic cascade. As such, following a thorough evaluation, the first step in management is to treat all nociceptive sources of pain, as ongoing nociceptive traffic can lead to peripheral nerve abnormalities. These include therapies such as artificial tears, topical anti-inflammatories (e.g., short term corticosteroids, cyclosporine, lifitegrast), nutritional supplements (e.g., omega-3 supplementation) and antibiotics (e.g. azithromycin). However, if pain persists despite these therapies or in individuals with the appropriate history and clinical findings (i.e. pain out of proportion to ocular surface signs, corneal hypersensitivity, persistent pain after anesthesia), therapies targeting underlying neural pathways should be considered.When starting therapy in an individual with NOP, a realistic understanding of the treatment approach is important. Important features include an understanding that:With these points in mind, within a multimodal approach, pain does improve to some extent in most people with NOP, followed by improvements in the ability work and function.In individuals with a suspected central component to pain, systemic neuromodulators are often used. α2δ-calcium channel blockers are first-line oral options for treating neuropathic pain and are used for eye pain, including gabapentin (initiated at 300 mg daily and titrated to a therapeutic goal of 600-900mg TID, must be adjusted for renal insufficiency) and pregabalin (initiated at 75 mg daily and titrated to 150mg BID).19 Other oral neuromodulators may be used alone or in conjunction with α2δ ligands. These include tricyclic antidepressants (TCAs, e.g., nortriptyline initiated at 10-25 mg and titrated to 50-100mg once daily), and serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., duloxetine initiated at 20 mg and titrated up to 60mg once daily).In individuals with a suspected peripheral component to pain, local therapies can be tried, including blood products.20 After a peripheral blood draw, serum is extracted and diluted for use as autologous serum tears (AST). ASTs contain several growth factors that are beneficial for nerve and epithelial health (e.g. nerve growth factor (NGF), epithelial growth factor (EGF), transforming growth factor-β (TGF-β) and other vitamins. Platelet rich plasma (PRP) is another blood-derived product that provides an even higher concentration of growth factors and cell adhesion molecules than AST and has been used to treat post-LASIK eye pain among other ocular surface conditions.21 Availability of blood products, however, may be limited to academic centers and blood-processing eye banks.There is a strong association between NOP and other neurologic and psychiatric mood disorders, and interdisciplinary treatment is imperative to the delivery of effective holistic care. Individuals with NOP frequently suffer from depression, anxiety, insomnia and post-traumatic stress disorder. Further, neuropathic eye pain often coexists with neuropathic pain elsewhere in the body, manifesting as joint/back pain, fibromyalgia and other chronic pain disorders. These conditions are common and can be functionally debilitating. Individualized and regular support from providers, both medical and mental health, can be instrumental in helping patients cope with these distressing and chronic conditions. Eye care providers should form partnerships with appropriate individuals to facilitate the holistic care of patients. The multidisciplinary team may include a neurologist, pain or headache specialist, acupuncturist, psychologist, psychiatrist and primary care physician, as appropriate. As in other pain conditions, psychotherapy techniques (e.g., cognitive behavioral, desensitization, relaxation and acceptance-based therapies) can be helpful. Restoring patient comfort and function are fundamental goals of treatment which requires the destigmatized management of underlying psychiatric and neurologic conditions with individualized and multitargeted systemic approaches.
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Overview of Neuropathy, Congenital Hypomyelination
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Congenital hypomyelination neuropathy (CHN) is a neurological disorder present at birth. Major symptoms may include respiratory difficulty, muscle weakness and incoordination, poor muscle tone (neonatal hypotonia), absence of reflexes (areflexia), difficulty in walking (ataxia), and/or impaired abilities to feel or move part of the body.
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Overview of Neuropathy, Congenital Hypomyelination. Congenital hypomyelination neuropathy (CHN) is a neurological disorder present at birth. Major symptoms may include respiratory difficulty, muscle weakness and incoordination, poor muscle tone (neonatal hypotonia), absence of reflexes (areflexia), difficulty in walking (ataxia), and/or impaired abilities to feel or move part of the body.
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Symptoms of Neuropathy, Congenital Hypomyelination
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Symptoms of congenital hypomyelination neuropathy and the severity of these symptoms vary from patient to patient. Major symptoms can include delayed motor (muscle) development (ability to turn over, stand, crawl, walk, etc.), muscle weakness, poor muscle tone (hypotonia), impaired muscle coordination, absence of reflexes (areflexia), difficulty in walking or crawling, and/or impaired ability to feel or move part of the body (mild distal palsy). In some infants, respiratory problems or difficulty in swallowing may occur. Abnormal microscopic changes in certain nerves such as sural nerves (located in the calf of the leg) can occur.
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Symptoms of Neuropathy, Congenital Hypomyelination. Symptoms of congenital hypomyelination neuropathy and the severity of these symptoms vary from patient to patient. Major symptoms can include delayed motor (muscle) development (ability to turn over, stand, crawl, walk, etc.), muscle weakness, poor muscle tone (hypotonia), impaired muscle coordination, absence of reflexes (areflexia), difficulty in walking or crawling, and/or impaired ability to feel or move part of the body (mild distal palsy). In some infants, respiratory problems or difficulty in swallowing may occur. Abnormal microscopic changes in certain nerves such as sural nerves (located in the calf of the leg) can occur.
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Causes of Neuropathy, Congenital Hypomyelination
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The exact cause of congenital hypomyelination neuropathy is not known. The cause of many disorders involving the myelin sheath (the protective sheath surrounding the nerves), such as multiple sclerosis, is unknown. A recurrent loss and repair of myelin causes congenital hypomyelination neuropathy. Scientists do not yet know why the myelin disappears, nor do they know why it grows back.Researchers have identified changes (mutations) in more than one gene involved in the process of myelin formation. However, it is not well understood at this time how such changes may be related to the development of congenital mypomyelination neuropathy.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. 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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. 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.
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Causes of Neuropathy, Congenital Hypomyelination. The exact cause of congenital hypomyelination neuropathy is not known. The cause of many disorders involving the myelin sheath (the protective sheath surrounding the nerves), such as multiple sclerosis, is unknown. A recurrent loss and repair of myelin causes congenital hypomyelination neuropathy. Scientists do not yet know why the myelin disappears, nor do they know why it grows back.Researchers have identified changes (mutations) in more than one gene involved in the process of myelin formation. However, it is not well understood at this time how such changes may be related to the development of congenital mypomyelination neuropathy.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. 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. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. 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.
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Affects of Neuropathy, Congenital Hypomyelination
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Congenital hypomyelination neuropathy is a rare disorder present at birth. It affects males and females in equal numbers.
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Affects of Neuropathy, Congenital Hypomyelination. Congenital hypomyelination neuropathy is a rare disorder present at birth. It affects males and females in equal numbers.
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Related disorders of Neuropathy, Congenital Hypomyelination
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Symptoms of the following diseases may be similar to those of congenital hypomyelination neuropathy.Dejerine-Sottas disease is a hereditary neurological disorder which progressively affects muscle function. Peripheral nerves become enlarged and thickened causing an irregular progression of muscle weakness. Pain, weakness, numbness, and a tingling, prickling or burning sensation can occur in the patient's legs. Other symptoms include loss of heat sensitivity, absence of reflexes and atrophy of leg muscles. The hand and forearm muscles may become weak in later stages. Mild vision difficulties may also occur. (For more information on this disorder, choose “Dejerine-Sottas” as your search term in the Rare Disease Database.)Guillain-Barre syndrome (acute idiopathic polyneuritis) occurs when the body's immune system (antibodies, lymphocytes) attacks the nerves, damaging the nerve's myelin and axon. Nerve signals are delayed and altered, causing weakness and paralysis of the muscles of the legs, arms, and other parts of the body along with abnormal sensations. When muscle nerves are damaged, the patient experiences aching and weak muscles, difficulty getting up from chairs or walking stairs, difficulty lifting objects, shortness of breath, and/or difficulty in swallowing. With proper treatment, most patients with Guillain-Barre syndrome can expect to lead full and active lives. (For more information on this disorder, choose “Guillain” as your search term in the Rare Disease Database.)
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Related disorders of Neuropathy, Congenital Hypomyelination. Symptoms of the following diseases may be similar to those of congenital hypomyelination neuropathy.Dejerine-Sottas disease is a hereditary neurological disorder which progressively affects muscle function. Peripheral nerves become enlarged and thickened causing an irregular progression of muscle weakness. Pain, weakness, numbness, and a tingling, prickling or burning sensation can occur in the patient's legs. Other symptoms include loss of heat sensitivity, absence of reflexes and atrophy of leg muscles. The hand and forearm muscles may become weak in later stages. Mild vision difficulties may also occur. (For more information on this disorder, choose “Dejerine-Sottas” as your search term in the Rare Disease Database.)Guillain-Barre syndrome (acute idiopathic polyneuritis) occurs when the body's immune system (antibodies, lymphocytes) attacks the nerves, damaging the nerve's myelin and axon. Nerve signals are delayed and altered, causing weakness and paralysis of the muscles of the legs, arms, and other parts of the body along with abnormal sensations. When muscle nerves are damaged, the patient experiences aching and weak muscles, difficulty getting up from chairs or walking stairs, difficulty lifting objects, shortness of breath, and/or difficulty in swallowing. With proper treatment, most patients with Guillain-Barre syndrome can expect to lead full and active lives. (For more information on this disorder, choose “Guillain” as your search term in the Rare Disease Database.)
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Diagnosis of Neuropathy, Congenital Hypomyelination
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Testing for congenital hypomyelination neuropathy includes measuring the velocity of transmission of electrical impulses produced by the muscles (electromyogram), as well as nerve and/or muscle biopsies.
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Diagnosis of Neuropathy, Congenital Hypomyelination. Testing for congenital hypomyelination neuropathy includes measuring the velocity of transmission of electrical impulses produced by the muscles (electromyogram), as well as nerve and/or muscle biopsies.
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Therapies of Neuropathy, Congenital Hypomyelination
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TreatmentTreatment of congenital hypomyelination neuropathy is symptomatic and supportive.
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Therapies of Neuropathy, Congenital Hypomyelination. TreatmentTreatment of congenital hypomyelination neuropathy is symptomatic and supportive.
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Overview of Neurotrophic Keratitis
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Summary Neurotrophic keratitis is a rare eye disorder that affects the cornea. The cornea is the clear (transparent) outer layer of the eye. It functions like a window that focuses the entry of light into the eye. The cornea bends light allowing it to pass through the pupil of the eye, eventually reaching the retina, where specialized cells called cones and rods convert light to nerve impulses. These impulses travel along the optic nerve to the brain to become images. Neurotrophic keratitis is caused when the nerves that serve (innervate) the cornea cannot function properly; these nerves carry impulses that help the cornea function. Neurotrophic keratitis causes reduced sensitivity of the cornea. When the cornea senses stimulation or pressure, the eyelids will close and tears will be produced to protect the cornea and the eye. Because these nerves do not function properly in neurotrophic keratitis, the outer layer of the cornea, called the epithelium, can break down, resulting in an epithelial defect. In more advanced neurotrophic keratitis, an interior layer called the cornea stroma can break down as well, resulting in thinning of the cornea. This is called stromal ‘melting’. In advanced stromal melting, the cornea can thin to a severe degree, which can result in a hole or opening to the inside of the eye, which can lead to infection and potentially loss of the eye. Neurotrophic keratitis can lead to a variety of complications, including poor wound healing of the cornea, scarring of the cornea, and loss of vision. There are many different conditions that can damage the nerves serving the cornea. A variety of therapies can be used to treat this disorder depending on how far the disorder has progressed in an individual.
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Overview of Neurotrophic Keratitis. Summary Neurotrophic keratitis is a rare eye disorder that affects the cornea. The cornea is the clear (transparent) outer layer of the eye. It functions like a window that focuses the entry of light into the eye. The cornea bends light allowing it to pass through the pupil of the eye, eventually reaching the retina, where specialized cells called cones and rods convert light to nerve impulses. These impulses travel along the optic nerve to the brain to become images. Neurotrophic keratitis is caused when the nerves that serve (innervate) the cornea cannot function properly; these nerves carry impulses that help the cornea function. Neurotrophic keratitis causes reduced sensitivity of the cornea. When the cornea senses stimulation or pressure, the eyelids will close and tears will be produced to protect the cornea and the eye. Because these nerves do not function properly in neurotrophic keratitis, the outer layer of the cornea, called the epithelium, can break down, resulting in an epithelial defect. In more advanced neurotrophic keratitis, an interior layer called the cornea stroma can break down as well, resulting in thinning of the cornea. This is called stromal ‘melting’. In advanced stromal melting, the cornea can thin to a severe degree, which can result in a hole or opening to the inside of the eye, which can lead to infection and potentially loss of the eye. Neurotrophic keratitis can lead to a variety of complications, including poor wound healing of the cornea, scarring of the cornea, and loss of vision. There are many different conditions that can damage the nerves serving the cornea. A variety of therapies can be used to treat this disorder depending on how far the disorder has progressed in an individual.
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Neurotrophic Keratitis
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Symptoms of Neurotrophic Keratitis
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Early on, affected individuals may not have any symptoms of the disorder (asymptomatic). Because the sensitivity of the cornea is reduced, affected individuals often do not complain of pain or discomfort in the eye. Blurred vision, red eyes, dry eyes, and decreased clarity (acuity) of vision can develop. Affected individuals may become extremely sensitive to light (photophobia). The affected cornea can be injured easily and it heals itself slower than an unaffected cornea does (poor wound healing). This leaves the cornea susceptible to damage. Affected individuals may experience frequent or recurrent corneal erosions, which is when an opening in the epithelial layer develops (epithelial defect). Since the epithelial layer is the protective layer of the cornea, an epithelial defect can leave the eye more susceptible to infection.More serious complications can develop including irregular astigmatism, a condition causing blurred vision that results when the cornea becomes irregularly shaped or abnormally curved. Affected individuals may develop scarring of the cornea. As the inner layer called the stroma breaks down and becomes thinner, the cornea can become even more irregularly shaped, and more severe scarring can develop. In the most severe instances, the cornea can perforate, resulting in loss of the inner fluid of the eye. Neurotrophic keratitis can lead to permanent loss of vision if not properly treated.
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Symptoms of Neurotrophic Keratitis. Early on, affected individuals may not have any symptoms of the disorder (asymptomatic). Because the sensitivity of the cornea is reduced, affected individuals often do not complain of pain or discomfort in the eye. Blurred vision, red eyes, dry eyes, and decreased clarity (acuity) of vision can develop. Affected individuals may become extremely sensitive to light (photophobia). The affected cornea can be injured easily and it heals itself slower than an unaffected cornea does (poor wound healing). This leaves the cornea susceptible to damage. Affected individuals may experience frequent or recurrent corneal erosions, which is when an opening in the epithelial layer develops (epithelial defect). Since the epithelial layer is the protective layer of the cornea, an epithelial defect can leave the eye more susceptible to infection.More serious complications can develop including irregular astigmatism, a condition causing blurred vision that results when the cornea becomes irregularly shaped or abnormally curved. Affected individuals may develop scarring of the cornea. As the inner layer called the stroma breaks down and becomes thinner, the cornea can become even more irregularly shaped, and more severe scarring can develop. In the most severe instances, the cornea can perforate, resulting in loss of the inner fluid of the eye. Neurotrophic keratitis can lead to permanent loss of vision if not properly treated.
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Neurotrophic Keratitis
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Causes of Neurotrophic Keratitis
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Neurotrophic keratitis can be caused by any condition or disorder that affects the nerves that serve the cornea. The main nerve that serves the cornea is called the trigeminal nerve, which is also called the fifth cranial nerve. Damage to the ophthalmic division of the trigeminal nerve, which serves the cornea, can cause neurotrophic keratitis. When the nerves that serve the cornea are damaged this causes reduced sensitivity of the cornea and can lead to neurotrophic keratitis.The cornea has no blood vessels. In order to remain wet and nourished, it must be regularly bathed with tears. Neurotrophic keratitis causes a decrease in reflex tears, which are the tears produced by the eye in response to foreign substances like dust. As corneal sensation decreases, less reflex tears are made in response to stimuli of the cornea, which can lead to the epithelium drying out and eventually breaking down.Two common causes of neurotrophic keratitis are the herpes simplex virus I (the same virus that causes cold sores), or the herpes zoster virus (the virus that causes shingles). Surgery involving the cornea or that occurs near or around the eye can potentially damage the cornea, leading to neurotrophic keratitis. This can include surgery for cataracts, orbital surgery, laser eye surgery to correct vision problems, and corneal transplants. Surgery to treat trigeminal neuralgia can also damage the nerve and result in neurotrophic keratitis. Trigeminal neuralgia is a disorder in which affected individuals experience episodes of pain ranging from a mild, dull pain to intense, significant pain involving the trigeminal nerve. (For more information on this disorder, choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)Chronic use (or overuse) of topical medications that can cause reduced corneal sensation can lead to the development of neurotrophic keratitis. Such medications can include timolol and betaxolol, which are used to treat glaucoma; sulfacetamide, which is a topical antibiotic; as well as diclofenac sodium and ketorolac, which are topical nonsteroidal anti-inflammatories drugs or NSAIDS.Disorders that affect the cornea can lead to neurotrophic keratitis including corneal dystrophies, a group of rare disorders in which foreign material builds up within the cornea. Lattice and granular corneal dystrophy are most often associated with neurotrophic keratitis. NORD has a separate report on these disorders. For more information, choose “corneal dystrophies” as your search term in the Rare Disease Database.There are a variety of other cause of neurotrophic keratitis. Long term use of contact lenses, as well as chemical or physical burns of the cornea can result in neurotrophic keratitis. Sometimes, the presence of a mass or tumor near the nerves that serve the cornea can cause neurotrophic keratitis. In these situations, the tumor pushes up against the trigeminal nerve causing compression of the nerve. An example of a tumor that can cause neurotrophic keratitis is an acoustic neuroma. An acoustic neuroma is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve that can sometimes grow large enough to press up against nearby nerves including the trigeminal nerve.Certain systemic diseases can be associated with neurotrophic keratitis including multiple sclerosis, diabetes, vitamin A deficiency, and leprosy.Neurotrophic keratitis is rare in children. When children develop the disorder, it usually occurs in association with another disorder including familial dysautonomia, Golderhar-Gorlin syndrome, Mobius syndrome, and congenital sensitivity to pain with anhidrosis. These rare disorders are present at birth (congenital). NORD has information on these disorders. For more information, choose the specific disorder name as your search term in the Rare Disease Database.
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Causes of Neurotrophic Keratitis. Neurotrophic keratitis can be caused by any condition or disorder that affects the nerves that serve the cornea. The main nerve that serves the cornea is called the trigeminal nerve, which is also called the fifth cranial nerve. Damage to the ophthalmic division of the trigeminal nerve, which serves the cornea, can cause neurotrophic keratitis. When the nerves that serve the cornea are damaged this causes reduced sensitivity of the cornea and can lead to neurotrophic keratitis.The cornea has no blood vessels. In order to remain wet and nourished, it must be regularly bathed with tears. Neurotrophic keratitis causes a decrease in reflex tears, which are the tears produced by the eye in response to foreign substances like dust. As corneal sensation decreases, less reflex tears are made in response to stimuli of the cornea, which can lead to the epithelium drying out and eventually breaking down.Two common causes of neurotrophic keratitis are the herpes simplex virus I (the same virus that causes cold sores), or the herpes zoster virus (the virus that causes shingles). Surgery involving the cornea or that occurs near or around the eye can potentially damage the cornea, leading to neurotrophic keratitis. This can include surgery for cataracts, orbital surgery, laser eye surgery to correct vision problems, and corneal transplants. Surgery to treat trigeminal neuralgia can also damage the nerve and result in neurotrophic keratitis. Trigeminal neuralgia is a disorder in which affected individuals experience episodes of pain ranging from a mild, dull pain to intense, significant pain involving the trigeminal nerve. (For more information on this disorder, choose “trigeminal neuralgia” as your search term in the Rare Disease Database.)Chronic use (or overuse) of topical medications that can cause reduced corneal sensation can lead to the development of neurotrophic keratitis. Such medications can include timolol and betaxolol, which are used to treat glaucoma; sulfacetamide, which is a topical antibiotic; as well as diclofenac sodium and ketorolac, which are topical nonsteroidal anti-inflammatories drugs or NSAIDS.Disorders that affect the cornea can lead to neurotrophic keratitis including corneal dystrophies, a group of rare disorders in which foreign material builds up within the cornea. Lattice and granular corneal dystrophy are most often associated with neurotrophic keratitis. NORD has a separate report on these disorders. For more information, choose “corneal dystrophies” as your search term in the Rare Disease Database.There are a variety of other cause of neurotrophic keratitis. Long term use of contact lenses, as well as chemical or physical burns of the cornea can result in neurotrophic keratitis. Sometimes, the presence of a mass or tumor near the nerves that serve the cornea can cause neurotrophic keratitis. In these situations, the tumor pushes up against the trigeminal nerve causing compression of the nerve. An example of a tumor that can cause neurotrophic keratitis is an acoustic neuroma. An acoustic neuroma is a rare benign (non-cancerous) growth that develops on the eighth cranial nerve that can sometimes grow large enough to press up against nearby nerves including the trigeminal nerve.Certain systemic diseases can be associated with neurotrophic keratitis including multiple sclerosis, diabetes, vitamin A deficiency, and leprosy.Neurotrophic keratitis is rare in children. When children develop the disorder, it usually occurs in association with another disorder including familial dysautonomia, Golderhar-Gorlin syndrome, Mobius syndrome, and congenital sensitivity to pain with anhidrosis. These rare disorders are present at birth (congenital). NORD has information on these disorders. For more information, choose the specific disorder name as your search term in the Rare Disease Database.
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Neurotrophic Keratitis
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Affects of Neurotrophic Keratitis
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Neurotrophic keratitis is a rare disorder. One estimate places the prevalence at below 5 people per every 10,000 in the general population. Prevalence is the number of people who have a disorder in a specific population at a given time; such as how many people have neurotrophic keratitis in the United States in a given year.
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Affects of Neurotrophic Keratitis. Neurotrophic keratitis is a rare disorder. One estimate places the prevalence at below 5 people per every 10,000 in the general population. Prevalence is the number of people who have a disorder in a specific population at a given time; such as how many people have neurotrophic keratitis in the United States in a given year.
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Related disorders of Neurotrophic Keratitis
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Symptoms of the following disorders can be similar to those of neurotrophic keratitis. Comparisons may be useful for a differential diagnosis.Corneal dystrophies are a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the clear (transparent) outer layer of the eye (cornea). Corneal dystrophies may not cause symptoms (asymptomatic) in some individuals; in others they may cause significant vision impairment. The age of onset and specific symptoms vary among the different forms of corneal dystrophy. The disorders have some similar characteristics – most forms of corneal dystrophy affect both eyes (bilateral), progress slowly, do not affect other areas of the body, and tend to run in families. Most forms are inherited in an autosomal dominant manner; a few are inherited in an autosomal recessive manner. (For more information on these disorders, choose “corneal dystrophies” as your search term in the Rare Disease Database.)Any conditions that can cause damage to the cornea can cause signs and symptoms that are similar to those seen in neurotrophic keratitis. This includes dry eye disease (keratoconjunctivitis sicca), exposure keratitis, limbal stem cell deficiency, damage to the cornea following surgery, and Sjogren syndrome.
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Related disorders of Neurotrophic Keratitis. Symptoms of the following disorders can be similar to those of neurotrophic keratitis. Comparisons may be useful for a differential diagnosis.Corneal dystrophies are a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the clear (transparent) outer layer of the eye (cornea). Corneal dystrophies may not cause symptoms (asymptomatic) in some individuals; in others they may cause significant vision impairment. The age of onset and specific symptoms vary among the different forms of corneal dystrophy. The disorders have some similar characteristics – most forms of corneal dystrophy affect both eyes (bilateral), progress slowly, do not affect other areas of the body, and tend to run in families. Most forms are inherited in an autosomal dominant manner; a few are inherited in an autosomal recessive manner. (For more information on these disorders, choose “corneal dystrophies” as your search term in the Rare Disease Database.)Any conditions that can cause damage to the cornea can cause signs and symptoms that are similar to those seen in neurotrophic keratitis. This includes dry eye disease (keratoconjunctivitis sicca), exposure keratitis, limbal stem cell deficiency, damage to the cornea following surgery, and Sjogren syndrome.
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Neurotrophic Keratitis
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Diagnosis of Neurotrophic Keratitis
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A diagnosis of neurotrophic keratitis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis should be suspected in individuals with unexplained signs of reduced corneal sensitivity and damage to the cornea.Clinical Testing and Workup
Doctors will use a device called an esthesiometer to measure corneal sensitivity. A handheld version called a Cochet-Bonnet may be used. The device resembles a large pen and has a thin, retractable strand of fiber. Pressure can be applied to the cornea by adjusting the length of the fiber. The fiber is fully extended and then is placed against the cornea. The length of the fiber is reduced until the patient feels pressure. Then, this is repeated with the other, unaffected cornea and the results are compared.Eye doctors will look at the cornea under magnification. This can involve coating the cornea with a harmless dye that aids microscopic examination of living tissue (vital staining). Direct examination of the cornea can reveal decreased thickness of the epithelium and other characteristic defects affecting the cornea. An eye doctor may use a slit-lamp, a device that allows an eye doctor to examine the eyes under high magnification to detect corneal changes.A specific method to evaluate the health and function of the cornea is called in vivo confocal microscopy or IVCM. This is a noninvasive technique that permits an eye doctor to obtain high resolution images of the cornea and other structures of the eye at a cellular level.Additional tests can be conducted to test how well the eyes create tears (lacrimal function tests), or to evaluate the limbus, which is the border of the cornea and the whites of the eyes (sclera). If foreign material (infiltrates) is found in the cornea, the substance should be tested for bacterial infection. Viral cultures or immunofluorescence may be necessary to diagnose herpes zoster or herpes simplex infection. An immunofluorescence test uses antibodies chemically linked to fluorescent dyes to identify or quantify antigens to viruses in a tissue sample.An advance imaging (x-ray) technique called magnetic resonance imaging (MRI) may be used to rule out other conditions or to try and determine the cause of neurotrophic keratitis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the cranial nerves can sometimes show damage or compression of the trigeminal nerve. An MRI of the brain may be ordered to rule out other conditions.Neurotrophic keratitis can be worse in individuals who have abnormalities affecting the eyelids. The eyelids are essential for the health and function of the eye, serving to help keep the eyes lubricated by promoting tears to form and by blinking to help dislodge foreign particles that build up in the eye. Individuals who have been diagnosed with neurotrophic keratitis should be evaluated for eyelid conditions including inflammation of the eyelids (blepharitis) and the inability to close the eyelids completely (lagophthalmos). Any eyelid conditions should be treated along with neurotrophic keratitis.Staging
After a diagnosis is confirmed, neurotrophic keratitis will be classified into one of three distinct stages. This is known as the Mackie classification. Generally, Stage 1 refers to mild disease with alterations in the health or structure of the epithelium; stage 2 refers to persistent damage to the epithelium; and stage 3 refers to severe damage including corneal ulceration and degeneration of the stromal level of the cornea.
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Diagnosis of Neurotrophic Keratitis. A diagnosis of neurotrophic keratitis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. A diagnosis should be suspected in individuals with unexplained signs of reduced corneal sensitivity and damage to the cornea.Clinical Testing and Workup
Doctors will use a device called an esthesiometer to measure corneal sensitivity. A handheld version called a Cochet-Bonnet may be used. The device resembles a large pen and has a thin, retractable strand of fiber. Pressure can be applied to the cornea by adjusting the length of the fiber. The fiber is fully extended and then is placed against the cornea. The length of the fiber is reduced until the patient feels pressure. Then, this is repeated with the other, unaffected cornea and the results are compared.Eye doctors will look at the cornea under magnification. This can involve coating the cornea with a harmless dye that aids microscopic examination of living tissue (vital staining). Direct examination of the cornea can reveal decreased thickness of the epithelium and other characteristic defects affecting the cornea. An eye doctor may use a slit-lamp, a device that allows an eye doctor to examine the eyes under high magnification to detect corneal changes.A specific method to evaluate the health and function of the cornea is called in vivo confocal microscopy or IVCM. This is a noninvasive technique that permits an eye doctor to obtain high resolution images of the cornea and other structures of the eye at a cellular level.Additional tests can be conducted to test how well the eyes create tears (lacrimal function tests), or to evaluate the limbus, which is the border of the cornea and the whites of the eyes (sclera). If foreign material (infiltrates) is found in the cornea, the substance should be tested for bacterial infection. Viral cultures or immunofluorescence may be necessary to diagnose herpes zoster or herpes simplex infection. An immunofluorescence test uses antibodies chemically linked to fluorescent dyes to identify or quantify antigens to viruses in a tissue sample.An advance imaging (x-ray) technique called magnetic resonance imaging (MRI) may be used to rule out other conditions or to try and determine the cause of neurotrophic keratitis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the cranial nerves can sometimes show damage or compression of the trigeminal nerve. An MRI of the brain may be ordered to rule out other conditions.Neurotrophic keratitis can be worse in individuals who have abnormalities affecting the eyelids. The eyelids are essential for the health and function of the eye, serving to help keep the eyes lubricated by promoting tears to form and by blinking to help dislodge foreign particles that build up in the eye. Individuals who have been diagnosed with neurotrophic keratitis should be evaluated for eyelid conditions including inflammation of the eyelids (blepharitis) and the inability to close the eyelids completely (lagophthalmos). Any eyelid conditions should be treated along with neurotrophic keratitis.Staging
After a diagnosis is confirmed, neurotrophic keratitis will be classified into one of three distinct stages. This is known as the Mackie classification. Generally, Stage 1 refers to mild disease with alterations in the health or structure of the epithelium; stage 2 refers to persistent damage to the epithelium; and stage 3 refers to severe damage including corneal ulceration and degeneration of the stromal level of the cornea.
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Neurotrophic Keratitis
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Therapies of Neurotrophic Keratitis
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Treatment
The treatment of neurotrophic keratitis 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 specialize in diagnosing and treating eye disorders (ophthalmologists), eye doctors who specialize in diagnosing and treating disorders of the cornea (corneal specialists), physicians who specialize in diagnosing and treating neurological disorders (neurologists), and other healthcare professionals may need to systematically and comprehensively plan treatment.Affected individuals should stop taking topical eye medications, especially those associated with the development of neurotrophic keratitis.In 2018, the U.S. Food and Drug Administration (FDA) approved cenegermin (Oxervate®) for the treatment of individuals with neurotrophic keratitis. Oxervate is a topical eye drop. In clinical studies, as many as 70% of affected individuals demonstrated complete corneal healing within an eight-week period of time.Other therapies that are used to treat neurotrophic keratitis include frequent lubrication and application of artificial tears in order to keep the cornea wet and clean. This treatment is recommended for all stages of neurotrophic keratitis.Topical antibiotic eyedrops are used to treat bacterial infection or for preventive (prophylactic) treatment of infection.When neurotrophic keratitis worsens despite treatment, surgery may become necessary. The most common surgery used is a partial or total tarsorrhaphy. Tarsorrhaphy is a surgical procedure in which the eyelids are partially sewn together to decrease the amount of space between the upper and lower eyelids. This helps to protect the cornea and allow corneal lesions to heal. In general, this is a safe and effective procedure and can be done for a short period of time or, sometimes, may be permanent.For corneal ulcerations that do not heal, or for people with a severely affected cornea, amniotic membrane placement may be considered. The amniotic membrane is the innermost layer of the placenta. The least invasive way to utilize amniotic membrane is to place it on the eye in the office. The most common version, called Prokera, consists of a layer of amniotic membrane sandwiched between two rings of a flexible plastic that allow the amniotic membrane material to rest directly on the cornea surface. In more advanced neurotrophic keratitis, surgeons will surgically transplant a single layer or multiple layers of the amniotic membrane onto the surface of the cornea.Neurotrophic keratitis can be treated with special contact lenses called scleral or corneal contact lenses. The scleral lens is dome-shaped and vaults over the cornea. The scleral lens is filled with a sterile saline solution in mild cases, while more advanced lubrication solutions can be used in later stages of neurotrophic keratitis. These solutions provide lubrication to the eye and assures that the cornea remains wet and that oxygen can reach cornea. The special contact lenses promote healing of the cornea, but can increase the risk of infection.
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Therapies of Neurotrophic Keratitis. Treatment
The treatment of neurotrophic keratitis 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 specialize in diagnosing and treating eye disorders (ophthalmologists), eye doctors who specialize in diagnosing and treating disorders of the cornea (corneal specialists), physicians who specialize in diagnosing and treating neurological disorders (neurologists), and other healthcare professionals may need to systematically and comprehensively plan treatment.Affected individuals should stop taking topical eye medications, especially those associated with the development of neurotrophic keratitis.In 2018, the U.S. Food and Drug Administration (FDA) approved cenegermin (Oxervate®) for the treatment of individuals with neurotrophic keratitis. Oxervate is a topical eye drop. In clinical studies, as many as 70% of affected individuals demonstrated complete corneal healing within an eight-week period of time.Other therapies that are used to treat neurotrophic keratitis include frequent lubrication and application of artificial tears in order to keep the cornea wet and clean. This treatment is recommended for all stages of neurotrophic keratitis.Topical antibiotic eyedrops are used to treat bacterial infection or for preventive (prophylactic) treatment of infection.When neurotrophic keratitis worsens despite treatment, surgery may become necessary. The most common surgery used is a partial or total tarsorrhaphy. Tarsorrhaphy is a surgical procedure in which the eyelids are partially sewn together to decrease the amount of space between the upper and lower eyelids. This helps to protect the cornea and allow corneal lesions to heal. In general, this is a safe and effective procedure and can be done for a short period of time or, sometimes, may be permanent.For corneal ulcerations that do not heal, or for people with a severely affected cornea, amniotic membrane placement may be considered. The amniotic membrane is the innermost layer of the placenta. The least invasive way to utilize amniotic membrane is to place it on the eye in the office. The most common version, called Prokera, consists of a layer of amniotic membrane sandwiched between two rings of a flexible plastic that allow the amniotic membrane material to rest directly on the cornea surface. In more advanced neurotrophic keratitis, surgeons will surgically transplant a single layer or multiple layers of the amniotic membrane onto the surface of the cornea.Neurotrophic keratitis can be treated with special contact lenses called scleral or corneal contact lenses. The scleral lens is dome-shaped and vaults over the cornea. The scleral lens is filled with a sterile saline solution in mild cases, while more advanced lubrication solutions can be used in later stages of neurotrophic keratitis. These solutions provide lubrication to the eye and assures that the cornea remains wet and that oxygen can reach cornea. The special contact lenses promote healing of the cornea, but can increase the risk of infection.
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Neurotrophic Keratitis
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Overview of Nevoid Basal Cell Carcinoma Syndrome
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Summary The nevoid basal cell carcinoma syndrome (NBCCS) is a rare, complex genetic disorder characterized by a wide variety of developmental abnormalities and a predisposition to developing certain forms of cancer, particularly a type of skin cancer known as basal cell carcinoma. The specific symptoms and severity of NBCCS can vary greatly from one individual to another, even among members of the same family. Multiple organ systems can become involved. Common symptoms include multiple basal cell carcinomas, recurrent keratocystic odontogenic tumors of the jaws, pits of the palms and soles, and skeletal malformations. Some affected individuals may have distinctive facial features. The onset of specific symptoms can vary, occurring anywhere from infancy through adulthood. Most cases of NBCCS are caused by changes (mutations) in the PTCH1 gene, but mutations in the SUFU and PTCH2 genes can cause a similar set of characteristics (phenotype). All three genetic forms of the disorder are inherited in and autosomal dominant pattern. However, sporadic cases due to new mutations are common.Introduction In 1894, the first patients with NBCCS were described in the medical literature by two different doctors. However, it was not until 1960 that two physicians (Drs. Robert Gorlin and Robert Goltz) wrote the first in-depth description of NBCCS as a distinct clinical entity. Consequently, the disorder is also known as Gorlin syndrome or Gorlin-Goltz syndrome. Over the years, case reports and series have continued to expand the range of symptoms and physical findings that can be associated with NBCCS, and there are now more than 100 different recognized features.
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Overview of Nevoid Basal Cell Carcinoma Syndrome. Summary The nevoid basal cell carcinoma syndrome (NBCCS) is a rare, complex genetic disorder characterized by a wide variety of developmental abnormalities and a predisposition to developing certain forms of cancer, particularly a type of skin cancer known as basal cell carcinoma. The specific symptoms and severity of NBCCS can vary greatly from one individual to another, even among members of the same family. Multiple organ systems can become involved. Common symptoms include multiple basal cell carcinomas, recurrent keratocystic odontogenic tumors of the jaws, pits of the palms and soles, and skeletal malformations. Some affected individuals may have distinctive facial features. The onset of specific symptoms can vary, occurring anywhere from infancy through adulthood. Most cases of NBCCS are caused by changes (mutations) in the PTCH1 gene, but mutations in the SUFU and PTCH2 genes can cause a similar set of characteristics (phenotype). All three genetic forms of the disorder are inherited in and autosomal dominant pattern. However, sporadic cases due to new mutations are common.Introduction In 1894, the first patients with NBCCS were described in the medical literature by two different doctors. However, it was not until 1960 that two physicians (Drs. Robert Gorlin and Robert Goltz) wrote the first in-depth description of NBCCS as a distinct clinical entity. Consequently, the disorder is also known as Gorlin syndrome or Gorlin-Goltz syndrome. Over the years, case reports and series have continued to expand the range of symptoms and physical findings that can be associated with NBCCS, and there are now more than 100 different recognized features.
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Nevoid Basal Cell Carcinoma Syndrome
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Symptoms of Nevoid Basal Cell Carcinoma Syndrome
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As stated above, NBCCS can potentially affect multiple organ systems in the body. However, it is important to note that affected individuals will not usually develop all of the symptoms discussed below. The severity of NBCCS can vary, and some individuals with mild forms can go undiagnosed, while others can have significant complications. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.Many affected individuals will develop basal cell carcinomas, a type of skin cancer. BCCs may appear as brownish, flesh-colored, or orange spots on the skin. They can also appear as red patches of skin or scars. In some patients, BCCs will be small growths or bumps (nodules), while in other individuals they may be flat or nearly flat. The number of BCCs that can develop ranges from only a few spots to thousands of lesions. These lesions can vary in size from less than 1 millimeter to approximately 10 millimeters. BCCs do not usually spread to other areas of the body, but they can become aggressive and invade local tissue. Localized infection can develop and these lesions can crust, bleed and ulcerate. Sun-exposed areas of the skin are affected more often than areas that are not commonly exposed to the sun. The face, nape of the neck, back, and chest are most commonly affected. If left untreated BCCs can cause disfigurement, especially if located on the face. The appearance and behavior of basal cell carcinomas in this syndrome do not differ in any way from sporadic BCCs. The term, “nevoid” reflects the multiplicity, but not the characteristics, of the BCCs.BCCs usually develop between puberty and the mid-30s, but can occur at almost any age. Cases have been reported in children as young as 2 years of age. At least one case was reported where BCCs did not develop until after 50 years of age. Approximately 10% of individuals with NBCCS, especially those with dark skin and limited sunlight exposure, do not develop any BCCs. Keratocystic odontogenic tumors, also known as odontogenic keratocytes or jaw cysts, are the first presenting sign in many individuals with NBCCS. These are growths that develop in the jaw bones, usually in the lower jaw bone (mandible). Affected individuals usually develop multiple cysts. These growths can develop as painless swellings in the jaws, but are often aggressive, progressing to cause pain, fractures, loose teeth or displacement of developing permanent teeth. The alignment of the jaw can be affected. There is a high recurrence rate. Because of their aggressive nature, prompt treatment is recommended. If left untreated, they can potentially damage large portions of the jaw. Keratocystic odontogenic tumors usually appear in the first or second decade of life and have been reported in children as young as 5 years of age. Although their peak occurrence is during the second decade of life, these cysts can occur throughout an affected individual’s life.Some individuals may develop hardening (calcification) of certain areas of the central nervous system such as the falx cerebri, which is the structure that divides the two hemispheres (cerebrum) of the brain. The falx cerebri consists of the dura mater, which is the outermost layer of the three membranes covering the brain. Other areas of the central nervous system may be affected as well. Abnormal calcification of structures within the central nervous system affects approximately 90% of affected individuals by the age of 20. This clinical finding is usually not associated with any symptoms.Affected individuals may develop multiple distinctive small pits on the palms of the hands and the soles of the feet (palmar-plantar pits). These pits are usually only 1-2 millimeters in size. They can be seen much more clearly after soaking the hands or feet in warm water for approximately 10 minutes. Affected individuals may also develop skin tags, which are common, soft small growths that hang off the skin. Individuals with NBCCS tend to develop more skin tags than would normally be seen. These growths are benign and painless, although they can be irritated by friction (e.g. clothes rubbing against them). Small, bumps (epidermal cysts) are also common findings, usually found on the limbs and trunk.At birth, infants may display certain characteristic features including macrocephaly, a condition characterized by a head circumference larger than would normally be expected based upon a child’s age and height. NBCCS is an overgrowth syndrome. Affected individuals are taller than their age- and sex-matched siblings. Additional early distinctive features include a bulging forehead (frontal bossing), widely spaced eyes (hypertelorism), tiny white bumps or cysts on the skin (facial milia) and coarse facial features. Facial milia are most often found below the eyes or on the forehead. Rarely, affected individuals may develop cleft palate or cleft lip or additional eye abnormalities including abnormally small eyes (microphthalmia), cataracts, rapid involuntary eye movements (nystagmus), and a partial absence of tissue from the iris or retina (coloboma). Crossed eyes (strabismus), which are common in the general population, occur a bit more frequently in NBCCS. The eyes may appear sunken due to frontal bossing.A variety of skeletal abnormalities may be associated with NBCCS including fused, splayed or missing ribs, abnormal curvature of the spine (scoliosis), extra fingers or toes (polydactyly), webbing of the fingers or toes (syndactyly), and Sprengel deformity, a condition characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to elevation of the shoulder blade. Affected individuals may exhibit a sunken chest (pectus carinatum) or a chest that protrudes outward (pectus excavatum). Some individuals may have spina bifida, a condition characterized by a malformation of the spinal column in which incomplete closure of certain vertebrae leaves a portion of the spinal cord exposed. Individuals with NBCSS generally have a mild form of spinal bifida, which may not be associated with symptoms, but can be associated with hydrocephalus in rare cases. Hydrocephalus is a condition in which accumulation of excess cerebrospinal fluid in the skull causes pressure on the brain.Approximately 1% to 5% of affected individuals develop a medulloblastoma, the most common type of malignant brain tumor in children. Medulloblastomas occur in the cerebellum, the part of the brain located at the base of the skull just above the brainstem. The cerebellum is involved in many functions including coordination of voluntary movements and regulating balance and posture. Symptoms associated with a medulloblastoma can include headaches in the morning that improve as the day goes on, recurrent vomiting and difficulty walking and with balance. Medulloblastomas can spread to affect other areas of the central nervous system. Medulloblastomas associated with NBCCS tend to occur around the age of 2, younger than in children without NBCCS (isolated medulloblastoma). In addition, when associated with NBCCS, this tumor is generally less aggressive than the isolated form. In most patients, the desmoplastic subtype of medulloblastoma develops. Medulloblastomas in NBCCS are more common in males than females by a ratio of approximately 3:1. (For more information on this disorder, choose “medulloblastoma” as your search term in the Rare Disease Database.)Individuals with NBCCS are at risk of developing additional tumors including cardiac or ovarian fibromas. Fibromas are benign tumors consisting of connective tissue. Cardiac fibromas are present at birth or shortly thereafter. These growths may not cause symptoms or they can cause irregular heartbeats (arrhythmias) or obstruct blood flow. Affected females may develop ovarian fibromas. These growths may not cause any symptoms unless they become large and calcified, potentially causing twisting (torsion) of the ovaries. Ovarian fibromas are not thought to affect fertility.Additional tumors can develop including tumors that arise from the membranes (meninges) that line the brain and spinal cord (meningiomas), tumors of the muscles attached to the bone (rhabdomyosarcoma), and a benign tumor normally located inside the heart (rhabdomyomoma). Other brain tumors have been reported individuals with NBCCS, but may occur secondary to radiation therapy.Cysts or polyps can form in various parts of the body including the bones, airway passages (bronchi), intestines, and the fold of tissue of the peritoneum that supports and attaches the intestines to the wall of the abdomen (mesentery). The peritoneum is the membrane that lines the abdominal cavity. Mesenteric cysts are common and usually do not produce symptoms. Cysts on the brain have been found as well.Additional symptoms and physical findings have been reported in individuals with NBCCS. These symptoms may include intellectual disability, seizures, middle ear anomalies, minor kidney abnormalities, absence of the internal carotid artery, an impaired ability to smell (anosmia), and hardening of the skin due to the accumulation of calcium deposits underneath the skin. Intellectual disability is unusual in patients with mutations limited to the PTCH1 gene and is often related to deletions or other chromosome rearrangements that affect PTCH1 along with surrounding genes.Various other forms of cancer have been reported to occur in individuals with NBCCS. However, it is unknown whether affected individuals have a predisposition to developing these cancers or whether their development is coincidental (i.e. independent of the disorder). More research is necessary to determine what forms of cancer are related to NBCCS and which forms are chance occurrences.
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Symptoms of Nevoid Basal Cell Carcinoma Syndrome. As stated above, NBCCS can potentially affect multiple organ systems in the body. However, it is important to note that affected individuals will not usually develop all of the symptoms discussed below. The severity of NBCCS can vary, and some individuals with mild forms can go undiagnosed, while others can have significant complications. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.Many affected individuals will develop basal cell carcinomas, a type of skin cancer. BCCs may appear as brownish, flesh-colored, or orange spots on the skin. They can also appear as red patches of skin or scars. In some patients, BCCs will be small growths or bumps (nodules), while in other individuals they may be flat or nearly flat. The number of BCCs that can develop ranges from only a few spots to thousands of lesions. These lesions can vary in size from less than 1 millimeter to approximately 10 millimeters. BCCs do not usually spread to other areas of the body, but they can become aggressive and invade local tissue. Localized infection can develop and these lesions can crust, bleed and ulcerate. Sun-exposed areas of the skin are affected more often than areas that are not commonly exposed to the sun. The face, nape of the neck, back, and chest are most commonly affected. If left untreated BCCs can cause disfigurement, especially if located on the face. The appearance and behavior of basal cell carcinomas in this syndrome do not differ in any way from sporadic BCCs. The term, “nevoid” reflects the multiplicity, but not the characteristics, of the BCCs.BCCs usually develop between puberty and the mid-30s, but can occur at almost any age. Cases have been reported in children as young as 2 years of age. At least one case was reported where BCCs did not develop until after 50 years of age. Approximately 10% of individuals with NBCCS, especially those with dark skin and limited sunlight exposure, do not develop any BCCs. Keratocystic odontogenic tumors, also known as odontogenic keratocytes or jaw cysts, are the first presenting sign in many individuals with NBCCS. These are growths that develop in the jaw bones, usually in the lower jaw bone (mandible). Affected individuals usually develop multiple cysts. These growths can develop as painless swellings in the jaws, but are often aggressive, progressing to cause pain, fractures, loose teeth or displacement of developing permanent teeth. The alignment of the jaw can be affected. There is a high recurrence rate. Because of their aggressive nature, prompt treatment is recommended. If left untreated, they can potentially damage large portions of the jaw. Keratocystic odontogenic tumors usually appear in the first or second decade of life and have been reported in children as young as 5 years of age. Although their peak occurrence is during the second decade of life, these cysts can occur throughout an affected individual’s life.Some individuals may develop hardening (calcification) of certain areas of the central nervous system such as the falx cerebri, which is the structure that divides the two hemispheres (cerebrum) of the brain. The falx cerebri consists of the dura mater, which is the outermost layer of the three membranes covering the brain. Other areas of the central nervous system may be affected as well. Abnormal calcification of structures within the central nervous system affects approximately 90% of affected individuals by the age of 20. This clinical finding is usually not associated with any symptoms.Affected individuals may develop multiple distinctive small pits on the palms of the hands and the soles of the feet (palmar-plantar pits). These pits are usually only 1-2 millimeters in size. They can be seen much more clearly after soaking the hands or feet in warm water for approximately 10 minutes. Affected individuals may also develop skin tags, which are common, soft small growths that hang off the skin. Individuals with NBCCS tend to develop more skin tags than would normally be seen. These growths are benign and painless, although they can be irritated by friction (e.g. clothes rubbing against them). Small, bumps (epidermal cysts) are also common findings, usually found on the limbs and trunk.At birth, infants may display certain characteristic features including macrocephaly, a condition characterized by a head circumference larger than would normally be expected based upon a child’s age and height. NBCCS is an overgrowth syndrome. Affected individuals are taller than their age- and sex-matched siblings. Additional early distinctive features include a bulging forehead (frontal bossing), widely spaced eyes (hypertelorism), tiny white bumps or cysts on the skin (facial milia) and coarse facial features. Facial milia are most often found below the eyes or on the forehead. Rarely, affected individuals may develop cleft palate or cleft lip or additional eye abnormalities including abnormally small eyes (microphthalmia), cataracts, rapid involuntary eye movements (nystagmus), and a partial absence of tissue from the iris or retina (coloboma). Crossed eyes (strabismus), which are common in the general population, occur a bit more frequently in NBCCS. The eyes may appear sunken due to frontal bossing.A variety of skeletal abnormalities may be associated with NBCCS including fused, splayed or missing ribs, abnormal curvature of the spine (scoliosis), extra fingers or toes (polydactyly), webbing of the fingers or toes (syndactyly), and Sprengel deformity, a condition characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to elevation of the shoulder blade. Affected individuals may exhibit a sunken chest (pectus carinatum) or a chest that protrudes outward (pectus excavatum). Some individuals may have spina bifida, a condition characterized by a malformation of the spinal column in which incomplete closure of certain vertebrae leaves a portion of the spinal cord exposed. Individuals with NBCSS generally have a mild form of spinal bifida, which may not be associated with symptoms, but can be associated with hydrocephalus in rare cases. Hydrocephalus is a condition in which accumulation of excess cerebrospinal fluid in the skull causes pressure on the brain.Approximately 1% to 5% of affected individuals develop a medulloblastoma, the most common type of malignant brain tumor in children. Medulloblastomas occur in the cerebellum, the part of the brain located at the base of the skull just above the brainstem. The cerebellum is involved in many functions including coordination of voluntary movements and regulating balance and posture. Symptoms associated with a medulloblastoma can include headaches in the morning that improve as the day goes on, recurrent vomiting and difficulty walking and with balance. Medulloblastomas can spread to affect other areas of the central nervous system. Medulloblastomas associated with NBCCS tend to occur around the age of 2, younger than in children without NBCCS (isolated medulloblastoma). In addition, when associated with NBCCS, this tumor is generally less aggressive than the isolated form. In most patients, the desmoplastic subtype of medulloblastoma develops. Medulloblastomas in NBCCS are more common in males than females by a ratio of approximately 3:1. (For more information on this disorder, choose “medulloblastoma” as your search term in the Rare Disease Database.)Individuals with NBCCS are at risk of developing additional tumors including cardiac or ovarian fibromas. Fibromas are benign tumors consisting of connective tissue. Cardiac fibromas are present at birth or shortly thereafter. These growths may not cause symptoms or they can cause irregular heartbeats (arrhythmias) or obstruct blood flow. Affected females may develop ovarian fibromas. These growths may not cause any symptoms unless they become large and calcified, potentially causing twisting (torsion) of the ovaries. Ovarian fibromas are not thought to affect fertility.Additional tumors can develop including tumors that arise from the membranes (meninges) that line the brain and spinal cord (meningiomas), tumors of the muscles attached to the bone (rhabdomyosarcoma), and a benign tumor normally located inside the heart (rhabdomyomoma). Other brain tumors have been reported individuals with NBCCS, but may occur secondary to radiation therapy.Cysts or polyps can form in various parts of the body including the bones, airway passages (bronchi), intestines, and the fold of tissue of the peritoneum that supports and attaches the intestines to the wall of the abdomen (mesentery). The peritoneum is the membrane that lines the abdominal cavity. Mesenteric cysts are common and usually do not produce symptoms. Cysts on the brain have been found as well.Additional symptoms and physical findings have been reported in individuals with NBCCS. These symptoms may include intellectual disability, seizures, middle ear anomalies, minor kidney abnormalities, absence of the internal carotid artery, an impaired ability to smell (anosmia), and hardening of the skin due to the accumulation of calcium deposits underneath the skin. Intellectual disability is unusual in patients with mutations limited to the PTCH1 gene and is often related to deletions or other chromosome rearrangements that affect PTCH1 along with surrounding genes.Various other forms of cancer have been reported to occur in individuals with NBCCS. However, it is unknown whether affected individuals have a predisposition to developing these cancers or whether their development is coincidental (i.e. independent of the disorder). More research is necessary to determine what forms of cancer are related to NBCCS and which forms are chance occurrences.
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Nevoid Basal Cell Carcinoma Syndrome
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Causes of Nevoid Basal Cell Carcinoma Syndrome
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Nearly all cases of NBCCS have been caused by a mutation in the PTCH1 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The PTCH1 gene is as a tumor suppressor gene. A tumor suppressor gene is a gene that slows down cell division, repairs damage to the DNA of cells, and/or tells cells when to die, a normal process called apoptosis. The PTCH1 gene creates (encodes) a protein that is involved in the sonic hedgehog pathway. This pathway involves a number of complex interactions that are critical for normal human development. These interactions involve the activation or repression of certain other genes. Impairment (dysregulation) of this pathway leads to human disease including cancer.Mutation of one of an individual’s two copies of the PTCH1 gene is believed to be sufficient to cause many of the developmental abnormalities associated with NBCCS such as rib/vertebrae abnormalities or macrocephaly. However, cancer development in affected individuals is believed to follow the “two-hit” theory. This theory states that a second hit, damage to the normal copy of the PTCH1 gene, is required before cancer can develop. This second hit can occur at any point after conception (somatically).Among those rare patients with NBCCS and no detectable mutation in PTCH1, some have been found to have mutations in PTCH2, a gene that is very similar to PTCH1; and some have been found to have mutations in SUFU, another hedgehog pathway gene that works in concert with PTCH1 to control cell growth and development.NBCCS follows an autosomal dominant pattern of inheritance. Autosomal dominant 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. The risk is the same for males and females.In cases without a positive family history of the disorder, the gene mutation may occur spontaneously for no apparent reason (sporadically) representing a new mutation. Approximately 35-50% of affected individuals represent a new mutation.NBCCS is characterized by complete penetrance, which means that all individuals who inherit the gene for the disorder will develop symptoms of the disorder. NBCCS is also characterized by variable expressivity, which means that widely varying signs and symptoms can occur among affected individuals.Exposure to ultraviolet light appears to play a role in the development of BCCs in individuals with NBCCS. BCCs are much more common in sun-exposed areas of the skin and more common in Caucasian individuals than individuals of African American descent. Additionally, individuals with NBCCS are particularly prone to develop BCCs in areas of the body exposed to high levels of ionizing radiation, such as radiation therapy.
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Causes of Nevoid Basal Cell Carcinoma Syndrome. Nearly all cases of NBCCS have been caused by a mutation in the PTCH1 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, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The PTCH1 gene is as a tumor suppressor gene. A tumor suppressor gene is a gene that slows down cell division, repairs damage to the DNA of cells, and/or tells cells when to die, a normal process called apoptosis. The PTCH1 gene creates (encodes) a protein that is involved in the sonic hedgehog pathway. This pathway involves a number of complex interactions that are critical for normal human development. These interactions involve the activation or repression of certain other genes. Impairment (dysregulation) of this pathway leads to human disease including cancer.Mutation of one of an individual’s two copies of the PTCH1 gene is believed to be sufficient to cause many of the developmental abnormalities associated with NBCCS such as rib/vertebrae abnormalities or macrocephaly. However, cancer development in affected individuals is believed to follow the “two-hit” theory. This theory states that a second hit, damage to the normal copy of the PTCH1 gene, is required before cancer can develop. This second hit can occur at any point after conception (somatically).Among those rare patients with NBCCS and no detectable mutation in PTCH1, some have been found to have mutations in PTCH2, a gene that is very similar to PTCH1; and some have been found to have mutations in SUFU, another hedgehog pathway gene that works in concert with PTCH1 to control cell growth and development.NBCCS follows an autosomal dominant pattern of inheritance. Autosomal dominant 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. The risk is the same for males and females.In cases without a positive family history of the disorder, the gene mutation may occur spontaneously for no apparent reason (sporadically) representing a new mutation. Approximately 35-50% of affected individuals represent a new mutation.NBCCS is characterized by complete penetrance, which means that all individuals who inherit the gene for the disorder will develop symptoms of the disorder. NBCCS is also characterized by variable expressivity, which means that widely varying signs and symptoms can occur among affected individuals.Exposure to ultraviolet light appears to play a role in the development of BCCs in individuals with NBCCS. BCCs are much more common in sun-exposed areas of the skin and more common in Caucasian individuals than individuals of African American descent. Additionally, individuals with NBCCS are particularly prone to develop BCCs in areas of the body exposed to high levels of ionizing radiation, such as radiation therapy.
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Nevoid Basal Cell Carcinoma Syndrome
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Affects of Nevoid Basal Cell Carcinoma Syndrome
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The exact prevalence of NBCCS is unknown. The figure most quoted in the medical literature is 1 individual per 57,000 people in the general population. This figure was based upon a population study in the United Kingdom. However, the authors of that study have revised that figure to approximately 1 in 30,000. The true prevalence of NBCCS in the general population may actually be higher because individuals, especially mild cases, can go undiagnosed or misdiagnosed. NBCCS affects males and females in equal numbers. Basal cell carcinoma of the skin (including isolated cases not associated with NBCCS) is the most common form of cancer in humans.
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Affects of Nevoid Basal Cell Carcinoma Syndrome. The exact prevalence of NBCCS is unknown. The figure most quoted in the medical literature is 1 individual per 57,000 people in the general population. This figure was based upon a population study in the United Kingdom. However, the authors of that study have revised that figure to approximately 1 in 30,000. The true prevalence of NBCCS in the general population may actually be higher because individuals, especially mild cases, can go undiagnosed or misdiagnosed. NBCCS affects males and females in equal numbers. Basal cell carcinoma of the skin (including isolated cases not associated with NBCCS) is the most common form of cancer in humans.
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Nevoid Basal Cell Carcinoma Syndrome
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Related disorders of Nevoid Basal Cell Carcinoma Syndrome
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Symptoms of the following disorders can be similar to those of NBCCS. Comparisons may be useful for a differential diagnosis.Several rare congenital disorders are characterized by the combination of macrocephaly with developmental defects and distinctive facial features. Such disorders include Beckwith-Wiedemann syndrome (BWS), Sotos syndrome, and Bannayan-Riley-Ruvalcaba syndrome (BRSS). BWS is a rare growth disorder characterized by a wide spectrum of symptoms that can include macrocephaly, above average birth and weight and increased growth after birth. Sotos syndrome is characterized by large size, a large head (dolichocephaly), intellectual impairment, and distinctive facial features including a prominent forehead, widely spaced eyes, a high narrow palate, a pointed chin and a long face. BRSS is characterized by macrocephaly, multiple benign fatty tumors (lipomas) and multiple benign polyps in the intestinal tract (intestinal hamartomatous polyposis). BRRS is also associated with an increased risk of cancer. These disorders are associated with additional signs and symptoms that can differentiate them from NBCCS. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are several extremely rare disorders that are associated with basal cell carcinomas including Bazex syndrome and Muir-Torre syndrome. Bazex syndrome is characterized by multiple BCCS, milia, reduced sweating (hypohidrosis), abnormal loss of hair (hypotrichosis), and follicular atrophoderma, a skin condition involving breakdown of the follicles of the skin and causing lesions, especially on the arms and legs. In most affected individuals, BCCs develop in the 20s or 30s. Additional symptoms can vary greatly from one person to another. Muir-Torre syndrome is characterized by a predisposition to skin cancer, including BCCs and sebaceous tumors, and gastrointestinal malignancies. This syndrome is a variant of Lynch syndrome and is usually caused by mutations in the MSH2 gene, an established Lynch syndrome gene. BCCs are seen to excess in albinism, xeroderma pigmentosum, Li-Fraumeni syndrome and several other rare syndromes that have prominent additional features distinguishing them from NBCCS.
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Related disorders of Nevoid Basal Cell Carcinoma Syndrome. Symptoms of the following disorders can be similar to those of NBCCS. Comparisons may be useful for a differential diagnosis.Several rare congenital disorders are characterized by the combination of macrocephaly with developmental defects and distinctive facial features. Such disorders include Beckwith-Wiedemann syndrome (BWS), Sotos syndrome, and Bannayan-Riley-Ruvalcaba syndrome (BRSS). BWS is a rare growth disorder characterized by a wide spectrum of symptoms that can include macrocephaly, above average birth and weight and increased growth after birth. Sotos syndrome is characterized by large size, a large head (dolichocephaly), intellectual impairment, and distinctive facial features including a prominent forehead, widely spaced eyes, a high narrow palate, a pointed chin and a long face. BRSS is characterized by macrocephaly, multiple benign fatty tumors (lipomas) and multiple benign polyps in the intestinal tract (intestinal hamartomatous polyposis). BRRS is also associated with an increased risk of cancer. These disorders are associated with additional signs and symptoms that can differentiate them from NBCCS. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are several extremely rare disorders that are associated with basal cell carcinomas including Bazex syndrome and Muir-Torre syndrome. Bazex syndrome is characterized by multiple BCCS, milia, reduced sweating (hypohidrosis), abnormal loss of hair (hypotrichosis), and follicular atrophoderma, a skin condition involving breakdown of the follicles of the skin and causing lesions, especially on the arms and legs. In most affected individuals, BCCs develop in the 20s or 30s. Additional symptoms can vary greatly from one person to another. Muir-Torre syndrome is characterized by a predisposition to skin cancer, including BCCs and sebaceous tumors, and gastrointestinal malignancies. This syndrome is a variant of Lynch syndrome and is usually caused by mutations in the MSH2 gene, an established Lynch syndrome gene. BCCs are seen to excess in albinism, xeroderma pigmentosum, Li-Fraumeni syndrome and several other rare syndromes that have prominent additional features distinguishing them from NBCCS.
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Nevoid Basal Cell Carcinoma Syndrome
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Diagnosis of Nevoid Basal Cell Carcinoma Syndrome
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A diagnosis of NBCCS is based either on detection of a pathogenic genetic variant in one of the known underlying genes or on identification of characteristic clinical findings. Most medical sources cite that the presence of specific clinical symptoms is sufficient for a diagnosis of NBCCS. These symptoms are grouped into major and minor categories. The specific number of major or minor criteria required for a diagnosis can vary based upon different sources. One commonly used diagnostic set of criteria for NBCCS involves the identification of two major and one minor diagnostic criteria or one major and three minor diagnostic criteria from the list below.Major criteriaMinor criteriaClinical Testing and Workup
Specialized imaging techniques can aid in obtaining a diagnosis of NBCCS. Such tests can include magnetic resonance imaging (MRI), abdominal ultrasound, a skeletal survey, and x-rays of the teeth and jaw. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal calcification of the falx cerebri or other structures. An abdominal ultrasound uses reflected sound waves to create an image of the abdomen and can reveal mesenteric cysts. A skeletal survey is a series of x-rays taken of bones all over the body. For example, an anteroposterior (AP) x-ray of the skull can reveal calcification of the falx cerebri.An echocardiogram may be performed to check for cardiac fibromas. During an echocardiogram, sound waves are bounced off the heart enabling physicians to study cardiac function and motion. An ovarian ultrasound may be performed to check for ovarian fibromas.A diagnosis of NBCCS can be confirmed through molecular genetic testing, which can detect mutations in the PTCH1 gene that is known to cause NBCCS. Because some cases of NBCCS are due to mutations in SUFU or PTCH2, many laboratories choose to test for all three genes at the same time. Molecular genetic testing is available on a clinical basis.
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Diagnosis of Nevoid Basal Cell Carcinoma Syndrome. A diagnosis of NBCCS is based either on detection of a pathogenic genetic variant in one of the known underlying genes or on identification of characteristic clinical findings. Most medical sources cite that the presence of specific clinical symptoms is sufficient for a diagnosis of NBCCS. These symptoms are grouped into major and minor categories. The specific number of major or minor criteria required for a diagnosis can vary based upon different sources. One commonly used diagnostic set of criteria for NBCCS involves the identification of two major and one minor diagnostic criteria or one major and three minor diagnostic criteria from the list below.Major criteriaMinor criteriaClinical Testing and Workup
Specialized imaging techniques can aid in obtaining a diagnosis of NBCCS. Such tests can include magnetic resonance imaging (MRI), abdominal ultrasound, a skeletal survey, and x-rays of the teeth and jaw. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal calcification of the falx cerebri or other structures. An abdominal ultrasound uses reflected sound waves to create an image of the abdomen and can reveal mesenteric cysts. A skeletal survey is a series of x-rays taken of bones all over the body. For example, an anteroposterior (AP) x-ray of the skull can reveal calcification of the falx cerebri.An echocardiogram may be performed to check for cardiac fibromas. During an echocardiogram, sound waves are bounced off the heart enabling physicians to study cardiac function and motion. An ovarian ultrasound may be performed to check for ovarian fibromas.A diagnosis of NBCCS can be confirmed through molecular genetic testing, which can detect mutations in the PTCH1 gene that is known to cause NBCCS. Because some cases of NBCCS are due to mutations in SUFU or PTCH2, many laboratories choose to test for all three genes at the same time. Molecular genetic testing is available on a clinical basis.
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Nevoid Basal Cell Carcinoma Syndrome
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Therapies of Nevoid Basal Cell Carcinoma Syndrome
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Treatment
The treatment of NBCCS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, oral surgeons, dentists, cardiologists, ophthalmologists, plastic surgeons, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; tumor size; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular therapies or procedures should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Odontogenic keratocysts usually require prompt surgical removal (excision). The goal of this therapy is to preserve as much of the jaw and teeth as possible because affected individuals often develop multiple cysts throughout adolescence and adulthood. With larger cysts, it is recommended that they be decompressed first, usually through the insertion of a small tube that allows water or saline solution to flush out the tumor, shrinking it in size.A wide variety of treatment options exist for individuals with BCCs including topical chemotherapy, surgery, drug therapy, cryotherapy, electrodessication and curettage, and photodynamic therapy.Topical chemotherapy involves the application of creams applied directly to the lesion. Two common topical medications used to treat NBCCS are 5-fluorouracil and imiquimod 5%. These treatments may be used alone or in conjunction with other therapies. 5-fluorouracil works by destroying the abnormal skin cells and may be used to treat small, superficial BCCs in low risk areas. The U.S. Food and Drug Administration (FDA) has approved the use of imiquimod 5% (Aldara®) topical cream for the treatment of superficial basal cell carcinoma.Many individuals with NBCCS opt for surgical removal lesions if the overall number of lesions is low. Straightforward surgical removal of a lesion involves cutting the lesion out and closing the wound with sutures. In certain cases, large lesions may require a skin graft from another area of the body. Surgical excision of a lesion can result in a scar. Recurrence is possible as well.A specific type of surgery called Mohs micrographic surgery may be recommended for some individuals with NBCCS. With this surgery, a surgeon uses a precise technique to remove diseased tissue one layer at a time. According to the medical literature, Mohs surgery has proven particularly effective in treating NBCCS and is useful for treating difficult tumors that may not respond to other standard treatments.Cryotherapy may also be used to treat NBCCS. Cryotherapy is the use of extreme cold to freeze and destroy the tissue and cells of skin lesions and is a minimally invasive treatment option. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the lesion. Cryotherapy is most effective for single or small lesions.Another surgical procedure used to treat individuals with NBCCS is electrodessication and curettage. With curettage, the lesion is scraped off the skin with a surgical instrument called a curette. The procedure is usually performed under anesthesia. In some cases, curettage may be followed by the use of an electrosurgical needle to apply heat and dry up the remaining cancerous tissue (electrodessication). This procedure may need to be repeated for some patients and will often leave a small white scar. This procedure is best for the treatment of small BCCs located in areas where the risk of recurrence is low. Electrodessication and curettage is often used as an alternative to topical chemotherapy.Laser vaporization is a newer procedure that is sometimes used alone or with curettage to treat BCCs, specifically individuals with multiple or superficial lesions. This procedure involves the use of a carbon dioxide laser to destroy (vaporize) abnormal tissue.Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with NBCCS who have large lesions. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to activate the drug which binds with oxygen creating a chemical that destroys the affected cells.In recent years, the FDA has approved two targeted drugs that specifically counteract the effect of PTCH1 mutations. Sonidegib (Odomzo®) and vismodegib (Erivedge®) specifically inhibit the hedgehog pathway. Both can be used for the treatment of adults with advanced basal cell carcinoma that has spread to other parts of the body or that has recurred following surgery. Vismodegib has been used also for treatment of medulloblastoma. With additional research and experience in clinical trials, these drugs may become first-line agents for treatment of BCCs.In the past, x-ray or radiation therapy (radiotherapy) was often used to treat individuals with NBCCS, especially individuals who were poor candidates for surgery or who had multiple lesions. Although radiotherapy was effective, researchers have determined that this therapy is highly likely to cause new BCCs to form in the treated areas. Because of this significant adverse side effect and because systemic medications have become available to treat widespread and advanced BCCs, radiotherapy is avoided in patients with NBCCS unless other modalities have failed. The same precaution extends to treatment of any other cancer that occurs in an individual with NBCCS. Therapeutic radiation is relatively contraindicated but can be used when the risk posed by suboptimal treatment of the cancer is higher that the risk posed by BCCs in the radiation field. It should be noted that exposure to diagnostic X-rays (exposure less than 1/100th of therapeutic radiation), including CT scans, has never been shown to cause BCCs or other NBCCS-related tumors.Prevention
Affected individuals are encouraged to avoid excess exposure to the sun and to take proper precautions when in the sun (e.g. using sunscreen, sunglasses). As noted above, exposure to therapeutic levels of ionizing radiation, but not diagnostic X-rays, should be avoided. Identifying and treating tumors and cysts early prevent severe complications. Affected individuals should receive a panoramic radiograph once a year from the age of 8. A panoramic radiograph is a specialized x-ray that allows physicians to assess the health of the jaws and surrounding areas such as the nasal cavity. These tests can detect keratocystic odontogenic tumors of the jaw.Likewise, semiannual dermatologic exams and treatment of small lesions prevents disfiguring or life-threatening advanced BCCs. Head circumference should be monitored throughout childhood. Any rapid enlargement should prompt an evaluation for hydrocephalus. Physical examination and assessment for a medulloblastoma during childhood is recommended.
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Therapies of Nevoid Basal Cell Carcinoma Syndrome. Treatment
The treatment of NBCCS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, dermatologists, oral surgeons, dentists, cardiologists, ophthalmologists, plastic surgeons, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; tumor size; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular therapies or procedures should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Odontogenic keratocysts usually require prompt surgical removal (excision). The goal of this therapy is to preserve as much of the jaw and teeth as possible because affected individuals often develop multiple cysts throughout adolescence and adulthood. With larger cysts, it is recommended that they be decompressed first, usually through the insertion of a small tube that allows water or saline solution to flush out the tumor, shrinking it in size.A wide variety of treatment options exist for individuals with BCCs including topical chemotherapy, surgery, drug therapy, cryotherapy, electrodessication and curettage, and photodynamic therapy.Topical chemotherapy involves the application of creams applied directly to the lesion. Two common topical medications used to treat NBCCS are 5-fluorouracil and imiquimod 5%. These treatments may be used alone or in conjunction with other therapies. 5-fluorouracil works by destroying the abnormal skin cells and may be used to treat small, superficial BCCs in low risk areas. The U.S. Food and Drug Administration (FDA) has approved the use of imiquimod 5% (Aldara®) topical cream for the treatment of superficial basal cell carcinoma.Many individuals with NBCCS opt for surgical removal lesions if the overall number of lesions is low. Straightforward surgical removal of a lesion involves cutting the lesion out and closing the wound with sutures. In certain cases, large lesions may require a skin graft from another area of the body. Surgical excision of a lesion can result in a scar. Recurrence is possible as well.A specific type of surgery called Mohs micrographic surgery may be recommended for some individuals with NBCCS. With this surgery, a surgeon uses a precise technique to remove diseased tissue one layer at a time. According to the medical literature, Mohs surgery has proven particularly effective in treating NBCCS and is useful for treating difficult tumors that may not respond to other standard treatments.Cryotherapy may also be used to treat NBCCS. Cryotherapy is the use of extreme cold to freeze and destroy the tissue and cells of skin lesions and is a minimally invasive treatment option. With cryotherapy a freezing substance such as liquid nitrogen or argon gas is applied directly to the lesion. Cryotherapy is most effective for single or small lesions.Another surgical procedure used to treat individuals with NBCCS is electrodessication and curettage. With curettage, the lesion is scraped off the skin with a surgical instrument called a curette. The procedure is usually performed under anesthesia. In some cases, curettage may be followed by the use of an electrosurgical needle to apply heat and dry up the remaining cancerous tissue (electrodessication). This procedure may need to be repeated for some patients and will often leave a small white scar. This procedure is best for the treatment of small BCCs located in areas where the risk of recurrence is low. Electrodessication and curettage is often used as an alternative to topical chemotherapy.Laser vaporization is a newer procedure that is sometimes used alone or with curettage to treat BCCs, specifically individuals with multiple or superficial lesions. This procedure involves the use of a carbon dioxide laser to destroy (vaporize) abnormal tissue.Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with NBCCS who have large lesions. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to activate the drug which binds with oxygen creating a chemical that destroys the affected cells.In recent years, the FDA has approved two targeted drugs that specifically counteract the effect of PTCH1 mutations. Sonidegib (Odomzo®) and vismodegib (Erivedge®) specifically inhibit the hedgehog pathway. Both can be used for the treatment of adults with advanced basal cell carcinoma that has spread to other parts of the body or that has recurred following surgery. Vismodegib has been used also for treatment of medulloblastoma. With additional research and experience in clinical trials, these drugs may become first-line agents for treatment of BCCs.In the past, x-ray or radiation therapy (radiotherapy) was often used to treat individuals with NBCCS, especially individuals who were poor candidates for surgery or who had multiple lesions. Although radiotherapy was effective, researchers have determined that this therapy is highly likely to cause new BCCs to form in the treated areas. Because of this significant adverse side effect and because systemic medications have become available to treat widespread and advanced BCCs, radiotherapy is avoided in patients with NBCCS unless other modalities have failed. The same precaution extends to treatment of any other cancer that occurs in an individual with NBCCS. Therapeutic radiation is relatively contraindicated but can be used when the risk posed by suboptimal treatment of the cancer is higher that the risk posed by BCCs in the radiation field. It should be noted that exposure to diagnostic X-rays (exposure less than 1/100th of therapeutic radiation), including CT scans, has never been shown to cause BCCs or other NBCCS-related tumors.Prevention
Affected individuals are encouraged to avoid excess exposure to the sun and to take proper precautions when in the sun (e.g. using sunscreen, sunglasses). As noted above, exposure to therapeutic levels of ionizing radiation, but not diagnostic X-rays, should be avoided. Identifying and treating tumors and cysts early prevent severe complications. Affected individuals should receive a panoramic radiograph once a year from the age of 8. A panoramic radiograph is a specialized x-ray that allows physicians to assess the health of the jaws and surrounding areas such as the nasal cavity. These tests can detect keratocystic odontogenic tumors of the jaw.Likewise, semiannual dermatologic exams and treatment of small lesions prevents disfiguring or life-threatening advanced BCCs. Head circumference should be monitored throughout childhood. Any rapid enlargement should prompt an evaluation for hydrocephalus. Physical examination and assessment for a medulloblastoma during childhood is recommended.
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Nevoid Basal Cell Carcinoma Syndrome
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nord_881_0
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Overview of Nevus Sebaceus Syndrome
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IntroductionNevus sebaceus syndrome is a rare multisystem disorder characterized by sebaceous nevus associated with other abnormalities outside the skin, which most commonly affect the brain, eyes and bones. The skin lesions associated with this disorder are called nevus sebaceus (also referred to as sebaceous nevi) because they consist of an increased number of malformed sebaceous glands (small oil-producing glands in the skin) along with an overgrowth (hyperplasia) of the epidermis.Nevus sebaceus is the most common type of organoid epidermal nevus (which broadly encompasses abnormally formed adnexal skin elements such as hair follicles and glands within the skin). Epidermal nevi are usually present at birth (congenital), although they might not be identified until later during childhood or after puberty. Affected individuals may also have abnormalities affecting the brain such as seizures or intellectual impairment, the eyes such as clouding (opacity) of the cornea or partial absence of tissue of the iris or retina (coloboma), and the skeleton such as spinal malformations, craniofacial defects, and deformities of the arms and legs. Nevus sebaceus syndrome occurs randomly for no apparent reason (sporadically) during the formation and development of the embryo (embryogenesis), due to a mutation of a gene (ras) that occurs after fertilization (postzygotic mutation) and is present in only some of the cells of the body (mosaic pattern). SummaryThe term “epidermal nevus syndrome” is used interchangeably with nevus sebaceous syndrome. However, epidermal nevus syndrome no longer refers to a single entity, but rather represents a group of distinct, but related multisystem disorders. Additional terms used to describe nevus sebaceus syndrome include Schimmelpenning syndrome, Schimmelpenning-Feuerstein-Mims syndrome, linear sebaceous nevus sequence, nevus sebaceous of Jadassohn, Jadassohn nevus phacomatosis and Jadassohn sebaceous nevus syndrome.
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Overview of Nevus Sebaceus Syndrome. IntroductionNevus sebaceus syndrome is a rare multisystem disorder characterized by sebaceous nevus associated with other abnormalities outside the skin, which most commonly affect the brain, eyes and bones. The skin lesions associated with this disorder are called nevus sebaceus (also referred to as sebaceous nevi) because they consist of an increased number of malformed sebaceous glands (small oil-producing glands in the skin) along with an overgrowth (hyperplasia) of the epidermis.Nevus sebaceus is the most common type of organoid epidermal nevus (which broadly encompasses abnormally formed adnexal skin elements such as hair follicles and glands within the skin). Epidermal nevi are usually present at birth (congenital), although they might not be identified until later during childhood or after puberty. Affected individuals may also have abnormalities affecting the brain such as seizures or intellectual impairment, the eyes such as clouding (opacity) of the cornea or partial absence of tissue of the iris or retina (coloboma), and the skeleton such as spinal malformations, craniofacial defects, and deformities of the arms and legs. Nevus sebaceus syndrome occurs randomly for no apparent reason (sporadically) during the formation and development of the embryo (embryogenesis), due to a mutation of a gene (ras) that occurs after fertilization (postzygotic mutation) and is present in only some of the cells of the body (mosaic pattern). SummaryThe term “epidermal nevus syndrome” is used interchangeably with nevus sebaceous syndrome. However, epidermal nevus syndrome no longer refers to a single entity, but rather represents a group of distinct, but related multisystem disorders. Additional terms used to describe nevus sebaceus syndrome include Schimmelpenning syndrome, Schimmelpenning-Feuerstein-Mims syndrome, linear sebaceous nevus sequence, nevus sebaceous of Jadassohn, Jadassohn nevus phacomatosis and Jadassohn sebaceous nevus syndrome.
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Nevus Sebaceus Syndrome
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Symptoms of Nevus Sebaceus Syndrome
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The specific symptoms and severity of nevus sebaceus syndrome can vary greatly from one person to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The characteristic skin lesion that affects individuals with nevus sebaceus syndrome is a sebaceous nevus, which is a type of epidermal nevus. The scalp, neck and face are most often affected. The arms, legs and trunk may also be affected. Sebaceous nevi are usually salmon or yellowed colored, hairless, smooth patches. Eventually (usually around puberty) they become more pronounced and may appear scaly, warty or thickened. When the scalp is involved, large lesions may be present with associated areas of hair loss (alopecia). Sebaceous nevi may be prominent and easily noticeable at birth or be subtle and unrecognized. Sometimes, sebaceous nevi do not become apparent until after puberty when they go through the above mentioned changes. The lesions, apart from their appearance, usually do not cause additional symptoms.Nevus sebaceous most often occurs as isolated finding and usually is not associated with any abnormalities in other organs. However, when it occurs with additional extra-cutaneous symptoms, the term, nevus sebaceus syndrome, is appropriate. Some researchers have noted that central facial epidermal nevi may be more likely to be associated with malformations of the brain, eyes and cranial bones.Neurological abnormalities often occur in individuals with nevus sebaceus syndrome including seizures, delays in attaining developmental milestones (developmental delays), intellectual impairment, damage to certain cranial nerves and abnormalities affecting certain structures of the brain. Such abnormalities include one side of the brain being larger than the other (hemimegalencephaly), malformation (dysplasia) of the certain brain vessels, absence (agenesis) of the bundle of nerves that connects the two cerebral hemispheres (corpus callosum), and defects of the folds of the brain including a smooth brain that lacks the distinctive folds (agyria), abnormally small folds (microgyria) and abnormally thickened folds (pachygyria).Individuals with nevus sebaceus syndrome may also have Dandy-Walker malformation, a rare malformation of the brain that is present at birth (congenital). It is characterized by an abnormally enlarged space at the back of the brain (cystic 4th ventricle) that interferes with the normal flow of cerebrospinal fluid through the openings between the ventricle and other parts of the brain (foramina of Magendiand Luschka). Excessive amounts of fluid accumulate around the brain and cause abnormally high pressure within the skull, swelling of the head (congenital hydrocephalus), and neurological impairment. Motor delays and learning problems may also occur. Dandy-Walker malformation is a form of “obstructive” or “internal noncommunicating hydrocephalus”, meaning that the normal flow of cerebrospinal fluid is blocked resulting in the widening of the ventricles. Dandy-Walker malformation is often associated with partial agenesis of part of the cerebellum known as the cerebellar vermis. (For more information on this disorder, choose “Dandy-Walker” as your search term in the Rare Disease Database.)Ocular abnormalities also occur in nevus sebaceus syndrome including a partial absence of tissue (coloboma) from the colored portion of the eye (iris) or the membrane lining the back of the eyes (retina), clouding (opacity) of the cornea, crossed eyes (strabismus), defects of the optic nerve and scarring degeneration or detachment of the retina. Some individuals may have a benign, yellowish-white, fatty tumor on the outer portion of the eyeball (epibulbarlipodermoid). A sebaceous nevus on the face can potentially involve structures in the eye including the eyelids and the thin, clear membrane that covers the outer surface of the eye (conjunctiva).Affected individuals may also have skeletal malformations including abnormal curvature of the spine, dislocation of the hip, and deformities of the limbs. Craniofacial defects such as an unusually prominent forehead (frontal bossing), underdeveloped nasal and orbital bones and asymmetry of the skull may also occur. Additional skeletal malformations may include bone cysts, underdevelopment of the pelvis and incomplete formation of certain bony structures including the ankle, foot and bones of the spinal column (vertebrae).Individuals with nevus sebaceus syndrome may also develop vitamin D-resistant rickets, a condition characterized by bow deformities of the legs, pain in the legs and progressive softening of the bone structure. In children, growth rates may be slow, ultimately resulting in short stature. Affected individuals may be prone to fractures.According to the medical literature, sebaceus nevi are associated with an increased risk of developing secondary benign skin tumors such as trichoblastoma or syringocystadenomapapilliferum, whereas malignant secondary tumors (basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma) arising in association with a sebaceous nevus are very rare.
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Symptoms of Nevus Sebaceus Syndrome. The specific symptoms and severity of nevus sebaceus syndrome can vary greatly from one person to another. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The characteristic skin lesion that affects individuals with nevus sebaceus syndrome is a sebaceous nevus, which is a type of epidermal nevus. The scalp, neck and face are most often affected. The arms, legs and trunk may also be affected. Sebaceous nevi are usually salmon or yellowed colored, hairless, smooth patches. Eventually (usually around puberty) they become more pronounced and may appear scaly, warty or thickened. When the scalp is involved, large lesions may be present with associated areas of hair loss (alopecia). Sebaceous nevi may be prominent and easily noticeable at birth or be subtle and unrecognized. Sometimes, sebaceous nevi do not become apparent until after puberty when they go through the above mentioned changes. The lesions, apart from their appearance, usually do not cause additional symptoms.Nevus sebaceous most often occurs as isolated finding and usually is not associated with any abnormalities in other organs. However, when it occurs with additional extra-cutaneous symptoms, the term, nevus sebaceus syndrome, is appropriate. Some researchers have noted that central facial epidermal nevi may be more likely to be associated with malformations of the brain, eyes and cranial bones.Neurological abnormalities often occur in individuals with nevus sebaceus syndrome including seizures, delays in attaining developmental milestones (developmental delays), intellectual impairment, damage to certain cranial nerves and abnormalities affecting certain structures of the brain. Such abnormalities include one side of the brain being larger than the other (hemimegalencephaly), malformation (dysplasia) of the certain brain vessels, absence (agenesis) of the bundle of nerves that connects the two cerebral hemispheres (corpus callosum), and defects of the folds of the brain including a smooth brain that lacks the distinctive folds (agyria), abnormally small folds (microgyria) and abnormally thickened folds (pachygyria).Individuals with nevus sebaceus syndrome may also have Dandy-Walker malformation, a rare malformation of the brain that is present at birth (congenital). It is characterized by an abnormally enlarged space at the back of the brain (cystic 4th ventricle) that interferes with the normal flow of cerebrospinal fluid through the openings between the ventricle and other parts of the brain (foramina of Magendiand Luschka). Excessive amounts of fluid accumulate around the brain and cause abnormally high pressure within the skull, swelling of the head (congenital hydrocephalus), and neurological impairment. Motor delays and learning problems may also occur. Dandy-Walker malformation is a form of “obstructive” or “internal noncommunicating hydrocephalus”, meaning that the normal flow of cerebrospinal fluid is blocked resulting in the widening of the ventricles. Dandy-Walker malformation is often associated with partial agenesis of part of the cerebellum known as the cerebellar vermis. (For more information on this disorder, choose “Dandy-Walker” as your search term in the Rare Disease Database.)Ocular abnormalities also occur in nevus sebaceus syndrome including a partial absence of tissue (coloboma) from the colored portion of the eye (iris) or the membrane lining the back of the eyes (retina), clouding (opacity) of the cornea, crossed eyes (strabismus), defects of the optic nerve and scarring degeneration or detachment of the retina. Some individuals may have a benign, yellowish-white, fatty tumor on the outer portion of the eyeball (epibulbarlipodermoid). A sebaceous nevus on the face can potentially involve structures in the eye including the eyelids and the thin, clear membrane that covers the outer surface of the eye (conjunctiva).Affected individuals may also have skeletal malformations including abnormal curvature of the spine, dislocation of the hip, and deformities of the limbs. Craniofacial defects such as an unusually prominent forehead (frontal bossing), underdeveloped nasal and orbital bones and asymmetry of the skull may also occur. Additional skeletal malformations may include bone cysts, underdevelopment of the pelvis and incomplete formation of certain bony structures including the ankle, foot and bones of the spinal column (vertebrae).Individuals with nevus sebaceus syndrome may also develop vitamin D-resistant rickets, a condition characterized by bow deformities of the legs, pain in the legs and progressive softening of the bone structure. In children, growth rates may be slow, ultimately resulting in short stature. Affected individuals may be prone to fractures.According to the medical literature, sebaceus nevi are associated with an increased risk of developing secondary benign skin tumors such as trichoblastoma or syringocystadenomapapilliferum, whereas malignant secondary tumors (basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma) arising in association with a sebaceous nevus are very rare.
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Nevus Sebaceus Syndrome
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Causes of Nevus Sebaceus Syndrome
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Recent research has identified individuals with nevus sebaceus syndrome have postzygotic mutations of the KRAS and HRAS genes. In addition, HRAS and KRAS mutations have been found in isolated sebaceous nevus (in the absence of associated extracutaneous abnormalities). More research is necessary to further explore the relationship of ras mutations and the complex phenotype seen in some affected patients.
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Causes of Nevus Sebaceus Syndrome. Recent research has identified individuals with nevus sebaceus syndrome have postzygotic mutations of the KRAS and HRAS genes. In addition, HRAS and KRAS mutations have been found in isolated sebaceous nevus (in the absence of associated extracutaneous abnormalities). More research is necessary to further explore the relationship of ras mutations and the complex phenotype seen in some affected patients.
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Nevus Sebaceus Syndrome
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Affects of Nevus Sebaceus Syndrome
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Nevus sebaceus syndrome affects males and females in equal numbers. The exact prevalence and incidence of the disorder in the general population are unknown. Epidermal nevi (as an isolated finding or a part of a syndrome) have been reported to occur in approximately 1 to 3 per 1,000 live births.
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Affects of Nevus Sebaceus Syndrome. Nevus sebaceus syndrome affects males and females in equal numbers. The exact prevalence and incidence of the disorder in the general population are unknown. Epidermal nevi (as an isolated finding or a part of a syndrome) have been reported to occur in approximately 1 to 3 per 1,000 live births.
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Nevus Sebaceus Syndrome
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Related disorders of Nevus Sebaceus Syndrome
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Keratinocytic epidermal nevus (KEN) syndrome is a form of epidermal nevus syndrome involving a keratinocytic epidermal nevus (characterized by epidermal hyperplasia without enlarged and malformed sebaceous glands). The associated extracutaneous manifestations are similar to those seen in nevus sebaceus syndrome. The exact same postzygotic mutations of the KRAS and HRAS genes have been identified in KEN. KEN has also been associated with mutations in FGF3 and keratins 1 and 10 (causing epidermolytic KEN).Phakomatosis pigmentokeratotica is a form of epidermal nevus syndrome characterized by the presence of a sebaceous nevus and a condition known as speckled lentiginous nevus of the papular type. Speckled lentiginous nevus is characterized by large, light-brown discoloration of the skin, superimposed by multiple darkened (melanocytic) spots (papules). While sebaceous nevus is present at birth, the characteristic papules of speckled lentiginous nevus may not develop until later in life, whereas the café-au-lait background macules showing a checkerboard arrangement tend likewise to be present in the newborn. Individuals with phacomatosis pigmentokeratotica may also develop additional abnormalities, especially neurological and skeletal abnormalities. Neurological abnormalities include seizures, intellectual impairment, muscle weakness, paralysis on one side of the body (hemiparesis), underdevelopment of one side of the boy (hemiatrophy), excessive sweating (hyperhidrosis), and cutaneous dysesthesia, a condition in which touching the skin causing a feeling of unpleasantness. Skeletal abnormalities may include abnormal side-to-side curvature of the spine (scoliosis) and vitamin D-resistant rickets, a condition characterized by bowing deformities of the legs, pain in the legs and progressive softening of the bone structure. In children, growth rates may be slow, ultimately resulting in short stature. Affected individuals may be prone to fractures. Additional findings that have been reported in this disorder include hearing loss in one ear, crossed eyes (strabismus), droopy of the upper eyelid (ptosis) and narrowing of the aorta (aortic stenosis). (For more information, choose “epidermal nevus syndromes” as your search term in the Rare Disease Database.)
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Related disorders of Nevus Sebaceus Syndrome. Keratinocytic epidermal nevus (KEN) syndrome is a form of epidermal nevus syndrome involving a keratinocytic epidermal nevus (characterized by epidermal hyperplasia without enlarged and malformed sebaceous glands). The associated extracutaneous manifestations are similar to those seen in nevus sebaceus syndrome. The exact same postzygotic mutations of the KRAS and HRAS genes have been identified in KEN. KEN has also been associated with mutations in FGF3 and keratins 1 and 10 (causing epidermolytic KEN).Phakomatosis pigmentokeratotica is a form of epidermal nevus syndrome characterized by the presence of a sebaceous nevus and a condition known as speckled lentiginous nevus of the papular type. Speckled lentiginous nevus is characterized by large, light-brown discoloration of the skin, superimposed by multiple darkened (melanocytic) spots (papules). While sebaceous nevus is present at birth, the characteristic papules of speckled lentiginous nevus may not develop until later in life, whereas the café-au-lait background macules showing a checkerboard arrangement tend likewise to be present in the newborn. Individuals with phacomatosis pigmentokeratotica may also develop additional abnormalities, especially neurological and skeletal abnormalities. Neurological abnormalities include seizures, intellectual impairment, muscle weakness, paralysis on one side of the body (hemiparesis), underdevelopment of one side of the boy (hemiatrophy), excessive sweating (hyperhidrosis), and cutaneous dysesthesia, a condition in which touching the skin causing a feeling of unpleasantness. Skeletal abnormalities may include abnormal side-to-side curvature of the spine (scoliosis) and vitamin D-resistant rickets, a condition characterized by bowing deformities of the legs, pain in the legs and progressive softening of the bone structure. In children, growth rates may be slow, ultimately resulting in short stature. Affected individuals may be prone to fractures. Additional findings that have been reported in this disorder include hearing loss in one ear, crossed eyes (strabismus), droopy of the upper eyelid (ptosis) and narrowing of the aorta (aortic stenosis). (For more information, choose “epidermal nevus syndromes” as your search term in the Rare Disease Database.)
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Nevus Sebaceus Syndrome
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Diagnosis of Nevus Sebaceus Syndrome
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A diagnosis of nevus sebaceus syndrome is made based upon identification of characteristic symptoms (e.g., a sebaceous nevus along with abnormalities affecting other organ systems), a detailed patient history and a thorough clinical evaluation.Clinical Testing and Work-Up
In some cases, a small sample of affected skin may be taken for microscopic study (biopsy). Additional tests may be required to detect the presence and extent of associated symptoms. Such tests include a skeletal survey, a complete ophthalmologic exam, chests x-rays and specialized imaging techniques to evaluate the brain. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Whether a child with a sebaceous nevus should undergo such imaging techniques is controversial. Some researchers believe that these tests should be avoided unless there are clinical signs of central nervous system involvement.
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Diagnosis of Nevus Sebaceus Syndrome. A diagnosis of nevus sebaceus syndrome is made based upon identification of characteristic symptoms (e.g., a sebaceous nevus along with abnormalities affecting other organ systems), a detailed patient history and a thorough clinical evaluation.Clinical Testing and Work-Up
In some cases, a small sample of affected skin may be taken for microscopic study (biopsy). Additional tests may be required to detect the presence and extent of associated symptoms. Such tests include a skeletal survey, a complete ophthalmologic exam, chests x-rays and specialized imaging techniques to evaluate the brain. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Whether a child with a sebaceous nevus should undergo such imaging techniques is controversial. Some researchers believe that these tests should be avoided unless there are clinical signs of central nervous system involvement.
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Nevus Sebaceus Syndrome
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Therapies of Nevus Sebaceus Syndrome
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Treatment
The treatment of nevus sebaceus 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, pediatric neurologists, dermatologists, orthopedists, orthopedic surgeons, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.The specific therapeutic procedures and interventions for individuals with nevus sebaceus syndrome will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual’s age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her 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 may be performed to improve cosmetic appearance of individuals with nevus sebaceus syndrome. In the past, surgery was recommended because of the risk of malignancy. However, now that the risk of malignancy is much less than previously believed, this view is no longer advocated, especially if surgery will be disfiguring. In addition, the surgical excision of a lesion may not always be possible due to the specific location of the nevus.Additional therapies for nevus sebaceus syndrome depend upon the specific abnormalities present and usually follow standard guidelines. For example, epilepsy may be treated by anti-seizure medications and certain skeletal and ocular malformations may also be treated surgically. In the medical literature, several cases have been reported where neurosurgery has been used to treat individuals with nevus sebaceus syndrome and epilepsy.Additional therapies that may be used to treat individuals with nevus sebaceus syndrome include remedial education, physical therapy and occupational therapy all of which should be individualized. Genetic counseling may be of benefit for affected individuals and their families.
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Therapies of Nevus Sebaceus Syndrome. Treatment
The treatment of nevus sebaceus 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, pediatric neurologists, dermatologists, orthopedists, orthopedic surgeons, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.The specific therapeutic procedures and interventions for individuals with nevus sebaceus syndrome will vary, depending upon numerous factors including the specific symptoms present, the extent of the disorder, an individual’s age and overall health, tolerance of certain medications or procedures, personal preference and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her 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 may be performed to improve cosmetic appearance of individuals with nevus sebaceus syndrome. In the past, surgery was recommended because of the risk of malignancy. However, now that the risk of malignancy is much less than previously believed, this view is no longer advocated, especially if surgery will be disfiguring. In addition, the surgical excision of a lesion may not always be possible due to the specific location of the nevus.Additional therapies for nevus sebaceus syndrome depend upon the specific abnormalities present and usually follow standard guidelines. For example, epilepsy may be treated by anti-seizure medications and certain skeletal and ocular malformations may also be treated surgically. In the medical literature, several cases have been reported where neurosurgery has been used to treat individuals with nevus sebaceus syndrome and epilepsy.Additional therapies that may be used to treat individuals with nevus sebaceus syndrome include remedial education, physical therapy and occupational therapy all of which should be individualized. Genetic counseling may be of benefit for affected individuals and their families.
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Overview of NF2-Related Schwannomatosis
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NF2-related schwannomatosis (NF2; previously known as neurofibromatosis 2) is a rare genetic disorder that is primarily characterized by noncancerous (benign) tumors of the nerves that transmit balance and sound impulses from the inner ears to the brain (bilateral acoustic neuromas/vestibular schwannomas). Symptoms may become apparent during childhood, adolescence, early adulthood or later in adult life. Depending on the exact location and size of the acoustic neuromas/vestibular schwannomas, or other schwannomas such findings may include problems with balance and walking (gait); dizziness; headache; facial weakness, numbness, or pain; but more typically ringing in the ears (tinnitus); and/or progressive hearing loss.In some individuals with NF2, additional abnormalities may be present. These may include clouding of the lenses of the eyes (juvenile posterior subcapsular opacities), progressive visual impairment, or an increased risk of developing certain tumors of the lining of the brain (meningiomas or ependymomas) and spinal cord (central nervous system).NF2 results from changes (mutations or variants) in the NF2 gene. The NF2 gene regulates the production of a protein that functions as a tumor suppressor. In more than half of individuals with NF2, the disorder is caused by spontaneous (new) variants in the gene. In other affected individuals, NF2 is inherited in an autosomal dominant pattern.IntroductionThe term “neurofibromatosis” is also used to describe the second, distinct, and much more common form of NF known as neurofibromatosis 1 (NF1). NF1 is primarily characterized by the development of multiple benign tumors of nerves and skin (neurofibromas) and areas of abnormally decreased or increased coloration (hypo- or hyperpigmentation) of the skin, such as pale tan or light brown discolorations (café-au-lait spots) on the skin of the trunk or other regions. In contrast, in individuals with NF2, benign fibrous tumors of the skin (cutaneous neurofibromas) and multiple areas of abnormal color (pigmentation) are considered relatively uncommon. As with NF2, NF1 may be inherited in an autosomal dominant pattern or occur randomly due to new gene variant. NF2 is now classified along with other forms of schwannoma predisposition such as SMARCB and LZTR1-related schwannomatosis.
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Overview of NF2-Related Schwannomatosis. NF2-related schwannomatosis (NF2; previously known as neurofibromatosis 2) is a rare genetic disorder that is primarily characterized by noncancerous (benign) tumors of the nerves that transmit balance and sound impulses from the inner ears to the brain (bilateral acoustic neuromas/vestibular schwannomas). Symptoms may become apparent during childhood, adolescence, early adulthood or later in adult life. Depending on the exact location and size of the acoustic neuromas/vestibular schwannomas, or other schwannomas such findings may include problems with balance and walking (gait); dizziness; headache; facial weakness, numbness, or pain; but more typically ringing in the ears (tinnitus); and/or progressive hearing loss.In some individuals with NF2, additional abnormalities may be present. These may include clouding of the lenses of the eyes (juvenile posterior subcapsular opacities), progressive visual impairment, or an increased risk of developing certain tumors of the lining of the brain (meningiomas or ependymomas) and spinal cord (central nervous system).NF2 results from changes (mutations or variants) in the NF2 gene. The NF2 gene regulates the production of a protein that functions as a tumor suppressor. In more than half of individuals with NF2, the disorder is caused by spontaneous (new) variants in the gene. In other affected individuals, NF2 is inherited in an autosomal dominant pattern.IntroductionThe term “neurofibromatosis” is also used to describe the second, distinct, and much more common form of NF known as neurofibromatosis 1 (NF1). NF1 is primarily characterized by the development of multiple benign tumors of nerves and skin (neurofibromas) and areas of abnormally decreased or increased coloration (hypo- or hyperpigmentation) of the skin, such as pale tan or light brown discolorations (café-au-lait spots) on the skin of the trunk or other regions. In contrast, in individuals with NF2, benign fibrous tumors of the skin (cutaneous neurofibromas) and multiple areas of abnormal color (pigmentation) are considered relatively uncommon. As with NF2, NF1 may be inherited in an autosomal dominant pattern or occur randomly due to new gene variant. NF2 is now classified along with other forms of schwannoma predisposition such as SMARCB and LZTR1-related schwannomatosis.
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NF2-Related Schwannomatosis
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Symptoms of NF2-Related Schwannomatosis
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The characteristic symptoms of NF2 usually develop around the time of puberty or during early adulthood. These symptoms may include problems with balance, buzzing or ringing in the ears (tinnitus) and/or gradual hearing loss. These symptoms usually result from the presence of benign tumors on both vestibular nerves pressing on the adjacent auditory nerves (acoustic neuromas vestibular schwannomas). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Other tumors of the central nervous system may also develop, and can include hybrid tumors, meningiomas, low grade ependymomas of the spinal cord), and non-vestibular schwannomas on the other cranial nerves, spinal nerves or peripheral nerves. The size, location, and number of tumors may vary in different people affected. (For more information on tinnitus, choose “tinnitus” as your search term in the Rare Disease Database.)Individuals with NF2 may also develop cloudiness on the lenses of the eyes (posterior capsular cataracts) at a younger age than would otherwise be expected. Symptoms of cataracts may include impaired vision, and, in some cases, the progressive loss of vision, although surgery is not usually required.People with NF2 generally have fewer brown spots (café-au-lait) on the skin than those who have NF1. Affected individuals may also experience spasms of the facial muscles; generalized muscle weakness, numbness, pain, and/or partial paralysis; difficulty swallowing; and/or impaired speech. Other neurological problems may also develop including headaches and/or seizures.
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Symptoms of NF2-Related Schwannomatosis. The characteristic symptoms of NF2 usually develop around the time of puberty or during early adulthood. These symptoms may include problems with balance, buzzing or ringing in the ears (tinnitus) and/or gradual hearing loss. These symptoms usually result from the presence of benign tumors on both vestibular nerves pressing on the adjacent auditory nerves (acoustic neuromas vestibular schwannomas). Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Other tumors of the central nervous system may also develop, and can include hybrid tumors, meningiomas, low grade ependymomas of the spinal cord), and non-vestibular schwannomas on the other cranial nerves, spinal nerves or peripheral nerves. The size, location, and number of tumors may vary in different people affected. (For more information on tinnitus, choose “tinnitus” as your search term in the Rare Disease Database.)Individuals with NF2 may also develop cloudiness on the lenses of the eyes (posterior capsular cataracts) at a younger age than would otherwise be expected. Symptoms of cataracts may include impaired vision, and, in some cases, the progressive loss of vision, although surgery is not usually required.People with NF2 generally have fewer brown spots (café-au-lait) on the skin than those who have NF1. Affected individuals may also experience spasms of the facial muscles; generalized muscle weakness, numbness, pain, and/or partial paralysis; difficulty swallowing; and/or impaired speech. Other neurological problems may also develop including headaches and/or seizures.
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Causes of NF2-Related Schwannomatosis
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NF2 is caused by a variant in the NF2 gene. The NF2 gene regulates (encodes for) the production of a protein known as merlin/schwannomin that plays a role in suppressing the development of certain tumors (tumor suppressor). According to investigators, merlin/schwannomin is related to a class of proteins (ezrin-radixin-moesin proteins) that serve to link the internal, supportive system within a cell (cytoskeleton) to proteins in cell membranes. Several different types of variants of the NF2 gene have been identified in individuals with the disorder (e.g., large deletions, nonsense, splice site, missense and frameshift variants). Investigators suggest that different variants in the gene may contribute to the wide variability of symptoms and findings in affected individuals.In some individuals with NF2, the disorder is inherited in an autosomal dominant pattern. 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. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.In other individuals with NF2, there is no family history of the disease. In such cases, NF2 is caused by a new gene variant.
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Causes of NF2-Related Schwannomatosis. NF2 is caused by a variant in the NF2 gene. The NF2 gene regulates (encodes for) the production of a protein known as merlin/schwannomin that plays a role in suppressing the development of certain tumors (tumor suppressor). According to investigators, merlin/schwannomin is related to a class of proteins (ezrin-radixin-moesin proteins) that serve to link the internal, supportive system within a cell (cytoskeleton) to proteins in cell membranes. Several different types of variants of the NF2 gene have been identified in individuals with the disorder (e.g., large deletions, nonsense, splice site, missense and frameshift variants). Investigators suggest that different variants in the gene may contribute to the wide variability of symptoms and findings in affected individuals.In some individuals with NF2, the disorder is inherited in an autosomal dominant pattern. 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. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.In other individuals with NF2, there is no family history of the disease. In such cases, NF2 is caused by a new gene variant.
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Affects of NF2-Related Schwannomatosis
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NF2 is a rare disorder that affects males and females in equal numbers. All races and ethnic groups are equally affected by this disorder. The estimated incidence of NF2 is 1 in 33,000 people worldwide. The symptoms of this disease typically become apparent during puberty or early adulthood. The average age of onset is 18 to 24 years.
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Affects of NF2-Related Schwannomatosis. NF2 is a rare disorder that affects males and females in equal numbers. All races and ethnic groups are equally affected by this disorder. The estimated incidence of NF2 is 1 in 33,000 people worldwide. The symptoms of this disease typically become apparent during puberty or early adulthood. The average age of onset is 18 to 24 years.
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Related disorders of NF2-Related Schwannomatosis
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Symptoms of the following disorders can be similar to those of neurofibromatosis 2. Comparisons may be useful for a differential diagnosis:Neurofibromatosis 1 (NF1)Neurofibromatosis1 (NF1) is a rare inherited disorder of the nervous system and is characterized by the development of tumors on the covering of nerves. The symptoms of this disorder include brown spots (café-au-lait) and freckles on the skin, especially under the arms and in the groin area. Small, orange-brownish, benign tumors may develop on the iris of the eyes (Lisch nodules). Multiple noncancerous (benign) tumors develop on the covering of the nerves. These tumors can grow on any nerve and may appear at any time, including childhood, adolescence or adulthood. Orthopedic problems may develop including curvature of the spine (scoliosis) and bone loss on weight- bearing long bones (pseudoarthrosis). (For more information on this disorder, choose “neurofibromatosis 1” as your search term in the Rare Disease Database.)Other forms of schwannomatosisSchwannomatosis is a disorder characterized by the presence of multiple schwannomas, nearly always without the vestibular schwannomas that are diagnostic of NF2. Patients with schwannomatosis may develop benign tumors in the brain, along the spinal or peripheral nerves. This condition may also be inherited in an autosomal dominant pattern. The other schwannomatoses are caused by different genes than for NF2, however, some patients with multiple non vestibular schwannomas eventually fulfill the diagnostic criteria for NF2.Unilateral vestibular schwannomaUnilateral vestibular schwannoma accounts for approximately 5% to 10% of all tumors in the brain. Vestibular schwannomas that are bilateral are associated with NF2. There is usually no genetic predisposition for developing an isolated unilateral vestibular schwannoma.MeningiomaA meningioma is a tumor that develops from the membranes that surround the spinal cord and brain (meninges). Multiple meningiomas typically occur in older adults, thus, finding a single meningioma in a younger individual may indicate an underlying genetic condition.The following disorders may be associated with NF2 as secondary characteristics. They are not necessary for a differential diagnosis:TinnitusTinnitus describes the experience of hearing sound that does not exist in the environment. The sounds associated with tinnitus have been described as clicking, buzzing, whistling, ringing and/or roaring. They may always be continuous, or they may come and go. Eventually hearing loss may occur. Many ear (auditory) disorders can be associated with tinnitus including various infections of the ear, obstructions, tumors, drug side effects, and other disorders such as NF2. (For more information on this disorder, choose “tinnitus” as your search term in the Rare Disease Database.)CataractsCataracts are abnormalities in the lens of the eye that cause a loss of transparency (opacity). They can occur in one or both eyes and are quite common in elderly people. Congenital cataracts affect babies or young children and are considered a rare birth defect. The symptoms of cataracts include cloudy vision and nearsightedness (myopia). In many cases, cataracts may result in blindness if left untreated. Cataracts may have a variety of causes. Some are inherited whereas others are due to injury, aging, or other diseases such as neurofibromatosis. Cataracts in NF2 rarely require surgery.
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Related disorders of NF2-Related Schwannomatosis. Symptoms of the following disorders can be similar to those of neurofibromatosis 2. Comparisons may be useful for a differential diagnosis:Neurofibromatosis 1 (NF1)Neurofibromatosis1 (NF1) is a rare inherited disorder of the nervous system and is characterized by the development of tumors on the covering of nerves. The symptoms of this disorder include brown spots (café-au-lait) and freckles on the skin, especially under the arms and in the groin area. Small, orange-brownish, benign tumors may develop on the iris of the eyes (Lisch nodules). Multiple noncancerous (benign) tumors develop on the covering of the nerves. These tumors can grow on any nerve and may appear at any time, including childhood, adolescence or adulthood. Orthopedic problems may develop including curvature of the spine (scoliosis) and bone loss on weight- bearing long bones (pseudoarthrosis). (For more information on this disorder, choose “neurofibromatosis 1” as your search term in the Rare Disease Database.)Other forms of schwannomatosisSchwannomatosis is a disorder characterized by the presence of multiple schwannomas, nearly always without the vestibular schwannomas that are diagnostic of NF2. Patients with schwannomatosis may develop benign tumors in the brain, along the spinal or peripheral nerves. This condition may also be inherited in an autosomal dominant pattern. The other schwannomatoses are caused by different genes than for NF2, however, some patients with multiple non vestibular schwannomas eventually fulfill the diagnostic criteria for NF2.Unilateral vestibular schwannomaUnilateral vestibular schwannoma accounts for approximately 5% to 10% of all tumors in the brain. Vestibular schwannomas that are bilateral are associated with NF2. There is usually no genetic predisposition for developing an isolated unilateral vestibular schwannoma.MeningiomaA meningioma is a tumor that develops from the membranes that surround the spinal cord and brain (meninges). Multiple meningiomas typically occur in older adults, thus, finding a single meningioma in a younger individual may indicate an underlying genetic condition.The following disorders may be associated with NF2 as secondary characteristics. They are not necessary for a differential diagnosis:TinnitusTinnitus describes the experience of hearing sound that does not exist in the environment. The sounds associated with tinnitus have been described as clicking, buzzing, whistling, ringing and/or roaring. They may always be continuous, or they may come and go. Eventually hearing loss may occur. Many ear (auditory) disorders can be associated with tinnitus including various infections of the ear, obstructions, tumors, drug side effects, and other disorders such as NF2. (For more information on this disorder, choose “tinnitus” as your search term in the Rare Disease Database.)CataractsCataracts are abnormalities in the lens of the eye that cause a loss of transparency (opacity). They can occur in one or both eyes and are quite common in elderly people. Congenital cataracts affect babies or young children and are considered a rare birth defect. The symptoms of cataracts include cloudy vision and nearsightedness (myopia). In many cases, cataracts may result in blindness if left untreated. Cataracts may have a variety of causes. Some are inherited whereas others are due to injury, aging, or other diseases such as neurofibromatosis. Cataracts in NF2 rarely require surgery.
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Diagnosis of NF2-Related Schwannomatosis
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The diagnosis of NF2 is confirmed by a thorough clinical evaluation and specialized testing (i.e., CT scan, magnetic resonance imaging (MRI), pneumoencephalogram, or arteriogram are very rarely used nowadays). Molecular genetic testing for variants in the NF2 gene is available for most affected individuals who have a positive family history.
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Diagnosis of NF2-Related Schwannomatosis. The diagnosis of NF2 is confirmed by a thorough clinical evaluation and specialized testing (i.e., CT scan, magnetic resonance imaging (MRI), pneumoencephalogram, or arteriogram are very rarely used nowadays). Molecular genetic testing for variants in the NF2 gene is available for most affected individuals who have a positive family history.
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Therapies of NF2-Related Schwannomatosis
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The treatment of vestibular (acoustic) neuromas associated with NF2 is the surgical removal of the tumors, when possible. The surgical procedure that is performed is based upon the size and precise location of the tumors. Radiation therapy may be considered for some individuals with this disorder, especially those who are not candidates for surgery. The VEGF inhibitor bevacizumab may also be considered to treat rapidly growing schwannomas.Other treatment is symptomatic and supportive.Regular monitoring may be required for affected or at-risk individuals. An annual magnetic resonance imaging (MRI) may be necessary beginning at approximately age 10 to 12 years and continuing until at least the fourth decade of life in addition to regular hearing evaluations. Earlier diagnosis and better treatment lend itself to improved survival in those affected.Genetic counseling is recommended for people with NF2 and their family members.
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Therapies of NF2-Related Schwannomatosis. The treatment of vestibular (acoustic) neuromas associated with NF2 is the surgical removal of the tumors, when possible. The surgical procedure that is performed is based upon the size and precise location of the tumors. Radiation therapy may be considered for some individuals with this disorder, especially those who are not candidates for surgery. The VEGF inhibitor bevacizumab may also be considered to treat rapidly growing schwannomas.Other treatment is symptomatic and supportive.Regular monitoring may be required for affected or at-risk individuals. An annual magnetic resonance imaging (MRI) may be necessary beginning at approximately age 10 to 12 years and continuing until at least the fourth decade of life in addition to regular hearing evaluations. Earlier diagnosis and better treatment lend itself to improved survival in those affected.Genetic counseling is recommended for people with NF2 and their family members.
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Overview of NGLY1 Deficiency
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NGLY1 deficiency is a rare disorder that can affect multiple systems of the body. Affected individuals may have delays in reaching developmental milestones, intellectual disability, movement disorders, seizures, liver disease, and an inability to produce tears when they cry (alacrima), or they may produce tears very infrequently. The specific symptoms and severity of this disorder can vary dramatically among affected individuals. Additional symptoms can develop in some children. NGLY1 deficiency is caused by a disease causing (pathogenic) variant (mutation) in the NGLY1 gene. This variant is inherited in an autosomal recessive pattern. As of April of 2021, fewer than 100 individuals with NGLY1 deficiency have been identified. It is possible that only the most severely affected children have been diagnosed and that descriptions of this disorder reflect these severely affected individuals. This happens because more severely affected children are more likely to be referred to specialists, receive genetic testing, and receive a diagnosis. Some researchers believe that affected individuals with milder forms of NGLY1 deficiency most likely exist.
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Overview of NGLY1 Deficiency. NGLY1 deficiency is a rare disorder that can affect multiple systems of the body. Affected individuals may have delays in reaching developmental milestones, intellectual disability, movement disorders, seizures, liver disease, and an inability to produce tears when they cry (alacrima), or they may produce tears very infrequently. The specific symptoms and severity of this disorder can vary dramatically among affected individuals. Additional symptoms can develop in some children. NGLY1 deficiency is caused by a disease causing (pathogenic) variant (mutation) in the NGLY1 gene. This variant is inherited in an autosomal recessive pattern. As of April of 2021, fewer than 100 individuals with NGLY1 deficiency have been identified. It is possible that only the most severely affected children have been diagnosed and that descriptions of this disorder reflect these severely affected individuals. This happens because more severely affected children are more likely to be referred to specialists, receive genetic testing, and receive a diagnosis. Some researchers believe that affected individuals with milder forms of NGLY1 deficiency most likely exist.
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Symptoms of NGLY1 Deficiency
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Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. As researchers learn more about the disorder, the potential spectrum or specific pattern of symptoms will be clearer. Therefore, it is important to note that every child is unique and that an individual child may not have all the symptoms discussed below.Affected infants often have diminished muscle tone (hypotonia), in which the baby is described as excessively “floppy.” About half have a low weight at birth and, despite a normal appetite, many infants will fail to gain weight or grow as would be expected based on their age and gender (failure to thrive). Some infants have difficulty swallowing and are at risk of food or liquids going down the wrong tube and ending up in the lungs (aspiration). Constipation can also occur. In some children, the circumference of the head, which is normal at birth, may be smaller than would be expected as they age (acquired microcephaly).Most affected infants and children may not produce tears or produce few tears when they cry (alacrima). This can lead to complications including inflammation of the eyelids (blepharitis), eye infection, irritation and open sores on the cornea, the transparent layer atop the eye (corneal ulceration). The eyes may not be aligned properly and may point in different directions (strabismus). In a few children, there was degeneration of the main nerve that transmits sensory input to the brain to form images (optic atrophy) and pigment changes in the membrane lining the back of the eyes (retina), and abnormalities of certain cells of the retina called cone cells (cone dystrophy). Vision impairment has been described in some children as well.Neurodevelopmental symptoms are common in NGLY1 deficiency including delays in reaching developmental milestones like sitting up, crawling, or walking. As they age, children may have difficulty walking independently or be unable to walk. There may be delays in speech development, and children are often unable to speak or can only speak a few words. Intellectual disability is common and can range from children with below average IQ scores to significant intellectual disability.Most affected children may have a complex movement disorder that includes quivering or shaking (tremulousness) and abnormally increased and sometimes uncontrollable muscle spasms (hyperkinesis). Specific movement abnormalities include choreoathetosis, action tremor, myoclonic movements, dystonic movements, and dysmetria. Choreoathetosis is characterized by irregular, rapid, jerky movements that may occur in association with slow, writhing movements. Other types of abnormal movements can develop including a slight tremor when trying to perform a task (action tremor), twitching or jerking (myoclonic movements) movements, involuntary muscle contractions that force the body into abnormal (and sometimes painful) movements or positions (dystonic movements), and a lack of coordination and accuracy in voluntary movements (dysmetria), which means affected individuals will under- or overreach when trying to grab an object, or under- or overstep when walking.Some children may have elevated levels of certain liver enzymes, which normally indicate liver dysfunction or damage. Mild scarring (fibrosis) of the liver can develop. One individual developed severe acute liver failure that resolved. Most of the time, the liver enzyme levels improve as a child ages. Sometimes, the liver may be larger than normal (hepatomegaly).Some children have developed seizures of various types. The age of onset for seizures has ranged from two months to 10 years old. Sometimes, the seizures have responded to medications and other times they have continued despite drug therapy (intractable seizures).A variety of skeletal problems have been reported including small hands or feet, recurrent fractures, a defect of the hip that causes the thigh bone to angle out to the side of the body (coxa valga), abnormal sideways curvature of the spine (scoliosis), joints that are loose and have a larger range of motion than normal (joint hypermobility), and partial (subluxation) or full dislocations of certain joints like the hip or shoulder.A few affected children have been prone to developing repeated, severe respiratory infections. Most children, however, are no different or have fewer infections than unaffected children.Some affected individuals develop peripheral neuropathy, a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain. As it progresses, peripheral neuropathy can lead to sores or infections in the feet that don’t heal, weakness, and balance and walking problems.
Some children experience hearing loss. The ears function normally, but the way the brain processes sound is abnormal (auditory neuropathy). Additional symptoms can include an abnormally large spleen (splenomegaly), temporary, recurrent interruptions of breathing during sleep (sleep apnea), a disturbed sleep pattern, diminished reflexes or an inability or reduced ability to sweat; this may make it difficult for affected individuals to regulate body temperature (causing them to overheat) during warm months.Adrenal insufficiency has been reported in NGLY1 deficiency. The adrenal glands, located on to of the kidneys, make hormones. In adrenal insufficiency, the adrenal glands cannot make enough hormones needed to respond to stress, regulate blood pressure, and regulate sexual development. This can lead to serious illness, especially in times of stress, such as during an infection.
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Symptoms of NGLY1 Deficiency. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. As researchers learn more about the disorder, the potential spectrum or specific pattern of symptoms will be clearer. Therefore, it is important to note that every child is unique and that an individual child may not have all the symptoms discussed below.Affected infants often have diminished muscle tone (hypotonia), in which the baby is described as excessively “floppy.” About half have a low weight at birth and, despite a normal appetite, many infants will fail to gain weight or grow as would be expected based on their age and gender (failure to thrive). Some infants have difficulty swallowing and are at risk of food or liquids going down the wrong tube and ending up in the lungs (aspiration). Constipation can also occur. In some children, the circumference of the head, which is normal at birth, may be smaller than would be expected as they age (acquired microcephaly).Most affected infants and children may not produce tears or produce few tears when they cry (alacrima). This can lead to complications including inflammation of the eyelids (blepharitis), eye infection, irritation and open sores on the cornea, the transparent layer atop the eye (corneal ulceration). The eyes may not be aligned properly and may point in different directions (strabismus). In a few children, there was degeneration of the main nerve that transmits sensory input to the brain to form images (optic atrophy) and pigment changes in the membrane lining the back of the eyes (retina), and abnormalities of certain cells of the retina called cone cells (cone dystrophy). Vision impairment has been described in some children as well.Neurodevelopmental symptoms are common in NGLY1 deficiency including delays in reaching developmental milestones like sitting up, crawling, or walking. As they age, children may have difficulty walking independently or be unable to walk. There may be delays in speech development, and children are often unable to speak or can only speak a few words. Intellectual disability is common and can range from children with below average IQ scores to significant intellectual disability.Most affected children may have a complex movement disorder that includes quivering or shaking (tremulousness) and abnormally increased and sometimes uncontrollable muscle spasms (hyperkinesis). Specific movement abnormalities include choreoathetosis, action tremor, myoclonic movements, dystonic movements, and dysmetria. Choreoathetosis is characterized by irregular, rapid, jerky movements that may occur in association with slow, writhing movements. Other types of abnormal movements can develop including a slight tremor when trying to perform a task (action tremor), twitching or jerking (myoclonic movements) movements, involuntary muscle contractions that force the body into abnormal (and sometimes painful) movements or positions (dystonic movements), and a lack of coordination and accuracy in voluntary movements (dysmetria), which means affected individuals will under- or overreach when trying to grab an object, or under- or overstep when walking.Some children may have elevated levels of certain liver enzymes, which normally indicate liver dysfunction or damage. Mild scarring (fibrosis) of the liver can develop. One individual developed severe acute liver failure that resolved. Most of the time, the liver enzyme levels improve as a child ages. Sometimes, the liver may be larger than normal (hepatomegaly).Some children have developed seizures of various types. The age of onset for seizures has ranged from two months to 10 years old. Sometimes, the seizures have responded to medications and other times they have continued despite drug therapy (intractable seizures).A variety of skeletal problems have been reported including small hands or feet, recurrent fractures, a defect of the hip that causes the thigh bone to angle out to the side of the body (coxa valga), abnormal sideways curvature of the spine (scoliosis), joints that are loose and have a larger range of motion than normal (joint hypermobility), and partial (subluxation) or full dislocations of certain joints like the hip or shoulder.A few affected children have been prone to developing repeated, severe respiratory infections. Most children, however, are no different or have fewer infections than unaffected children.Some affected individuals develop peripheral neuropathy, a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain. As it progresses, peripheral neuropathy can lead to sores or infections in the feet that don’t heal, weakness, and balance and walking problems.
Some children experience hearing loss. The ears function normally, but the way the brain processes sound is abnormal (auditory neuropathy). Additional symptoms can include an abnormally large spleen (splenomegaly), temporary, recurrent interruptions of breathing during sleep (sleep apnea), a disturbed sleep pattern, diminished reflexes or an inability or reduced ability to sweat; this may make it difficult for affected individuals to regulate body temperature (causing them to overheat) during warm months.Adrenal insufficiency has been reported in NGLY1 deficiency. The adrenal glands, located on to of the kidneys, make hormones. In adrenal insufficiency, the adrenal glands cannot make enough hormones needed to respond to stress, regulate blood pressure, and regulate sexual development. This can lead to serious illness, especially in times of stress, such as during an infection.
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Causes of NGLY1 Deficiency
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NGLY1 deficiency is caused by disease causing (pathogenic) variants in the NGLY1 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.Researchers have determined that the NGLY1 gene produces a specialized protein (enzyme) called N-glycanase that helps to remove and recycle damaged proteins within the body. This enzyme is involved in a process called deglycosylation, in which sugar molecules called sugar ‘trees’ or glycans are removed from proteins. This step is essential in breaking down damaged or misshaped (misfolded) proteins so that components can be recycled. Some researchers believe these misfolded proteins buildup in certain tissues of the body. The enzyme is also important in activating some proteins that need to have their glycans removed at the right time to work properly. Because of the mutation in the NGLY1 gene, affected individuals do not develop sufficient levels or develop an ineffective form of N-glycanase and cannot properly cleave off the sugar chains from proteins. N-glycanase is also important in regulating some aspects of reading DNA (DNA transcription). The exact manner the deficiency of the N-glycanase protein ultimately causes the symptoms of the disorder is not fully understood yet.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. NGLY1 deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Causes of NGLY1 Deficiency. NGLY1 deficiency is caused by disease causing (pathogenic) variants in the NGLY1 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.Researchers have determined that the NGLY1 gene produces a specialized protein (enzyme) called N-glycanase that helps to remove and recycle damaged proteins within the body. This enzyme is involved in a process called deglycosylation, in which sugar molecules called sugar ‘trees’ or glycans are removed from proteins. This step is essential in breaking down damaged or misshaped (misfolded) proteins so that components can be recycled. Some researchers believe these misfolded proteins buildup in certain tissues of the body. The enzyme is also important in activating some proteins that need to have their glycans removed at the right time to work properly. Because of the mutation in the NGLY1 gene, affected individuals do not develop sufficient levels or develop an ineffective form of N-glycanase and cannot properly cleave off the sugar chains from proteins. N-glycanase is also important in regulating some aspects of reading DNA (DNA transcription). The exact manner the deficiency of the N-glycanase protein ultimately causes the symptoms of the disorder is not fully understood yet.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. NGLY1 deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
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Affects of NGLY1 Deficiency
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NGLY1 deficiency is an extremely rare disorder that was first reported in the medical literature in 2012. According to the NGLY1 Foundation, as of April 2021, there are approximately 75 individuals worldwide who have been identified with the disorder. Rare diseases like NGLY1 deficiency often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Affects of NGLY1 Deficiency. NGLY1 deficiency is an extremely rare disorder that was first reported in the medical literature in 2012. According to the NGLY1 Foundation, as of April 2021, there are approximately 75 individuals worldwide who have been identified with the disorder. Rare diseases like NGLY1 deficiency often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.
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Related disorders of NGLY1 Deficiency
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Symptoms of the following disorders can be similar to those of NGLY1 deficiency. Comparisons may be useful for a differential diagnosis.Congenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of rare genetic, metabolic disorders due to defects in complex chemical process known as glycosylation. Glycosylation is the process by which sugar ‘trees’ (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems. CDG can affect any part of the body, and there is often an important neurological component. CDG can be associated with a broad variety of symptoms and can vary in severity from mild cases to severe, disabling or life-threatening cases. CDG are usually apparent from infancy. Individual CDG are caused by a mutation to a specific gene. Most CDG are inherited as autosomal recessive conditions. CDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues. More than 100 different forms of CDG have been identified in the ensuing years. Several different names have been used to describe these disorders including carbohydrate-deficient glycoprotein syndromes. Recently, Jaeken and colleagues have proposed a classification system that names each subtype by the official abbreviation of its defective gene followed by a dash and CDG. For example, congenital disorder of glycosylation type 1a is now known as PMM2-CDG. PMM2 is the defective gene that causes this subtype of CDG. (For more information on this disorder, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are additional neurodevelopmental disorders that can have symptoms that overlap with those associated with NGLY1 deficiency. These disorders include hereditary sensory and autonomic neuropathies; Rett syndrome; MECP2 duplication syndrome; triple-A syndrome; creatine deficiency syndromes including creatine transporter deficiency, guanidinoacetate methyltransferase deficiency, and L-arginine: glycine amidinotransferase deficiency; and neurotransmitter deficiencies like Segawa syndrome and tyrosine hydroxylase deficiency. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. (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 NGLY1 Deficiency. Symptoms of the following disorders can be similar to those of NGLY1 deficiency. Comparisons may be useful for a differential diagnosis.Congenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of rare genetic, metabolic disorders due to defects in complex chemical process known as glycosylation. Glycosylation is the process by which sugar ‘trees’ (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems. CDG can affect any part of the body, and there is often an important neurological component. CDG can be associated with a broad variety of symptoms and can vary in severity from mild cases to severe, disabling or life-threatening cases. CDG are usually apparent from infancy. Individual CDG are caused by a mutation to a specific gene. Most CDG are inherited as autosomal recessive conditions. CDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues. More than 100 different forms of CDG have been identified in the ensuing years. Several different names have been used to describe these disorders including carbohydrate-deficient glycoprotein syndromes. Recently, Jaeken and colleagues have proposed a classification system that names each subtype by the official abbreviation of its defective gene followed by a dash and CDG. For example, congenital disorder of glycosylation type 1a is now known as PMM2-CDG. PMM2 is the defective gene that causes this subtype of CDG. (For more information on this disorder, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial disease. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)There are additional neurodevelopmental disorders that can have symptoms that overlap with those associated with NGLY1 deficiency. These disorders include hereditary sensory and autonomic neuropathies; Rett syndrome; MECP2 duplication syndrome; triple-A syndrome; creatine deficiency syndromes including creatine transporter deficiency, guanidinoacetate methyltransferase deficiency, and L-arginine: glycine amidinotransferase deficiency; and neurotransmitter deficiencies like Segawa syndrome and tyrosine hydroxylase deficiency. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of NGLY1 Deficiency
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A diagnosis of NGLY1 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A combination of characteristic symptoms including developmental delays, alacrima, hyperkinetic movement disorders, and liver disease may prompt testing for the disorder.Clinical Testing and Workup
Most individuals are diagnosed through molecular genetic (DNA) testing. Molecular genetic testing can detect mutations in the NGLY1 gene known to cause NGLY1 deficiency but is available only as a diagnostic service at specialized laboratories.If molecular genetic testing identifies variants in the NGLY1 gene that have never been seen before, research is necessary to confirm a diagnosis. Sometimes the research testing needs a small sample of skin tissue that is obtained by cutting off a small piece of skin (skin biopsy), which is then studied under a microscope.Liver chemistry tests can reveal elevated levels of certain liver enzymes, aspartate transaminase (AST) and alanine transaminase (ALT) in the blood. Sometimes, there is elevation of alpha-fetoprotein (AFP). Elevation of these liver enzymes can occur in a variety of diseases and is not diagnostic of NGLY1 deficiency on their own. The levels of these enzymes in children normalize with age, and this testing is not effective for older children.Researchers have discovered that testing the urine of affected individuals may reveal abnormalities of certain long sugar chains called oligosaccharides. Testing in blood spots has also noted an increase level of a specific sugar attached to protein called aspartylglucosamine.
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Diagnosis of NGLY1 Deficiency. A diagnosis of NGLY1 deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A combination of characteristic symptoms including developmental delays, alacrima, hyperkinetic movement disorders, and liver disease may prompt testing for the disorder.Clinical Testing and Workup
Most individuals are diagnosed through molecular genetic (DNA) testing. Molecular genetic testing can detect mutations in the NGLY1 gene known to cause NGLY1 deficiency but is available only as a diagnostic service at specialized laboratories.If molecular genetic testing identifies variants in the NGLY1 gene that have never been seen before, research is necessary to confirm a diagnosis. Sometimes the research testing needs a small sample of skin tissue that is obtained by cutting off a small piece of skin (skin biopsy), which is then studied under a microscope.Liver chemistry tests can reveal elevated levels of certain liver enzymes, aspartate transaminase (AST) and alanine transaminase (ALT) in the blood. Sometimes, there is elevation of alpha-fetoprotein (AFP). Elevation of these liver enzymes can occur in a variety of diseases and is not diagnostic of NGLY1 deficiency on their own. The levels of these enzymes in children normalize with age, and this testing is not effective for older children.Researchers have discovered that testing the urine of affected individuals may reveal abnormalities of certain long sugar chains called oligosaccharides. Testing in blood spots has also noted an increase level of a specific sugar attached to protein called aspartylglucosamine.
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Therapies of NGLY1 Deficiency
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Treatment
The treatment of NGLY1 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children (pediatric neurologists), neurologists, a physician who specializes in the diagnosis and treatment of disorders of the eye (ophthalmologists), a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract (gastroenterologist), a physician who specializes in the diagnosis and treatment of liver disorders (hepatologist), a physician who specializes in the diagnosis and treatment of skeletal disorders (orthopedist), a physician who specializes in the diagnosis and treatment of genetic disorders (medical geneticist), speech pathologist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, 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 NGLY1 deficiency.Infants with NGLY1 deficiency should be evaluated for feeding issues and treated with standard methods if necessary. This may include the insertion of a feeding tube. A feeding tube may run through the nose and down the esophagus into the stomach, or may be directly inserted into the stomach through a small surgical opening in the abdominal wall. A feeding tube ensures that affected individuals receive sufficient nutrients.Poor production or lack of production of tears may be treated with lubricating eye drops or bland ointments. Anti-seizures medications called anti-epileptics may be tried. Sometimes, these medications are effective, but other times the seizures continue (intractable seizures). Braces and other orthotic devices can help children walk. Some children will require a wheelchair.Individuals with an inability to sweat may require access to water to remain hydrated, especially when involved in physical exertion. Items like a cooling vest or access to cool environments (e.g. those with air conditioning or other cooling methods) is also beneficial.Affected children may benefit from occupational, physical, and speech therapy. Water and music therapy have also been beneficial for some affected children. Assistive and augmentative communication devices can help children express thoughts, wants, needs and ideas. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.Many symptoms associated with NGLY1 deficiency including constipation, scoliosis, sleep apnea, and hearing loss follow standard or routine treatment options.
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Therapies of NGLY1 Deficiency. Treatment
The treatment of NGLY1 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children (pediatric neurologists), neurologists, a physician who specializes in the diagnosis and treatment of disorders of the eye (ophthalmologists), a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract (gastroenterologist), a physician who specializes in the diagnosis and treatment of liver disorders (hepatologist), a physician who specializes in the diagnosis and treatment of skeletal disorders (orthopedist), a physician who specializes in the diagnosis and treatment of genetic disorders (medical geneticist), speech pathologist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, 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 NGLY1 deficiency.Infants with NGLY1 deficiency should be evaluated for feeding issues and treated with standard methods if necessary. This may include the insertion of a feeding tube. A feeding tube may run through the nose and down the esophagus into the stomach, or may be directly inserted into the stomach through a small surgical opening in the abdominal wall. A feeding tube ensures that affected individuals receive sufficient nutrients.Poor production or lack of production of tears may be treated with lubricating eye drops or bland ointments. Anti-seizures medications called anti-epileptics may be tried. Sometimes, these medications are effective, but other times the seizures continue (intractable seizures). Braces and other orthotic devices can help children walk. Some children will require a wheelchair.Individuals with an inability to sweat may require access to water to remain hydrated, especially when involved in physical exertion. Items like a cooling vest or access to cool environments (e.g. those with air conditioning or other cooling methods) is also beneficial.Affected children may benefit from occupational, physical, and speech therapy. Water and music therapy have also been beneficial for some affected children. Assistive and augmentative communication devices can help children express thoughts, wants, needs and ideas. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.Many symptoms associated with NGLY1 deficiency including constipation, scoliosis, sleep apnea, and hearing loss follow standard or routine treatment options.
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NGLY1 Deficiency
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Overview of Niemann Pick Disease Type C
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SummaryNiemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. This leads to the abnormal accumulation of these substances within various tissues of the body, including brain tissue. The accumulation of these substances damages the affected areas. NPC is highly variable and the age of onset and specific symptoms can vary from one person to another, sometimes even among members of the same family. NPC can range from a fatal disorder within the first few months after birth (neonatal period) to a late onset, chronic progressive disorder that remains undiagnosed well into adulthood. Most cases are detected during childhood and progress to cause life-threatening complications by the second or third decade of life. NPC is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C) and is inherited in an autosomal recessive manner. IntroductionNPC belongs to a larger group of more than 50 disorders known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Abnormal functioning of a transport protein leads to the accumulation of cholesterol and other fatty substances in various tissues of the body, including brain tissue. NPC used to be grouped together with two other disorders, named Niemann-Pick disease type A and Niemann-Pick disease type B. However, researchers have determined that the underlying defect in types A and B involves mutations in the SMPD1 gene and deficiency of the enzyme acid sphingomyelinase, which does not occur in NPC. Niemann-Pick disease types A and B are now considered a distinct disorder called acid sphingomyelinase deficiency. NORD has a separate report in the Rare Disease Database on this disorder. Niemann-Pick disease type D is an obsolete term for a condition in a group of individuals in Nova Scotia, Canada who have NPC due to a specific founder mutation of the NPC1 gene. This form is clinically indistinguishable from NPC. Additional terms have been used in the past to describe NPC including DAF (down gaze palsy, ataxia, foam cells) syndrome, juvenile dystonic lipidosis, lipid histiocytosis, and sea blue histiocyte disease. These terms are now considered obsolete.
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Overview of Niemann Pick Disease Type C. SummaryNiemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. This leads to the abnormal accumulation of these substances within various tissues of the body, including brain tissue. The accumulation of these substances damages the affected areas. NPC is highly variable and the age of onset and specific symptoms can vary from one person to another, sometimes even among members of the same family. NPC can range from a fatal disorder within the first few months after birth (neonatal period) to a late onset, chronic progressive disorder that remains undiagnosed well into adulthood. Most cases are detected during childhood and progress to cause life-threatening complications by the second or third decade of life. NPC is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C) and is inherited in an autosomal recessive manner. IntroductionNPC belongs to a larger group of more than 50 disorders known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Abnormal functioning of a transport protein leads to the accumulation of cholesterol and other fatty substances in various tissues of the body, including brain tissue. NPC used to be grouped together with two other disorders, named Niemann-Pick disease type A and Niemann-Pick disease type B. However, researchers have determined that the underlying defect in types A and B involves mutations in the SMPD1 gene and deficiency of the enzyme acid sphingomyelinase, which does not occur in NPC. Niemann-Pick disease types A and B are now considered a distinct disorder called acid sphingomyelinase deficiency. NORD has a separate report in the Rare Disease Database on this disorder. Niemann-Pick disease type D is an obsolete term for a condition in a group of individuals in Nova Scotia, Canada who have NPC due to a specific founder mutation of the NPC1 gene. This form is clinically indistinguishable from NPC. Additional terms have been used in the past to describe NPC including DAF (down gaze palsy, ataxia, foam cells) syndrome, juvenile dystonic lipidosis, lipid histiocytosis, and sea blue histiocyte disease. These terms are now considered obsolete.
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Symptoms of Niemann Pick Disease Type C
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Individuals with NPC can have onset of symptoms at different ages that have been grouped historically as: perinatal (shortly before and after birth), early infantile (3 months to < 2 years), late infantile (2 to < 6 years), juvenile (6 to < 15 years), and adult (15 years and greater). NPC affects neurologic and psychiatric functions, as well as various internal organs (visceral). Symptoms arise at different times and follow independent progression. Visceral symptoms are more typically seen in individuals presenting at a younger age. Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups.Because NPC is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique. Some children will develop severe, life-threatening complications early in life; others have a mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis.In perinatal NPC, the accumulation of fluid in the fetal abdomen (fetal ascites) may be present and persist after birth. These infants often have prolonged severe interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) or spleen (splenomegaly) is present in a high percentage of affected individuals in this age group. Lipid-containing (foam) cells may accumulate in the lungs, resulting in lung disease. Liver and lung disease can progress to cause life-threatening complications during this period. Surviving individuals will develop neurological symptoms at a later age.In the early infantile period, affected individuals may present with abnormal enlargement of the liver or spleen as the only noticeable symptom (isolated hepato-/splenomegaly), and that may remain the only symptom for many years. In other cases, additional symptoms develop including lack of muscle tone (hypotonia) often by 1 or 2 years of age. Affected individuals may also experience delays in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development).A characteristic early finding in children with NPC is impairment of the ability to look upward and downward (vertical supranuclear gaze palsy or VSGP). Specifically, affected children lose their ability to rapidly move their eyes up and down. To compensate, they may blink their eyes, jerk their heads, or make abnormal movements. Eventually, vertical eye movements are lost, and side to side (horizontal) eye movements are also affected.Hearing loss can occur in some individuals with NPC. Affected individuals may develop high frequency sensorineural hearing loss, in which transmission of sensory inputs from the auditory nerves to the brain is impaired. Up to 74% of individuals develop clinically significant hearing loss in at least one ear. Hearing loss may be the first problem seen in adults.The classic presentation of NPC occurs during middle to late childhood with clumsiness or difficulty in drawing and writing, often noted by teachers and parents. VSGP may be first reported during this time from a careful neurological exam or observations by the parents. Other neurological abnormalities may be the first apparent symptoms, specifically lack of muscle coordination (cerebellar ataxia). Children with cerebellar ataxia often have difficulties with balance and trouble with walking (unsteady gait). They may fall frequently and be considered clumsy. Affected children may also experience progressive difficulty speaking (dysarthria), resulting in slurred and eventually unintelligible speech. Children may lose previously acquired speech skills. Difficulty swallowing (dysphagia) may also develop and can become progressively worse, so that modifications such as thickening fluids or using special utensils may be recommended. Eventually a feeding tube may be required to maintain adequate nutrition. The dysphagia can lead to trouble swallowing saliva and other secretions. This may result in the inhalation of foreign materials into the airways and lungs (aspiration pneumonia).During this time, affected individuals may also develop slowly progressive impairment of intellectually ability (cognitive impairment) that can initially be mistaken for learning disabilities. Furthermore, psychiatric disturbances and the progressive loss of memory and intellectual ability (dementia) can develop.Additional neurologic findings can include drooling, epileptic seizures, and cataplexy. Cataplexy is characterized by a sudden loss of muscle tone and strength that can cause a sudden head drop, a weak, rubbery sensation in the legs, or in severe cases collapse. Cataplexy is often caused by strong emotions, typically laughter, in individuals with NPC (gelastic cataplexy). Dystonia, a large group of movement disorders, is also common. Dystonia is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Some individuals may develop a tremor marked by rhythmic, jerking movements (myoclonic tremor). Sleep disturbances or irregularities such as narcolepsy or sleep apnea have also been reported.Adolescent or adult onset of NPC may be associated with a similar neurological presentation as in childhood onset. However, the rate of progression is often much slower. Specific manifestations may vary, but can include cerebellar ataxia, dysarthria, dysphagia, cognitive impairment, and other movement disorders such as dystonia or tremor. VSGP is invariably present, but can be difficult to appreciate initially. Although systemic symptoms are more common in infancy or childhood, they can also occur in individuals with adolescent or adult onset NPC. Isolated splenomegaly may be the presenting symptom in some adolescents or adults.Psychiatric issues that have been described in individuals with adolescent onset of NPC include learning difficulties, behavioral problems, difficulty with expressive language, and attention deficit-hyperactivity disorder. Psychotic or manic episodes may occur in some affected individuals. Adults greater than 30 years of age may experience impairment of executive functions (dysexecutive syndrome) characterized by problems with complex thinking and reasoning tasks such as difficulty with organization and planning.In some cases, older adults may first be misdiagnosed with dementia or psychiatric illness such as major depression or schizophrenia. Individuals have been described in the medical literature with other psychiatric manifestations such as obsessive-compulsive disorder, bipolar disorders, and hallucinations.Following a long term gradual neurological decline death often results from aspiration pneumonia and subsequent respiratory failure, or intractable epilepsy not responding to medical intervention.
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Symptoms of Niemann Pick Disease Type C. Individuals with NPC can have onset of symptoms at different ages that have been grouped historically as: perinatal (shortly before and after birth), early infantile (3 months to < 2 years), late infantile (2 to < 6 years), juvenile (6 to < 15 years), and adult (15 years and greater). NPC affects neurologic and psychiatric functions, as well as various internal organs (visceral). Symptoms arise at different times and follow independent progression. Visceral symptoms are more typically seen in individuals presenting at a younger age. Neurologic and psychiatric symptoms often occur slowly over time, and thus feature more prominently in individuals presenting in the later age groups.Because NPC is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique. Some children will develop severe, life-threatening complications early in life; others have a mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis.In perinatal NPC, the accumulation of fluid in the fetal abdomen (fetal ascites) may be present and persist after birth. These infants often have prolonged severe interruption or suppression of the flow of bile from the liver (cholestasis). Features of cholestasis include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) or spleen (splenomegaly) is present in a high percentage of affected individuals in this age group. Lipid-containing (foam) cells may accumulate in the lungs, resulting in lung disease. Liver and lung disease can progress to cause life-threatening complications during this period. Surviving individuals will develop neurological symptoms at a later age.In the early infantile period, affected individuals may present with abnormal enlargement of the liver or spleen as the only noticeable symptom (isolated hepato-/splenomegaly), and that may remain the only symptom for many years. In other cases, additional symptoms develop including lack of muscle tone (hypotonia) often by 1 or 2 years of age. Affected individuals may also experience delays in the acquisition of skills requiring the coordination of mental and physical activities (delayed psychomotor development).A characteristic early finding in children with NPC is impairment of the ability to look upward and downward (vertical supranuclear gaze palsy or VSGP). Specifically, affected children lose their ability to rapidly move their eyes up and down. To compensate, they may blink their eyes, jerk their heads, or make abnormal movements. Eventually, vertical eye movements are lost, and side to side (horizontal) eye movements are also affected.Hearing loss can occur in some individuals with NPC. Affected individuals may develop high frequency sensorineural hearing loss, in which transmission of sensory inputs from the auditory nerves to the brain is impaired. Up to 74% of individuals develop clinically significant hearing loss in at least one ear. Hearing loss may be the first problem seen in adults.The classic presentation of NPC occurs during middle to late childhood with clumsiness or difficulty in drawing and writing, often noted by teachers and parents. VSGP may be first reported during this time from a careful neurological exam or observations by the parents. Other neurological abnormalities may be the first apparent symptoms, specifically lack of muscle coordination (cerebellar ataxia). Children with cerebellar ataxia often have difficulties with balance and trouble with walking (unsteady gait). They may fall frequently and be considered clumsy. Affected children may also experience progressive difficulty speaking (dysarthria), resulting in slurred and eventually unintelligible speech. Children may lose previously acquired speech skills. Difficulty swallowing (dysphagia) may also develop and can become progressively worse, so that modifications such as thickening fluids or using special utensils may be recommended. Eventually a feeding tube may be required to maintain adequate nutrition. The dysphagia can lead to trouble swallowing saliva and other secretions. This may result in the inhalation of foreign materials into the airways and lungs (aspiration pneumonia).During this time, affected individuals may also develop slowly progressive impairment of intellectually ability (cognitive impairment) that can initially be mistaken for learning disabilities. Furthermore, psychiatric disturbances and the progressive loss of memory and intellectual ability (dementia) can develop.Additional neurologic findings can include drooling, epileptic seizures, and cataplexy. Cataplexy is characterized by a sudden loss of muscle tone and strength that can cause a sudden head drop, a weak, rubbery sensation in the legs, or in severe cases collapse. Cataplexy is often caused by strong emotions, typically laughter, in individuals with NPC (gelastic cataplexy). Dystonia, a large group of movement disorders, is also common. Dystonia is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Some individuals may develop a tremor marked by rhythmic, jerking movements (myoclonic tremor). Sleep disturbances or irregularities such as narcolepsy or sleep apnea have also been reported.Adolescent or adult onset of NPC may be associated with a similar neurological presentation as in childhood onset. However, the rate of progression is often much slower. Specific manifestations may vary, but can include cerebellar ataxia, dysarthria, dysphagia, cognitive impairment, and other movement disorders such as dystonia or tremor. VSGP is invariably present, but can be difficult to appreciate initially. Although systemic symptoms are more common in infancy or childhood, they can also occur in individuals with adolescent or adult onset NPC. Isolated splenomegaly may be the presenting symptom in some adolescents or adults.Psychiatric issues that have been described in individuals with adolescent onset of NPC include learning difficulties, behavioral problems, difficulty with expressive language, and attention deficit-hyperactivity disorder. Psychotic or manic episodes may occur in some affected individuals. Adults greater than 30 years of age may experience impairment of executive functions (dysexecutive syndrome) characterized by problems with complex thinking and reasoning tasks such as difficulty with organization and planning.In some cases, older adults may first be misdiagnosed with dementia or psychiatric illness such as major depression or schizophrenia. Individuals have been described in the medical literature with other psychiatric manifestations such as obsessive-compulsive disorder, bipolar disorders, and hallucinations.Following a long term gradual neurological decline death often results from aspiration pneumonia and subsequent respiratory failure, or intractable epilepsy not responding to medical intervention.
| 884 |
Niemann Pick Disease Type C
|
nord_884_2
|
Causes of Niemann Pick Disease Type C
|
Individuals with NPC have mutations in one of two genes, NPC1 or NPC2. Approximately 95% of affected individuals have mutations in NPC1. Genes provide instructions for producing proteins that play a critical role in many functions of the body. Mutations in a gene may lead to the production of a protein that has reduced or abnormal functions, or to the absence of the protein. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.Investigators have determined that the NPC1 gene is located on the long arm (q) of chromosome 18 (18q11.2). The NPC2 gene is located on the long arm of chromosome 14 (14q24.3). Chromosomes, present in the nucleus of human cells, carry the genes that contain genetic information for each individual. Human body cells normally have 46 chromosomes, 23 inherited from each parent. Pairs of corresponding 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.”Genetic diseases are determined by the combination of the pair of genes for a particular trait received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal (mutated) gene for the same trait from each parent. If an individual receives one normal gene and one mutated gene, the person will be a carrier for the disease, but usually will not show symptoms. For a couple who are both carriers the risk with each pregnancy for them to have an affected child is 25%, a child who is a carrier is 50%, and a child who is unaffected and is not a carrier is 25%. In recessive genetic disorders such as NPC the risk is the same for male and female offspring.The exact function of the NPC1 and NPC2 proteins is not fully understood. Researchers do know that the protein products of these genes are involved in the movements (trafficking) of large molecules within cells. When NPC1 or NPC2 gene is mutated insufficient levels of functional protein products are made. This causes abnormal accumulation of cholesterol in the peripheral tissues of the body such as the liver and spleen, and accumulation of cholesterol and glycosphingolipids (complex compounds consisting of fatty material and carbohydrates) in the brain. The accumulation of these materials causes the various observable symptoms of NPC.
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Causes of Niemann Pick Disease Type C. Individuals with NPC have mutations in one of two genes, NPC1 or NPC2. Approximately 95% of affected individuals have mutations in NPC1. Genes provide instructions for producing proteins that play a critical role in many functions of the body. Mutations in a gene may lead to the production of a protein that has reduced or abnormal functions, or to the absence of the protein. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.Investigators have determined that the NPC1 gene is located on the long arm (q) of chromosome 18 (18q11.2). The NPC2 gene is located on the long arm of chromosome 14 (14q24.3). Chromosomes, present in the nucleus of human cells, carry the genes that contain genetic information for each individual. Human body cells normally have 46 chromosomes, 23 inherited from each parent. Pairs of corresponding 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.”Genetic diseases are determined by the combination of the pair of genes for a particular trait received from the father and the mother. Recessive genetic disorders occur when an individual inherits an abnormal (mutated) gene for the same trait from each parent. If an individual receives one normal gene and one mutated gene, the person will be a carrier for the disease, but usually will not show symptoms. For a couple who are both carriers the risk with each pregnancy for them to have an affected child is 25%, a child who is a carrier is 50%, and a child who is unaffected and is not a carrier is 25%. In recessive genetic disorders such as NPC the risk is the same for male and female offspring.The exact function of the NPC1 and NPC2 proteins is not fully understood. Researchers do know that the protein products of these genes are involved in the movements (trafficking) of large molecules within cells. When NPC1 or NPC2 gene is mutated insufficient levels of functional protein products are made. This causes abnormal accumulation of cholesterol in the peripheral tissues of the body such as the liver and spleen, and accumulation of cholesterol and glycosphingolipids (complex compounds consisting of fatty material and carbohydrates) in the brain. The accumulation of these materials causes the various observable symptoms of NPC.
| 884 |
Niemann Pick Disease Type C
|
nord_884_3
|
Affects of Niemann Pick Disease Type C
|
NPC affects males and females in equal numbers, and can affect individuals of any ethnic background (pan ethnic). NPC is estimated to occur in 1 in 100,000-120,000 live births. However, many cases go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
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Affects of Niemann Pick Disease Type C. NPC affects males and females in equal numbers, and can affect individuals of any ethnic background (pan ethnic). NPC is estimated to occur in 1 in 100,000-120,000 live births. However, many cases go misdiagnosed or undiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
| 884 |
Niemann Pick Disease Type C
|
nord_884_4
|
Related disorders of Niemann Pick Disease Type C
|
Symptoms of the following disorders can be similar to those of NPC. Comparisons may be useful in considering other potential diagnoses.Other potential disorders with symptoms similar to those seen in NPC vary based upon the age of onset. In newborns and infants, disorders such as alpha-1-antitrypsin deficiency, tyrosinemia, other lysosomal storage diseases including Niemann-Pick disease type A or Gaucher disease, those causing neonatal cholestasis such as idiopathic neonatal cholestasis, and various congenital infections can present similarly. In children, NPC may need to be differentiated from various metabolic disorders including other lysosomal storage diseases, maple syrup urine disease, GM2 gangliosidosis, organic acidemias, attention deficit hyperactivity disorder (ADHD), learning disabilities, dopa-responsive dystonia, Wilson disease, and certain mitochondrial disorders. In adults, Alzheimer disease, frontotemporal dementia, progressive supranuclear palsy, Pick disease (an adult-onset type of frontotemporal dementia unrelated to Niemann-Pick disease), and various psychiatric disorders need to be considered. (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 Niemann Pick Disease Type C. Symptoms of the following disorders can be similar to those of NPC. Comparisons may be useful in considering other potential diagnoses.Other potential disorders with symptoms similar to those seen in NPC vary based upon the age of onset. In newborns and infants, disorders such as alpha-1-antitrypsin deficiency, tyrosinemia, other lysosomal storage diseases including Niemann-Pick disease type A or Gaucher disease, those causing neonatal cholestasis such as idiopathic neonatal cholestasis, and various congenital infections can present similarly. In children, NPC may need to be differentiated from various metabolic disorders including other lysosomal storage diseases, maple syrup urine disease, GM2 gangliosidosis, organic acidemias, attention deficit hyperactivity disorder (ADHD), learning disabilities, dopa-responsive dystonia, Wilson disease, and certain mitochondrial disorders. In adults, Alzheimer disease, frontotemporal dementia, progressive supranuclear palsy, Pick disease (an adult-onset type of frontotemporal dementia unrelated to Niemann-Pick disease), and various psychiatric disorders need to be considered. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 884 |
Niemann Pick Disease Type C
|
nord_884_5
|
Diagnosis of Niemann Pick Disease Type C
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Niemann-Pick disease type C is diagnosed based on characteristic symptoms obtained from a thorough clinical evaluation (see under Signs and Symptoms), and confirmed by a variety of specialized tests. Proper diagnosis of NPC requires physicians to suspect the diagnosis based upon symptoms, and to follow up with appropriate laboratory tests to evaluate the function of the protein or the presence of accumulated byproducts (biochemical tests), and to identify mutations in the NPC1 or NPC2 gene (gene sequencing).Many physicians have little experience with NPC. Thus, affected individuals and families often face a significant delay in diagnosis. Clinical experts on NPC have developed a Suspicion Index Tool to help physicians unfamiliar with the disorder to diagnose NPC (Wraith JE, 2014). This tool creates a risk prediction score based on the specific manifestations present in an individual, broken down into visceral, neurological, and psychiatric categories. The original tool was effective in diagnosing individuals over the age of 4 years. Subsequently the same group derived a version that improved on diagnosing NPC in children younger than 4 years (Pineda M et al, 2016). Further study and refinement of the Suspicion Index Tool is necessary to determine its usefulness in clinical practice.Clinical Testing and Workup
Traditionally the confirmation of an NPC diagnosis was done by staining the affected individual’s skin cells (fibroblasts) for level of cholesterol accumulation (filipin staining). Testing for the cells’ ability to modify cholesterol (cholesterol esterification test) has also been used for diagnostic purpose. Recently, blood-based testing for biomarkers (oxysterols, lysosphingolipids, bile acid metabolites) and molecular gene sequencing of NPC1 and NPC2 have replaced these traditional methods. Outside of the neonatal period, the combination of biomarkers and gene sequencing has improved the detection rate (sensitivity) and accuracy (specificity) of diagnosing NPC. In cases where the test results are equivocal, experts in the NPC field should be consulted to discuss their interpretation.
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Diagnosis of Niemann Pick Disease Type C. Niemann-Pick disease type C is diagnosed based on characteristic symptoms obtained from a thorough clinical evaluation (see under Signs and Symptoms), and confirmed by a variety of specialized tests. Proper diagnosis of NPC requires physicians to suspect the diagnosis based upon symptoms, and to follow up with appropriate laboratory tests to evaluate the function of the protein or the presence of accumulated byproducts (biochemical tests), and to identify mutations in the NPC1 or NPC2 gene (gene sequencing).Many physicians have little experience with NPC. Thus, affected individuals and families often face a significant delay in diagnosis. Clinical experts on NPC have developed a Suspicion Index Tool to help physicians unfamiliar with the disorder to diagnose NPC (Wraith JE, 2014). This tool creates a risk prediction score based on the specific manifestations present in an individual, broken down into visceral, neurological, and psychiatric categories. The original tool was effective in diagnosing individuals over the age of 4 years. Subsequently the same group derived a version that improved on diagnosing NPC in children younger than 4 years (Pineda M et al, 2016). Further study and refinement of the Suspicion Index Tool is necessary to determine its usefulness in clinical practice.Clinical Testing and Workup
Traditionally the confirmation of an NPC diagnosis was done by staining the affected individual’s skin cells (fibroblasts) for level of cholesterol accumulation (filipin staining). Testing for the cells’ ability to modify cholesterol (cholesterol esterification test) has also been used for diagnostic purpose. Recently, blood-based testing for biomarkers (oxysterols, lysosphingolipids, bile acid metabolites) and molecular gene sequencing of NPC1 and NPC2 have replaced these traditional methods. Outside of the neonatal period, the combination of biomarkers and gene sequencing has improved the detection rate (sensitivity) and accuracy (specificity) of diagnosing NPC. In cases where the test results are equivocal, experts in the NPC field should be consulted to discuss their interpretation.
| 884 |
Niemann Pick Disease Type C
|
nord_884_6
|
Therapies of Niemann Pick Disease Type C
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Treatment
Treatment of NPC may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, ophthalmologists, pulmonologists, gastroenterologists, 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 would benefit affected individuals and their families.Current treatment is directed toward the specific symptoms apparent in each individual. Difficulty swallowing (dysphagia) should be monitored and evaluated regularly for the risk of aspiration. Swallowing difficulties may first be managed by softening solids and thickening liquids. A speech therapist can work with the individual to optimize swallowing function. Eventually, a gastronomy tube may be required to meet adequate caloric needs. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food or medicine.Seizures often respond, at least partially, to anti-seizure medications (antiepileptics). Eventually, in an advanced stage of the disease, seizures may no longer respond to such medications (refractory seizures). Cataplexy may be treated by specific drugs including tricyclic antidepressants and central nervous system stimulants such as clomipramine, protriptyline or modafinil. Drugs that block the neurotransmitter acetylcholine (anticholinergic agents) have been effective in treating dystonia and tremor. Botulinum toxin injections can be used to treat severe dystonia. Drugs have also been used to treat various psychiatric illnesses, such as antipsychotic medications to treat psychosis and antidepressants to treat mood disorders.Sleep abnormalities observed in NPC are diverse. Many individuals suffer from poor sleep quality due to fragmented myoclonus during slow wave sleep. Total sleep time, and time spent in different stages of sleep (REM and slow wave) may be decreased. Some individuals may suffer from insomnia which can be linked to underlying psychiatric diseases, such as anxiety or depression. When hypotonia is severe, especially in combination with enlarged adenoids and tonsils, disordered breathing with long respiratory pauses during sleep (obstructive sleep apnea) may occur. This diagnosis often requires an overnight sleep study. If the obstructive sleep apnea is severe, the patients may need a machine supplying continuous positive air pressure (CPAP) with a mask to keep the airways open during sleep. Insomnia and other sleep problems should be treated with melatonin, and if needed nocturnal sedatives.Various services that may be beneficial to affected patients include an individualized educational plan encompassing physical therapy, speech therapy and occupational therapy. Parents, siblings, and other family members of affected individuals may find support, resources for respite care, and information on NPC through their primary pediatrician and the various professional and parent organizations listed below.Studies have shown that miglustat (Zavesca®) may be able to slow the progression of neurological symptoms associated with NPC. Miglustat blocks the synthesis of glycosphingolipids, one of the substances that accumulates in the brain of individuals with NPC. The U.S. Food and Drug Administration (FDA) has not approved miglustat for the treatment of individuals with NPC, although the drug is approved for the treatment of another lysosomal storage disease known as Gaucher disease. Miglustat has been used off-label in the U.S. to treat individuals with NPC. Miglustat is available for the treatment of NPC in Australia, Canada, New Zealand, and several countries in Asia, Europe, and South America as Zavesca®, and in Japan as Brazaves®.NPC affects the processing of cholesterols produced within neurons, and not those outside of the cells. Thus, diets low in fats and cholesterols do not affect the neurological disease course.
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Therapies of Niemann Pick Disease Type C. Treatment
Treatment of NPC may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, ophthalmologists, pulmonologists, gastroenterologists, 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 would benefit affected individuals and their families.Current treatment is directed toward the specific symptoms apparent in each individual. Difficulty swallowing (dysphagia) should be monitored and evaluated regularly for the risk of aspiration. Swallowing difficulties may first be managed by softening solids and thickening liquids. A speech therapist can work with the individual to optimize swallowing function. Eventually, a gastronomy tube may be required to meet adequate caloric needs. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for the direct intake of food or medicine.Seizures often respond, at least partially, to anti-seizure medications (antiepileptics). Eventually, in an advanced stage of the disease, seizures may no longer respond to such medications (refractory seizures). Cataplexy may be treated by specific drugs including tricyclic antidepressants and central nervous system stimulants such as clomipramine, protriptyline or modafinil. Drugs that block the neurotransmitter acetylcholine (anticholinergic agents) have been effective in treating dystonia and tremor. Botulinum toxin injections can be used to treat severe dystonia. Drugs have also been used to treat various psychiatric illnesses, such as antipsychotic medications to treat psychosis and antidepressants to treat mood disorders.Sleep abnormalities observed in NPC are diverse. Many individuals suffer from poor sleep quality due to fragmented myoclonus during slow wave sleep. Total sleep time, and time spent in different stages of sleep (REM and slow wave) may be decreased. Some individuals may suffer from insomnia which can be linked to underlying psychiatric diseases, such as anxiety or depression. When hypotonia is severe, especially in combination with enlarged adenoids and tonsils, disordered breathing with long respiratory pauses during sleep (obstructive sleep apnea) may occur. This diagnosis often requires an overnight sleep study. If the obstructive sleep apnea is severe, the patients may need a machine supplying continuous positive air pressure (CPAP) with a mask to keep the airways open during sleep. Insomnia and other sleep problems should be treated with melatonin, and if needed nocturnal sedatives.Various services that may be beneficial to affected patients include an individualized educational plan encompassing physical therapy, speech therapy and occupational therapy. Parents, siblings, and other family members of affected individuals may find support, resources for respite care, and information on NPC through their primary pediatrician and the various professional and parent organizations listed below.Studies have shown that miglustat (Zavesca®) may be able to slow the progression of neurological symptoms associated with NPC. Miglustat blocks the synthesis of glycosphingolipids, one of the substances that accumulates in the brain of individuals with NPC. The U.S. Food and Drug Administration (FDA) has not approved miglustat for the treatment of individuals with NPC, although the drug is approved for the treatment of another lysosomal storage disease known as Gaucher disease. Miglustat has been used off-label in the U.S. to treat individuals with NPC. Miglustat is available for the treatment of NPC in Australia, Canada, New Zealand, and several countries in Asia, Europe, and South America as Zavesca®, and in Japan as Brazaves®.NPC affects the processing of cholesterols produced within neurons, and not those outside of the cells. Thus, diets low in fats and cholesterols do not affect the neurological disease course.
| 884 |
Niemann Pick Disease Type C
|
nord_885_0
|
Overview of Nocardiosis
|
Nocardiosis is an infectious pulmonary disease characterized by abscesses in the lungs. These abscesses may extend through the chest wall. The infection is spread through the body via the bloodstream by a microorganism called Nocardia asteroides.
|
Overview of Nocardiosis. Nocardiosis is an infectious pulmonary disease characterized by abscesses in the lungs. These abscesses may extend through the chest wall. The infection is spread through the body via the bloodstream by a microorganism called Nocardia asteroides.
| 885 |
Nocardiosis
|
nord_885_1
|
Symptoms of Nocardiosis
|
Most cases of nocardiosis begin as pulmonary infections that develop into lung abscesses. Symptoms may include chest pain, cough, bloody sputum, sweats, chills, weakness, lack of appetite, weight loss and difficult or labored breathing. Nocardiosis symptoms are similar to those of pneumonia and tuberculosis.The infection may spread through the bloodstream resulting in abscesses in the brain, where they are very serious indeed, or less frequently and less seriously, in the kidney, intestines or other organs. Approximately one-third of reported cases develop brain abscesses if left untreated or if treatment is delayed. Symptoms associated with brain abscesses may include severe headache and focal, sensory and motor disturbances.Skin abscesses occur in approximately one-third of all cases of nocardiosis, and are usually found scattered across the hand, chest wall and buttocks. In patients whose immune system is suppressed due to HIV infection or to corticosteroid or cytotoxic drugs, ulcerative colitis, malignancy of the lymph system or a variety of other diseases, progression of the disease can be very rapid.Nocardiosis may last from several months to years. It is essential that the infection be diagnosed and differentiated from tuberculosis and pneumonia.
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Symptoms of Nocardiosis. Most cases of nocardiosis begin as pulmonary infections that develop into lung abscesses. Symptoms may include chest pain, cough, bloody sputum, sweats, chills, weakness, lack of appetite, weight loss and difficult or labored breathing. Nocardiosis symptoms are similar to those of pneumonia and tuberculosis.The infection may spread through the bloodstream resulting in abscesses in the brain, where they are very serious indeed, or less frequently and less seriously, in the kidney, intestines or other organs. Approximately one-third of reported cases develop brain abscesses if left untreated or if treatment is delayed. Symptoms associated with brain abscesses may include severe headache and focal, sensory and motor disturbances.Skin abscesses occur in approximately one-third of all cases of nocardiosis, and are usually found scattered across the hand, chest wall and buttocks. In patients whose immune system is suppressed due to HIV infection or to corticosteroid or cytotoxic drugs, ulcerative colitis, malignancy of the lymph system or a variety of other diseases, progression of the disease can be very rapid.Nocardiosis may last from several months to years. It is essential that the infection be diagnosed and differentiated from tuberculosis and pneumonia.
| 885 |
Nocardiosis
|
nord_885_2
|
Causes of Nocardiosis
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Nocardiosis is caused by Nocardia asteroides, a bacterium that is carried up into the air from the ground and may be inhaled. Other species of the same family of bacteria such as Nocardia brasiliensis, Nocardia caviae, and Nocardia farcinica, are also known to cause disease. The organism usually enters the body through the lungs or, more rarely, through the gastrointestinal tract or the skin.People whose immune systems are not functioning properly (immunocompromised) are at risk for nocardial infections. People whose immune systems are functioning properly but who are taking immunosuppressive drugs as part of the routine for organ transplantation are at greater than normal risk as well.
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Causes of Nocardiosis. Nocardiosis is caused by Nocardia asteroides, a bacterium that is carried up into the air from the ground and may be inhaled. Other species of the same family of bacteria such as Nocardia brasiliensis, Nocardia caviae, and Nocardia farcinica, are also known to cause disease. The organism usually enters the body through the lungs or, more rarely, through the gastrointestinal tract or the skin.People whose immune systems are not functioning properly (immunocompromised) are at risk for nocardial infections. People whose immune systems are functioning properly but who are taking immunosuppressive drugs as part of the routine for organ transplantation are at greater than normal risk as well.
| 885 |
Nocardiosis
|
nord_885_3
|
Affects of Nocardiosis
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Nocardiosis occurs worldwide. Those affected tend to be older adults, and males are more often affected than are females.In the USA, about 500 to 1,000 new cases of nocardiosis are diagnosed each year.
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Affects of Nocardiosis. Nocardiosis occurs worldwide. Those affected tend to be older adults, and males are more often affected than are females.In the USA, about 500 to 1,000 new cases of nocardiosis are diagnosed each year.
| 885 |
Nocardiosis
|
nord_885_4
|
Related disorders of Nocardiosis
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Symptoms of the following disorders can be similar to those of Nocardiosis. Comparisons may be useful for a differential diagnosis:Actinomycosis is a chronic infectious disease characterized by draining sinuses. The microorganisms which cause Acitnomycosis are often found on the gums, tonsils and teeth. Actinomycosis most commonly affects adult males. The most common entry into the body for the infecting microorganism is through decayed teeth. Pulmonary or abdominal disease may also occur due to this infection. The infection causes small abscesses which spread to adjoining tissue. The abdominal form of the infection produces symptoms of pain, fever, vomiting, diarrhea or constipation and emaciation. There may be an abdominal mass with signs of intestinal obstruction, and draining pus may develop in the abdominal wall. In the thoracic form of the infection, lung infection may resemble tuberculosis with chest pain, fever and a cough with sputum.Tuberculosis (TB) is an acute or chronic bacterial infection found most commonly in the lungs. The infection is spread like a cold, mainly through airborne droplets breathed into the air by a person infected with TB. In the lungs these tubercules produce breathing impairment, coughing and release of sputum. Tuberculosis may also affect the kidneys, bones, lymph nodes, and membranes surrounding the brain. Initial symptoms include fever, loss of appetite, weight loss, weakness, and dry cough. In later stages, symptoms may include blood in the sputum. (For more information on this disorder, choose “Tuberculosis” as your search term in the Rare Disease Database.)Pneumonia is a common bacterial infection of the lungs. Onset is sudden, and usually presents itself as fever and shaking chills. Symptoms may include fever, pain or difficulty in breathing, cough and the production of sputum. Fever rises rapidly, sometimes to 105 degrees F. There may also be nausea, vomiting and a general feeling of ill health. Initially there may be a dry cough that later worsens and produces blood-streaked sputum. (For more information on this disorder, choose “Pneumonia” as your search term in the Rare Disease Database.)
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Related disorders of Nocardiosis. Symptoms of the following disorders can be similar to those of Nocardiosis. Comparisons may be useful for a differential diagnosis:Actinomycosis is a chronic infectious disease characterized by draining sinuses. The microorganisms which cause Acitnomycosis are often found on the gums, tonsils and teeth. Actinomycosis most commonly affects adult males. The most common entry into the body for the infecting microorganism is through decayed teeth. Pulmonary or abdominal disease may also occur due to this infection. The infection causes small abscesses which spread to adjoining tissue. The abdominal form of the infection produces symptoms of pain, fever, vomiting, diarrhea or constipation and emaciation. There may be an abdominal mass with signs of intestinal obstruction, and draining pus may develop in the abdominal wall. In the thoracic form of the infection, lung infection may resemble tuberculosis with chest pain, fever and a cough with sputum.Tuberculosis (TB) is an acute or chronic bacterial infection found most commonly in the lungs. The infection is spread like a cold, mainly through airborne droplets breathed into the air by a person infected with TB. In the lungs these tubercules produce breathing impairment, coughing and release of sputum. Tuberculosis may also affect the kidneys, bones, lymph nodes, and membranes surrounding the brain. Initial symptoms include fever, loss of appetite, weight loss, weakness, and dry cough. In later stages, symptoms may include blood in the sputum. (For more information on this disorder, choose “Tuberculosis” as your search term in the Rare Disease Database.)Pneumonia is a common bacterial infection of the lungs. Onset is sudden, and usually presents itself as fever and shaking chills. Symptoms may include fever, pain or difficulty in breathing, cough and the production of sputum. Fever rises rapidly, sometimes to 105 degrees F. There may also be nausea, vomiting and a general feeling of ill health. Initially there may be a dry cough that later worsens and produces blood-streaked sputum. (For more information on this disorder, choose “Pneumonia” as your search term in the Rare Disease Database.)
| 885 |
Nocardiosis
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